Subjects -> CHEMISTRY (Total: 928 journals)
    - ANALYTICAL CHEMISTRY (59 journals)
    - CHEMISTRY (661 journals)
    - CRYSTALLOGRAPHY (23 journals)
    - ELECTROCHEMISTRY (28 journals)
    - INORGANIC CHEMISTRY (45 journals)
    - ORGANIC CHEMISTRY (47 journals)
    - PHYSICAL CHEMISTRY (65 journals)

CHEMISTRY (661 journals)            First | 1 2 3 4 | Last

Showing 401 - 600 of 735 Journals sorted alphabetically
Journal of Molecular Liquids     Hybrid Journal   (Followers: 3)
Journal of Molecular Modeling     Hybrid Journal   (Followers: 5)
Journal of Molecular Recognition     Hybrid Journal   (Followers: 2)
Journal of Molecular Spectroscopy     Hybrid Journal   (Followers: 6)
Journal of Molecular Structure     Hybrid Journal   (Followers: 6)
Journal of Nanoparticles     Open Access   (Followers: 4)
Journal of Nanostructure in Chemistry     Open Access   (Followers: 8)
Journal of Organometallic Chemistry     Hybrid Journal   (Followers: 24)
Journal of Photochemistry and Photobiology     Open Access  
Journal of Photochemistry and Photobiology A: Chemistry     Hybrid Journal   (Followers: 3)
Journal of Photochemistry and Photobiology B: Biology     Hybrid Journal   (Followers: 4)
Journal of Photochemistry and Photobiology C: Photochemistry Reviews     Full-text available via subscription   (Followers: 3)
Journal of Polymer & Composites     Full-text available via subscription   (Followers: 17)
Journal of Polymer and Biopolymer Physics Chemistry     Open Access   (Followers: 7)
Journal of Polymer Science Part A: Polymer Chemistry     Hybrid Journal   (Followers: 92)
Journal of Polymers     Open Access   (Followers: 7)
Journal of Porphyrins and Phthalocyanines     Hybrid Journal   (Followers: 1)
Journal of Progressive Research in Chemistry     Open Access  
Journal of Pure and Applied Chemistry Research     Open Access   (Followers: 3)
Journal of Raman Spectroscopy     Hybrid Journal   (Followers: 14)
Journal of Research and Education Chemistry     Open Access   (Followers: 1)
Journal of Research Updates in Polymer Science     Hybrid Journal   (Followers: 2)
Journal of Rubber Research     Hybrid Journal   (Followers: 1)
Journal of Saudi Chemical Society     Open Access  
Journal of Solid State Chemistry     Hybrid Journal   (Followers: 13)
Journal of Solution Chemistry     Hybrid Journal   (Followers: 1)
Journal of Structural Chemistry     Hybrid Journal   (Followers: 1)
Journal of Sulfur Chemistry     Hybrid Journal   (Followers: 1)
Journal of Supercritical Fluids     Hybrid Journal   (Followers: 3)
Journal of Superhard Materials     Hybrid Journal  
Journal of Surface Science and Technology     Hybrid Journal  
Journal of Surfactants and Detergents     Hybrid Journal   (Followers: 3)
Journal of Taibah University for Science     Open Access  
Journal of the American Chemical Society     Hybrid Journal   (Followers: 326)
Journal of the American Society for Mass Spectrometry     Hybrid Journal   (Followers: 31)
Journal of the American Society of Brewing Chemists     Full-text available via subscription   (Followers: 2)
Journal of the Chilean Chemical Society     Open Access   (Followers: 2)
Journal of the Chinese Chemical Society     Hybrid Journal  
Journal of the Indian Chemical Society     Hybrid Journal  
Journal of The Indonesian Society of Integrated Chemistry     Open Access  
Journal of the Iranian Chemical Society     Hybrid Journal   (Followers: 1)
Journal of the Korean Society for Applied Biological Chemistry     Hybrid Journal  
Journal of the Mexican Chemical Society     Open Access   (Followers: 1)
Journal of the Serbian Chemical Society     Open Access  
Journal of the Turkish Chemical Society, Section A : Chemistry     Open Access  
Journal of Theoretical and Computational Chemistry     Hybrid Journal   (Followers: 9)
Jurnal Inovasi Pendidikan Kimia     Open Access  
Jurnal Kimia (Journal of Chemistry)     Open Access  
Jurnal Kimia Riset     Open Access  
Jurnal Pendidikan Kimia     Open Access  
Jurnal Penelitian Sains (JPS)     Open Access  
Karbala International Journal of Modern Science     Open Access  
Kinetics and Catalysis     Hybrid Journal   (Followers: 4)
Konfigurasi : Jurnal Pendidikan Kimia dan Terapan     Open Access  
Korea-Australia Rheology Journal     Hybrid Journal   (Followers: 1)
Langmuir     Hybrid Journal   (Followers: 58)
Lebensmittelchemie     Hybrid Journal   (Followers: 1)
Lipid Insights     Open Access  
Luminescence     Hybrid Journal   (Followers: 2)
Macromolecular Materials & Engineering     Hybrid Journal   (Followers: 5)
Macromolecular Rapid Communications     Hybrid Journal   (Followers: 10)
Macromolecular Research     Hybrid Journal   (Followers: 2)
Macromolecular Symposia     Hybrid Journal   (Followers: 3)
Macromolecular Theory and Simulations     Hybrid Journal   (Followers: 2)
Macromolecules     Hybrid Journal   (Followers: 48)
Magnetic Resonance in Chemistry     Hybrid Journal   (Followers: 8)
Magnetochemistry     Open Access  
Marine Chemistry     Hybrid Journal   (Followers: 6)
Marine Drugs     Open Access   (Followers: 1)
MATEC Web of Conferences     Open Access  
Materials Advances     Open Access   (Followers: 2)
Materials and Devices     Open Access  
Materials Characterization     Hybrid Journal   (Followers: 32)
Materials Chemistry Frontiers     Hybrid Journal   (Followers: 4)
Materials Horizons     Hybrid Journal   (Followers: 6)
Materials Research Bulletin     Hybrid Journal   (Followers: 25)
Materials Science-Poland     Open Access   (Followers: 1)
Materials Sciences and Applications     Open Access   (Followers: 2)
Medicinal Chemistry Research     Hybrid Journal   (Followers: 8)
Mediterranean Journal of Chemistry     Open Access  
Metallography, Microstructure, and Analysis     Hybrid Journal   (Followers: 1)
Micro and Nano Systems Letters     Open Access   (Followers: 6)
Microchimica Acta     Hybrid Journal   (Followers: 2)
Microporous and Mesoporous Materials     Hybrid Journal   (Followers: 9)
Modern Chemistry & Applications     Open Access   (Followers: 1)
Modern Research in Catalysis     Open Access  
Molbank     Open Access  
Molecular Catalysis     Hybrid Journal   (Followers: 5)
Molecules     Open Access   (Followers: 4)
Molecules and Cells     Hybrid Journal   (Followers: 1)
Monatshefte für Chemie - Chemical Monthly     Hybrid Journal   (Followers: 4)
Mongolian Journal of Chemistry     Open Access  
Moscow University Chemistry Bulletin     Hybrid Journal   (Followers: 1)
MRS Bulletin     Full-text available via subscription   (Followers: 4)
Nachrichten aus der Chemie     Hybrid Journal   (Followers: 13)
Nano Convergence     Open Access   (Followers: 1)
Nano Materials Science     Open Access   (Followers: 1)
Nano Reviews & Experiments     Open Access   (Followers: 14)
Nano Select     Open Access  
Nanochemistry Research     Open Access   (Followers: 1)
Nanoscale     Hybrid Journal   (Followers: 18)
Nanoscale Advances     Open Access  
Nanoscale Horizons     Hybrid Journal  
Nanoscale Research Letters     Open Access   (Followers: 8)
Nanoscience and Nanotechnology Letters     Full-text available via subscription   (Followers: 24)
Natural Product Communications     Open Access  
Natural Product Reports     Hybrid Journal   (Followers: 10)
Natural Science     Open Access   (Followers: 8)
Natural Volatiles & Essential Oils     Open Access  
Nature Chemistry     Full-text available via subscription   (Followers: 96)
Nature Protocols     Full-text available via subscription   (Followers: 73)
Nature Reviews Chemistry     Hybrid Journal   (Followers: 17)
New Journal of Chemistry     Hybrid Journal   (Followers: 16)
Nitric Oxide     Hybrid Journal  
Nitrogen     Open Access  
Nukleonika     Open Access  
Open Chemistry Journal     Open Access  
Open Conference Proceedings Journal     Open Access  
Open Journal of Chemistry     Open Access  
Open Journal of Composite Materials     Open Access   (Followers: 22)
Open Journal of Inorganic Non-metallic Materials     Open Access   (Followers: 2)
Open Journal of Medicinal Chemistry     Open Access   (Followers: 4)
Open Journal of Polymer Chemistry     Open Access   (Followers: 12)
Open Journal of Synthesis Theory and Applications     Open Access  
Open Medicinal Chemistry Journal     Open Access  
Orbital - The Electronic Journal of Chemistry     Open Access   (Followers: 1)
Organic & Biomolecular Chemistry     Hybrid Journal   (Followers: 55)
Organometallics     Hybrid Journal   (Followers: 18)
Oxidation of Metals     Hybrid Journal   (Followers: 16)
Passer Journal of Basic and Applied Sciences     Open Access  
Peptide Science     Full-text available via subscription  
Pharmaceuticals     Open Access   (Followers: 4)
Pharmaceutics     Open Access   (Followers: 5)
Phosphorus, Sulfur, and Silicon and the Related Elements     Hybrid Journal   (Followers: 2)
Photochemistry and Photobiology     Hybrid Journal   (Followers: 3)
Physical Science International Journal     Open Access  
Physics and Materials Chemistry     Open Access   (Followers: 1)
Phytochemistry     Hybrid Journal   (Followers: 4)
Phytochemistry Letters     Full-text available via subscription   (Followers: 1)
Plasma     Open Access   (Followers: 3)
Plasma Chemistry and Plasma Processing     Hybrid Journal   (Followers: 3)
Polycyclic Aromatic Compounds     Hybrid Journal  
Polyhedron     Hybrid Journal   (Followers: 4)
Polymer Chemistry     Hybrid Journal   (Followers: 24)
Polymer crystallization     Hybrid Journal  
Polymer Degradation and Stability     Hybrid Journal   (Followers: 23)
Polymer Engineering & Science     Hybrid Journal   (Followers: 14)
Polymer Reviews     Hybrid Journal   (Followers: 32)
Polymer Science Series D     Hybrid Journal   (Followers: 3)
Polymer Testing     Hybrid Journal   (Followers: 198)
Polymer-Plastics Technology and Materials     Hybrid Journal   (Followers: 5)
Polymers     Open Access   (Followers: 21)
Polymers from Renewable Resources     Hybrid Journal  
Proceedings of the Combustion Institute     Full-text available via subscription   (Followers: 8)
Processes     Open Access  
Progress in Lipid Research     Hybrid Journal   (Followers: 3)
Progress in Organic Coatings     Hybrid Journal   (Followers: 7)
Progress in Polymer Science     Full-text available via subscription   (Followers: 36)
Progress in Reaction Kinetics and Mechanism     Open Access  
Progress in Solid State Chemistry     Full-text available via subscription   (Followers: 3)
Progress in Surface Science     Full-text available via subscription   (Followers: 3)
Protein Science     Hybrid Journal   (Followers: 43)
Radiochemistry     Hybrid Journal   (Followers: 1)
Rapid Communications in Mass Spectrometry     Hybrid Journal   (Followers: 32)
Reaction Chemistry & Engineering     Hybrid Journal  
Reaction Kinetics, Mechanisms and Catalysis     Hybrid Journal   (Followers: 3)
Reactions     Open Access  
Reportes Científicos de la FaCEN     Open Access  
Research Journal of Phytochemistry     Open Access   (Followers: 1)
Resources Chemicals and Materials     Full-text available via subscription   (Followers: 5)
Results in Chemistry     Open Access  
Results in Geochemistry     Open Access  
Results in Surfaces and Interfaces     Open Access  
Review Journal of Chemistry     Hybrid Journal   (Followers: 1)
Reviews in Mineralogy and Geochemistry     Hybrid Journal   (Followers: 4)
Revista Boliviana de Química     Open Access  
Revista CENIC. Ciencias Quimicas     Open Access  
Revista Colombiana de Ciencias Químico-Farmacéuticas     Open Access  
Revista Colombiana de Química     Open Access  
Revista Cubana de Química     Open Access  
Revista de Ciencia y Tecnología     Open Access  
Revista de Ciencias     Open Access  
Revista de la Academia Colombiana de Ciencias Exactas, Físicas y Naturales     Open Access  
Revista de la Sociedad Química del Perú     Open Access  
Revista de la Societat Catalana de Química     Open Access  
Revista de Química     Open Access   (Followers: 6)
Revista Debates em Ensino de Química     Open Access  
Revista ION     Open Access  
RSC Advances     Open Access   (Followers: 27)
RSC Chemical Biology     Open Access  
RSC Medicinal Chemistry     Hybrid Journal   (Followers: 6)
Russian Journal of Bioorganic Chemistry     Hybrid Journal   (Followers: 1)
Russian Journal of Coordination Chemistry     Hybrid Journal   (Followers: 1)
Russian Journal of General Chemistry     Hybrid Journal   (Followers: 1)
Russian Journal of Inorganic Chemistry     Hybrid Journal  
Sainstek : Jurnal Sains dan Teknologi     Open Access  
Science China Chemistry     Hybrid Journal   (Followers: 2)
Science Talks     Full-text available via subscription   (Followers: 4)
Sciences & Technologie A : sciences exactes     Open Access  
Scientific Journal of Frontier Chemical Development     Open Access   (Followers: 2)

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Pharmaceuticals
Journal Prestige (SJR): 1.293
Citation Impact (citeScore): 4
Number of Followers: 4  

  This is an Open Access Journal Open Access journal
ISSN (Print) 1424-8247
Published by MDPI Homepage  [84 journals]
  • Pharmaceuticals, Vol. 15, Pages 768: Novel Potent and Selective Agonists
           of the GPR55 Receptor Based on the 3-Benzylquinolin-2(1H)-One Scaffold

    • Authors: Costanza Ceni, Michael J. Benko, Kawthar A. Mohamed, Giulio Poli, Miriana Di Stefano, Tiziano Tuccinardi, Maria Digiacomo, Massimo Valoti, Robert B. Laprairie, Marco Macchia, Simone Bertini
      First page: 768
      Abstract: A growing body of evidence underlines the crucial role of GPR55 in physiological and pathological conditions. In fact, GPR55 has recently emerged as a therapeutic target for several diseases, including cancer and neurodegenerative and metabolic disorders. Several lines of evidence highlight GPR55′s involvement in the regulation of microglia-mediated neuroinflammation, although the exact molecular mechanism has not been yet elucidated. Nevertheless, there are only a limited number of selective GPR55 ligands reported in the literature. In this work, we designed and synthesized a series of novel GPR55 ligands based on the 3-benzylquinolin-2(1H)-one scaffold, some of which showed excellent binding properties (with Ki values in the low nanomolar range) and almost complete selectivity over cannabinoid receptors. The full agonist profile of all the new derivatives was assessed using the p-ERK activation assay and a computational study was conducted to predict the key interactions with the binding site of the receptor. Our data outline a preliminary structure–activity relationship (SAR) for this class of molecules at GPR55. Some of our compounds are among the most potent GPR55 agonists developed to date and could be useful as tools to validate this receptor as a therapeutic target.
      Citation: Pharmaceuticals
      PubDate: 2022-06-21
      DOI: 10.3390/ph15070768
      Issue No: Vol. 15, No. 7 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 769: Synthesis of Prussian Blue
           Nanoparticles and Their Antibacterial, Antiinflammation and Antitumor
           Applications

    • Authors: Li, Liu, Li, Fu, Wang, Lai, Zhao, Zhang
      First page: 769
      Abstract: In recent years, Prussian blue nanoparticles (PBNPs), also named Prussian blue nano-enzymes, have been shown to demonstrate excellent multi-enzyme simulation activity and anti-inflammatory properties, and can be used as reactive oxygen scavengers. Their good biocompatibility and biodegradability mean that they are ideal candidates for in vivo use. PBNPs are highly efficient electron transporters with oxidation and reduction activities. PBNPs also show considerable promise as nano-drug carriers and biological detection sensors owing to their huge specific surface area, good chemical characteristics, and changeable qualities, which might considerably increase the therapeutic impact. More crucially, PBNPs, as therapeutic and diagnostic agents, have made significant advances in biological nanomedicine. This review begins with a brief description of the synthesis methods of PBNPs, then focuses on the applications of PBNPs in tissue regeneration and inflammation according to the different properties of PBNPs. This article will provide a timely reference for further study of PBNPs as therapeutic agents.
      Citation: Pharmaceuticals
      PubDate: 2022-06-21
      DOI: 10.3390/ph15070769
      Issue No: Vol. 15, No. 7 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 770: Roles of Bacterial Mechanosensitive
           Channels in Infection and Antibiotic Susceptibility

    • Authors: Sidarta, Baruah, Wenzel
      First page: 770
      Abstract: Bacteria accumulate osmolytes to prevent cell dehydration during hyperosmotic stress. A sudden change to a hypotonic environment leads to a rapid water influx, causing swelling of the protoplast. To prevent cell lysis through osmotic bursting, mechanosensitive channels detect changes in turgor pressure and act as emergency-release valves for the ions and osmolytes, restoring the osmotic balance. This adaptation mechanism is well-characterized with respect to the osmotic challenges bacteria face in environments such as soil or an aquatic habitat. However, mechanosensitive channels also play a role during infection, e.g., during host colonization or release into environmental reservoirs. Moreover, recent studies have proposed roles for mechanosensitive channels as determinants of antibiotic susceptibility. Interestingly, some studies suggest that they serve as entry gates for antimicrobials into cells, enhancing antibiotic efficiency, while others propose that they play a role in antibiotic-stress adaptation, reducing susceptibility to certain antimicrobials. These findings suggest different facets regarding the relevance of mechanosensitive channels during infection and antibiotic exposure as well as illustrate that they may be interesting targets for antibacterial chemotherapy. Here, we summarize the recent findings on the relevance of mechanosensitive channels for bacterial infections, including transitioning between host and environment, virulence, and susceptibility to antimicrobials, and discuss their potential as antibacterial drug targets.
      Citation: Pharmaceuticals
      PubDate: 2022-06-21
      DOI: 10.3390/ph15070770
      Issue No: Vol. 15, No. 7 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 771: Anti-Inflammatory Activity of
           Piquerol Isolated from Piqueria trinervia Cav.

    • Authors: Nimsi Campos-Xolalpa, Ana Esquivel-Campos, Rubria Martínez-Casares, Salud Pérez-Gutiérrez, Julia Pérez-Ramos, Ernesto Sánchez-Mendoza
      First page: 771
      Abstract: Background: Inflammation is a complex process as a response to several stimuli, such as infection, a chemical irritant, and the attack of a foreign body. Piquerol was isolated from Piqueria trinervia, and its anti-inflammatory activity was evaluated using in vivo and in vitro models. Methods: Piquerol is a monoterpene that was identified using NMR, FT-IR spectroscopy, and mass spectrometry analysis. The anti-inflammatory activity was tested in vivo in ear edema induced with TPA in mice. Piquerol was also tested on J774A.1 macrophages stimulated with lipopolysaccharide (LPS), and the levels of NO, NF-κB, TNF-α, IL-1β, IL-6, and IL-10 were determined using ELISA. Results: The results show that piquerol diminished ear edema (66.19%). At 150.51 µM, it also inhibited the levels of NO (31.7%), TNF-α (49.8%), IL-1β (69.9%), IL-6 (47.5%), and NF-κB (26.7%), and increased the production of IL-10 (62.3%). Piquerol has a membrane stabilization property in erythrocyte, and at 100 µg/mL, the membrane protection was of 86.17%. Conclusions: Piquerol has anti-inflammatory activity, and its possible mechanism of action is through the inhibition of pro-inflammatory mediators. This compound could be a candidate in the development of new drugs to treat inflammatory problems.
      Citation: Pharmaceuticals
      PubDate: 2022-06-21
      DOI: 10.3390/ph15070771
      Issue No: Vol. 15, No. 7 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 672: Bio-Oriented Synthesis of Novel
           (S)-Flurbiprofen Clubbed Hydrazone Schiff’s Bases for Diabetic
           Management: In Vitro and In Silico Studies

    • Authors: Aftab Alam, Mumtaz Ali, Najeeb Ur Rehman, Saeed Ullah, Sobia Ahsan Halim, Abdul Latif, Zainab, Ajmal Khan, Obaid Ullah, Shujaat Ahmad, Ahmed Al-Harrasi, Manzoor Ahmad
      First page: 672
      Abstract: A new series of (S)-flurbiprofen derivatives 4a–4p and 5a–5n were synthesized with different aromatic or aliphatic aldehydes and ketones to produce Schiff’s bases and their structures were confirmed through HR-ESI-MS, 1H, and 13C-NMR spectroscopy. The α-glucosidase inhibitory activities of the newly synthesized compounds were scrutinized, in which six compounds 5k, 4h, 5h, 4d, 4b, and 5i showed potent inhibition in the range of 0.93 to 10.26 µM, respectively, whereas fifteen compounds 4c, 4g, 4i, 4j, 4l, 4m, 4o, 4p, 5c, 5d, 5j, 5l, 5m, 5n and 1 exhibited significant inhibitory activity with IC50 in range of = 11.42 to 48.39 µM. In addition, compounds 5g, 5f, 4k, 4n, and 4f displayed moderate-to-low activities. The modes of binding of all the active compounds were determined through the molecular docking approach, which revealed that two residues, specifically Glu277 and His351 are important in the stabilization of the active compounds in the active site of α-glucosidase. Furthermore, these compounds block the active site with high binding energies (−7.51 to −3.36 kcal/mol) thereby inhibiting the function of the enzyme.
      Citation: Pharmaceuticals
      PubDate: 2022-05-27
      DOI: 10.3390/ph15060672
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 673: Design, Synthesis, and In Vitro, In
           Silico and In Cellulo Evaluation of New Pyrimidine and Pyridine Amide and
           Carbamate Derivatives as Multi-Functional Cholinesterase Inhibitors

    • Authors: Martina Bortolami, Fabiana Pandolfi, Valeria Tudino, Antonella Messore, Valentina Noemi Madia, Daniela De Vita, Roberto Di Santo, Roberta Costi, Isabella Romeo, Stefano Alcaro, Marisa Colone, Annarita Stringaro, Alba Espargaró, Raimon Sabatè, Luigi Scipione
      First page: 673
      Abstract: Alzheimer disease is an age-linked neurodegenerative disorder representing one of the greatest medical care challenges of our century. Several drugs are useful in ameliorating the symptoms, even if none could stop or reverse disease progression. The standard approach is represented by the cholinesterase inhibitors (ChEIs) that restore the levels of acetylcholine (ACh) by inhibiting the acetylcholinesterase (AChE). Still, their limited efficacy has prompted researchers to develop new ChEIs that could also reduce the oxidative stress by exhibiting antioxidant properties and by chelating the main metals involved in the disease. Recently, we developed some derivatives constituted by a 2-amino-pyrimidine or a 2-amino-pyridine moiety connected to various aromatic groups by a flexible amino-alkyl linker as new dual inhibitors of AChE and butyrylcholinesterase (BChE). Following our previous studies, in this work we explored the role of the flexible linker by replacing the amino group with an amide or a carbamic group. The most potent compounds showed higher selectivity against BChE in respect to AChE, proving also to possess a weak anti-aggregating activity toward Aβ42 and tau and to be able to chelate Cu2+ and Fe3+ ions. Molecular docking and molecular dynamic studies proposed possible binding modes with the enzymes. It is noteworthy that these compounds were predicted as BBB-permeable and showed low cytotoxicity on the human brain cell line.
      Citation: Pharmaceuticals
      PubDate: 2022-05-27
      DOI: 10.3390/ph15060673
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 674: Protective Effect of Pycnogenol
           against Methotrexate-Induced Hepatic, Renal, and Cardiac Toxicity: An In
           Vivo Study

    • Authors: Faten Al-Abkal, Basel A. Abdel-Wahab, Hanaa F. Abd El-Kareem, Yasser M. Moustafa, Dina M. Khodeer
      First page: 674
      Abstract: Methotrexate (MTX) is one of the most commonly used chemotherapies for various types of cancer, including leukemia, breast cancer, hepatocarcinoma, and gastric cancers. However, the efficacy of MTX is frequently limited by serious side effects. Several studies have reported that the cytotoxic effect of MTX is not limited to cancer cells but can also affect normal tissues, leading to prospective damage to many organs. In the present study, we extensively investigated the molecular and microscopic basis of MTX-induced toxicity in different organs (liver, kidney, and heart) and explored the possible protective effect of pycnogenol, a polyphenolic component extracted from the bark of P. pinaster, to attenuate these effects. Biochemical analysis revealed that administration of MTX significantly reduced the function of the liver, kidney, and heart. Histological and immunohistochemical analysis indicated that MTX treatment caused damage to tissues of different organs. Interestingly, administration of pycnogenol (10, 20, and 30 mg/kg) significantly attenuated the deterioration effects of MTX on different organs in a dose-dependent manner, as demonstrated by biochemical and histological analysis. Our results reveal that pycnogenol successfully ameliorated oxidative damage and reduced toxicity, inflammatory response, and histological markers induced by methotrexate treatment. Taken together, this study provides solid evidence for the pharmacological application of pycnogenol to attenuate damage to different organs induced by MTX treatment.
      Citation: Pharmaceuticals
      PubDate: 2022-05-27
      DOI: 10.3390/ph15060674
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 675: Pharmacovigilance Signals of the
           Opioid Epidemic over 10 Years: Data Mining Methods in the Analysis of
           Pharmacovigilance Datasets Collecting Adverse Drug Reactions (ADRs)
           Reported to EudraVigilance (EV) and the FDA Adverse Event Reporting System
           (FAERS)

    • Authors: Stefania Chiappini, Rachel Vickers-Smith, Amira Guirguis, John M. Corkery, Giovanni Martinotti, Daniel R. Harris, Fabrizio Schifano
      First page: 675
      Abstract: In the past twenty years, the consumption of opioid medications has reached significant proportions, leading to a rise in drug misuse and abuse and increased opioid dependence and related fatalities. Thus, the purpose of this study was to determine whether there are pharmacovigilance signals of abuse, misuse, and dependence and their nature for the following prescription opioids: codeine, dihydrocodeine, fentanyl, oxycodone, pentazocine, and tramadol. Both the pharmacovigilance datasets EudraVigilance (EV) and the FDA Adverse Events Reporting System (FAERS) were analyzed to identify and describe possible misuse-/abuse-/dependence-related issues. A descriptive analysis of the selected Adverse Drug Reactions (ADRs) was performed, and pharmacovigilance signal measures (i.e., reporting odds ratio, proportional reporting ratio, information component, and empirical Bayesian geometric mean) were computed for preferred terms (PTs) of abuse, misuse, dependence, and withdrawal, as well as PTs eventually related to them (e.g., aggression). From 2003 to 2018, there was an increase in ADR reports for the selected opioids in both datasets. Overall, 16,506 and 130,293 individual ADRs for the selected opioids were submitted to EV and FAERS, respectively. Compared with other opioids, abuse concerns were mostly recorded in relation to fentanyl and oxycodone, while tramadol and oxycodone were more strongly associated with drug dependence and withdrawal. Benzodiazepines, antidepressants, other opioids, antihistamines, recreational drugs (e.g., cocaine and alcohol), and several new psychoactive substances, including mitragynine and cathinones, were the most commonly reported concomitant drugs. ADRs reports in pharmacovigilance databases confirmed the availability of data on the abuse and dependence of prescription opioids and should be considered a resource for monitoring and preventing such issues. Psychiatrists and clinicians prescribing opioids should be aware of their misuse and dependence liability and effects that may accompany their use, especially together with concomitant drugs.
      Citation: Pharmaceuticals
      PubDate: 2022-05-27
      DOI: 10.3390/ph15060675
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 676: Accurate Mass Identification of an
           Interfering Water Adduct and Strategies in Development and Validation of
           an LC-MS/MS Method for Quantification of MPI8, a Potent SARS-CoV-2 Main
           Protease Inhibitor, in Rat Plasma in Pharmacokinetic Studies

    • Authors: Wang, Xie, Alugubelli, Ma, Xu, Ma, Liu, Liang
      First page: 676
      Abstract: MPI8, a peptidyl aldehyde, is a potent antiviral agent against coronavirus. Due to unique tri-peptide bonds and the formyl functional group, the bioassay of MPI8 in plasma was challenged by a strong interference from water MPI8. Using QTOF LC-MS/MS, we identified MPI8•H2O as the major interference form that co-existed with MPI8 in aqueous and biological media. To avoid the resolution of MPI8 and MPI8•H2O observed on reverse phase columns, we found that a Kinetex hydrophilic interaction liquid chromatography (HILIC) column provided co-elution of both MPI8 and MPI8•H2O with a good single chromatographic peak and column retention of MPI8 which is suitable for quantification. Thus, a sensitive, specific, and reproducible LC-MS/MS method for the quantification of MPI8 in rat plasma was developed and validated using a triple QUAD LC-MS/MS. The chromatographic separation was achieved on a Kinetex HILIC column with a flow rate of 0.4 mL/min under gradient elution. The calibration curves were linear (r2 > 0.99) over MPI8 concentrations from 0.5–500 ng/mL. The accuracy and precision are within acceptable guidance levels. The mean matrix effect and recovery were 139% and 73%, respectively. No significant degradation of MPI8 occurred under the experimental conditions. The method was successfully applied to a pharmacokinetic study of MPI8 after administration of MPI8 sulfonate in rats.
      Citation: Pharmaceuticals
      PubDate: 2022-05-27
      DOI: 10.3390/ph15060676
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 677: European Safety Analysis of mRNA and
           Viral Vector COVID-19 Vaccines on Glucose Metabolism Events

    • Authors: Gabriella di Mauro, Annamaria Mascolo, Miriam Longo, Maria Ida Maiorino, Lorenzo Scappaticcio, Giuseppe Bellastella, Katherine Esposito, Annalisa Capuano
      First page: 677
      Abstract: Few data have been published on the effects of impaired glucose metabolism induced by COVID-19 vaccines. We decided to perform a study to describe Individual Case Safety Reports (ICSRs) of impaired glucose metabolism events reported in the European database (Eudravigilance, EV). ICSRs were retrieved from the online website of Eudravigilance. The reporting odds ratios (ROR) were computed to assess the reporting frequency for COVID-19 mRNA vaccines compared to COVID-19 viral vector-based vaccines. A total of 3917 ICSRs with a COVID-19 vaccine suspected were retrieved, with a total of 4275 impaired glucose metabolism events. Overall, the most reported events were related to “high glucose levels” (2012; 47.06%). The mRNA vaccines were associated with an increased reporting frequency of “type 1 diabetes mellitus” (ROR 1.86; 95% CI 1.33–2.60), “type 2 diabetes mellitus” (ROR 1.58; 95% CI 1.03–2.42), “high glucose levels” (ROR 1.16; 95% CI 1.06–1.27), “diabetes mellitus inadequate control” (ROR 1.63; 95% CI 1.25–2.11), and “hypoglycemia” (ROR 1.62; 95% CI 1.41–1.86) compared to viral vector-based vaccines. mRNA COVID-19 vaccines were associated with an increased reporting frequency of alterations of glucose homeostasis compared to viral-vector COVID-19 vaccines. Clinicians should be aware of these events to better manage glycemic perturbations. Larger nationwide studies are warranted to verify these findings.
      Citation: Pharmaceuticals
      PubDate: 2022-05-27
      DOI: 10.3390/ph15060677
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 678: Three-Dimensional (3D) Printing in
           Cancer Therapy and Diagnostics: Current Status and Future Perspectives

    • Authors: Safhi
      First page: 678
      Abstract: Three-dimensional (3D) printing is a technique where the products are printed layer-by-layer via a series of cross-sectional slices with the exact deposition of different cell types and biomaterials based on computer-aided design software. Three-dimensional printing can be divided into several approaches, such as extrusion-based printing, laser-induced forward transfer-based printing systems, and so on. Bio-ink is a crucial tool necessary for the fabrication of the 3D construct of living tissue in order to mimic the native tissue/cells using 3D printing technology. The formation of 3D software helps in the development of novel drug delivery systems with drug screening potential, as well as 3D constructs of tumor models. Additionally, several complex structures of inner tissues like stroma and channels of different sizes are printed through 3D printing techniques. Three-dimensional printing technology could also be used to develop therapy training simulators for educational purposes so that learners can practice complex surgical procedures. The fabrication of implantable medical devices using 3D printing technology with less risk of infections is receiving increased attention recently. A Cancer-on-a-chip is a microfluidic device that recreates tumor physiology and allows for a continuous supply of nutrients or therapeutic compounds. In this review, based on the recent literature, we have discussed various printing methods for 3D printing and types of bio-inks, and provided information on how 3D printing plays a crucial role in cancer management.
      Citation: Pharmaceuticals
      PubDate: 2022-05-27
      DOI: 10.3390/ph15060678
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 679: Design, Synthesis, In Vitro
           Biological Activity Evaluation and Stabilized Nanostructured Lipid Carrier
           Formulation of Newly Synthesized Schiff Bases-Based TMP Moieties

    • Authors: Syed Nasir Abbas Bukhari, Mohamed Y. Zakaria, Muhammad Usman Munir, Naveed Ahmad, Mervat A Elsherif, Rasha Emad Badr, Ahmad Khalaf Hassan, Ali H. Abu Almaaty, Islam Zaki
      First page: 679
      Abstract: A series of novel Schiff bases-based TMP moieties have been designed and synthesized as potential anticancer agents. The target Schiff bases were screened for their cytotoxic activity against the MDA-MB-231 breast cancer cell line. Most of the tested molecules revealed good cytotoxic activity, especially compounds 4h, 4j and 5d. Being the most potent, compound 4h showed good tubulin polymerization inhibition activity as revealed by immunofluorescence analysis and ELISA assay. Additionally, compound 4h was screened for cell cycle disturbance and apoptosis induction. Pre-G1 apoptosis and cell growth halt at the G2/M phase were discovered to be caused by it. Moreover, compound 4h induced apoptosis via p53 and Bax activation, as well as reduced the level of Bcl-2. Additionally, the most potent compound 4h was lodged on nanostructured lipid carriers (NLCs). 23 full factorial design was involved to govern the influence of the fabrication variables on the in vitro characters of the casted NLCs. F3 was picked as the optimum formula exhibiting dominant desirability value 0.805, EE% 95.6 ± 2.4, PS 222.4 ±18.7, PDI 0.23 ± 0.05 and ZP −39.2 ± 3.9 Mv. Furthermore, F3 affirmed improved solubility and release over the drug suspension. In the comparative cytotoxic activity, F3 was capable of diminishing the IC50 by around 2.15 times for pure 4h, while nearly close to the IC50 of the reference drug. Thus, NLCs could be a potential platform for boosted antitumor activity.
      Citation: Pharmaceuticals
      PubDate: 2022-05-28
      DOI: 10.3390/ph15060679
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 680: In Vitro, In Vivo and In Silico
           Characterization of a Novel Kappa-Opioid Receptor Antagonist

    • Authors: Kristina Puls, Aina-Leonor Olivé-Marti, Szymon Pach, Birgit Pinter, Filippo Erli, Gerhard Wolber, Mariana Spetea
      First page: 680
      Abstract: Kappa-opioid receptor (KOR) antagonists are promising innovative therapeutics for the treatment of the central nervous system (CNS) disorders. The new scaffold opioid ligand, Compound A, was originally found as a mu-opioid receptor (MOR) antagonist but its binding/selectivity and activation profile at the KOR and delta-opioid receptor (DOR) remain elusive. In this study, we present an in vitro, in vivo and in silico characterization of Compound A by revealing this ligand as a KOR antagonist in vitro and in vivo. In the radioligand competitive binding assay, Compound A bound at the human KOR, albeit with moderate affinity, but with increased affinity than to the human MOR and without specific binding at the human DOR, thus displaying a preferential KOR selectivity profile. Following subcutaneous administration in mice, Compound A effectively reverse the antinociceptive effects of the prototypical KOR agonist, U50,488. In silico investigations were carried out to assess the structural determinants responsible for opioid receptor subtype selectivity of Compound A. Molecular docking, molecular dynamics simulations and dynamic pharmacophore (dynophore) generation revealed differences in the stabilization of the chlorophenyl moiety of Compound A within the opioid receptor binding pockets, rationalizing the experimentally determined binding affinity values. This new chemotype bears the potential for favorable ADMET properties and holds promise for chemical optimization toward the development of potential therapeutics.
      Citation: Pharmaceuticals
      PubDate: 2022-05-28
      DOI: 10.3390/ph15060680
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 681: Clinical Utility of Medication-Based
           Risk Scores to Reduce Polypharmacy and Potentially Avoidable Healthcare
           Utilization

    • Authors: Armando Silva-Almodóvar, Milap C. Nahata
      First page: 681
      Abstract: The management of multiple chronic health conditions often requires patients to be exposed to polypharmacy to improve their health and enhance their quality of life. However, exposure to polypharmacy has been associated with an increased risk for adverse effects, drug-drug interactions, inappropriate prescribing, medication nonadherence, increased healthcare utilization such as emergency department visits and hospitalizations, and costs. Medication-based risk scores have been utilized to identify patients who may benefit from deprescribing interventions and reduce rates of inappropriate prescribing. These risk scores may also be utilized to prompt targeted discussions between patients and providers regarding medications or medication classes contributing to an individual’s risk for harm, eventually leading to the deprescribing of the offending medication(s). This opinion will describe existing medication-based risk scores in the literature, their utility in identifying patients at risk for specific adverse events, and how they may be incorporated in healthcare settings to reduce rates of potentially inappropriate polypharmacy and avoidable healthcare utilization and costs.
      Citation: Pharmaceuticals
      PubDate: 2022-05-28
      DOI: 10.3390/ph15060681
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 682: Enhancing Colistin Activity against
           Colistin-Resistant Escherichia coli through Combination with Alginate
           Nanoparticles and Small Molecules

    • Authors: Noura Hazime, Yanath Belguesmia, Isabelle Kempf, Alexandre Barras, Djamel Drider, Rabah Boukherroub
      First page: 682
      Abstract: Bacterial resistance to antibiotics has become a major public health problem worldwide, with the yearly number of deaths exceeding 700,000. To face this well-acknowledged threat, new molecules and therapeutic methods are considered. In this context, the application of nanotechnology to fight bacterial infection represents a viable approach and has experienced tremendous developments in the last decades. Escherichia coli (E. coli) is responsible for severe diarrhea, notably in the breeding sector, and especially in pig farming. The resulting infection (named colibacillosis) occurs in young piglets and could lead to important economic losses. Here, we report the design of several new formulations based on colistin loaded on alginate nanoparticles (Alg NPs) in the absence, but also in the presence, of small molecules, such as components of essential oils, polyamines, and lactic acid. These new formulations, which are made by concomitantly binding colistin and small molecules to Alg NPs, were successfully tested against E. coli 184, a strain resistant to colistin. When colistin was associated with Alg NPs, the minimal inhibition concentration (MIC) decreased from 8 to 1 µg/mL. It is notable that when menthol or lactic acid was co-loaded with colistin on Alg NPs, the MIC of colistin drastically decreased, reaching 0.31 or 0.62 µg/mL, respectively. These novel bactericidal formulations, whose innocuity towards eukaryotic HT-29 cells was established in vitro, are presumed to permeabilize the bacterial membrane and provoke the leakage of intracellular proteins. Our findings revealed the potentiating effect of the Alg NPs on colistin, but also of the small molecules mentioned above. Such ecological and economical formulations are easy to produce and could be proposed, after confirmation by in vivo and toxicology tests, as therapeutic strategies to replace fading antibiotics.
      Citation: Pharmaceuticals
      PubDate: 2022-05-28
      DOI: 10.3390/ph15060682
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 683: Bacterial Cellulose—Adaptation
           of a Nature-Identical Material to the Needs of Advanced Chronic Wound Care
           

    • Authors: Paul Zahel, Uwe Beekmann, Thomas Eberlein, Michael Schmitz, Oliver Werz, Dana Kralisch
      First page: 683
      Abstract: Modern wound treatment calls for hydroactive dressings. Among the variety of materials that have entered the field of wound care in recent years, the carbohydrate polymer bacterial cellulose (BC) represents one of the most promising candidates as the biomaterial features a high moisture-loading and donation capacity, mechanical stability, moldability, and breathability. Although BC has already gained increasing relevance in the treatment of burn wounds, its potential and clinical performance for “chronic wound” indications have not yet been sufficiently investigated. This article focuses on experimental and clinical data regarding the application of BC within the indications of chronic, non-healing wounds, especially venous and diabetic ulcers. A recent clinical observation study in a chronic wound setting clearly demonstrated its wound-cleansing properties and ability to induce healing in stalling wounds. Furthermore, the material parameters of BC dressings obtained through the static cultivation of Komagataeibacter xylinus were investigated for the first time in standardized tests and compared to various advanced wound-care products. Surprisingly, a free swell absorptive capacity of a BC dressing variant containing 97% moisture was found, which was higher than that of alginate or even hydrofiber dressings. We hypothesize that the fine-structured, open porous network and the resulting capillary forces are among the main reasons for this unexpected result.
      Citation: Pharmaceuticals
      PubDate: 2022-05-30
      DOI: 10.3390/ph15060683
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 684: Discovery of a Multifunctional
           Octapeptide from Lingzhi with Antioxidant and Tyrosinase Inhibitory
           Activity

    • Authors: Yodying Yingchutrakul, Sucheewin Krobthong, Kiattawee Choowongkomon, Phakorn Papan, Pawitrabhorn Samutrtai, Thanisorn Mahatnirunkul, Thitikorn Chomtong, Nitipol Srimongkolpithak, Theeranuch Jaroenchuensiri, Chanat Aonbangkhen
      First page: 684
      Abstract: Ganoderma lucidum or Lingzhi is a fungus species widely known as a traditional medicine. Exploring the beneficial peptides by hydrolysis using pepsin and trypsin has been extensively performed to identify new bioactive natural products. A multifunctional peptide that expresses potential scavenging activity and tyrosinase inhibition is valuable in therapeutic and cosmetic applications. This study aimed to identify and investigate the effects of a novel multifunctional peptide from Lingzhi on the melanogenic enzymes in melanoma cells by a targeted-proteomics approach. The multifunctional peptide was de novo sequenced by LC-MS/MS to be NH2-PVRSSNCA-CO2H (octapeptide). This sequence was chemically synthesized by solid-phase peptide synthesis (SPPS). The antioxidant ability of the synthesized octapeptide was measured by the DPPH, ABTS, and FRAP assays. The results showed that the peptide exhibited an antioxidant activity equal to 0.121 ± 0.01 mg equivalent to ascorbic acid, 0.173 ± 0.03 mg equivalent to gallic acid, and 2.21 ± 0.23 mM equivalent to FeSO4, respectively, which is comparable to these well-known antioxidants. The proteomics approach identified a total of 5804 proteins and several pathways involved in the effects of the octapeptide in melanoma cells. Targeted proteomics revealed three specific proteins associated with pigmentation including Rab29, Dct, and Tyrp1. The Rab29 and Dct were upregulated whereas Tyrp1 was downregulated in the octapeptide treatment group. These findings could be used in the understanding of the molecular functions of the multifunctional octapeptide on melanogenic enzymes, supporting its potential as a therapeutic and cosmetic ingredient.
      Citation: Pharmaceuticals
      PubDate: 2022-05-30
      DOI: 10.3390/ph15060684
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 685: Recent Advances in the Development of
           Tetrazine Ligation Tools for Pretargeted Nuclear Imaging

    • Authors: Rocío García-Vázquez, Umberto Maria Battisti, Matthias M. Herth
      First page: 685
      Abstract: Tetrazine ligation has gained interest as a bio-orthogonal chemistry tool within the last decade. In nuclear medicine, tetrazine ligation is currently being explored for pretargeted approaches, which have the potential to revolutionize state-of-the-art theranostic strategies. Pretargeting has been shown to increase target-to-background ratios for radiopharmaceuticals based on nanomedicines, especially within early timeframes. This allows the use of radionuclides with short half-lives which are more suited for clinical applications. Pretargeting bears the potential to increase the therapeutic dose delivered to the target as well as reduce the respective dose to healthy tissue. Combined with the possibility to be applied for diagnostic imaging, pretargeting could be optimal for theranostic approaches. In this review, we highlight efforts that have been made to radiolabel tetrazines with an emphasis on imaging.
      Citation: Pharmaceuticals
      PubDate: 2022-05-30
      DOI: 10.3390/ph15060685
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 686: Exorbitant Drug Loading of Metformin
           and Sitagliptin in Mucoadhesive Buccal Tablet: In Vitro and In Vivo
           Characterization in Healthy Volunteers

    • Authors: Shakir, Hanif, Salawi, Arshad, Sarfraz, Irfan, Raza, Barkat, Sabei, Almoshari, Alshamrani, Syed
      First page: 686
      Abstract: The aim of the proposed study is to develop a mucoadhesive buccal delivery system for the sustained delivery of metformin (MET) and sitagliptin (SIT) against diabetes mellitus (DM) with improved bioavailability. Polymeric blend of Carbopol® 940 (CP), agarose (AG) or polyvinylpyrrolidone K30 (PVP) as mucoadhesive agents in formulations (R1–R15) were compressed via the direct compression technique. Tablets were characterized for solid state studies, physicochemical and in vivo mucoadhesion studies in healthy volunteers. Outcomes did not reveal any unusual peak or interaction between the drugs and polymers in the physical mixture through Fourier Transform Infrared Spectroscopy (FTIR) and DSC analysis. The mucoadhesive blend of CP and PVP was superior compared to other blends. The formulation R4 revealed exorbitant loading of drugs with complete drug release for 6 h with ex vivo mucoadhesive strength and time of 26.99 g and 8.1 h, respectively. It was further scrutinized to evaluate it as an optimized formulation where it was found to be stable for up to 6 months. The formulation R4 depicted Korsmeyer–Peppas model and first-order mode of release correspondingly for SIT and MET. Moreover, it showed hemocompatibility, biocompatibility and stability with non-significant changes in the dissolution profile. Overall, the CP blend with PVP was found appropriate to yield the desired release coupled with the optimized mucoadhesive properties of the buccal tablets, ensuring sufficient pharmaceutical stability.
      Citation: Pharmaceuticals
      PubDate: 2022-05-30
      DOI: 10.3390/ph15060686
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 687: In Silico Antiprotozoal Evaluation of
           1,4-Naphthoquinone Derivatives against Chagas and Leishmaniasis Diseases
           Using QSAR, Molecular Docking, and ADME Approaches

    • Authors: Lina S. Prieto Cárdenas, Karen A. Arias Soler, Diana L. Nossa González, Wilson E. Rozo Núñez, Agobardo Cárdenas-Chaparro, Pablo R. Duchowicz, Jovanny A. Gómez Castaño
      First page: 687
      Abstract: Chagas and leishmaniasis are two neglected diseases considered as public health problems worldwide, for which there is no effective, low-cost, and low-toxicity treatment for the host. Naphthoquinones are ligands with redox properties involved in oxidative biological processes with a wide variety of activities, including antiparasitic. In this work, in silico methods of quantitative structure–activity relationship (QSAR), molecular docking, and calculation of ADME (absorption, distribution, metabolism, and excretion) properties were used to evaluate naphthoquinone derivatives with unknown antiprotozoal activity. QSAR models were developed for predicting antiparasitic activity against Trypanosoma cruzi, Leishmania amazonensis, and Leishmania infatum, as well as the QSAR model for toxicity activity. Most of the evaluated ligands presented high antiparasitic activity. According to the docking results, the family of triazole derivatives presented the best affinity with the different macromolecular targets. The ADME results showed that most of the evaluated compounds present adequate conditions to be administered orally. Naphthoquinone derivatives show good biological activity results, depending on the substituents attached to the quinone ring, and perhaps the potential to be converted into drugs or starting molecules.
      Citation: Pharmaceuticals
      PubDate: 2022-05-31
      DOI: 10.3390/ph15060687
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 688: Design, Synthesis, and In Vitro
           Evaluation of Novel 8-Amino-Quinoline Combined with Natural Antioxidant
           Acids

    • Authors: Andrea Bacci, Francesca Corsi, Massimiliano Runfola, Simona Sestito, Ilaria Piano, Clementina Manera, Giuseppe Saccomanni, Claudia Gargini, Simona Rapposelli
      First page: 688
      Abstract: Overproduction of reactive oxygen species (ROS) and alterations in metallostasis are common and related hallmarks in several neurodegenerative diseases (NDDs). Nature-based derivatives always represent an attractive tool in MTDL drug design, especially against ROS in NDDs. On this notion, we designed a new series of 8-quinoline-N-substituted derivatives with a natural antioxidant portion (i.e., lipoic, caffeic, and ferulic acids). These compounds were shown to chelate copper, a metal involved in ROS-induced degeneration, and scavenger oxygen radicals in DPPH assay. Then, selected compounds 4 and 5 were evaluated in an in vitro model of oxidative stress and shown to possess cytoprotective effects in 661W photoreceptor-like cells. The obtained results may represent a starting point for the application of the proposed class of compounds in retinal neurodegenerative diseases such as retinitis pigmentosa (RP), comprising a group of hereditary rod–cone dystrophies that represent a major cause of blindness in patients of working age, where the progression of the disease is a multifactorial event, with oxidative stress contributing predominantly.
      Citation: Pharmaceuticals
      PubDate: 2022-05-31
      DOI: 10.3390/ph15060688
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 689: Size-Dependent Antibacterial,
           Antidiabetic, and Toxicity of Silver Nanoparticles Synthesized Using
           Solvent Extraction of Rosa indica L. Petals

    • Authors: Satheesh Kumar Balu, Swetha Andra, Fouad Damiri, Anandhi Sivaramalingam, Manisha Vidyavathy Sudandaradoss, Karthikeyan Kumarasamy, Kishore Bhakthavachalam, Faraat Ali, Milton Kumar Kundu, Md. Habibur Rahman, Mohammed Berrada, Simona Cavalu
      First page: 689
      Abstract: In this study, silver nanoparticles (AgNPs) are synthesized through a green approach by employing Rosa indica L. petal (RE) extracts as reducing and stabilizing agents, which are extracted using three different solvents: ethanol (Et), acetone (Ac), and water (Aq). The phase formation of the AgNPs is confirmed using X-ray diffraction (XRD). Morphological analysis is performed using a field-emission scanning electron microscope (FESEM), which reveals that the AgNPs are spherical in shape. The size is estimated using ImageJ software, which is found to be ~12, 18, and 770 nm for RE-Ac-Ag, RE-Et-Ag, and RE-Aq-Ag, respectively. The phytochemicals of Rosa indica L. petals involved in the formation of the AgNPs are studied using Fourier transform infrared spectroscopy (FTIR). Finally, these materials are studied for their antibacterial, antidiabetic, antioxidant, and hemolytic activity, as well as cell toxicity properties. The materials, RE-Ac-Ag and RE-Et-Ag, are found to be more effective than RE-Aq-Ag in inhibiting E. coli (Gram-negative bacteria) and S. aureus (Gram-positive bacteria). Hemolytic studies reveal that all of the samples show concentration-dependent activity up to 50 µg/mL. RE-Ac-Ag and RE-Et-Ag exhibit nonhemolytic behavior, whereas RE-Aq-Ag remains nonhemolytic until 100 µg/mL. The antidiabetic ability of the AgNPs is evaluated using α-amylase inhibition assay (DNSA assay) and α-glucosidase inhibition assay. The results are found to be effective, with IC50 values of α-amylase and α-glycosidase being 50, 50, and 75 µg/mL for RE-Et-Ag, RE-Ac-Ag, and RE-Aq-Ag, respectively. DPPH assay shows that the AgNPs inhibited the antioxidants well, with IC50 values of 40 µg/mL for RE-Et-Ag and RE-Ac-Ag and 60 µg/mL for RE-Aq-Ag. The toxicity study reveals that the AgNPs show size- and concentration-dependent behavior. Overall, it is realized from the findings that RE-Ac-Ag, RE-Et-Ag, and RE-Aq-Ag show size-dependent antibacterial, antidiabetic, and toxicity properties.
      Citation: Pharmaceuticals
      PubDate: 2022-05-31
      DOI: 10.3390/ph15060689
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 690: Dihydropyrazole-Carbohydrazide
           Derivatives with Dual Activity as Antioxidant and Anti-Proliferative Drugs
           on Breast Cancer Targeting the HDAC6

    • Authors: Irving Balbuena-Rebolledo, Astrid M. Rivera-Antonio, Yudibeth Sixto-López, José Correa-Basurto, Martha C. Rosales-Hernández, Jessica Elena Mendieta-Wejebe, Francisco J. Martínez-Martínez, Ivonne María Olivares-Corichi, José Rubén García-Sánchez, Juan Alberto Guevara-Salazar, Martiniano Bello, Itzia I. Padilla-Martínez
      First page: 690
      Abstract: Breast cancer (BC) is the most frequently diagnosed cancer and is the second-most common cause of death in women worldwide. Because of this, the search for new drugs and targeted therapy to treat BC is an urgent and global need. Histone deacetylase 6 (HDAC6) is a promising anti-BC drug target associated with its development and progression. In the present work, the design and synthesis of a new family of dihydropyrazole-carbohydrazide derivatives (DPCH) derivatives focused on HDAC6 inhibitory activity is presented. Computational chemistry approaches were employed to rationalize the design and evaluate their physicochemical and toxic-biological properties. The new family of nine DPCH was synthesized and characterized. Compounds exhibited optimal physicochemical and toxicobiological properties for potential application as drugs to be used in humans. The in silico studies showed that compounds with –Br, –Cl, and –OH substituents had good affinity with the catalytic domain 2 of HDAC6 like the reference compounds. Nine DPCH derivatives were assayed on MCF-7 and MDA-MB-231 BC cell lines, showing antiproliferative activity with IC50 at μM range. Compound 2b showed, in vitro, an IC50 value of 12 ± 3 µM on human HDAC6. The antioxidant activity of DPCH derivatives showed that all the compounds exhibit antioxidant activity similar to that of ascorbic acid. In conclusion, the DPCH derivatives are promising drugs with therapeutic potential for the epigenetic treatment of BC, with low cytotoxicity towards healthy cells and important antioxidant activity.
      Citation: Pharmaceuticals
      PubDate: 2022-05-31
      DOI: 10.3390/ph15060690
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 691: In Silico Prediction of Plasmodium
           falciparum Cytoadherence Inhibitors That Disrupt Interaction between
           gC1qR-DBLβ12 Complex

    • Authors: Abdul Hafiz, Rowaida Bakri, Mohammad Alsaad, Obadah M. Fetni, Lojain I. Alsubaihi, Hina Shamshad
      First page: 691
      Abstract: Malaria causes about half a million deaths per year, mainly in children below 5 years of age. Cytoadherence of Plasmodium falciparum infected erythrocytes in brain and placenta has been linked to severe malaria and malarial related deaths. Cytoadherence is mediated by binding of human receptor gC1qR to the DBLβ12 domain of a P. falciparum erythrocyte membrane protein family 1 (PfEMP1) protein. In the present work, molecular dynamic simulation was extensively studied for the gC1qR-DBLβ12 complex. The stabilized protein complex was used to study the protein–protein interface interactions and mapping of interactive amino acid residues as hotspot were performed. Prediction of inhibitors were performed by using virtual protein–protein inhibitor database Timbal screening of about 15,000 compounds. In silico mutagenesis studies, binding profile and protein ligand interaction fingerprinting were used to strengthen the screening of the potential inhibitors of gC1qR-DBLβ12 interface. Six compounds were selected and were further subjected to the MAIP analysis and ADMET studies. From these six compounds, the compounds 3, 5, and 6 were found to outperform on all screening criteria from the rest selected compounds. These compounds may provide novel drugs to treat and manage severe falciparum malaria. Additionally. the identified hotspots can be used in future for designing novel interventions for disruption of interface interactions, such as through peptides or vaccines. Futher in vitro and in vivo studies are required for the confirmation of these compounds as potential inhibitors of gC1qR-DBLβ12 interaction.
      Citation: Pharmaceuticals
      PubDate: 2022-05-31
      DOI: 10.3390/ph15060691
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 692: A Pivotal Role of Nrf2 in
           Neurodegenerative Disorders: A New Way for Therapeutic Strategies

    • Authors: Suzen, Tucci, Profumo, Buttari, Saso
      First page: 692
      Abstract: Clinical and preclinical research indicates that neurodegenerative diseases are characterized by excess levels of oxidative stress (OS) biomarkers and by lower levels of antioxidant protection in the brain and peripheral tissues. Dysregulations in the oxidant/antioxidant balance are known to be a major factor in the pathogenesis of neurodegenerative diseases and involve mitochondrial dysfunction, protein misfolding, and neuroinflammation, all events that lead to the proteostatic collapse of neuronal cells and their loss. Nuclear factor-E2-related factor 2 (Nrf2) is a short-lived protein that works as a transcription factor and is related to the expression of many cytoprotective genes involved in xenobiotic metabolism and antioxidant responses. A major emerging function of Nrf2 from studies over the past decade is its role in resistance to OS. Nrf2 is a key regulator of OS defense and research supports a protective and defending role of Nrf2 against neurodegenerative conditions. This review describes the influence of Nrf2 on OS and in what way Nrf2 regulates antioxidant defense for neurodegenerative conditions. Furthermore, we evaluate recent research and evidence for a beneficial and potential role of specific Nrf2 activator compounds as therapeutic agents.
      Citation: Pharmaceuticals
      PubDate: 2022-05-31
      DOI: 10.3390/ph15060692
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 693: Applications in Which Aptamers Are
           Needed or Wanted in Diagnostics and Therapeutics

    • Authors: John G. Bruno
      First page: 693
      Abstract: One strategy for bringing aptamers more into the mainstream of biomedical diagnostics and therapeutics is to exploit niche applications where aptamers are truly needed or wanted for their innate differences versus antibodies. This brief review article highlights some of those relatively rare applications in which aptamers are necessary or better suited to the user requirements than antibodies with explanations for why the aptamer is a necessary or superior choice. These situations include when no commercial antibody exists, when antibodies are excessively difficult to develop against a particular target because the target is highly toxic to host animals, when antibodies fail to discriminate closely related targets, when a smaller size is preferable to penetrate a tissue, when humanized monoclonal antibodies are too expensive and when the target is rapidly evolving or mutating. Examples of each are provided to illustrate these points.
      Citation: Pharmaceuticals
      PubDate: 2022-06-01
      DOI: 10.3390/ph15060693
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 694: Analytical Performance Evaluation of
           

    • Authors: Margaux Fresnais, Siwen Liang, Marius Breitkopf, Joshua Raoul Lindner, Emmanuelle Claude, Steven Pringle, Pavel A. Levkin, Konstantin Demir, Julia Benzel, Julia Sundheimer, Britta Statz, Kristian W. Pajtler, Stefan M. Pfister, Walter E. Haefeli, Jürgen Burhenne, Rémi Longuespée
      First page: 694
      Abstract: Desorption/ionization (DI)-mass spectrometric (MS) methods offer considerable advantages of rapidity and low-sample input for the analysis of solid biological matrices such as tissue sections. The concept of desorption electrospray ionization (DESI) offers the possibility to ionize compounds from solid surfaces at atmospheric pressure, without the addition of organic compounds to initiate desorption. However, severe drawbacks from former DESI hardware stability made the development of assays for drug quantification difficult. In the present study, the potential of new prototype source setups (High Performance DESI Sprayer and Heated Transfer Line) for the development of drug quantification assays in tissue sections was evaluated. It was demonstrated that following dedicated optimization, new DESI XS enhancements present promising options regarding targeted quantitative analyses. As a model compound for these developments, ulixertinib, an inhibitor of extracellular signal-regulated kinase (ERK) 1 and 2 was used.
      Citation: Pharmaceuticals
      PubDate: 2022-06-01
      DOI: 10.3390/ph15060694
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 695: A More Biomimetic Cell Migration
           Assay with High Reliability and Its Applications

    • Authors: Di Yin, Hongbo Zhang, Chun Yang, Wenjun Zhang, Shihmo Yang
      First page: 695
      Abstract: Cell migration refers to the directional movement of cells to the surrounding cell-free zone in response to chemical and mechanical stimuli. A cell migration assay is an essential device for studying pharmaceutical and medical problems. In this paper, we present a novel approach to a cell migration assay on a chip with two merits, namely (i) simultaneous creation of many cell samples on the same condition and (ii) cells migrating while being stressed in a fluidic environment. The first merit has addressed the problem of poor reproducibility in experimental studies for medical problems such as wound healing, and the second merit has made the cell migration device, which is an in vitro environment, more biomimetic. The two merits are attributed to a novel mechanical method to simultaneously create many cell-free zones and to the design of a microfluidic process to create shear stress in cells uniformly. Two applications were studied on our device to explore its effectiveness. The first application is regarding the combination chemotherapy of cisplatin and doxorubicin (Adriamycin) on cervical cancer cells (HeLa). The second application is regarding inhibiting the migration of endothelial cells (HUVEC) in the process of anti-angiogenesis.
      Citation: Pharmaceuticals
      PubDate: 2022-06-01
      DOI: 10.3390/ph15060695
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 696: Analgesics Induce Alterations in the
           Expression of SARS-CoV-2 Entry and Arachidonic-Acid-Metabolizing Genes in
           the Mouse Lungs

    • Authors: Fatima Khirfan, Yazun Jarrar, Tariq Al-Qirim, Khang Wen Goh, Qais Jarrar, Chrismawan Ardianto, Mohammad Awad, Hamzeh J. Al-Ameer, Wajdy Al-Awaida, Said Moshawih, Long Chiau Ming
      First page: 696
      Abstract: Paracetamol and nonsteroidal anti-inflammatory drugs are widely used in the management of respiratory viral infections. This study aimed to determine the effects of the most commonly used analgesics (paracetamol, ibuprofen, and diclofenac) on the mRNA expression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry and arachidonic-acid-metabolizing genes in mouse lungs. A total of twenty eight Balb/c mice were divided into four groups and treated separately with vehicle, paracetamol, ibuprofen, and diclofenac in clinically equivalent doses for 14 days. Then, the expressions of SARS-CoV-2 entry, ACE2, TMPRSS2, and Ctsl genes, in addition to the arachidonic-acid-metabolizing cyp450, cox, and alox genes, were analyzed using real-time PCR. Paracetamol increased the expressions of TMPRSS2 and Ctsl genes by 8.5 and 5.6 folds, respectively, while ibuprofen and diclofenac significantly decreased the expression of the ACE2 gene by more than 2.5 folds. In addition, all tested drugs downregulated (p < 0.05) cox2 gene expression, and paracetamol reduced the mRNA levels of cyp4a12 and 2j5. These molecular alterations in diclofenac and ibuprofen were associated with pathohistological alterations, where both analgesics induced the infiltration of inflammatory cells and airway wall thickening. It is concluded that analgesics such as paracetamol, ibuprofen, and diclofenac alter the expression of SARS-CoV-2 entry and arachidonic-acid-metabolizing genes in mouse lungs.
      Citation: Pharmaceuticals
      PubDate: 2022-06-01
      DOI: 10.3390/ph15060696
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 697: Imaging of Clear Cell Renal Carcinoma
           with Immune Checkpoint Targeting Aptamer-Based Probe

    • Authors: Stanisław Malicki, Barbara Pucelik, Edyta Żyła, Małgorzata Benedyk-Machaczka, Wojciech Gałan, Anna Golda, Alicja Sochaj-Gregorczyk, Marta Kamińska, João Crispim Encarnação, Barbara Chruścicka, Hans-Peter Marti, Tony Jialiang Chen, Katarzyna Magiera-Mularz, Bartosz Zięba, Tad A. Holak, Janusz M. Dąbrowski, Anna Czarna, Joanna Kozieł, Piotr Mydel, Grzegorz Dubin
      First page: 697
      Abstract: Immune checkpoint targeting immunotherapy has revolutionized the treatment of certain cancers in the recent years. Determination of the status of immune checkpoint expression in particular cancers may assist decision making. Here, we describe the development of a single-stranded aptamer-based molecular probe specifically recognizing human PD-L1. Target engaging aptamers are selected by iterative enrichment from a random ssDNA pool and the binding is characterized biochemically. Specificity and dose dependence is demonstrated in vitro in the cell culture using human kidney tumor cells (786-0), human melanoma cells (WM115 and WM266.4) and human glioblastoma LN18 cancer cells. The utility of the probe in vivo is demonstrated using two mouse tumor models, where we show that the probe exhibits excellent potential in imaging. We postulate that further development of the probe may allow universal imaging of different types of tumors depending on their PD-L1 status, which may find utility in cancer diagnosis.
      Citation: Pharmaceuticals
      PubDate: 2022-06-01
      DOI: 10.3390/ph15060697
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 698: Antiproliferative Activity of a New
           Quinazolin-4(3H)-One Derivative via Targeting Aurora Kinase A in Non-Small
           Cell Lung Cancer

    • Authors: Ji Yun Lee, Huarong Yang, Donghwa Kim, Kay Zin Kyaw, Ruoci Hu, Yanhua Fan, Sang Kook Lee
      First page: 698
      Abstract: Non-small cell lung cancer (NSCLC) is the most common lung cancer subtype. Although chemotherapy and targeted therapy are used for the treatment of patients with NSCLC, the survival rate remains very low. Recent findings suggested that aurora kinase A (AKA), a cell cycle regulator, is a potential target for NSCLC therapy. Previously, we reported that a chemical entity of quinazolin-4(3H)-one represents a new template for AKA inhibitors, with antiproliferative activity against cancer cells. A quinazolin-4(3H)-one derivative was further designed and synthesized in order to improve the pharmacokinetic properties and antiproliferation activity against NSCLC cell lines. The derivative, BIQO-19 (Ethyl 6-(4-oxo-3-(pyrimidin-2-ylmethyl)-3,4-dihydroquinazolin-6-yl)imidazo [1,2-a]pyridine-2-carboxylate), exhibited improved solubility and antiproliferative activity in NSCLC cells, including epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI)-resistant NSCLC cells. BIQO-19 effectively inhibited the growth of the EGFR-TKI-resistant H1975 NSCLC cells, with the suppression of activated AKA (p-AKA) expression in these cells. The inhibition of AKA by BIQO-19 significantly induced G2/M phase arrest and subsequently evoked apoptosis in H1975 cells. In addition, the combination of gefitinib and BIQO-19 exhibited synergistic antiproliferative activity in NSCLC cells. These findings suggest the potential of BIQO-19 as a novel therapeutic agent for restoring the sensitivity of gefitinib in EGFR-TKI-resistant NSCLC cells.
      Citation: Pharmaceuticals
      PubDate: 2022-06-02
      DOI: 10.3390/ph15060698
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 699: In Vitro Evaluation of the
           Antioxidant Activity and Chemopreventive Potential in Human Breast Cancer
           Cell Lines of the Standardized Extract Obtained from the Aerial Parts of
           Zigzag Clover (Trifolium medium L.)

    • Authors: Grażyna Zgórka, Magdalena Maciejewska-Turska, Anna Makuch-Kocka, Tomasz Plech
      First page: 699
      Abstract: The aboveground parts of Trifolium medium L. (zigzag clover), a little-known representative of the family Fabaceae, collected during flowering in a wild stand (Sławin-Szerokie district, Lublin, Poland), were used in this study. Our previous investigations confirmed the higher content of phytoestrogenic isoflavones (especially biochanin A and formononetin derivatives) in T. medium compared to the closely related medicinal plant T. pratense (red clover) and the involvement of these compounds in anti-osteoporotic effects in ovariectomized female rats. The current study focused on evaluating other antibiodegenerative (antioxidant, chemopreventive, and cytostatic) effects for the lyophilisate (TML) obtained from wild zigzag clover. For this purpose, efficient ultrasound-assisted extraction (UAE) was employed, followed by vacuum drying and phytochemical standardization using a newly developed reversed-phase high-performance liquid chromatography (RP-LC) coupled with a PDA detection. Malonylglycosides of biochanin A and formononetin were the predominant compounds and were found to contribute more than 54% to the total isoflavone content determined in the standardized extract of zigzag clover. The antioxidant potential of TML was examined in vitro using the Folin–Ciocalteu and cupric ion-reducing (CUPRAC) methods in addition to the free radical (DPPH• and ABTS•+) scavenging assays. The cytotoxic effects of TML, formononetin, and ononin were evaluated on MCF-7 (estrogen-dependent) and MDA-MB-231 (estrogen-independent) human breast cancer cell lines using the MTT assay. The important role of malonyl isoflavone derivatives has been indicated both in chemoprevention and potential cytotoxic effects of TML against certain types of breast cancer.
      Citation: Pharmaceuticals
      PubDate: 2022-06-02
      DOI: 10.3390/ph15060699
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 700: In Vitro Anticancer Activity
           Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual
           Inhibitors and Apoptosis Inducers

    • Authors: Rana M. Abdelnaby, Afaf A. El-Malah, Rasha R. FakhrEldeen, Marwa M. Saeed, Rania I. Nadeem, Nancy S. Younis, Hanaa M. Abdel-Rahman, Nehad M. El-Dydamony
      First page: 700
      Abstract: Protein kinases are seen as promising targets in controlling cell proliferation and survival in treating cancer where fused thiophene synthon was utilized in many kinase inhibitors approved by the FDA. Accordingly, this work focused on adopting fused thienopyrrole and pyrrolothienopyrimidine scaffolds in preparing new inhibitors, which were evaluated as antiproliferative agents in the HepG2 and PC-3 cell lines. The compounds 3b (IC50 = 3.105 and 2.15 μM) and 4c (IC50 = 3.023 and 3.12 μM) were the most promising candidates on both cells with good selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where 4c inhibited VEGFR-2 and AKT at IC50 = 0.075 and 4.60 μM, respectively, while 3b showed IC50 = 0.126 and 6.96 μM, respectively. Moreover, they resulted in S phase cell cycle arrest with subsequent caspase-3-induced apoptosis. Lastly, docking studies evaluated the binding patterns of these active derivatives and demonstrated a similar fitting pattern to the reference ligands inside the active sites of both VEGFR-2 and AKT (allosteric pocket) crystal structures. To conclude, these thiophene derivatives represent promising antiproliferative leads inhibiting both VEGFR-2 and AKT and inducing apoptosis in liver cell carcinoma.
      Citation: Pharmaceuticals
      PubDate: 2022-06-02
      DOI: 10.3390/ph15060700
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 701: Low-Energy Electron Induced Reactions
           in Metronidazole at Different Solvation Conditions

    • Authors: Christine Lochmann, Thomas F. M. Luxford, Samanta Makurat, Andriy Pysanenko, Jaroslav Kočišek, Janusz Rak, Stephan Denifl
      First page: 701
      Abstract: Metronidazole belongs to the class of nitroimidazole molecules and has been considered as a potential radiosensitizer for radiation therapy. During the irradiation of biological tissue, secondary electrons are released that may interact with molecules of the surrounding environment. Here, we present a study of electron attachment to metronidazole that aims to investigate possible reactions in the molecule upon anion formation. Another purpose is to elucidate the effect of microhydration on electron-induced reactions in metronidazole. We use two crossed electron/molecular beam devices with the mass-spectrometric analysis of formed anions. The experiments are supported by quantum chemical calculations on thermodynamic properties such as electron affinities and thresholds of anion formation. For the single molecule, as well as the microhydrated condition, we observe the parent radical anion as the most abundant product anion upon electron attachment. A variety of fragment anions are observed for the isolated molecule, with NO2− as the most abundant fragment species. NO2− and all other fragment anions except weakly abundant OH− are quenched upon microhydration. The relative abundances suggest the parent radical anion of metronidazole as a biologically relevant species after the physicochemical stage of radiation damage. We also conclude from the present results that metronidazole is highly susceptible to low-energy electrons.
      Citation: Pharmaceuticals
      PubDate: 2022-06-02
      DOI: 10.3390/ph15060701
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 702: Identification of Angiogenic Cargoes
           in Human Fibroblasts-Derived Extracellular Vesicles and Induction of Wound
           Healing

    • Authors: Prakash Gangadaran, Eun Jung Oh, Ramya Lakshmi Rajendran, Hyun Mi Kim, Ji Min Oh, Suin Kwak, Chae Moon Hong, Kang Young Choi, Ho Yun Chung, Byeong-Cheol Ahn
      First page: 702
      Abstract: A complete redevelopment of the skin remains a challenge in the management of acute and chronic wounds. Recently, the application of extracellular vesicles (EVs) for soft tissue wound healing has received much attention. As fibroblasts are fundamental cells for soft tissues and skin, we investigate the proangiogenic factors in human normal fibroblast-derived EVs (hNF-EVs) and their effects on wound healing. Normal fibroblasts were isolated from human skin tissues and characterized by immunofluorescence (IF) and Western blotting (WB). hNF-EVs were isolated by ultracentrifugation and characterized using transmission electron microscopy and WB. The proangiogenic cargos in hNF-EVs were identified by a TaqMan assay and a protein array. Other in vitro assays, including internalization assays, cell counting kit-8 analysis, scratch wound assays, WBs, and tube formation assays were conducted to assess the effects of hNF-EVs on fibroblasts and endothelial cells. A novel scaffold-free noninvasive delivery of hNF-EVs with or without fibrin glue was applied onto full-thickness skin wounds in mice. The wound healing therapeutical effect of hNF-EVs was assessed by calculating the rate of wound closure and through histological analysis. Isolated hNF was confirmed by verifying the expression of the fibroblast markers vimentin, αSMA, Hsp70, and S100A4. Isolated hNF-EVs showed intact EVs with round morphology, enriched in CD81 and CD63, and devoid of the cell markers GM130, Calnexin, and Cytochrome C. Our TaqMan assay showed that hNF-EVs were enriched in miR130a and miR210, and protein arrays showed enriched levels of the proangiogenic proteins’ vascular endothelial growth factor (VEGF)-D and CXCL8. Next, we found that the internalization of hNF-EVs into hNF increased the proliferation and migration of hNF, in addition to increasing the expression of bFGF, MMP2, and αSMA. The internalization of hNF-EVs into the endothelial cells increased their proliferation and tube formation. A scaffold-free noninvasive delivery of hNF-EVs with or without fibrin glue accelerated the wound healing rate in full-thickness skin wounds in mice, and the treatments increased the cellular density, deposition, and maturation of collagens in the wounds. Moreover, the scaffold-free noninvasive delivery of hNF-EVs with or without fibrin glue increased the VEGF and CD31 expression in the wounds, indicating that hNF-EVs have an angiogenic ability to achieve complete skin regeneration. These findings open up for new treatment strategies to be developed for wound healing. Further, we offer a new approach to the efficient, scaffold-free noninvasive delivery of hNF-EVs to wounds.
      Citation: Pharmaceuticals
      PubDate: 2022-06-02
      DOI: 10.3390/ph15060702
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 703: Nano-Silica Carriers Coated by
           Chloramphenicol: Synthesis, Characterization, and Grinding Trial as a Way
           to Improve the Release Profile

    • Authors: Radosław Balwierz, Dawid Bursy, Paweł Biernat, Nataliia Hudz, Mariia Shanaida, Łukasz Krzemiński, Paweł Skóra, Monika Biernat, Wioletta Ochędzan Siodłak
      First page: 703
      Abstract: Silica nanoparticles were applied as the carrier of chloramphenicol (2,2-dichloro-N-[(1R,2R)-1,3-dihydroxy-1-(4-nitrophenyl)propan-2-yl]acetamide), and were loaded in a 1% carbopol-based gel (poly(acrylic acid)), which allowed obtainment of an upgraded drug form. The samples of silica materials were obtained by means of modified Stöber synthesis, and their morphological properties were analyzed using Fourier transform infrared spectroscopy (FTIR), Brunauer–Emmett–Teller (BET) method, elemental analysis (EA), thermogravimetric analysis (TGA), analysis of the specific surface properties, X-ray diffraction study (XRD), scanning electron microscope (SEM), and dynamic light scattering (DLS) methods, which permitted the selection of the drug carrier. The two obtained silica carriers were coated with chloramphenicol and loaded into 1% carbopol gel. The release studies were then performed. The release results were evaluated using mathematical models as well as model-independent analysis. It was found that the modification of the synthesis of the silica by the sol-gel method to form a product coated with chloramphenicol and further grinding of the silica material influenced the release of the active substance, thus allowing the modification of its pharmaceutical availability. The change in the parameters of silica synthesis influenced the structure and morphological properties of the obtained silica carrier. The grinding process determined the way of adsorption of the active substance on its surface. The studies showed that the proper choice of silica carrier has a considerable effect on the release profile of the prepared hydrogel formulations.
      Citation: Pharmaceuticals
      PubDate: 2022-06-02
      DOI: 10.3390/ph15060703
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 704: Assessing Gene Expression Related to
           Cisplatin Resistance in Human Oral Squamous Cell Carcinoma Cell Lines

    • Authors: Hyeong Sim Choi, Young-Kyun Kim, Pil-Young Yun
      First page: 704
      Abstract: Cisplatin-based chemotherapy has been effectively used to treat oral cancer, but treatment often fails owing to the development of drug resistance. However, the important gene expression alterations associated with these resistances remain unclear. In this study, we aimed to identify the gene expressions related to cisplatin resistance in oral squamous cell carcinoma (OSCC) cell lines. RNA samples were obtained from three cisplatin-resistant (YD-8/CIS, YD-9/CIS, and YD-38/CIS) and -sensitive (YD-8, YD-9, and YD-38) cell lines. Global gene expression was analyzed using RNA sequencing (RNA-Seq). Differentially expressed genes were determined. Based on the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, functional enrichment and signaling pathways analyses were performed. Candidate genes selected from RNA-Seq analysis were validated by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The YD-8/CIS and YD-9/CIS samples had very similar expression patterns. qRT-PCR analysis was performed on selected genes commonly expressed between the two samples. The expression levels of 11 genes were changed in cisplatin-resistant samples compared with their parental samples; several of these genes were related to cell adhesion molecules and proteoglycans in cancer pathways. Our data provide candidate genes associated with cisplatin resistance in OSCC, but further study is required to determine which genes have an important role. Nevertheless, these results may provide new ideas to improve the clinical therapeutic outcomes of OSCC.
      Citation: Pharmaceuticals
      PubDate: 2022-06-03
      DOI: 10.3390/ph15060704
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 705: Recent Progress in the Synthesis of
           Drugs and Bioactive Molecules Incorporating Nitro(het)arene Core

    • Authors: Bastrakov, Starosotnikov
      First page: 705
      Abstract: Aromatic nitro compounds play a unique role in the synthesis of drugs and pharmaceutically oriented molecules. This field of organic chemistry continues to be in demand and relevant. A significant number of papers are published annually on new general methods for the synthesis of nitrodrugs and related biomolecules. This review is an analysis of the literature on methods for the synthesis of both new and already-known aromatic and heteroaromatic nitrodrugs covering the period from 2010 to the present.
      Citation: Pharmaceuticals
      PubDate: 2022-06-03
      DOI: 10.3390/ph15060705
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 706: Lower Inspiratory Breathing Depth
           Enhances Pulmonary Delivery Efficiency of ProAir Sprays

    • Authors: Mohamed Talaat, Xiuhua April Si, Jinxiang Xi
      First page: 706
      Abstract: Effective pulmonary drug delivery using a metered-dose inhaler (MDI) requires a match between the MDI sprays, the patient’s breathing, and respiratory physiology. Different inhalers generate aerosols with distinct aerosol sizes and speeds, which require specific breathing coordination to achieve optimized delivery efficiency. Inability to perform the instructed breathing maneuver is one of the frequently reported issues during MDI applications; however, their effects on MDI dosimetry are unclear. The objective of this study is to systemically evaluate the effects of breathing depths on regional deposition in the respiratory tract using a ProAir-HFA inhaler. An integrated inhaler mouth-throat-lung geometry model was developed that extends to the ninth bifurcation (G9). Large-eddy simulation (LES) was used to compute the airflow dynamics due to concurrent inhalation and orifice flows. The discrete-phase Lagrangian model was used to track droplet motions. Experimental measurements of ProAir spray droplet sizes and speeds were used as initial and boundary conditions to develop the computational model for ProAir-pulmonary drug delivery. The time-varying spray plume from a ProAir-HFA inhaler into the open air was visualized using a high-speed imaging system and was further used to validate the computational model. The inhalation dosimetry of ProAir spray droplets in the respiratory tract was compared among five breathing depths on a regional, sub-regional, and local basis. The results show remarkable differences in airflow dynamics within the MDI mouthpiece and the droplet deposition distribution in the oral cavity. The inhalation depth had a positive relationship with the deposition in the mouth and a negative relationship with the deposition in the five lobes beyond G9 (small airways). The highest delivery efficiency to small airways was highest at 15 L/min and declined with an increasing inhalation depth. The drug loss inside the MDI was maximal at 45–60 L/min. Comparisons to previous experimental and numerical studies revealed a high dosimetry sensitivity to the inhaler type and patient breathing condition. Considering the appropriate inhalation waveform, spray actuation time, and spray properties (size and velocity) is essential to accurately predict inhalation dosimetry from MDIs. The results highlight the importance of personalized inhalation therapy to match the patient’s breathing patterns for optimal delivery efficiencies. Further complimentary in vitro or in vivo experiments are needed to validate the enhanced pulmonary delivery at 15 L/min.
      Citation: Pharmaceuticals
      PubDate: 2022-06-03
      DOI: 10.3390/ph15060706
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 707: MPMABP: A CNN and Bi-LSTM-Based
           Method for Predicting Multi-Activities of Bioactive Peptides

    • Authors: You Li, Xueyong Li, Yuewu Liu, Yuhua Yao, Guohua Huang
      First page: 707
      Abstract: Bioactive peptides are typically small functional peptides with 2–20 amino acid residues and play versatile roles in metabolic and biological processes. Bioactive peptides are multi-functional, so it is vastly challenging to accurately detect all their functions simultaneously. We proposed a convolution neural network (CNN) and bi-directional long short-term memory (Bi-LSTM)-based deep learning method (called MPMABP) for recognizing multi-activities of bioactive peptides. The MPMABP stacked five CNNs at different scales, and used the residual network to preserve the information from loss. The empirical results showed that the MPMABP is superior to the state-of-the-art methods. Analysis on the distribution of amino acids indicated that the lysine preferred to appear in the anti-cancer peptide, the leucine in the anti-diabetic peptide, and the proline in the anti-hypertensive peptide. The method and analysis are beneficial to recognize multi-activities of bioactive peptides.
      Citation: Pharmaceuticals
      PubDate: 2022-06-03
      DOI: 10.3390/ph15060707
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 708: Focusing on Future Applications and
           Current Challenges of Plant Derived Extracellular Vesicles

    • Authors: Yuchen Wang, Junfeng Wang, Jinqian Ma, Yun Zhou, Rong Lu
      First page: 708
      Abstract: Plant derived extracellular vesicles (EVs) are nano-sized membranous vesicles released by plant cells, which contain lipids, proteins, nucleic acids and specific pharmacologically active substances. They are safe, widely available and expediently extractive. They have gratifyingly biological activity against inflammation, cancer, bacteria and oxidative aging, especially for the prevention or treatment of colitis, cancer, alcoholic liver, and COVID-19. In addition, as natural drug carriers, plant derived EVs have the potential to target the delivery of small molecule drugs and nucleic acid through oral, transdermal, injection. With the above advantages, plant derived EVs are expected to have excellent strong competitiveness in clinical application or preventive health care products in the future. We comprehensively reviewed the latest separation methods and physical characterization techniques of plant derived EVs, summarized the application of them in disease prevention or treatment and as a new drug carrier, and analyzed the clinical application prospect of plant derived EVs as a new drug carrier in the future. Finally, the problems hindering the development of plant derived EVs at present and consideration of the standardized application of them are discussed.
      Citation: Pharmaceuticals
      PubDate: 2022-06-03
      DOI: 10.3390/ph15060708
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 709: Model-Based Prediction of Acid
           Suppression and Proposal of a New Dosing Regimen of Fexuprazan in Humans

    • Authors: Kim, Lee, Lee, Chae, Chung, Lee
      First page: 709
      Abstract: Fexuprazan is a potassium-competitive acid blocker (P-CAB). The compounds in this newly developed drug family suppress intragastric acidity. As there are already other acid-suppressing drugs on the market, such as H2 antagonists and proton pump inhibitors (PPIs), it would be informative to compare the biological effects of fexuprazan against another approved drug with the same indication. The drug concentration predicted by the pharmacokinetic (PK) model could serve as an input function for a pharmacodynamic (PD) model. The apparent pharmacokinetics of fexuprazan could be described by a simpler model. However, a physiologically based pharmacokinetic (PBPK) model was developed in a previous study. A one-compartment model was also proposed in the present study. Both the newly suggested model and the previously validated PBPK model were used as input functions of the PD models. Our simulation revealed that the effects of fexuprazan could be effectively simulated by the proposed PK–PD models. A PK–PD model was also proposed for the oral administration of the PPI reference drug esomeprazole. A model-based analysis was then performed for intragastric pH using several dosing methods. The expected pH could be predicted for both drugs under several dosing regimens using the proposed PK–PD models.
      Citation: Pharmaceuticals
      PubDate: 2022-06-03
      DOI: 10.3390/ph15060709
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 710: Mepirapim, a Novel Synthetic
           Cannabinoid, Induces Addiction-Related Behaviors through Neurochemical
           Maladaptation in the Brain of Rodents

    • Authors: Kwang-Hyun Hur, YouYoung Lee, Audrey Lynn Donio, Shi-Xun Ma, Bo-Ram Lee, Seon-Kyung Kim, Jae-Gyeong Lee, Young-Jung Kim, MinJeong Kim, SeolMin Yoon, SooYeun Lee, Yong-Sup Lee, Seok-Yong Lee, Choon-Gon Jang
      First page: 710
      Abstract: Mepirapim is a synthetic cannabinoid that has recently been abused for recreational purposes. Although serious side effects have been reported from users, the dangerous pharmacological effects of Mepirapim have not been scientifically demonstrated. In this study, we investigated the addictive potential of Mepirapim through an intravenous self-administration test and a conditioned place preference test in rodents. Moreover, to determine whether the pharmacological effects of Mepirapim are mediated by cannabinoid receptors, we investigated whether Mepirapim treatment induces cannabinoid tetrad symptoms in mice. Lastly, to identify Mepirapim induced neurochemical maladaptation in the brains of mice, we performed microdialysis, western blots and neurotransmitter enzyme-linked immunosorbent assays. In the results, Mepirapim supported the maintenance of intravenous self-administration and the development of conditioned place preference. As a molecular mechanism of Mepirapim addiction, we identified a decrease in GABAeric signalling and an increase in dopaminergic signalling in the brain reward circuit. Finally, by confirming the Mepirapim-induced expression of cannabinoid tetrad symptoms, we confirmed that Mepirapim acts pharmacologically through cannabinoid receptor one. Taken together, we found that Mepirapim induces addiction-related behaviours through neurochemical maladaptation in the brain. On the basis of these findings, we propose the strict regulation of recreational abuse of Mepirapim.
      Citation: Pharmaceuticals
      PubDate: 2022-06-03
      DOI: 10.3390/ph15060710
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 711: High-Dose Vitamin C for Cancer
           Therapy

    • Authors: Mussa, Mohd Idris, Ahmed, Ahmad, Murtadha, Tengku Din, Yean, Wan Abdul Rahman, Mat Lazim, Uskoković, Hajissa, Mokhtar, Mohamud, Hassan
      First page: 711
      Abstract: In recent years, the idea that Vitamin C (Vit-C) could be utilized as a form of anti-cancer therapy has generated many contradictory arguments. Recent insights into the physiological characteristics of Vit-C, its pharmacokinetics, and results from preclinical reports, however, suggest that high-dose Vit-C could be effectively utilized in the management of various tumor types. Studies have shown that the pharmacological action of Vit-C can attack various processes that cancerous cells use for their growth and development. Here, we discuss the anti-cancer functions of Vit-C, but also the potential for the use of Vit-C as an epigenetic regulator and immunotherapy enhancer. We also provide a short overview of the current state of systems for scavenging reactive oxygen species (ROS), especially in the context of their influencing high-dose Vit-C toxicity for the inhibition of cancer growth. Even though the mechanisms of Vit-C action are promising, they need to be supported with robust randomized and controlled clinical trials. Moreover, upcoming studies should focus on how to define the most suitable cancer patient populations for high-dose Vit-C treatments and develop effective strategies that combine Vit-C with various concurrent cancer treatment regimens.
      Citation: Pharmaceuticals
      PubDate: 2022-06-03
      DOI: 10.3390/ph15060711
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 712: Synthesis of Coumarin and
           Homoisoflavonoid Derivatives and Analogs: The Search for New Antifungal
           Agents

    • Authors: Alana R. Ferreira, Danielle da N. Alves, Ricardo D. de Castro, Yunierkis Perez-Castillo, Damião P. de Sousa
      First page: 712
      Abstract: A set of twenty-four synthetic derivatives, with coumarin and homoisoflavonoid cores and structural analogs, were submitted for evaluation of antifungal activity against various species of Candida. The broth microdilution test was used to determine the Minimum Inhibitory Concentration (MIC) of the compounds and to verify the possible antifungal action mechanisms. The synthetic derivatives were obtained using various reaction methods, and six new compounds were obtained. The structures of the synthesized products were characterized by FTIR spectroscopy: 1H-NMR, 13C-NMR, and HRMS. The coumarin derivative 8 presented the best antifungal profile, suggesting that the pentyloxy substituent at the C-7 position of coumarin ring could potentiate the bioactivity. Compound 8 was then evaluated against the biofilm of C. tropicalis ATCC 13803, which showed a statistically significant reduction in biofilm at concentrations of 0.268 µmol/mL and 0.067 µmol/mL, when compared to the growth control group. For a better understanding of their antifungal activity, compounds 8 and 21 were submitted to a study of the mode of action on the fungal cell wall and plasma membrane. It was observed that neither compound interacted directly with ergosterol present in the fungal plasma membrane or with the fungal cell wall. This suggests that their bioactivity was due to interaction involving other pharmacological targets. Compound 8 was also subjected to a molecular modeling study, which showed that its antifungal action mechanism occurred mainly through interference in the redox balance of the fungal cell, and by compromising the plasma membrane; not by direct interaction, but by interference in ergosterol synthesis. Another important finding was the antifungal capacity of homoisoflavonoids 23 and 24. Derivative 23 presented slightly higher antifungal activity, possibly due to the presence of the methoxyl substituent in the meta position in ring B.
      Citation: Pharmaceuticals
      PubDate: 2022-06-03
      DOI: 10.3390/ph15060712
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 713: Safety of Antibiotics in Hospitalized
           Children in Romania: A Prospective Observational Study

    • Authors: Noémi-Beátrix Bulik, Andreea Farcaș, Camelia Bucșa, Irina Iaru, Ovidiu Oniga
      First page: 713
      Abstract: Antibiotics are among the most prescribed drugs in pediatric inpatients and are frequently associated with adverse drug reactions (ADRs) in children. This study aimed to assess the frequency and type of ADRs related to the use of antibiotics in pediatric inpatients through a prospective observational study, conducted over 6 months, covering the winter and spring seasons when the incidence of infections peaks in Romania. ADRs were evaluated for causality, avoidability and severity. Among the 266 included children, 25 (9.4%) experienced 30 ADRs. ADR frequency tended to be higher in ≤ 2-year-olds (13 of 25, 52.0%) than in other age categories. Gastrointestinal and hematological ADRs were most frequently observed. Diarrhea was the most common ADR associated with antibiotics (8 of 30, 26.7%). Ceftriaxone (16 of 30, 53.3%), cefuroxime, ceftazidime and azithromycin (3 of 30, 10.0% each) were most commonly responsible for ADRs. After causality assessment, 2 (6.7%) ADRs were considered definite, 12 (40.0%) probable and 16 (53.3%) possible. One ADR was classified as definitely avoidable and one as possibly avoidable. Seven children required treatment for ADRs. Antibiotic treatment was discontinued in 4 children. Antibiotics frequently caused ADRs in ≤ 2-year-olds and were commonly associated with gastrointestinal symptoms. Close monitoring of antibiotic-associated ADRs remains important in the pediatric population.
      Citation: Pharmaceuticals
      PubDate: 2022-06-03
      DOI: 10.3390/ph15060713
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 714: Protocetraric and Salazinic Acids as
           Potential Inhibitors of SARS-CoV-2 3CL Protease: Biochemical, Cytotoxic,
           and Computational Characterization of Depsidones as Slow-Binding
           Inactivators

    • Authors: Lorenza Fagnani, Lisaurora Nazzicone, Pierangelo Bellio, Nicola Franceschini, Donatella Tondi, Andrea Verri, Sabrina Petricca, Roberto Iorio, Gianfranco Amicosante, Mariagrazia Perilli, Giuseppe Celenza
      First page: 714
      Abstract: The study investigated the inhibitory activity of protocetraric and salazinic acids against SARS-CoV-2 3CLpro. The kinetic parameters were determined by microtiter plate-reading fluorimeter using a fluorogenic substrate. The cytotoxic activity was tested on murine Sertoli TM4 cells. In silico analysis was performed to ascertain the nature of the binding with the 3CLpro. The compounds are slow-binding inactivators of 3CLpro with a Ki of 3.95 μM and 3.77 μM for protocetraric and salazinic acid, respectively, and inhibitory efficiency kinact/Ki at about 3 × 10−5 s−1µM−1. The mechanism of inhibition shows that both compounds act as competitive inhibitors with the formation of a stable covalent adduct. The viability assay on epithelial cells revealed that none of them shows cytotoxicity up to 80 μM, which is well below the Ki values. By molecular modelling, we predicted that the catalytic Cys145 makes a nucleophilic attack on the carbonyl carbon of the cyclic ester common to both inhibitors, forming a stably acyl-enzyme complex. The computational and kinetic analyses confirm the formation of a stable acyl-enzyme complex with 3CLpro. The results obtained enrich the knowledge of the already numerous biological activities exhibited by lichen secondary metabolites, paving the way for developing promising scaffolds for the design of cysteine enzyme inhibitors.
      Citation: Pharmaceuticals
      PubDate: 2022-06-04
      DOI: 10.3390/ph15060714
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 715: Antistaphylococcal Activities and
           ADME-Related Properties of Chlorinated Arylcarbamoylnaphthalenylcarbamates
           

    • Authors: Tomas Gonec, Dominika Pindjakova, Lucia Vrablova, Tomas Strharsky, Hana Michnova, Tereza Kauerova, Peter Kollar, Michal Oravec, Izabela Jendrzejewska, Alois Cizek, Josef Jampilek
      First page: 715
      Abstract: Pattern 1-hydroxy-N-(2,4,5-trichlorophenyl)-2-naphthamide and the thirteen original carbamates derived from it were prepared and characterized. All the compounds were tested against Staphylococcus aureus ATCC 29213 as a reference and quality control strain and in addition against three clinical isolates of methicillin-resistant S. aureus (MRSA). Moreover, the compounds were evaluated against Enterococcus faecalis ATCC 29212, and preliminary in vitro cytotoxicity of the compounds was assessed using the human monocytic leukemia cell line (THP-1). The lipophilicity of the prepared compounds was experimentally determined and correlated with biological activity. While pattern anilide had no antibacterial activity, the prepared carbamates demonstrated high antistaphylococcal activity comparable to the used standards (ampicillin and ciprofloxacin), which unfortunately were ineffective against E. feacalis. 2-[(2,4,5-Trichlorophenyl)carba- moyl]naphthalen-1-yl ethylcarbamate (2) and 2-[(2,4,5-trichlorophenyl)carbamoyl]naphthalen-1-yl butylcarbamate (4) expressed the nanomolar minimum inhibitory concentrations (MICs 0.018–0.064 μM) against S. aureus and at least two other MRSA isolates. Microbicidal effects based on the minimum bactericidal concentrations (MBCs) against all the tested staphylococci were found for nine carbamates, while 2-[(2,4,5-trichlorophenyl)carbamoyl]naphthalen-1-yl heptylcarbamate (7) and 2-[(2,4,5-trichlorophenyl)carbamoyl]naphthalen-1-yl (4-phenylbutyl)carbamate (14) demonstrated MBCs in the range of 0.124–0.461 μM. The selectivity index (SI) for most investigated carbamates was >20 and for some derivatives even >100. The performed tests did not show an effect on the damage to the bacterial membrane, while the compounds were able to inhibit the respiratory chain of S. aureus.
      Citation: Pharmaceuticals
      PubDate: 2022-06-05
      DOI: 10.3390/ph15060715
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 716: Bisimidazolium Salt
           Glycosyltransferase Inhibitors Suppress Hepatocellular Carcinoma
           Progression In Vitro and In Vivo

    • Authors: Luan, Sun, Zhao, Wang, Han, Gao
      First page: 716
      Abstract: Hepatocellular carcinoma is a leading cause of cancer death, and the disease progression has been related to glycophenotype modifications. Previously synthesized bisimidazolium salts (C20 and C22) have been shown to selectively inhibit the activity of glycosyltransferases in cultured cancer cell homogenates. The current study investigated the anticancer effects of C20/C22 and the possible pathways through which these effects are achieved. The therapeutic value of C20/C22 in terms of inhibiting cancer cell proliferation, metastasis, and angiogenesis, as well as inducing apoptosis, were examined with hepatic cancer cell line HepG2 and a xenograft mouse model. C20/C22 treatment downregulated the synthesis of SLex and Ley sugar epitopes and suppressed selectin-mediated cancer cell metastasis. C20/C22 inhibited HepG2 proliferation, induced cell-cycle arrest, increased intracellular ROS level, led to ER stress, and eventually induced apoptosis through the intrinsic pathway. Furthermore, C20/C22 upregulated the expressions of death receptors DR4 and DR5, substantially increasing the sensitivity of HepG2 to TRAIL-triggered apoptosis. In vivo, C20/C22 effectively inhibited tumor growth and angiogenesis in the xenograft mouse model without adverse effects on major organs. In summary, C20 and C22 are new promising anti-hepatic cancer agents with multiple mechanisms in controlling cancer cell growth, metastasis, and apoptosis, and they merit further development into anticancer drugs.
      Citation: Pharmaceuticals
      PubDate: 2022-06-05
      DOI: 10.3390/ph15060716
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 717: The Diverse Biological Activity of
           Recently Synthesized Nitro Compounds

    • Authors: Saúl Noriega, Jaime Cardoso-Ortiz, Argelia López-Luna, Ma Del Refugio Cuevas-Flores, Juan Armando Flores De La Torre
      First page: 717
      Abstract: The search for new and efficient pharmaceuticals is a constant struggle for medicinal chemists. New substances are needed in order to treat different pathologies affecting the health of humans and animals, and these new compounds should be safe, effective and have the fewest side effects possible. Some functional groups are known for having biological activity; in this matter, the nitro group (NO2) is an efficient scaffold when synthesizing new bioactive molecules. Nitro compounds display a wide spectrum of activities that include antineoplastic, antibiotic, antihypertensive, antiparasitic, tranquilizers and even herbicides, among many others. Most nitro molecules exhibit antimicrobial activity, and several of the compounds mentioned in this review may be further studied as lead compounds for the treatment of H. pylori, P. aeruginosa, M. tuberculosis and S. mutans infections, among others. The NO2 moiety triggers redox reactions within cells causing toxicity and the posterior death of microorganisms, not only bacteria but also multicellular organisms such as parasites. The same effect may be present in humans as well, so the nitro groups can be considered both a pharmacophore and a toxicophore at the same time. The role of the nitro group itself also has a deep effect on the polarity and electronic properties of the resulting molecules, and hence favors interactions with some amino acids in proteins. For these reasons, it is fundamental to analyze the recently synthesized nitro molecules that show any potential activity in order to develop new pharmacological treatments that enhance human health.
      Citation: Pharmaceuticals
      PubDate: 2022-06-05
      DOI: 10.3390/ph15060717
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 718: Enhanced Thrombin Generation Is
           Associated with Worse Left Ventricular Scarring after ST-Segment Elevation
           Myocardial Infarction: A Cohort Study

    • Authors: Ching-Hui Sia, Sock-Hwee Tan, Siew-Pang Chan, Stephanie Marchesseau, Hui-Wen Sim, Leonardo Carvalho, Ruth Chen, Nor Hanim Mohd Amin, Alan Yean-Yip Fong, Arthur Mark Richards, Christina Yip, Mark Y. Chan
      First page: 718
      Abstract: Acute myocardial infarction (AMI) is associated with heightened thrombin generation. There are limited data relating to thrombin generation and left ventricular (LV) scarring and LV dilatation in post-MI LV remodeling. We studied 113 patients with ST-segment elevation myocardial infarction (STEMI) who had undergone primary percutaneous coronary intervention (PPCI) (n = 76) or pharmaco-invasive management (thrombolysis followed by early PCI, n = 37). Endogenous thrombin potential (ETP) was measured at baseline, 1 month and 6 months. Cardiovascular magnetic resonance imaging was performed at baseline and 6 months post-MI. Outcomes studied were an increase in scar change, which was defined as an increase in left ventricular infarct size of any magnitude detected by late gadolinium enhancement, adverse LV remodeling, defined as dilatation (increase) of left ventricular end-diastolic volume (LVEDV) by more than 20% and an increase in left ventricular ejection fraction (LVEF). The mean age was 55.19 ± 8.25 years and 91.2% were men. The baseline ETP was similar in the PPCI and pharmaco-invasive groups (1400.3 nM.min vs. 1334.1 nM.min, p = 0.473). Each 10-unit increase in baseline ETP was associated with a larger scar size (adjusted OR 1.020, 95% CI 1.002–1.037, p = 0.027). Baseline ETP was not associated with adverse LV remodeling or an increase in LVEF. There was no difference in scar size or adverse LV remodeling among patients undergoing PPCI vs. pharmaco-invasive management or patients receiving ticagrelor vs. clopidogrel. Enhanced thrombin generation after STEMI is associated with a subsequent increase in myocardial scarring but not LV dilatation or an increase in LVEF at 6 months post-MI.
      Citation: Pharmaceuticals
      PubDate: 2022-06-06
      DOI: 10.3390/ph15060718
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 719: Adrenomedullin Improves Cardiac
           Remodeling and Function in Obese Rats with Hypertension

    • Authors: Pei Qian, Qian Wang, Fang-Zheng Wang, Hang-Bing Dai, Hong-Yu Wang, Qing Gao, Hong Zhou, Ye-Bo Zhou
      First page: 719
      Abstract: This study aimed to determine whether adrenomedullin (ADM, 7.2 μg/kg/day, ip), an important endogenous active peptide, has a protective role in cardiac remodeling and function in obesity-related hypertension (OH) rats. A high-fat diet (HFD) was used to induce OH for 20 weeks. H9c2 cells incubated with palmitate (PA, 200 μM) to mimic high free fatty acid in obesity were used as an in vitro model. In OH rats, ADM not only decreased body weight (BW) and blood pressure (BP) but also improved systemic inflammation and oxidative stress. Moreover, ADM still had a greater inhibitory effect on local inflammation and oxidative stress in the hearts of OH rats, and the same anti-inflammatory and antioxidant effects were also confirmed in PA-treated H9c2 cells. The ADM receptor antagonist or Akt inhibitor effectively attenuated the inhibitory effects of ADM on inflammation and oxidative stress in PA-stimulated H9c2 cells. Furthermore, ADM application effectively normalized heart function, and hematoxylin-eosin and Masson staining and collagen volume fraction results showed that ADM improved cardiac remodeling in hearts of OH rats. ADM attenuated cardiac inflammation and oxidative stress via the receptor-Akt pathway, which involves the improvement of cardiac remodeling and function in OH rats.
      Citation: Pharmaceuticals
      PubDate: 2022-06-06
      DOI: 10.3390/ph15060719
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 720: Discrepancy between the Actions of
           Glucagon-like Peptide-1 Receptor Ligands in the Protection of the Heart
           against Ischemia Reperfusion Injury

    • Authors: Ali Ismaeil, Fawzi Babiker, Suleiman Al-Sabah
      First page: 720
      Abstract: Tirzepatide is a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist and a promising therapy for type 2 diabetes mellitus (T2DM). GLP-1 is an incretin hormone with therapeutic potential beyond type 2 diabetes mellitus. However, GLP-1 is rapidly degraded by dipeptdyl peptidase-IV (DPP-IV) to GLP-1 (9-36). Exendin-4 (Ex-4) is a DPP-IV-resistant GLP-1 receptor agonist which, when truncated to Ex-4 (9-39), acts as a GLP-1 receptor antagonist. In the present study, hearts isolated from Wistar rats (n = 8 per group) were perfused with a modified Langendorff preparation. Left ventricular (LV) contractility and cardiovascular hemodynamics were evaluated by a data acquisition program and infarct size was evaluated by 2,3,5-Triphenyl-2H-tetrazolium chloride (TTC) staining and cardiac enzyme levels. Hearts were subjected to 30 min regional ischemia, produced by ligation of the left anterior descending (LAD) coronary artery followed by 30 min reperfusion. Hearts were treated during reperfusion with either the non-lipidated precursor of tirzepatide (NLT), GLP-1, GLP-1 (9-36), or Ex-4 in the presence or absence of Ex-4 (9-39). Infusion of GLP-1 (9-36) or Ex-4 protected the heart against I/R injury (p > 0.01) by normalizing cardiac hemodynamic and enzyme levels. Neither GLP-1, NLT, nor Ex-4 (9-39) showed any protection. Interestingly, Ex-4 (9-39) blocked Ex-4-mediated protection but not that of GLP-1 (9-36). These data suggest that Ex-4-mediated protection is GLP-1-receptor-dependent but GLP-1 (9-36)-mediated protection is not.
      Citation: Pharmaceuticals
      PubDate: 2022-06-06
      DOI: 10.3390/ph15060720
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 721: Design and Synthesis of a
           Mitochondria-Targeting Radioprotectant for Promoting Skin Wound Healing
           Combined with Ionizing Radiation Injury

    • Authors: Zaizhi Du, Han Liu, Xie Huang, Yang Li, Liting Wang, Jing Liu, Shuang Long, Rong Li, Qiang Xiang, Shenglin Luo
      First page: 721
      Abstract: Wound healing is seriously retarded when combined with ionizing radiation injury, because radiation-induced excessive reactive oxygen species (ROS) profoundly affect cell growth and wound healing. Mitochondria play vital roles not only as cellular energy factories but also as the main source of endogenous ROS, and in this work a mitochondria-targeting radioprotectant (CY-TMP1) is reported for radiation injury-combined wound repair. It was designed, synthesized and screened out from different conjugates between mitochondria-targeting heptamethine cyanine dyes and a peroxidation inhibitor 2,2,6,6-tetramethylpiperidinyloxy (TEMPO). CY-TMP1 specifically accumulated in mitochondria, efficiently mitigated mitochondrial ROS and total intracellular ROS induced by 6 Gy of X-ray ionizing irradiation, thereby exhibiting a notable radioprotective effect. The mechanism study further demonstrated that CY-TMP1 protected mitochondria from radiation-induced injury, including maintaining mitochondrial membrane potential (MMP) and ATP generation, thereby reducing the ratio of cell apoptotic death. Particularly, an in vivo experiment showed that CY-TMP1 could effectively accelerate wound closure of mice after 6 Gy of whole-body ionizing radiation. Immunohistochemical staining further indicated that CY-TMP1 may improve wound repair through angiogenesis and re-epithelialization. Therefore, mitochondria-targeting ROS scavengers may present a feasible strategy to conquer refractory wound combined with radiation injury.
      Citation: Pharmaceuticals
      PubDate: 2022-06-06
      DOI: 10.3390/ph15060721
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 722: Combination of Photodynamic Therapy
           and Oral Antifungals for the Treatment of Onychomycosis

    • Authors: Alba Navarro-Bielsa, Tamara Gracia-Cazaña, Pilar Robres, Concepción Lopez, María Dolores Calvo-Priego, Carmen Aspiroz, Yolanda Gilaberte
      First page: 722
      Abstract: Onychomycosis accounts for 50% of nail disorders, making it one of the most prevalent fungal diseases and a therapeutic challenge. Photodynamic therapy (PDT) could constitute a therapeutic alternative, owing to its good adherence, the low probability of resistance, the lack of interaction with antimicrobials, and its favorable adverse effect profile. This retrospective observational study included all patients with a microbiological diagnosis of onychomycosis treated with PDT at Miguel Servet University Hospital, Zaragoza (Spain), between January 2013 and June 2021. The protocol consisted of pre-treatment with 40% urea for 7 days, followed by 16% methyl-aminolevulinate (MAL) for 3 h and subsequent irradiation with a red-light LED lamp (37 J/cm2), every 1 or 2 weeks. Combined treatment with oral and/or topical antifungals was recorded. Of the 20 patients included (mean age, 59 ± 17 years), 55% were men. The most frequently detected microorganism was Trichophyton rubrum (55%). The most commonly affected location was the feet (90%): 50% of these cases were associated with tinea pedis. The median (standard deviation) number of PDT sessions was 6 (2.8). PDT was combined with systemic terbinafine (250 mg/day) in 10 cases (in 8 cases, this was administered for only 1 month), and with topical terbinafine in 3 cases. A complete clinical response was achieved in 80% (16) of cases and microbiological cure in 60% (12). PDT is a therapeutic alternative for onychomycosis, and can be administered either in monotherapy or combined with antifungals, allowing for a reduction in the duration and possible adverse effects of antifungal treatment and achieving higher cure rates than those obtained with either treatment alone.
      Citation: Pharmaceuticals
      PubDate: 2022-06-07
      DOI: 10.3390/ph15060722
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 723: Production of GMP-Compliant Clinical
           Amounts of Copper-61 Radiopharmaceuticals from Liquid Targets

    • Authors: Alexandra I. Fonseca, Vítor H. Alves, Sérgio J. C. do Carmo, Magda Silva, Ivanna Hrynchak, Francisco Alves, Amílcar Falcão, Antero J. Abrunhosa
      First page: 723
      Abstract: PET imaging has gained significant momentum in the last few years, especially in the area of oncology, with an increasing focus on metal radioisotopes owing to their versatile chemistry and favourable physical properties. Copper-61 (t1/2 = 3.33 h, 61% β+, Emax = 1.216 MeV) provides unique advantages versus the current clinical standard (i.e., gallium-68) even though, until now, no clinical amounts of 61Cu-based radiopharmaceuticals, other than thiosemicarbazone-based molecules, have been produced. This study aimed to establish a routine production, using a standard medical cyclotron, for a series of widely used somatostatin analogues, currently labelled with gallium-68, that could benefit from the improved characteristics of copper-61. We describe two possible routes to produce the radiopharmaceutical precursor, either from natural zinc or enriched zinc-64 liquid targets and further synthesis of [61Cu]Cu-DOTA-NOC, [61Cu]Cu-DOTA-TOC and [61Cu]Cu-DOTA-TATE with a fully automated GMP-compliant process. The production from enriched targets leads to twice the amount of activity (3.28 ± 0.41 GBq vs. 1.84 ± 0.24 GBq at EOB) and higher radionuclidic purity (99.97% vs. 98.49% at EOB). Our results demonstrate, for the first time, that clinical doses of 61Cu-based radiopharmaceuticals can easily be obtained in centres with a typical biomedical cyclotron optimised to produce 18F-based radiopharmaceuticals.
      Citation: Pharmaceuticals
      PubDate: 2022-06-07
      DOI: 10.3390/ph15060723
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 724: Purification, Characterization and
           Evaluation of the Antitumoral Activity of a Phospholipase A2 from the
           Snake Bothrops moojeni

    • Authors: Breno Emanuel Farias Frihling, Ana Paula de Araújo Boleti, Caio Fernando Ramalho de Oliveira, Simone Camargo Sanches, Pedro Henrique de Oliveira Cardoso, Newton Verbisck, Maria Lígia Rodrigues Macedo, Paula Helena Santa Rita, Cristiano Marcelo Espinola Carvalho, Ludovico Migliolo
      First page: 724
      Abstract: Nature presents a wide range of biomolecules with pharmacological potential, including venomous animal proteins. Among the protein components from snake venoms, phospholipases (PLA2) are of great importance for the development of new anticancer compounds. Thus, we aimed to evaluate the PLA2 anticancer properties from Bothrops moojeni venom. The crude venom was purified through three chromatographic steps, monitored by enzymatic activity and SDS-PAGE (12%). The purified PLA2 denominated BmPLA2 had its molecular mass and N-terminal sequence identified by mass spectrometry and Edman degradation, respectively. BmPLA2 was assayed against human epithelial colorectal adenocarcinoma cells (Caco-2), human rhabdomyosarcoma cells (RD) and mucoepidermoid carcinoma of the lung (NCI-H292), using human fibroblast cells (MRC-5) and microglia cells (BV-2) as a cytotoxicity control. BmPLA2 presented 13,836 Da and a 24 amino acid-residue homologue with snake PLA2, which showed a 90% similarity with other Bothrops moojeni PLA2. BmPLA2 displayed an IC50 of 0.6 µM against Caco-2, and demonstrated a selectivity index of 1.85 (compared to MRC-5) and 6.33 (compared to BV-2), supporting its selectivity for cancer cells. In conclusion, we describe a new acidic phospholipase, which showed antitumor activity and is a potential candidate in the development of new biotechnological tools.
      Citation: Pharmaceuticals
      PubDate: 2022-06-07
      DOI: 10.3390/ph15060724
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 725: A New Chalcone and Antimicrobial
           Chemical Constituents of Dracaena stedneuri

    • Authors: Cédric M. Mouzié, Michel-Gael F. Guefack, Boris Y. Kianfé, Héritier U. Serondo, Beaudelaire K. Ponou, Xavier Siwe-Noundou, Rémy B. Teponno, Rui W. M. Krause, Victor Kuete, Léon A. Tapondjou
      First page: 725
      Abstract: Microbial infections are leading causes of death and morbidity all over the world due to the development of the resistance to antibiotics by certain microorganisms. In this study, the chemical exploration of the ethanol (EtOH) extract of the aerial part of Dracaena stedneuri (Dracaenaceae) led to the isolation of one previously unreported chalcone derivative, i.e., 2′,4′-dihydroxy-2,3′-dimethoxychalcone (1), together with 12 known compounds: 8-(C)-methylquercetagetin-3,6,3′-trimethyl ether (2), methylgalangine (3), quercetin (4), kaempferol (5), 6,8-dimethylchrysin (6), ombuine-3-O-rutinoside (4ʹ,7-dimethylquercetin-3-O-α-L-rhamnopyranosyl-(1 → 6) -β-D-glucopyranoside) (7), alliospiroside A (8), β-sitosterol 3-O-glucopyranoside (9), ishigoside (10), betulinic acid (11), oleanolic acid (12), and lupeol (13). The structures were determined by spectroscopic and spectrometric analysis including 1- and 2-Dimensional Nuclear Magnetic Resonance (1D- and 2D-NMR), High-Resolution Electrospray Ionization Mass Spectrometry (HRESIMS), and comparison with literature data. The isolated secondary metabolites and crude extract displayed antibacterial activity against some multidrug-resistant strains with minimal inhibitory concentration (MIC) values ranging from 32 to 256 μg/mL. The antibacterial activity of compound 13 against Enterobacter aerogenes ATCC13048 (MIC value: 32 μg/mL) was higher than that of chloramphenicol used as the reference drug (MIC = 64 μg/mL).
      Citation: Pharmaceuticals
      PubDate: 2022-06-07
      DOI: 10.3390/ph15060725
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 726: [6]-Shogaol Attenuates
           Oxaliplatin-Induced Allodynia through Serotonergic Receptors and GABA in
           the Spinal Cord in Mice

    • Authors: Suyong Kim, Juan Gang, Ji-Hwan Lee, Hyejin Yang, Chunhoo Cheon, Seong-Gyu Ko, Hyunsu Bae, Woojin Kim
      First page: 726
      Abstract: Although oxaliplatin is a well-known anti-cancer agent used for the treatment of colorectal cancer, treated patients often experience acute cold and mechanical allodynia as side effects. Unfortunately, no optimal treatment has been developed yet. In this study, [6]-shogaol (10 mg/kg, i.p.), which is one of the major bioactive components of Zingiber officinale roscoe (Z. officinale), significantly alleviated allodynia induced by oxaliplatin (6 mg/kg, i.p.) injection. Cold and mechanical allodynia were assessed by acetone drop and von Frey filament tests, respectively. The analgesic effect of [6]-shogaol was blocked by the intrathecal injection of 5-HT1A, 5-HT3, and GABAB receptor antagonists, NAN-190 (1 μg), MDL-72222 (15 μg), and CGP 55845 (10 μg), respectively. Furthermore, oxaliplatin injection lowered the GABA concentration in the superficial laminae of the spinal dorsal horn, whereas [6]-shogaol injection significantly elevated it. The GAD (glutamic acid decarboxylase) 65 concentration also increased after [6]-shogaol administration. However, pre-treatment of NAN-190 completely inhibited the increased GABA induced by [6]-shogaol in the spinal dorsal horn, whereas MDL-72222 partially blocked the effect. Altogether, these results suggest that [6]-shogaol could attenuate oxaliplatin-induced cold and mechanical allodynia through 5-HT1A and 5-HT3 receptor antagonists located in the GABAergic neurons in the spinal dorsal horn in mice.
      Citation: Pharmaceuticals
      PubDate: 2022-06-08
      DOI: 10.3390/ph15060726
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 727: Polydatin Incorporated in
           Polycaprolactone Nanofibers Improves Osteogenic Differentiation

    • Authors: Stefania Lama, Amalia Luce, Giuseppe Bitti, Pilar Chacon-Millan, Annalisa Itro, Pasquale Ferranti, Giovanni D’Auria, Marcella Cammarota, Giovanni Francesco Nicoletti, Giuseppe Andrea Ferraro, Chiara Schiraldi, Michele Caraglia, Evzen Amler, Paola Stiuso
      First page: 727
      Abstract: Polycaprolactone nanofibers are used as scaffolds in the field of tissue engineering for tissue regeneration or drug delivery. Polycaprolactone (PCL) is a biodegradable hydrophobic polyester used to obtain implantable nanostructures, which are clinically applicable due to their biological safety. Polydatin (PD), a glycosidic precursor of resveratrol, is known for its antioxidant, antitumor, antiosteoporotic, and bone regeneration activities. We aimed to use the osteogenic capacity of polydatin to create a biomimetic innovative and patented scaffold consisting of PCL-PD for bone tissue engineering. Both osteosarcoma cells (Saos-2) and mesenchymal stem cells (MSCs) were used to test the in vitro cytocompatibility of the PD-PCL scaffold. Reverse-phase (RP) HPLC was used to evaluate the timing release of PD from the PCL-PD nanofibers and the MTT assay, scanning electron microscopy, and alkaline phosphatase (ALP) activity were used to evaluate the proliferation, adhesion, and cellular differentiation in both osteosarcoma and human mesenchymal stem cells (MSCs) seeded on PD-PCL nanofibers. The proliferation of osteosarcoma cells (Saos-2) on the PD-PCL scaffold decreased when compared to cells grown on PLC nanofibers, whereas the proliferation of MSCs was comparable in both PCL and PD-PCL nanofibers. Noteworthy, after 14 days, the ALP activity was higher in both Saos-2 cells and MSCs cultivated on PD-PCL than on empty scaffolds. Moreover, the same cells showed a spindle-shaped morphology after 14 days when grown on PD-PCL as shown by SEM. In conclusion, we provide evidence that nanofibers appropriately coated with PD support the adhesion and promote the osteogenic differentiation of both human osteosarcoma cells and MSCs.
      Citation: Pharmaceuticals
      PubDate: 2022-06-08
      DOI: 10.3390/ph15060727
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 728: Copper-67-Labeled Bombesin Peptide
           for Targeted Radionuclide Therapy of Prostate Cancer

    • Authors: Truc T. Huynh, Ellen M. van Dam, Sreeja Sreekumar, Cedric Mpoy, Benjamin J. Blyth, Fenella Muntz, Matthew J. Harris, Buck E. Rogers
      First page: 728
      Abstract: The gastrin-releasing peptide receptor (GRPR) is a promising molecular target for imaging and therapy of prostate cancer using bombesin peptides that bind to the receptor with high affinity. Targeted copper theranostics (TCTs) using copper radionuclides, 64Cu for imaging and 67Cu for therapy, offer significant advantages in the development of next-generation theranostics. [64Cu]Cu-SAR-BBN is in clinical development for PET imaging of GRPR-expressing cancers. This study explores the therapeutic efficacy of [67Cu]Cu-SAR-BBN in a pre-clinical mouse model. The peptide was radiolabeled with 67Cu, and specific binding of the radiolabeled peptide towards GRPR-positive PC-3 prostate cancer cells was confirmed with 52.2 ± 1.4% total bound compared to 5.8 ± 0.1% with blocking. A therapy study with [67Cu]Cu-SAR-BBN was conducted in mice bearing PC-3 tumors by injecting 24 MBq doses a total of six times. Tumor growth was inhibited by 93.3% compared to the control group on day 19, and median survival increased from 34.5 days for the control group to greater than 54 days for the treatment group. The ease and stability of the radiochemistry, favorable biodistribution, and the positive tumor inhibition demonstrate the suitability of this copper-based theranostic agent for clinical assessment in the treatment of cancers expressing GRPR.
      Citation: Pharmaceuticals
      PubDate: 2022-06-08
      DOI: 10.3390/ph15060728
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 729: [99mTc]Tc-iFAP/SPECT Tumor Stroma
           Imaging: Acquisition and Analysis of Clinical Images in Six Different
           Cancer Entities

    • Authors: Paola Vallejo-Armenta, Guillermina Ferro-Flores, Clara Santos-Cuevas, Francisco Osvaldo García-Pérez, Pamela Casanova-Triviño, Bayron Sandoval-Bonilla, Blanca Ocampo-García, Erika Azorín-Vega, Myrna Luna-Gutiérrez
      First page: 729
      Abstract: Fibroblast activation protein (FAP) is highly expressed on the cancer-associated fibroblasts (CAF) of the tumor stroma. Recently, we reported the preclinical evaluation and clinical biokinetics of a novel 99mTc-labeled FAP inhibitor radioligand ([99mTc]Tc-iFAP). This research aimed to evaluate [99mTc]Tc-iFAP for the tumor stroma imaging of six different cancerous entities and analyze them from the perspective of stromal heterogeneity. [99mTc]Tc-iFAP was prepared from freeze-dried kits with a radiochemical purity of 98 ± 1%. The study included thirty-two patients diagnosed with glioma (n = 5); adrenal cortex neuroendocrine tumor (n = 1); and breast (n = 21), lung (n = 2), colorectal (n = 1) and cervical (n = 3) cancer. Patients with glioma had been evaluated with a previous cranial MRI scan and the rest of the patients had been involved in a [18F]FDG PET/CT study. All oncological diagnoses were corroborated histopathologically. The patients underwent SPECT/CT brain imaging (glioma) or thoracoabdominal imaging 1 h after [99mTc]Tc-iFAP administration (i.v., 735 ± 63 MBq). The total lesions (n = 111) were divided into three categories: primary tumors (PT), lymph node metastases (LNm), and distant metastases (Dm). [99mTc]Tc-iFAP brain imaging was positive in four high-grade WHO III–IV gliomas and negative in one treatment-naive low-grade glioma. Both [99mTc]Tc-iFAP and [18F]FDG detected 26 (100%) PT, although the number of positive LNm and Dm was significantly higher with [18F]FDG [82 (96%)], in comparison to [99mTc]Tc-iFAP imaging (35 (41%)). Peritoneal carcinomatosis lesions in a patient with recurrent colorectal cancer were only visualized with [99mTc]Tc-iFAP. In patients with breast cancer, a significant positive correlation was demonstrated among [99mTc]Tc-iFAP uptake values (Bq/cm3) of PT and the molecular subtype, being higher for subtypes HER2+ and Luminal B HER2-enriched. Four different CAF subpopulations have previously been described for LNm of breast cancer (from CAF-S1 to CAF-S4). The only subpopulation that expresses FAP is CAF-S1, which is preferentially detected in aggressive subtypes (HER2 and triple-negative), confirming that FAP+ is a marker for poor disease prognosis. The results of this pilot clinical research show that [99mTc]Tc-iFAP SPECT imaging is a promising tool in the prognostic assessment of some solid tumors, particularly breast cancer.
      Citation: Pharmaceuticals
      PubDate: 2022-06-09
      DOI: 10.3390/ph15060729
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 730: A Comparative Study of the
           Pharmaceutical Properties between Amorphous Drugs Loaded-Mesoporous Silica
           and Pure Amorphous Drugs Prepared by Solvent Evaporation

    • Authors: Arif Budiman, Diah Lia Aulifa
      First page: 730
      Abstract: The formulation of poorly water-soluble drugs is one of the main challenges in the pharmaceutical industry, especially in the development of oral dosage forms. Meanwhile, there is an increase in the number of poorly soluble drugs that have been discovered as new chemical entities. It was also reported that the physical transformation of a drug from a crystalline form into an amorphous state could be used to increase its solubility. Therefore, this study aims to evaluate the pharmaceutical properties of amorphous drug loaded-mesoporous silica (MPS) and pure amorphous drugs. Ritonavir (RTV) was used as a model of a poorly water-soluble drug due to its low recrystallization tendency. RTV loaded-MPS (RTV/MPS) and RTV amorphous were prepared using the solvent evaporation method. Based on observation, a halo pattern in the powder X-ray diffraction pattern and a single glass transition (Tg) in the modulated differential scanning calorimetry (MDSC) curve was discovered in RTV amorphous, indicating its amorphization. The Tg was not detected in RTV/MPS, which showed that the loading RTV was completed. The solid-state NMR and FT-IR spectroscopy also showed the interaction between RTV and the surface of MPS in the mesopores. The high supersaturation of RTV was not achieved for both RTV/MPS and the amorphous state due to its strong interaction with the surface of MPS and was not properly dispersed in the medium, respectively. In the dissolution test, the molecular dispersion of RTV within MPS caused rapid dissolution at the beginning, while the amorphous showed a low rate due to its agglomeration. The stability examination showed that the loading process significantly improved the physical and chemical stability of RTV amorphous. These results indicated that the pharmaceutical properties of amorphous drugs could be improved by loaded-MPS.
      Citation: Pharmaceuticals
      PubDate: 2022-06-09
      DOI: 10.3390/ph15060730
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 731: Impact of the Gram-Negative-Selective
           Inhibitor MAC13243 on In Vitro Simulated Gut Microbiota

    • Authors: Frida Svanberg Frisinger, Mattia Pirolo, Duncan Y. K. Ng, Xiaotian Mao, Dennis Sandris Nielsen, Luca Guardabassi
      First page: 731
      Abstract: New Gram-negative-selective antimicrobials are desirable to avoid perturbations in the gut microbiota leading to antibiotic-induced dysbiosis. We investigated the impact of a prototype drug (MAC13243) interfering with the Gram-negative outer membrane protein LolA on the faecal microbiota. Faecal suspensions from two healthy human donors were exposed to MAC13243 (16, 32, or 64 mg/L) using an in vitro gut model (CoMiniGut). Samples collected 0, 4, and 8 h after exposure were subjected to viable cell counts, 16S rRNA gene quantification and V3-V4 sequencing using the Illumina MiSeq platform. MAC13243 exhibited concentration-dependent killing of coliforms in both donors after 8 h. Concentrations of ≤32 mg/L reduced the growth of aerobic bacteria without influencing the microbiota composition and diversity. An expansion of Firmicutes at the expense of Bacteroidetes and Actinobacteria was observed in the faecal microbiota from one donor following exposure to 64 mg/L of MAC13242. At all concentrations tested, MAC13243 did not lead to the proliferation of Escherichia coli nor a reduced abundance of beneficial bacteria, which are typical changes observed in antibiotic-induced dysbiosis. These results support our hypothesis that a drug interfering with a specific target in Gram-negative bacteria has a low impact on the commensal gut microbiota and, therefore, a low risk of inducing dysbiosis.
      Citation: Pharmaceuticals
      PubDate: 2022-06-09
      DOI: 10.3390/ph15060731
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 732: The Use of Endo-Cellulase and
           Endo-Xylanase for the Extraction of Apple Pectins as Factors Modifying
           Their Anticancer Properties and Affecting Their Synergy with the Active
           Form of Irinotecan

    • Authors: Jerzy Maksymowicz, Anna Palko-Łabuz, Beata Sobieszczańska, Mateusz Chmielarz, Mirosława Ferens-Sieczkowska, Magdalena Skonieczna, Agnieszka Wikiera, Olga Wesołowska, Kamila Środa-Pomianek
      First page: 732
      Abstract: Pectin constitutes an essential component of dietary fiber. Modified pectins from various sources possess potent anticancer and immunomodulatory activities. In this study, two pectins isolated from apple pomace by Trichoderma enzyme treatment, PX (with endo-xylanase) and PCX (with both endo-cellulase and endo-xylanase), were studied in colon cancer cell lines (HCT 116, Caco-2, and HT-29). Both pectins reduced colon cancer cell viability, induced apoptosis, and increased intracellular amounts of reactive oxygen species. Additionally, synergy between pectin and an active form of irinotecan, SN-38, in all aspects mentioned above, was discovered. This drug is a common component of cytotoxic combinations recommended as treatment for colon cancer patients. PX and PCX demonstrated significant anti-inflammatory activity in lipopolysaccharide-stimulated cells. Interaction of apple pectins with galectin-3 and Toll-like Receptor 4 (TLR4) was suggested to be responsible for their anticancer and anti-inflammatory effect. Since PCX was more active than PX in almost all experiments, the role of the enzyme used to obtain the pectin for its biological activity was discussed. It was concluded that co-operation between both enzymes was needed to obtain the molecule of the most beneficial properties. The low molecular mass of PCX together with a high proportion of rhamnogalacturonan I (RG I) regions seemed to be crucial for its superior activity.
      Citation: Pharmaceuticals
      PubDate: 2022-06-09
      DOI: 10.3390/ph15060732
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 733: Sesamol Loaded Albumin Nanoparticles:
           A Boosted Protective Property in Animal Models of Oxidative Stress

    • Authors: Sara Zaher, Mahmoud E. Soliman, Mahmoud Elsabahy, Rania M. Hathout
      First page: 733
      Abstract: The current study evaluated the ability of sesamol-loaded albumin nanoparticles to impart protection against oxidative stress induced by anthracyclines in comparison to the free drug. Albumin nanoparticles were prepared via the desolvation technique and then freeze-dried with the cryoprotectant, trehalose. Albumin concentration, pH, and type of desolvating agent were assessed as determining factors for successful albumin nanoparticle fabrication. The optimal nanoparticles were spherical in shape, and they had an average particle diameter of 127.24 ± 2.12 nm with a sesamol payload of 96.89 ± 2.4 μg/mg. The drug cellular protection was tested on rat hepatocytes pretreated with 1 µM doxorubicin, which showed a 1.2-fold higher protective activity than the free sesamol. In a pharmacokinetic study, the loading of a drug onto nanoparticles resulted in a longer half-life and mean residence time, as compared to the free drug. Furthermore, in vivo efficacy and biochemical assessment of lipid peroxidation, cardiac biomarkers, and liver enzymes were significantly ameliorated after administration of the sesamol-loaded albumin nanoparticles. The biochemical assessments were also corroborated with the histopathological examination data. Sesamol-loaded albumin nanoparticles, prepared under controlled conditions, may provide an enhanced protective effect against off-target doxorubicin toxicity.
      Citation: Pharmaceuticals
      PubDate: 2022-06-10
      DOI: 10.3390/ph15060733
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 734: HIF-PH Encoded by EGLN1 Is a
           Potential Therapeutic Target for Chronic Lymphocytic Leukemia

    • Authors: Wancheng Guo, Daomiao Liang, Peilong Wang, Le Yin, Huifang Zhang, Cheng Xing, Zineng Huang, Yinghua Wu, Heng Li, Zhao Cheng, Xiaojuan Xiao, Jing Liu, Zhihua Wang, Hongling Peng
      First page: 734
      Abstract: Owing to the recent emergence of drug resistance to Bruton’s tyrosine kinase inhibitors (BTK) in chronic lymphocytic leukemia (CLL) treatment, it is crucial to identify alternative therapeutic targets. Therefore, we aimed to identify therapeutic options for CLL besides BTK. We identified that HIF1A expression was higher in CLL patients than in controls, which may suggest good prognosis. We used a lentiviral knockdown of EGLN1 (encoding hypoxia-inducible factor prolyl hydroxylase [HIF-PH]) and found that the growth of MEC-1 cells slowed in the knockdown group. Treatment of CLL cell lines MEC-1 and HG3 with the HIF-PH inhibitor molidustat showed that molidustat could induce apoptosis in a concentration-dependent manner in CLL cells and had low cytotoxicity at this concentration. CXCR4, HIF1A, SLC2AI, and VEGF, the downstream molecules of the HIF pathway, were upregulated after molidustat treatment. Western blotting results indicated that molidustat increased HIF1A expression in CLL cell lines and cells from CLL patients, and sequencing/quantitative PCR analysis demonstrated that the ribosome biogenesis pathway was inhibited in MEC-1 cells after molidustat treatment. We further identified synergistic cytotoxicity of molidustat in combination with ibrutinib on the MEC-1 and HG3 cell lines at certain concentrations. Therefore, molidustat is a potential therapeutic option for CLL.
      Citation: Pharmaceuticals
      PubDate: 2022-06-10
      DOI: 10.3390/ph15060734
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 735: Antioxidant and Antibacterial
           Activity of Helichrysum italicum (Roth) G. Don. from Central Europe

    • Authors: Zenon Węglarz, Olga Kosakowska, Ewelina Pióro-Jabrucka, Jarosław L. Przybył, Małgorzata Gniewosz, Karolina Kraśniewska, Marek S. Szyndel, Rosaria Costa, Katarzyna Barbara Bączek
      First page: 735
      Abstract: Helichrysum italicum (Roth) G. Don. is one of the most important cosmetic and medicinal plants originating from the Mediterranean region of Europe. The aim of this study was to assess the chemical profile as well as antioxidant and antibacterial potential of the species cultivated in the temperate climate of Central Europe. The analyses were carried out using herbs and inflorescences. The content of essential oil ranged from 0.25 g × 100 g−1 in the herb to 0.31 g × 100 g−1 in the inflorescences. Neryl acetate, accompanied by α-pinene in the herb (10.42%), and nerol in inflorescences (15.73%) were the dominants here. Rutoside, as well as rosmarinic, chlorogenic, neochlorogenic, isochlorogenic b and cichoric acids, were detected in both raw materials using HPLC-DAD. Within this group, cichoric acid was the dominant (2647.90 mg × 100 g−1 in the herb, 1381.06 mg × 100 g−1 in the inflorescences). The herb appeared to be more abundant in phenolics in comparison with the inflorescences. When given antioxidant activity (determined using DPPH and ABTS assays), both methanolic extract and essential oil obtained from the herb indicated higher potential than those originating from the inflorescences (74.72, 61.38 and 63.81, 58.59% in the case of DPPH, respectively). In turn, regarding antimicrobial activity, the essential oil from inflorescences was distinguished by stronger bacteriostatic power than the herb essential oil. Gram-positive bacteria were more sensitive to both essential oils in comparison with Gram-negative ones, with S. aureus ATCC 25923 as the most susceptible (MIC 1; MBC 16 mg × mL−1) among tested strains.
      Citation: Pharmaceuticals
      PubDate: 2022-06-10
      DOI: 10.3390/ph15060735
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 736: Tigecycline and Gentamicin-Combined
           Treatment Enhances Renal Damage: Oxidative Stress, Inflammatory Reaction,
           and Apoptosis Interplay

    • Authors: Dina Elgazzar, Mohamed Aboubakr, Heba Bayoumi, Amany N. Ibrahim, Safwa M. Sorour, Mohamed El-Hewaity, Abulmaaty M. Elsayed, Shaimaa A. Shehata, Khaled A. Bayoumi, Mohammed Alsieni, Maged Behery, Doaa Abdelrahaman, Samah F. Ibrahim, Ahmed Abdeen
      First page: 736
      Abstract: Although the combination of antibiotics is generally well-tolerated, they may have nephrotoxic effects. This study investigated whether tigecycline (TG) and gentamicin (GM) co-administration could accelerate renal damage. Male Wistar rats were randomly divided into six experimental groups: the control, TG7 (tigecycline, 7 mg/kg), TG14 (tigecycline, 14 mg/kg), GM (gentamicin, 80 mg/kg), TG7+GM, and TG14+GM groups. The combination of TG and GM evoked renal damage seen by the disruption of kidney function tests. The perturbation of renal tissue was mainly confounded to the TG and GM-induced oxidative damage, which was exhibited by marked increases in renal MDA (malondialdehyde) along with a drastic reduction in GSH (reduced-glutathione) content and CAT (catalase) activity compared to their individual treatments. More obvious apoptotic events and inflammation were also revealed by elevating the annexin-V and interleukin-6 (IL-6) levels, aside from the upregulation of renal PCNA (proliferating cell nuclear antigen) expression in the TG and GM concurrent treatment. The principal component analysis indicated that creatinine, urea, annexin-V, IL-6, and MDA all played a role in discriminating the TG and GM combined toxicity. Oxidative stress, inflammatory response, and apoptosis were the key mechanisms involved in this potentiated toxicity.
      Citation: Pharmaceuticals
      PubDate: 2022-06-10
      DOI: 10.3390/ph15060736
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 737: Sirtuins and Hypoxia in EMT Control

    • Authors: Aventaggiato, Barreca, Sansone, Pellegrini, Russo, Cordani, Tafani
      First page: 737
      Abstract: Epithelial–mesenchymal transition (EMT), a physiological process during embryogenesis, can become pathological in the presence of different driving forces. Reduced oxygen tension or hypoxia is one of these forces, triggering a large number of molecular pathways with aberrant EMT induction, resulting in cancer and fibrosis onset. Both hypoxia-induced factors, HIF-1α and HIF-2α, act as master transcription factors implicated in EMT. On the other hand, hypoxia-dependent HIF-independent EMT has also been described. Recently, a new class of seven proteins with deacylase activity, called sirtuins, have been implicated in the control of both hypoxia responses, HIF-1α and HIF-2α activation, as well as EMT induction. Intriguingly, different sirtuins have different effects on hypoxia and EMT, acting as either activators or inhibitors, depending on the tissue and cell type. Interestingly, sirtuins and HIF can be activated or inhibited with natural or synthetic molecules. Moreover, recent studies have shown that these natural or synthetic molecules can be better conveyed using nanoparticles, representing a valid strategy for EMT modulation. The following review, by detailing the aspects listed above, summarizes the interplay between hypoxia, sirtuins, and EMT, as well as the possible strategies to modulate them by using a nanoparticle-based approach.
      Citation: Pharmaceuticals
      PubDate: 2022-06-10
      DOI: 10.3390/ph15060737
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 738: Target Therapies for Systemic
           Mastocytosis: An Update

    • Authors: Mariarita Sciumè, Claudio De Magistris, Nicole Galli, Eleonora Ferretti, Giulia Milesi, Pasquale De Roberto, Sonia Fabris, Federica Irene Grifoni
      First page: 738
      Abstract: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MCs) in extra-cutaneous organs. It could be divided into indolent SM, smoldering SM, SM with an associated hematologic (non-MC lineage) neoplasm, aggressive SM, and mast cell leukemia. SM is generally associated with the presence of a gain-of-function somatic mutation in KIT at codon 816. Clinical features could be related to MC mediator release or to uncontrolled infiltration of MCs in different organs. Whereas indolent forms have a near-normal life expectancy, advanced diseases have a poor prognosis with short survival times. Indolent forms should be considered for symptom-directed therapy, while cytoreductive therapy represents the first-line treatment for advanced diseases. Since the emergence of tyrosine kinase inhibitors (TKIs), KIT inhibition has been an attractive approach. Initial reports showed that only the rare KITD816V negative cases were responsive to first-line TKI imatinib. The development of new TKIs with activity against the KITD816V mutation, such as midostaurin or avapritinib, has changed the management of this disease. This review aims to focus on the available clinical data of therapies for SM and provide insights into possible future therapeutic targets.
      Citation: Pharmaceuticals
      PubDate: 2022-06-11
      DOI: 10.3390/ph15060738
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 739: Will the Use of Pharmacogenetics
           Improve Treatment Efficiency in COVID-19'

    • Authors: Beata Franczyk, Jacek Rysz, Jarosław Miłoński, Tomasz Konecki, Magdalena Rysz-Górzyńska, Anna Gluba-Brzózka
      First page: 739
      Abstract: The COVID-19 pandemic is associated with a global health crisis and the greatest challenge for scientists and doctors. The virus causes severe acute respiratory syndrome with an outcome that is fatal in more vulnerable populations. Due to the need to find an efficient treatment in a short time, there were several drugs that were repurposed or repositioned for COVID-19. There are many types of available COVID-19 therapies, including antiviral agents (remdesivir, lopinavir/ritonavir, oseltamivir), antibiotics (azithromycin), antiparasitics (chloroquine, hydroxychloroquine, ivermectin), and corticosteroids (dexamethasone). A combination of antivirals with various mechanisms of action may be more efficient. However, the use of some of these medicines can be related to the occurrence of adverse effects. Some promising drug candidates have been found to be ineffective in clinical trials. The knowledge of pharmacogenetic issues, which translate into variability in drug conversion from prodrug into drug, metabolism as well as transport, could help to predict treatment efficiency and the occurrence of adverse effects in patients. However, many drugs used for the treatment of COVID-19 have not undergone pharmacogenetic studies, perhaps as a result of the lack of time.
      Citation: Pharmaceuticals
      PubDate: 2022-06-13
      DOI: 10.3390/ph15060739
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 740: Rational Design by Structural Biology
           of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists
           

    • Authors: Lei Sun, Zhi-Ming Zheng, Chang-Sheng Shao, Zhi-Yong Zhang, Ming-Wei Li, Li Wang, Han Wang, Gen-Hai Zhao, Peng Wang
      First page: 740
      Abstract: Glucagon-like peptide-1 (GLP-1) is easily degraded by dipeptidyl peptidase-4 (DPP-4) in the human body, limiting its therapeutic effect on type II diabetes. Therefore, improving GLP-1 receptor agonist (GLP-1RA) stability is a major obstacle for drug development. We analyzed human GLP-1, DPP-4, and GLP-1 receptor structures and designed three GLP-1RAs, which were introduced into fusion protein fragments and changed in the overall conformation. This modification effectively prevented GLP-1RAs from entering the DPP-4 active center without affecting GLP-1RAs’ ability to bind to GLP-1R, the new GLP-1RA hypoglycemic effect lasting for >24 h. Through molecular modeling, molecular dynamics calculation, and simulation, possible tertiary structure models of GLP-1RAs were obtained; molecular docking with DPP-4 and GLP-1R showed access to the fusion protein. The overall conformational change of GLP-1RAs prevented DPP-4 binding, without affecting GLP-1RAs’ affinity to GLP-1R. This study provides important drug design ideas for GLP-1RA development and a new example for application of structural biology-based protein design in drug development.
      Citation: Pharmaceuticals
      PubDate: 2022-06-13
      DOI: 10.3390/ph15060740
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 741: Computational Investigations of
           Traditional Chinese Medicinal Compounds against the Omicron Variant of
           SARS-CoV-2 to Rescue the Host Immune System

    • Authors: Ziad Tareq Naman, Salim Kadhim, Zahraa J. K. Al-Isawi, Christopher J. Butch, Ziyad Tariq Muhseen
      First page: 741
      Abstract: Macrodomain-I of the NSP3 (non-structural protein 3) is responsible for immune response hijacking in the SARS-CoV-2 infection known as COVID-19. In the omicron variant (B.1.1.529), this domain harbors a new mutation, V1069I, which may increase the binding of ADPr and consequently the infection severity. This macrodomain-I, due to its significant role in infection, is deemed to be an important drug target. Hence, using structural bioinformatics and molecular simulation approaches, we performed a virtual screening of the traditional Chinese medicines (TCM) database for potential anti-viral drugs. The screening of 57,000 compounds yielded the 10 best compounds with docking scores better than the control ADPr. Among the top ten, the best three hits—TCM42798, with a docking score of −13.70 kcal/mol, TCM47007 of −13.25 kcal/mol, and TCM30675 of −12.49 kcal/mol—were chosen as the best hits. Structural dynamic features were explored including stability, compactness, flexibility, and hydrogen bonding, further demonstrating the anti-viral potential of these hits. Using the MM/GBSA approach, the total binding free energy for each complex was reported to be −69.78 kcal/mol, −50.11 kcal/mol, and −47.64 kcal/mol, respectively, which consequently reflect the stronger binding and inhibitory potential of these compounds. These agents might suppress NSP3 directly, allowing the host immune system to recuperate. The current study lays the groundwork for the development of new drugs to combat SARS-CoV-2 and its variants.
      Citation: Pharmaceuticals
      PubDate: 2022-06-13
      DOI: 10.3390/ph15060741
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 742: Longitudinal Consumption of
           Ergothioneine Reduces Oxidative Stress and Amyloid Plaques and Restores
           Glucose Metabolism in the 5XFAD Mouse Model of Alzheimer’s Disease

    • Authors: Clayton A. Whitmore, Justin R. Haynes, William J. Behof, Adam J. Rosenberg, Mohammed N. Tantawy, Brian C. Hachey, Brian E. Wadzinski, Benjamin W. Spiller, Todd E. Peterson, Krista C. Paffenroth, Fiona E. Harrison, Robert B. Beelman, Printha Wijesinghe, Joanne A. Matsubara, Wellington Pham
      First page: 742
      Abstract: Background: Ergothioneine (ERGO) is a unique antioxidant and a rare amino acid available in fungi and various bacteria but not in higher plants or animals. Substantial research data indicate that ERGO is a physiological antioxidant cytoprotectant. Different from other antioxidants that need to breach the blood–brain barrier to enter the brain parenchyma, a specialized transporter called OCTN1 has been identified for transporting ERGO to the brain. Purpose: To assess whether consumption of ERGO can prevent the progress of Alzheimer’s disease (AD) on young (4-month-old) 5XFAD mice. Methods and materials: Three cohorts of mice were tested in this study, including ERGO-treated 5XFAD, non-treated 5XFAD, and WT mice. After the therapy, the animals went through various behavioral experiments to assess cognition. Then, mice were scanned with PET imaging to evaluate the biomarkers associated with AD using [11C]PIB, [11C]ERGO, and [18F]FDG radioligands. At the end of imaging, the animals went through cardiac perfusion, and the brains were isolated for immunohistology. Results: Young (4-month-old) 5XFAD mice did not show a cognitive deficit, and thus, we observed modest improvement in the treated counterparts. In contrast, the response to therapy was clearly detected at the molecular level. Treating 5XFAD mice with ERGO resulted in reduced amyloid plaques, oxidative stress, and rescued glucose metabolism. Conclusions: Consumption of high amounts of ERGO benefits the brain. ERGO has the potential to prevent AD. This work also demonstrates the power of imaging technology to assess response during therapy.
      Citation: Pharmaceuticals
      PubDate: 2022-06-13
      DOI: 10.3390/ph15060742
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 743: In Vivo and In Vitro Antioxidant
           Activity of Less Polar Fractions of Dasycladus vermicularis (Scopoli)
           Krasser 1898 and the Chemical Composition of Fractions and Macroalga
           Volatilome

    • Authors: Sanja Radman, Ana-Marija Cikoš, Sanja Babić, Lara Čižmek, Rozelindra Čož-Rakovac, Stela Jokić, Igor Jerković
      First page: 743
      Abstract: The present research is a comprehensive investigation of Dasycladus vermicularis (Scopoli) Krasser 1898 from the Adriatic Sea (Croatia) regarding volatilome–volatile organic compounds (VOCs, mostly nonpolar compounds) and less polar nonvolatile compounds for the first time. Headspace solid-phase microextraction (HS-SPME) and hydrodistillation (HD) were used showing the great volatilome variability among fresh (HS-FrDV and HD-FrDV) and dried (HS-DrDV and HD-DrDV) samples after GC–MS analysis. Aromatic aldehydes were dominant in both fresh and air-dried HS samples with benzaldehyde as the most abundant in fresh samples and decreasing 2.7–3.7 times after drying together with 2-phenylbut-2-enal that was not present after drying. Aliphatic compounds (unsaturated hydrocarbons in HS-FrDV; saturated hydrocarbons in HS-DrDV) were also present. C11-hydrocarbons (dictyopterpene C’ and dictyopterpene D’) were detected in HS-FrDV. (E)-Phytol was the most dominant compound in HD-FrDV and HD-DrDV. Diterpene alcohols (cembra-4,7,11,15-tetraen-3-ol and (Z)-falcarinol) and sesquiterpene alcohol, cubenol, were dominant in HD-FrDV, and their abundance decreased after drying. C13-norisoprenoides (α-ionone and β-ionone) increased after drying. Aliphatic compounds were present in both HD-FrDV and HD-DrDV samples. The less polar nonvolatile compounds in the obtained fractions F3 and F4 were analysed and identified by UHPLC-ESI(+)-HRMS. Identified compounds belonged to a group of pigments (7 compounds), fatty acid derivatives (13 compounds), as well as steroids and terpenes (10 compounds). Porphyrin-based compounds (C55H74N4O5–7), xanthophylls, sphingolipid compounds, fatty acid amides, and phytosterols represented the majority of identified compounds. By implementing both in vitro and in vivo assays for antioxidant activity determination, F3 showed a higher activity than F4. Inhibitory concentrations (IC50) for F3 and F4 were 498.00 ± 0.01 µg/mL and 798.00 ± 0.81 µg/mL, respectively, while a 1.5-fold reduction in the ROS level was observed after pre-treatment of zebrafish larvae with 45 µg/mL of F3.
      Citation: Pharmaceuticals
      PubDate: 2022-06-13
      DOI: 10.3390/ph15060743
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 744: Discovery of Triple Inhibitors of
           Both SARS-CoV-2 Proteases and Human Cathepsin L

    • Authors: Ittipat Meewan, Jacob Kattoula, Julius Y. Kattoula, Danielle Skinner, Pavla Fajtová, Miriam A. Giardini, Brendon Woodworth, James H. McKerrow, Jair Lage de Siqueira-Neto, Anthony J. O’Donoghue, Ruben Abagyan
      First page: 744
      Abstract: One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 papain-like protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by an idea to find a better alternative than disulfiram, an approved treatment for chronic alcoholism that is currently in phase 2 clinical trials against SARS-CoV-2. Our goal was to find more potent inhibitors that target both viral proteases and one essential human protease to reduce the dosage, improve the efficacy, and minimize the adverse effects associated with these agents. We found that compounds coded as RI175, RI173, and RI172 were the most potent inhibitors in an enzymatic assay against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L, with IC50s of 300, 200, and 200 nM, which is about 5-, 19-, and 11-fold more potent than disulfiram, respectively. In addition, RI173 was tested against SARS-CoV-2 in a cell-based and toxicity assay and was shown to have a greater antiviral effect than disulfiram. The identified compounds demonstrated the promising potential of thiuram disulfide or dithiobis-(thioformate) as a reactive functional group in small molecules that could be further developed for treatment of the COVID-19 virus or related variants.
      Citation: Pharmaceuticals
      PubDate: 2022-06-13
      DOI: 10.3390/ph15060744
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 745: Mechanistic Analysis of Chemically
           Diverse Bromodomain-4 Inhibitors Using Balanced QSAR Analysis and
           Supported by X-ray Resolved Crystal Structures

    • Authors: Magdi E. A. Zaki, Sami A. Al-Hussain, Aamal A. Al-Mutairi, Vijay H. Masand, Abdul Samad, Rahul D. Jawarkar
      First page: 745
      Abstract: Bromodomain-4 (BRD-4) is a key enzyme in post-translational modifications, transcriptional activation, and many other cellular processes. Its inhibitors find their therapeutic usage in cancer, acute heart failure, and inflammation to name a few. In the present study, a dataset of 980 molecules with a significant diversity of structural scaffolds and composition was selected to develop a balanced QSAR model possessing high predictive capability and mechanistic interpretation. The model was built as per the OECD (Organisation for Economic Co-operation and Development) guidelines and fulfills the endorsed threshold values for different validation parameters (R2tr = 0.76, Q2LMO = 0.76, and R2ex = 0.76). The present QSAR analysis identified that anti-BRD-4 activity is associated with structural characters such as the presence of saturated carbocyclic rings, the occurrence of carbon atoms near the center of mass of a molecule, and a specific combination of planer or aromatic nitrogen with ring carbon, donor, and acceptor atoms. The outcomes of the present analysis are also supported by X-ray-resolved crystal structures of compounds with BRD-4. Thus, the QSAR model effectively captured salient as well as unreported hidden pharmacophoric features. Therefore, the present study successfully identified valuable novel pharmacophoric features, which could be beneficial for the future optimization of lead/hit compounds for anti-BRD-4 activity.
      Citation: Pharmaceuticals
      PubDate: 2022-06-14
      DOI: 10.3390/ph15060745
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 746: L-Asparaginase from Penicillium
           sizovae Produced by a Recombinant Komagataella phaffii Strain

    • Authors: Marcela Freitas, Paula Souza, Mauricio Homem-de-Mello, Yris M. Fonseca-Bazzo, Damaris Silveira, Edivaldo X. Ferreira Filho, Adalberto Pessoa Junior, Dipak Sarker, David Timson, João Inácio, Pérola O. Magalhães
      First page: 746
      Abstract: L-asparaginase is an important enzyme in the pharmaceutical field used as treatment for acute lymphoblastic leukemia due to its ability to hydrolyze L-asparagine, an essential amino acid synthesized by normal cells, but not by neoplastic cells. Adverse effects of L-asparaginase formulations are associated with its glutaminase activity and bacterial origin; therefore, it is important to find new sources of L-asparaginase produced by eukaryotic microorganisms with low glutaminase activity. This work aimed to identify the L-asparaginase gene sequence from Penicillium sizovae, a filamentous fungus isolated from the Brazilian Savanna (Cerrado) soil with low glutaminase activity, and to biosynthesize higher yields of this enzyme in the yeast Komagataella phaffii. The L-asparaginase gene sequence of P. sizovae was identified by homology to L-asparaginases from species of Penicillium of the section Citrina: P. citrinum and P. steckii. Partial L-asparaginase from P. sizovae, lacking the periplasmic signaling sequence, was cloned, and expressed intracellularly with highest enzymatic activity achieved by a MUT+ clone cultured in BMM expression medium; a value 5-fold greater than that obtained by native L-asparaginase in P. sizovae cells. To the best of our knowledge, this is the first literature report of the heterologous production of an L-asparaginase from a filamentous fungus by a yeast.
      Citation: Pharmaceuticals
      PubDate: 2022-06-14
      DOI: 10.3390/ph15060746
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 747: Development of Radiotracers for
           Imaging of the PD-1/PD-L1 Axis

    • Authors: Fabian Krutzek, Klaus Kopka, Sven Stadlbauer
      First page: 747
      Abstract: Immune checkpoint inhibitor (ICI) therapy has emerged as a major treatment option for a variety of cancers. Among the immune checkpoints addressed, the programmed death receptor 1 (PD-1) and its ligand PD-L1 are the key targets for an ICI. PD-L1 has especially been proven to be a reproducible biomarker allowing for therapy decisions and monitoring therapy success. However, the expression of PD-L1 is not only heterogeneous among and within tumor lesions, but the expression is very dynamic and changes over time. Immunohistochemistry, which is the standard diagnostic tool, can only inadequately address these challenges. On the other hand, molecular imaging techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) provide the advantage of a whole-body scan and therefore fully address the issue of the heterogeneous expression of checkpoints over time. Here, we provide an overview of existing PET, SPECT, and optical imaging (OI) (radio)tracers for the imaging of the upregulation levels of PD-1 and PD-L1. We summarize the preclinical and clinical data of the different molecule classes of radiotracers and discuss their respective advantages and disadvantages. At the end, we show possible future directions for developing new radiotracers for the imaging of PD-1/PD-L1 status in cancer patients.
      Citation: Pharmaceuticals
      PubDate: 2022-06-14
      DOI: 10.3390/ph15060747
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 748: Pharmacophore-Based Discovery of
           Viral RNA Conformational Modulators

    • Authors: María Martín-Villamil, Isaías Sanmartín, Ángela Moreno, José Gallego
      First page: 748
      Abstract: New RNA-binding small-molecule scaffolds are needed to unleash the pharmacological potential of RNA targets. Here we have applied a pharmacophore-based virtual screening approach, seldom used in the RNA recognition field, to identify novel conformational inhibitors of the hepatitis C virus internal ribosome entry site. The conformational effect of the screening hits was assessed with a fluorescence resonance energy transfer assay, and the affinity, specificity, and binding site of the ligands were determined using a combination of fluorescence intensity and NMR spectroscopy experiments. The results indicate that this strategy can be successfully applied to discover RNA conformational inhibitors bearing substantially less positive charge than the reference ligands. This methodology can potentially be accommodated to other RNA motifs of pharmacological interest, facilitating the discovery of novel RNA-targeted molecules.
      Citation: Pharmaceuticals
      PubDate: 2022-06-14
      DOI: 10.3390/ph15060748
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 749: Adverse Drug Reactions of Olanzapine,
           Clozapine and Loxapine in Children and Youth: A Systematic Pharmacogenetic
           Review

    • Authors: Merino, Fernandez, Gérard, Ben Othman, Rocher, Askenazy, Verstuyft, Drici, Thümmler
      First page: 749
      Abstract: Children and youth treated with antipsychotic drugs (APs) are particularly vulnerable to adverse drug reactions (ADRs) and prone to poor treatment response. In particular, interindividual variations in drug exposure can result from differential metabolism of APs by cytochromes, subject to genetic polymorphism. CYP1A2 is pivotal in the metabolism of the APs olanzapine, clozapine, and loxapine, whose safety profile warrants caution. We aimed to shed some light on the pharmacogenetic profiles possibly associated with these drugs’ ADRs and loss of efficacy in children and youth. We conducted a systematic review relying on four databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 recommendations and checklist, with a quality assessment. Our research yielded 32 publications. The most frequent ADRs were weight gain and metabolic syndrome (18; 56.3%), followed by lack of therapeutic effect (8; 25%) and neurological ADRs (7; 21.8%). The overall mean quality score was 11.3/24 (±2.7). In 11 studies (34.3%), genotyping focused on the study of cytochromes. Findings regarding possible associations were sometimes conflicting. Nonetheless, cases of major clinical improvement were fostered by genotyping. Yet, CYP1A2 remains poorly investigated. Further studies are required to improve the assessment of the risk–benefit balance of prescription for children and youth treated with olanzapine, clozapine, and/or loxapine.
      Citation: Pharmaceuticals
      PubDate: 2022-06-14
      DOI: 10.3390/ph15060749
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 750: Multifunctional Gel Films of Marine
           Polysaccharides Cross-Linked with Poly-Metal Ions for Wound Healing

    • Authors: Di Zhao, Chao Shi, Tingting Guo, Kun Zhang, Shenghao Cui, Liqi Chen, Faming Yang, Jingdi Chen
      First page: 750
      Abstract: The development of an efficient and convenient material to improve skin tissue regeneration is a major challenge in healthcare. Inspired by the theory of moist wound healing, portable chitooligosaccharide (COS)/sodium alginate (SA) dual-net gel films containing multiple metal ions were prepared by a casting and in -situ spray method, which can be used to significantly promote wound healing without the use of therapeutic drugs. A variety of divalent cations was introduced in this experiment to improve the advantages of each metal ion by forming metal ion chelates with COS. Moreover, the physicochemical properties and antioxidant properties of nIon2+-COS/SA gel films were systematically characterized and evaluated by in vitro experiments. The gel films showed good antibacterial activity against Gram-negative and Gram-positive bacteria. In addition, the gel films showed good cytocompatibility in cellular experiments, and the gel films with Zn2+ and Sr2+ addition significantly accelerated wound healing in whole skin defect model experiments. Therefore, this nIon2+-COS/SA gel film is an ideal candidate material for wound dressing.
      Citation: Pharmaceuticals
      PubDate: 2022-06-15
      DOI: 10.3390/ph15060750
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 751: The Synthesis, Characterization,
           Molecular Docking, and In Vitro Antitumor Activity of Benzothiazole
           Aniline (BTA) Conjugated Metal-Salen Complexes as Non-Platinum
           Chemotherapeutic Agents

    • Authors: Md. Kamrul Islam, Seongmin Ha, Ah-Rum Baek, Byeong-Woo Yang, Yeoun-Hee Kim, Hyun-Jin Park, Minsup Kim, Sung-Wook Nam, Gang-Ho Lee, Yongmin Chang
      First page: 751
      Abstract: Here, we describe the synthesis, characterization, and in vitro biological evaluation of a series of transition metal complexes containing benzothiazole aniline (BTA). We employed BTA, which is known for its selective anticancer activity, and a salen-type Schiff-based ligand to coordinate several transition metals to achieve selective and synergistic cytotoxicity. The compounds obtained were characterized by NMR spectroscopy, mass spectrometry, Fourier transform infrared spectroscopy, and elemental analysis. The compounds L, MnL, FeL, CoL, and ZnL showed promising in vitro cytotoxicity against cancer cells, and they had a lower IC50 than that of the clinically used cisplatin. In particular, MnL had synergistic cytotoxicity against liver, breast, and colon cancer cells. Moreover, MnL, CoL, and CuL promoted the production of reactive oxygen species in HepG2 tumor cell lines. The lead compound of this series, MnL, remained stable in physiological settings, and docking results showed that it interacted rationally with the minor groove of DNA. Therefore, MnL may serve as a viable alternative to platinum-based chemotherapy.
      Citation: Pharmaceuticals
      PubDate: 2022-06-15
      DOI: 10.3390/ph15060751
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 752: Application of In Silico Filtering
           and Isothermal Titration Calorimetry for the Discovery of Small Molecule
           Inhibitors of MDM2

    • Authors: Hen Alali, Itai Bloch, Irena Rapaport, Luisa Rodrigues, Inbal Sher, Tamar Ansbacher, Maayan Gal
      First page: 752
      Abstract: The initial discovery phase of protein modulators, which consists of filtering molecular libraries and in vitro direct binding validation, is central in drug discovery. Thus, virtual screening of large molecular libraries, together with the evaluation of binding affinity by isothermal calorimetry, generates an efficient experimental setup. Herein, we applied virtual screening for discovering small molecule inhibitors of MDM2, a major negative regulator of the tumor suppressor p53, and thus a promising therapeutic target. A library of 20 million small molecules was screened against an averaged model derived from multiple structural conformations of MDM2 based on published structures. Selected molecules originating from the computational filtering were tested in vitro for their direct binding to MDM2 via isothermal titration calorimetry. Three new molecules, representing distinct chemical scaffolds, showed binding to MDM2. These were further evaluated by exploring structure-similar chemical analogues. Two scaffolds were further evaluated by de novo synthesis of molecules derived from the initial molecules that bound MDM2, one with a central oxoazetidine acetamide and one with benzene sulfonamide. Several molecules derived from these scaffolds increased wild-type p53 activity in MCF7 cancer cells. These set a basis for further chemical optimization and the development of new chemical entities as anticancer drugs.
      Citation: Pharmaceuticals
      PubDate: 2022-06-16
      DOI: 10.3390/ph15060752
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 753: Pharmacological Induction of Fetal
           Hemoglobin in β-Thalassemia and Sickle Cell Disease: An Updated
           Perspective

    • Authors: Rayan Bou-Fakhredin, Lucia De Franceschi, Irene Motta, Maria Domenica Cappellini, Ali T. Taher
      First page: 753
      Abstract: A significant amount of attention has recently been devoted to the mechanisms involved in hemoglobin (Hb) switching, as it has previously been established that the induction of fetal hemoglobin (HbF) production in significant amounts can reduce the severity of the clinical course in diseases such as β-thalassemia and sickle cell disease (SCD). While the induction of HbF using lentiviral and genome-editing strategies has been made possible, they present limitations. Meanwhile, progress in the use of pharmacologic agents for HbF induction and the identification of novel HbF-inducing strategies has been made possible as a result of a better understanding of γ-globin regulation. In this review, we will provide an update on all current pharmacological inducer agents of HbF in β-thalassemia and SCD in addition to the ongoing research into other novel, and potentially therapeutic, HbF-inducing agents.
      Citation: Pharmaceuticals
      PubDate: 2022-06-16
      DOI: 10.3390/ph15060753
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 754: Quercetin-Rich Extracts from Onions
           (Allium cepa) Play Potent Cytotoxicity on Adrenocortical Carcinoma Cell
           Lines, and Quercetin Induces Important Anticancer Properties

    • Authors: Alan A. Veiga, Ana Carolina Irioda, Bassam F. Mogharbel, Sandro J. R. Bonatto, Lauro M. Souza
      First page: 754
      Abstract: Adrenocortical carcinoma (ACC) is a rare subtype of cancer, with a poor prognosis in children and adults. Mitotane is the only approved adrenolytic drug for the treatment of ACC, which has controversies regarding its efficacy and side effects on patients. Onion (Allium cepa), a worldwide consumed food, is associated with many health benefits. Along with its glycosides, the flavonoid quercetin is abundant in onions. After evaluating the cytotoxicity of A. cepa extracts on adrenocortical carcinoma cell line (H295R), the rich quercetin fractions had better results. Then, we aimed to compare the quercetin vs. mitotane effectiveness, using adrenocortical carcinoma cell lines H295R and SW-13. Quercetin showed a higher cytotoxicity response on both cancerous cell lines after 10 µM concentration, while mitotane only after 30 µM. Cell cycle dynamics were altered upon quercetin treatments, with G2 phase increase with 30 µM of quercetin on H295R cell line and G1 arrest on SW-13 cell line with 15 µM. Early and late apoptosis, alongside intracellular calcium, were increased on SW-13 treated with 30 µM of quercetin, and ROS rates were reduced by quercetin on H295R. Therefore, quercetin-rich onions have the potential to be a natural source of anticancer agents for adrenocortical carcinoma.
      Citation: Pharmaceuticals
      PubDate: 2022-06-16
      DOI: 10.3390/ph15060754
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 755: Development and Validation of an
           HPLC-UV Method for the Dissolution Studies of 3D-Printed Paracetamol
           Formulations in Milk-Containing Simulated Gastrointestinal Media

    • Authors: Natalia Manousi, Christina Karavasili, Dimitrios G. Fatouros, Paraskevas D. Tzanavaras, Constantinos K. Zacharis
      First page: 755
      Abstract: Herein, a simple and rapid HPLC method for the determination of paracetamol milk-containing biorelevant media is proposed. The separation of the analyte from the milk-containing biorelevant media was accomplished isocratically using a mobile phase containing 25 mM phosphate buffer (pH = 3.0) and methanol, 80:20, v/v at a flow rate of 1 mL min−1. Following a protein precipitation-based sample clean-up, a thorough investigation of the effect of the precipitation reagent (methanol, acetonitrile, 10% v/v trifluoroacetic acid solution) on the analyte recovery was performed. The matrix effect was assessed in each biorelevant medium by comparing the slopes of the calibration curves of aqueous and matrix-matched calibration curves. The method was comprehensively validated using the accuracy profiles. The β-expectation tolerance intervals did not exceed the acceptance criteria of ±15%, meaning that 95% of future results will be included in the defined bias limits. The relative bias ranged between −4.5 and +3.9% for all analytes, while the RSD values for repeatability and intermediate precision were less than 2.7% and 3.0%, respectively. The achieved limit of detection (LOD) was 0.02 μg mL−1 and the lower limits of quantitation (LLOQ) were established as 10 μg mL−1, which corresponded to 2% of the highest expected concentration of paracetamol. The proposed scheme was utilized for the determination of paracetamol in dissolution studies of its 3D-printed formulation in milk-containing biorelevant media.
      Citation: Pharmaceuticals
      PubDate: 2022-06-16
      DOI: 10.3390/ph15060755
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 756: Tetanus Toxin Fragment C: Structure,
           Drug Discovery Research and Production

    • Authors: Caroline Bayart, Angélique Mularoni, Nada Hemmani, Soumeya Kerachni, Joachim Jose, Patrice Gouet, Joseph Paladino, Marc Le Borgne
      First page: 756
      Abstract: Tetanus toxoid (TTd) plays an important role in the pharmaceutical world, especially in vaccines. The toxoid is obtained after formaldehyde treatment of the tetanus toxin. In parallel, current emphasis in the drug discovery field is put on producing well-defined and safer drugs, explaining the interest in finding new alternative proteins. The tetanus toxin fragment C (TTFC) has been extensively studied both as a neuroprotective agent for central nervous system disorders owing to its neuronal properties and as a carrier protein in vaccines. Indeed, it is derived from a part of the tetanus toxin and, as such, retains its immunogenic properties without being toxic. Moreover, this fragment has been well characterized, and its entire structure is known. Here, we propose a systematic review of TTFC by providing information about its structural features, its properties and its methods of production. We also describe the large uses of TTFC in the field of drug discovery. TTFC can therefore be considered as an attractive alternative to TTd and remarkably offers a wide range of uses, including as a carrier, delivery vector, conjugate, booster, inducer, and neuroprotector.
      Citation: Pharmaceuticals
      PubDate: 2022-06-17
      DOI: 10.3390/ph15060756
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 757: Effect of Norelgestromin and
           Ethinylestradiol in Transdermal Patches on the Clinical Outcomes and
           

    • Authors: Cortés-Algara Alfredo, Cárdenas-Rodríguez Noemí, Reyes-Long Samuel, Ortega-Cuellar Daniel, Ruz-Barros Rodrigo, Mondragón-Terán Paul, Escamilla-Tilch Mónica, Correa-Basurto José, Lara-Padilla Eleazar, Alfaro-Rodríguez Alfonso, Cortes-Altamirano José Luis, Bandala Cindy
      First page: 757
      Abstract: The disease caused by SARS-CoV-2 is still considered a global pandemic. Transdermal patches (TP) with immunoregulators such as estrogen and progesterone compounds could be a feasible option to treat COVID-19 because of their accessibility and relative safety. The objective of the current study was to evaluate the additional treatment with norelgestromin and ethinylestradiol in TP on the clinical and biochemical evolution of COVID-19 patients. The present is a clinical-trial pilot study that included subjects diagnosed with COVID-19, randomized into two groups; the experimental Evra® TP (norelgestromin 6 mg and ethinylestradiol 0.60 mg) was administered such that it was applied on arrival and replaced at day 8 and day 15. The control continued with the conventional COVID-19 treatment protocol. A blood sample was taken each week in order to evaluate relevant biochemical parameters, clinical signs, and evolution. In total, 44 subjects participated in this study, 30 in the experimental group and 14 in the control group. Both groups were homogeneous in terms of age and comorbidities. The experimental group had a significantly lower hospital stay (p = 0.01), high flow supplemental oxygen (p = 0.001), mechanical ventilation (p = 0.003), and intubation (p = 0.01), and the oxygen saturation significantly increased (p = 0.01) in comparison with control group when patients were exposed to room air. A decrease in ferritin (p < 0.05) was observed, with no significant increase in ESR (p > 0.05), D dimer (p > 0.05) and platelets (p > 0.05) in an auto-controlled analysis in the experimental group. Norelgestromin and ethinylestradiol TP could be a safe and effective treatment for moderate and severe COVID-19 patients.
      Citation: Pharmaceuticals
      PubDate: 2022-06-17
      DOI: 10.3390/ph15060757
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 758: Ginsenoside Rh3 Inhibits Lung Cancer
           Metastasis by Targeting Extracellular Signal-Regulated Kinase: A Network
           Pharmacology Study

    • Authors: Xiaodan Xue, Yannan Liu, Linlin Qu, Cuiying Fan, Xiaoxuan Ma, Pingkai Ouyang, Daidi Fan
      First page: 758
      Abstract: Lung cancer has a high mortality rate and is very common. One of the main reasons for the poor prognosis of patients with lung cancer is the high incidence of metastasis. Ginsenoside Rh3, a rare ginsenoside extracted from Panax notoginseng, exhibits excellent anti-inflammatory and anti-tumor effects. Nonetheless, the inhibitory potential of Rh3 against lung cancer remains unknown. The target genes of Rh3 were screened by the PharmMapper database; the proliferation of lung cancer cells was detected by MTT assay; the migration and invasion of cells were detected by the Transwell method; and the expression of extracellular signal-regulated kinase (ERK) and EMT-related proteins in vivo and in vitro were detected by Western blotting. In addition, we established a lung metastasis model in nude mice using A549 cells to assess the effect of Rh3 on NSCLC tumor metastasis in vivo. Our findings suggest that Rh3 significantly inhibited lung cancer metastasis both in vivo and in vitro. It was determined by flow cytometry analysis that Rh3 notably inhibited cell proliferation by blocking the G1 phase. In addition, Rh3 inhibited metastasis in lung cancer cells and regulated the expression of metastasis-related proteins under hypoxia. Mechanistic studies suggested that Rh3 targeted ERK to inhibit lung cancer metastasis. The ERK inhibitor U0126 or siRNA-mediated knockdown of ERK had an enhanced effect on Rh3’s ability to inhibit lung cancer metastasis. The studies revealed that the inhibitory effect of Rh3 on the metastatic ability of lung cancer cells may be supported by ERK-related signaling pathways.
      Citation: Pharmaceuticals
      PubDate: 2022-06-17
      DOI: 10.3390/ph15060758
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 759: Use of an Electronic Medication
           Management Support System in Patients with Polypharmacy in General
           Practice: A Quantitative Process Evaluation of the AdAM Trial

    • Authors: Robin Brünn, Dorothea Lemke, Jale Basten, Petra Kellermann-Mühlhoff, Juliane Köberlein-Neu, Christiane Muth, Marjan van den Akker, on behalf of the AdAM Study Group on behalf of the AdAM Study Group
      First page: 759
      Abstract: Polypharmacy is associated with a risk of negative health outcomes. Potentially inappropriate medications, interactions resulting from contradicting medical guidelines, and inappropriate monitoring, all increase the risk. This process evaluation (PE) of the AdAM study investigates implementation and use of a computerized decision-support system (CDSS). The CDSS analyzes medication appropriateness by including claims data, and hence provides general practitioners (GPs) with full access to patients’ medical treatments. We based our PE on pseudonymized logbook entries into the CDSS and used the four dimensions of the Medical Research Council PE framework. Reach, which examines the extent to which the intended study population was included, and Dose, Fidelity, and Tailoring, which examine how the software was actually used by GPs. The PE was explorative and descriptive. Study participants were representative of the target population, except for patients receiving a high level of nursing care, as they were treated less frequently. GPs identified and corrected inappropriate prescriptions flagged by the CDSS. The frequency and intensity of interventions documented in the form of logbook entries lagged behind expectations, raising questions about implementation barriers to the intervention and the limitations of the PE. Impossibility to connect the CDSS to GPs’ electronic medical records (EMR) of GPs due to technical conditions in the German healthcare system may have hindered the implementation of the intervention. Data logged in the CDSS may underestimate medication changes in patients, as documentation was voluntary and already included in EMR.
      Citation: Pharmaceuticals
      PubDate: 2022-06-17
      DOI: 10.3390/ph15060759
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 760: Development of a Citric-Acid-Modified
           Cellulose Adsorbent Derived from Moringa peregrina Leaf for Adsorptive
           Removal of Citalopram HBr in Aqueous Solutions

    • Authors: Syed Najmul Hejaz Azmi, Wafa Mustafa Al Lawati, Umaima Hamed Abdullah Al Hoqani, Ekhlas Al Aufi, Khalsa Al Hatmi, Jumana Salim Al Zadjali, Nafisur Rahman, Mohd Nasir, Habibur Rahman, Shah A. Khan
      First page: 760
      Abstract: A citric-acid-modified Moringa peregrina leaf substrate was prepared and studied as an effective adsorbent for the adsorptive removal of citalopram HBr (CTM). FTIR spectra were utilized to characterize the prepared solid. The effects of experimental variables on the percentage removal of citalopram HBr were investigated using response surface methodology. The optimum conditions selected for removal of CTM were 7 and 4 min, 0.17 g per 50 mL and 35 mg·L−1 for pH, contact time, adsorbent dose and initial concentration of CTM, respectively. Under the optimized experimental conditions, 82.59% CTM (35 mg·L−1) was removed. The Langmuir isotherm, Freundlich isotherm, pseudo second-order kinetic model and diffusion-chemisorption model explained the adsorption data successfully. The maximum adsorption capacity at 298 K was 8.58 mg·g−1. A thermodynamic study illustrated that CTM adsorption was spontaneous and endothermic in nature.
      Citation: Pharmaceuticals
      PubDate: 2022-06-17
      DOI: 10.3390/ph15060760
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 761: Multi-Dose Intravenous Administration
           of Neutral and Cationic Liposomes in Mice: An Extensive Toxicity Study

    • Authors: Stéphanie Andrade, Joana A. Loureiro, Santiago Ramirez, Celso S. G. Catumbela, Claudio Soto, Rodrigo Morales, Maria Carmo Pereira
      First page: 761
      Abstract: Liposomes are widely used as delivery systems for therapeutic purposes. However, the toxicity associated with the multi-dose administration of these nanoparticles is not fully elucidated. Here, we evaluated the toxicity of the prolonged administration of liposomes composed of neutral or cationic phospholipids often used in drug and gene delivery. For that purpose, adult wild-type mice (C57Bl6) were randomly distributed into three groups receiving either vehicle (PBS), neutral, or cationic liposomes and subjected to repeated intravenous injections for a total of 10 doses administered over 3 weeks. Several parameters, including mortality, body weight, and glucose levels, were monitored throughout the trial. While these variables did not change in the group treated with neutral liposomes, the group treated with the positively charged liposomes displayed a mortality rate of 45% after 10 doses of administration. Additional urinalysis, blood tests, and behavioral assays to evaluate impairments of motor functions or lesions in major organs were also performed. The cationic group showed less forelimb peak force than the control group, alterations at the hematological level, and inflammatory components, unlike the neutral group. Overall, the results demonstrate that cationic liposomes are toxic for multi-dose administration, while the neutral liposomes did not induce changes associated with toxicity. Therefore, our results support the use of the well-known neutral liposomes as safe drug shuttles, even when repetitive administrations are needed.
      Citation: Pharmaceuticals
      PubDate: 2022-06-18
      DOI: 10.3390/ph15060761
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 762: A Review on the Role of Pilocarpine
           on the Management of Xerostomia and the Importance of the Topical
           Administration Systems Development

    • Authors: Afroditi Kapourani, Konstantinos N. Kontogiannopoulos, Panagiotis Barmpalexis
      First page: 762
      Abstract: Xerostomia is linked to an increased risk of dental caries, oral fungal infections, and speaking/swallowing difficulties, factors that may significantly degrade patients’ life, socially- or emotionally-wise. Consequently, there is an increasing interest in developing management approaches for confronting this oral condition, at which pilocarpine, a parasympathomimetic agent, plays a vital role. Although the therapeutic effects of orally administrated pilocarpine on the salivary gland flow and the symptoms of xerostomia have been proved by numerous studies, the systemic administration of this drug is affiliated with various adverse effects. Some of the typical adverse effects include sweating, nausea, vomiting, diarrhea, rhinitis, dizziness and increased urinary frequency. In this vein, new strategies to develop novel and effective dosage forms for topical (i.e., in the oral cavity) pilocarpine administration, in order for the salivary flow to be enhanced with minimal systemic manifestations, have emerged. Therefore, the purpose of the current review is to survey the literature concerning the performance of topical pilocarpine delivery systems. According to the findings, the topical delivery of pilocarpine can be regarded as the equivalent to systemic delivery of the drug, efficacy-wise, but with improved patient tolerance and less adverse effects.
      Citation: Pharmaceuticals
      PubDate: 2022-06-18
      DOI: 10.3390/ph15060762
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 763: Advanced Analytical Approach Based on
           Combination of FT-IR and Chemometrics for Quality Control of
           Pharmaceutical Preparations

    • Authors: Martina Foschi, Mariagrazia Marziale, Alessandra Biancolillo
      First page: 763
      Abstract: Background: The present work represents a feasibility study for the realization of an analytical method finalized to the detection of expired antibiotic tablets. The work focuses on a specific antibiotic drug and represents the preliminary study upstream of a larger-scale work. Methods: attenuated Total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) spectra coupled with sequential preprocessing through an orthogonalization (SPORT) chemometric approach were used to discriminate between expired and compliant tablets. Conclusions: The highest predictive accuracy (93.3% of correct classification rate in external validation, corresponding to 1 misclassified test sample over 15) was achieved by analyzing intact tablets. This represents an excellent result because it gives indications regarding the possibility of determining, in a completely non-destructive way, the presence of expired drugs.
      Citation: Pharmaceuticals
      PubDate: 2022-06-18
      DOI: 10.3390/ph15060763
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 764: Discovery of Therapeutics Targeting
           Oxidative Stress in Autosomal Recessive Cerebellar Ataxia: A Systematic
           Review

    • Authors: Sze Yuen Lew, Michael Weng Lok Phang, Pit Shan Chong, Jaydeep Roy, Chi Him Poon, Wing Shan Yu, Lee Wei Lim, Kah Hui Wong
      First page: 764
      Abstract: Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of rare neurodegenerative inherited disorders. The resulting motor incoordination and progressive functional disabilities lead to reduced lifespan. There is currently no cure for ARCAs, likely attributed to the lack of understanding of the multifaceted roles of antioxidant defense and the underlying mechanisms. This systematic review aims to evaluate the extant literature on the current developments of therapeutic strategies that target oxidative stress for the management of ARCAs. We searched PubMed, Web of Science, and Science Direct Scopus for relevant peer-reviewed articles published from 1 January 2016 onwards. A total of 28 preclinical studies fulfilled the eligibility criteria for inclusion in this systematic review. We first evaluated the altered cellular processes, abnormal signaling cascades, and disrupted protein quality control underlying the pathogenesis of ARCA. We then examined the current potential therapeutic strategies for ARCAs, including aromatic, organic and pharmacological compounds, gene therapy, natural products, and nanotechnology, as well as their associated antioxidant pathways and modes of action. We then discussed their potential as antioxidant therapeutics for ARCAs, with the long-term view toward their possible translation to clinical practice. In conclusion, our current understanding is that these antioxidant therapies show promise in improving or halting the progression of ARCAs. Tailoring the therapies to specific disease stages could greatly facilitate the management of ARCAs.
      Citation: Pharmaceuticals
      PubDate: 2022-06-19
      DOI: 10.3390/ph15060764
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 765: Cardio- and Neurotoxicity of Selected
           Anti-COVID-19 Drugs

    • Authors: Martin W. Nicholson, Ching-Ying Huang, Jyun-Yuan Wang, Chien-Yu Ting, Yu-Che Cheng, Darien Z. H. Chan, Yi-Chan Lee, Ching-Chuan Hsu, Yu-Hung Hsu, Cindy M. C. Chang, Marvin L. Hsieh, Yuan-Yuan Cheng, Yi-Ling Lin, Chien-Hsiun Chen, Ying-Ta Wu, Timothy A. Hacker, Joseph C. Wu, Timothy J. Kamp, Patrick C. H. Hsieh
      First page: 765
      Abstract: Since December 2019, the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected ~435 million people and caused ~6 million related deaths as of March 2022. To combat COVID-19, there have been many attempts to repurpose FDA-approved drugs or revive old drugs. However, many of the current treatment options have been known to cause adverse drug reactions. We employed a population-based drug screening platform using 13 human leukocyte antigen (HLA) homozygous human induced pluripotent cell (iPSC) lines to assess the cardiotoxicity and neurotoxicity of the first line of anti-COVID-19 drugs. We also infected iPSC-derived cells to understand the viral infection of cardiomyocytes and neurons. We found that iPSC-derived cardiomyocytes express the ACE2 receptor which correlated with a higher infection of the SARS-CoV-2 virus (r = 0.86). However, we were unable to detect ACE2 expression in neurons which correlated with a low infection rate. We then assessed the toxicity of anti-COVID-19 drugs and identified two cardiotoxic compounds (remdesivir and arbidol) and four neurotoxic compounds (arbidol, remdesivir, hydroxychloroquine, and chloroquine). These data show that this platform can quickly and easily be employed to further our understanding of cell-specific infection and identify drug toxicity of potential treatment options helping clinicians better decide on treatment options.
      Citation: Pharmaceuticals
      PubDate: 2022-06-20
      DOI: 10.3390/ph15060765
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 766: Inhibitors of O-Acetylserine
           Sulfhydrylase with a Cyclopropane-Carboxylic Acid Scaffold Are Effective
           Colistin Adjuvants in Gram Negative Bacteria

    • Authors: Giannamaria Annunziato, Costanza Spadini, Marialaura Marchetti, Nina Franko, Marialaura Pavone, Mattia Iannarelli, Agostino Bruno, Marco Pieroni, Stefano Bettati, Clotilde Silvia Cabassi, Barbara Campanini, Gabriele Costantino
      First page: 766
      Abstract: Antibacterial adjuvants are of great significance, since they allow one to downscale the therapeutic dose of conventional antibiotics and reduce the insurgence of antibacterial resistance. Herein, we report that O-acetylserine sulfhydrylase (OASS) inhibitors could be used as colistin adjuvants to treat infections caused by critical pathogens spreading worldwide, Escherichia coli, Salmonella enterica serovar Typhimurium, and Klebsiella pneumoniae. Starting from a hit compound endowed with a nanomolar dissociation constant, we have rationally designed and synthesized a series of derivatives to be tested against S. Typhimurium OASS isoenzymes, StOASS-A and StOASS-B. All acidic derivatives have shown good activities in the nanomolar range against both OASS isoforms in vitro. Minimal Inhibitory Concentrations (MICs) were then evaluated, as well as compounds’ toxicity. The compounds endowed with good activity in vitro and low cytotoxicity have been challenged as a potential colistin adjuvant against pathogenic bacteria in vitro and the fractional inhibitory concentration (FIC) index has been calculated to define additive or synergistic effects. Finally, the target engagement inside the S. Typhimurium cells was confirmed by using a mutant strain in which the OASS enzymes were inactivated. Our results provide a robust proof of principle supporting OASS as a potential nonessential antibacterial target to develop a new class of adjuvants.
      Citation: Pharmaceuticals
      PubDate: 2022-06-20
      DOI: 10.3390/ph15060766
      Issue No: Vol. 15, No. 6 (2022)
       
  • Pharmaceuticals, Vol. 15, Pages 767: The Potential Application of Natural
           Photosensitizers Used in Antimicrobial Photodynamic Therapy against Oral
           Infections

    • Authors: Shima Afrasiabi, Alireza Partoazar, Nasim Chiniforush, Ramin Goudarzi
      First page: 767
      Abstract: Oral health problems and the emergence of antimicrobial resistance among pathogenic bacterial strains have become major global challenges and are essential elements that negatively affect general well-being. Antimicrobial photodynamic therapy (APDT) is based on a light source and oxygen that activates a nontoxic photosensitizer, resulting in microbial destruction. Synthetic and natural products can be used to help the APDT against oral microorganisms. The undesirable consequences of conventional photosensitizers, including toxicity, and cost encourage researchers to explore new promising photosensitizers based on natural compounds such as curcumin, chlorella, chlorophyllin, phycocyanin, 5-aminolevulinic acid, and riboflavin. In this review, we summarize in vitro studies describing the potential use of APDT therapy conjugated with some natural products against selected microorganisms that are considered to be responsible for oral infections.
      Citation: Pharmaceuticals
      PubDate: 2022-06-20
      DOI: 10.3390/ph15060767
      Issue No: Vol. 15, No. 6 (2022)
       
 
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