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  Subjects -> PHARMACY AND PHARMACOLOGY (Total: 575 journals)
Showing 401 - 253 of 253 Journals sorted alphabetically
Microbial Drug Resistance     Hybrid Journal   (Followers: 3)
Molecular Informatics     Hybrid Journal   (Followers: 5)
Molecular Pharmacology     Hybrid Journal   (Followers: 2)
Molekul     Open Access   (Followers: 3)
Natural Product Communications     Open Access  
Nature Reviews Drug Discovery     Full-text available via subscription   (Followers: 319)
Naunyn-Schmiedeberg's Archives of Pharmacology     Hybrid Journal  
NeuroMolecular Medicine     Hybrid Journal  
Neuropharmacology     Hybrid Journal   (Followers: 5)
Neuropsychopharmacology     Hybrid Journal   (Followers: 17)
Neuropsychopharmacology Reports     Open Access  
Nigerian Journal of Natural Products and Medicine     Full-text available via subscription  
OA Drug Design & Delivery     Open Access  
OA Medical Hypothesis     Open Access  
Obesity Facts     Open Access   (Followers: 8)
Open Pharmacoeconomics & Health Economics Journal     Open Access   (Followers: 1)
Open Pharmacology Journal     Open Access  
OpenNano     Open Access   (Followers: 1)
Orbital - The Electronic Journal of Chemistry     Open Access   (Followers: 1)
Oriental Pharmacy and Experimental Medicine     Partially Free   (Followers: 2)
Pain and Therapy     Open Access   (Followers: 3)
Particulate Science and Technology: An International Journal     Hybrid Journal   (Followers: 1)
PDA Journal of Pharmaceutical Science and Technology     Full-text available via subscription   (Followers: 34)
Pediatric Drugs     Full-text available via subscription   (Followers: 3)
Pediatric Pharmacology     Open Access   (Followers: 1)
Pharmaceutica Analytica Acta     Open Access  
Pharmaceutical Biology     Open Access  
Pharmaceutical Care-La Farmacoterapia     Open Access  
Pharmaceutical Chemistry Journal     Hybrid Journal  
Pharmaceutical Development and Technology     Hybrid Journal   (Followers: 19)
Pharmaceutical Executive     Full-text available via subscription   (Followers: 2)
Pharmaceutical Fronts     Open Access   (Followers: 10)
Pharmaceutical Historian     Open Access  
Pharmaceutical Journal     Free   (Followers: 8)
Pharmaceutical Journal of Sri Lanka     Open Access  
Pharmaceutical Medicine     Full-text available via subscription   (Followers: 4)
Pharmaceutical Nanotechnology     Hybrid Journal  
Pharmaceutical Patent Analyst     Full-text available via subscription   (Followers: 3)
Pharmaceutical Research     Hybrid Journal   (Followers: 93)
Pharmaceutical Statistics     Hybrid Journal   (Followers: 15)
Pharmaceutical Technology     Full-text available via subscription   (Followers: 7)
Pharmaceuticals     Open Access   (Followers: 4)
Pharmacia     Open Access  
Pharmaciana     Open Access  
PharmacoEconomics     Full-text available via subscription   (Followers: 25)
PharmacoEconomics & Outcomes News     Full-text available via subscription   (Followers: 2)
PharmacoEconomics German Research Articles     Full-text available via subscription  
PharmacoEconomics Spanish Research Articles     Hybrid Journal   (Followers: 1)
Pharmacoepidemiology and Drug Safety     Hybrid Journal   (Followers: 33)
Pharmacogenetics and Genomics     Hybrid Journal   (Followers: 1)
Pharmacogenomics     Hybrid Journal   (Followers: 7)
Pharmacogenomics and Personalized Medicine     Open Access   (Followers: 2)
Pharmacogenomics Journal     Hybrid Journal   (Followers: 5)
Pharmacognosy Communications     Partially Free  
Pharmacognosy Magazine     Open Access   (Followers: 2)
Pharmacognosy Research     Open Access   (Followers: 2)
Pharmacological Reports     Hybrid Journal  
Pharmacological Research     Hybrid Journal   (Followers: 1)
Pharmacological Research - Modern Chinese Medicine     Open Access  
Pharmacological Reviews     Hybrid Journal   (Followers: 2)
Pharmacology     Full-text available via subscription  
Pharmacology & Therapeutics     Hybrid Journal   (Followers: 3)
Pharmacology & Pharmacy     Open Access   (Followers: 1)
Pharmacology Biochemistry and Behavior     Hybrid Journal   (Followers: 2)
Pharmacology Research & Perspectives     Open Access  
Pharmacon : Jurnal Farmasi Indonesia     Open Access  
Pharmacopsychiatry     Hybrid Journal   (Followers: 3)
Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy     Hybrid Journal   (Followers: 38)
Pharmactuel     Open Access   (Followers: 1)
Pharmacy     Open Access   (Followers: 4)
Pharmacy & Pharmacology     Open Access   (Followers: 1)
Pharmacy Education     Full-text available via subscription   (Followers: 11)
Pharmacy Practice (Internet)     Open Access   (Followers: 8)
Pharmakon : Arzneimittel in Wissenschaft und Praxis     Full-text available via subscription   (Followers: 1)
PharmaNutrition     Hybrid Journal   (Followers: 3)
PharmaTutor     Open Access  
Pharmazeutische Industrie     Full-text available via subscription   (Followers: 9)
Pharmazeutische Zeitung     Full-text available via subscription   (Followers: 11)
Pharmazie in Unserer Zeit (Pharmuz)     Hybrid Journal   (Followers: 10)
Physiology International     Full-text available via subscription   (Followers: 3)
Plant Products Research Journal     Full-text available via subscription  
Planta Medica     Hybrid Journal   (Followers: 4)
Planta Medica International Open     Open Access  
Prescriber     Hybrid Journal   (Followers: 9)
Progress in Neuro-Psychopharmacology and Biological Psychiatry     Hybrid Journal   (Followers: 8)
Psychiatry and Clinical Psychopharmacology     Open Access   (Followers: 1)
Psychopharmacology     Hybrid Journal   (Followers: 15)
Pulmonary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 2)
PZ Prisma : Materialien zur Fort- und Weiterbildung     Full-text available via subscription  
Redox Report     Open Access  
Regulatory Mechanisms in Biosystems     Open Access   (Followers: 1)
Regulatory Toxicology and Pharmacology     Hybrid Journal   (Followers: 41)
Research & Reviews : A Journal of Drug Design & Discovery     Full-text available via subscription  
Research & Reviews : A Journal of Pharmaceutical Science     Full-text available via subscription  
Research & Reviews : A Journal of Pharmacognosy     Full-text available via subscription  
Research & Reviews : A Journal of Pharmacology     Full-text available via subscription   (Followers: 1)
Research in Pharmaceutical Sciences     Open Access   (Followers: 3)
Research in Social and Administrative Pharmacy     Hybrid Journal   (Followers: 3)
Research Journal of Pharmacognosy     Open Access  
Research Results in Pharmacology     Open Access  
Reviews of Physiology, Biochemistry and Pharmacology     Hybrid Journal   (Followers: 4)
Reviews on Clinical Pharmacology and Drug Therapy     Full-text available via subscription  
Revista Colombiana de Ciencias Químico-Farmacéuticas     Open Access  
Revista Cubana de Plantas Medicinales     Open Access   (Followers: 1)
Revista de Ciências Farmacêuticas Básica e Aplicada     Open Access  
Revista Mexicana de Ciencias Farmaceuticas     Open Access  
Revue de Médecine et de Pharmacie     Full-text available via subscription  
Safety and Risk of Pharmacotherapy     Open Access   (Followers: 1)
Saudi Pharmaceutical Journal     Open Access  
Scandinavian Journal of Clinical and Laboratory Investigation     Hybrid Journal   (Followers: 7)
Scientia Pharmaceutica     Open Access  
Seminars in Hematology     Hybrid Journal   (Followers: 12)
Seminars in Oncology Nursing     Full-text available via subscription   (Followers: 10)
Separation Science plus (SSC plus)     Hybrid Journal  
Side Effects of Drugs Annual     Full-text available via subscription   (Followers: 2)
Skin Pharmacology and Physiology     Full-text available via subscription   (Followers: 6)
Substance Abuse : Research and Treatment     Open Access   (Followers: 5)
Suchttherapie     Hybrid Journal   (Followers: 1)
Sustainable Chemistry and Pharmacy     Full-text available via subscription   (Followers: 1)
Synfacts     Hybrid Journal   (Followers: 5)
SynOpen     Open Access  
The Botulinum J.     Hybrid Journal  
The Brown University Psychopharmacology Update     Hybrid Journal   (Followers: 2)
The Medical Letter     Full-text available via subscription   (Followers: 18)
The Pink Sheet     Full-text available via subscription   (Followers: 13)
The Pink Sheet Daily     Full-text available via subscription   (Followers: 4)
Therapeutic Advances in Drug Safety     Open Access   (Followers: 3)
Therapeutic Advances in Psychopharmacology     Open Access   (Followers: 4)
Therapeutic Advances in Vaccines     Hybrid Journal   (Followers: 1)
Therapeutic Drug Monitoring     Hybrid Journal   (Followers: 3)
Therapeutic Innovation & Regulatory Science     Hybrid Journal   (Followers: 7)
Thérapie     Full-text available via subscription   (Followers: 1)
TheScientist     Free   (Followers: 5)
Toxicological & Environmental Chemistry     Hybrid Journal   (Followers: 2)
Toxicological Research     Hybrid Journal  
Toxicological Sciences     Hybrid Journal   (Followers: 11)
Toxicology     Hybrid Journal   (Followers: 18)
Toxicology and Applied Pharmacology     Hybrid Journal   (Followers: 24)
Toxicology and Industrial Health     Hybrid Journal   (Followers: 6)
Toxicology in Vitro     Hybrid Journal   (Followers: 11)
Toxicology International     Full-text available via subscription   (Followers: 5)
Toxicology Letters     Hybrid Journal   (Followers: 15)
Toxicology Mechanisms and Methods     Hybrid Journal   (Followers: 7)
Toxicology Research     Partially Free   (Followers: 8)
Toxicon     Hybrid Journal   (Followers: 5)
Toxicon : X     Open Access  
Toxin Reviews     Hybrid Journal  
Translational Psychiatry     Open Access   (Followers: 15)
Trends in Peptide and Protein Sciences     Open Access  
Trends in Pharmacological Sciences     Full-text available via subscription   (Followers: 19)
Tropical Journal of Pharmaceutical Research     Open Access  
Ukrainian Biopharmaceutical Journal     Open Access  
Vascular Pharmacology     Hybrid Journal   (Followers: 2)
World Mycotoxin Journal     Hybrid Journal   (Followers: 3)
Yakugaku Zasshi     Open Access   (Followers: 1)
Zeitschrift für Phytotherapie     Hybrid Journal   (Followers: 1)
Актуальні питання фармацевтичної та медичної науки та практики     Open Access  
Фармацевтичний часопис     Open Access  

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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 906: Impaired Vitamin D Metabolism in
           Hospitalized COVID-19 Patients

    • Authors: Alexandra Povaliaeva, Viktor Bogdanov, Ekaterina Pigarova, Larisa Dzeranova, Nino Katamadze, Natalya Malysheva, Vitaliy Ioutsi, Larisa Nikankina, Liudmila Rozhinskaya, Natalia Mokrysheva
      First page: 906
      Abstract: There is increasing data regarding the association between vitamin D and COVID-19. This study aimed to reveal the alterations of vitamin D metabolism in the setting of COVID-19. We examined 119 adult COVID-19 inpatients and 44 apparently healthy adult individuals with similar serum 25OH-D3 levels as a reference group. The assessment included serum biochemical parameters (total calcium, albumin, phosphorus, creatinine), parathyroid hormone (PTH), vitamin D-binding protein (DBP), vitamin D metabolites (25OH-D3, 25OH-D2, 1,25(OH)2D3, 3-epi-25OH-D3, 24,25(OH)2D3 and D3) and free 25OH-D. COVID-19 patients had in general very low vitamin D levels (median 25OH-D3 equals 10.8 ng/mL), accompanied by an increased production of the active vitamin D metabolite (1,25(OH)2D3), estimated as higher 1,25(OH)2D3 serum levels (61 [44; 81] vs. 40 [35; 50] pg/mL, p < 0.001) and lower 25OH-D3/1,25(OH)2D3 ratio (175 [112; 260] vs. 272 [200; 433], p < 0.001) which is presumably aimed at preventing hypocalcemia. Patients with COVID-19 also had elevated DBP (450 [386; 515] vs. 392 [311; 433] mg/L, p < 0.001) and low free 25OH-D levels (<LoB vs. 3.9 [3.2; 4.4] pg/mL, p < 0.001). Follow-up assessment of the COVID-19 inpatients showed recovery of the observed changes. Overall, hospitalized patients with an acute course of COVID-19 have not only very low levels of 25OH-D but also profound abnormalities in the metabolism of vitamin D regardless of the clinical course of the disease. These alterations might exacerbate existing vitamin D deficiency and its negative impact.
      Citation: Pharmaceuticals
      PubDate: 2022-07-22
      DOI: 10.3390/ph15080906
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 907: Royal Jelly Components Encapsulation
           in a Controlled Release System—Skin Functionality and Biochemical
           Activity for Skin Applications

    • Authors: Spanidi, Athanasopoulou, Liakopoulou, Chaidou, Hatziantoniou, Gardikis
      First page: 907
      Abstract: Royal jelly is a yellowish-white substance with a gel texture that is secreted from the hypopharyngeal and mandibular glands of young worker bees. It consists mainly of water (50–56%), proteins (18%), carbohydrates (15%), lipids (3%–6%), minerals (1.5%), and vitamins, and has many beneficial properties such as antimicrobial, anti-inflammatory, anticancer, antioxidant, antidiabetic, immunomodulatory, and anti-aging. Royal jelly has been used since ancient times in traditional medicine, cosmetics and as a functional food due to its high nutritional value. The main bioactive substances are royalactin, and 10-hydroxy-2-decenoic acid (10-HDA). Other important bioactive molecules with antioxidant and photoprotective skin activity are polyphenols. However, they present difficulties in extraction and in use as they are unstable physicochemically, and a higher temperature causes color change and component degradation. In the present study, a new encapsulation and delivery system consisting of liposomes and cyclodextrins incorporating royal jelly has been developed. The new delivery system aims to the elimination of the stability disadvantages of royal jelly’s sensitive component 10-HDA, but also to the controlled release of its ingredients and, more particularly, 10-HDA, for an enhanced bioactivity in cosmeceutical applications.
      Citation: Pharmaceuticals
      PubDate: 2022-07-22
      DOI: 10.3390/ph15080907
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 908: A Combined Chronic Low-Dose Soluble
           Epoxide Hydrolase and Acetylcholinesterase Pharmacological Inhibition
           Promotes Memory Reinstatement in Alzheimer’s Disease Mice Models

    • Authors: Jarne-Ferrer, Griñán-Ferré, Bellver-Sanchis, Vázquez, Muñoz-Torrero, Pallàs
      First page: 908
      Abstract: Alzheimer’s disease (AD) is a progressive neurological disorder with multifactorial and heterogeneous causes. AD involves several etiopathogenic mechanisms such as aberrant protein accumulation, neurotransmitter deficits, synaptic dysfunction and neuroinflammation, which lead to cognitive decline. Unfortunately, the currently available anti-AD drugs only alleviate the symptoms temporarily and provide a limited therapeutic effect. Thus, new therapeutic strategies, including multitarget approaches, are urgently needed. It has been demonstrated that a co-treatment of acetylcholinesterase (AChE) inhibitor with other neuroprotective agents has beneficial effects on cognition. Here, we have assessed the neuroprotective effects of chronic dual treatment with a soluble epoxide hydrolase (sEH) inhibitor (TPPU) and an AChE inhibitor (6-chlorotacrine or rivastigmine) in in vivo studies. Interestingly, we have found beneficial effects after chronic low-dose co-treatment with TPPU and 6-chlorotacrine in the senescence-accelerated mouse prone 8 (SAMP8) mouse model as well as with TPPU and rivastigmine co-treatment in the 5XFAD mouse model, in comparison with the corresponding monotherapy treatments. In the SAMP8 model, no substantial improvements in synaptic plasticity markers were found, but the co-treatment of TPPU and 6-chlorotacrine led to a significantly reduced gene expression of neuroinflammatory markers, such as interleukin 6 (Il-6), triggering receptor expressed on myeloid cell 2 (Trem2) and glial fibrillary acidic protein (Gfap). In 5XFAD mice, chronic low-dose co-treatment of TPPU and rivastigmine led to enhanced protein levels of synaptic plasticity markers, such as the phospho-cAMP response element-binding protein (p-CREB) ratio, brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95), and also to a reduction in neuroinflammatory gene expression. Collectively, these results support the neuroprotectant role of chronic low-dose co-treatment strategy with sEH and AChE inhibitors in AD mouse models, opening new avenues for effective AD treatment.
      Citation: Pharmaceuticals
      PubDate: 2022-07-22
      DOI: 10.3390/ph15080908
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 909: The Medicinal Chemistry of Artificial
           Nucleic Acids and Therapeutic Oligonucleotides

    • Authors: Miklós Bege, Anikó Borbás
      First page: 909
      Abstract: Nucleic acids play a central role in human biology, making them suitable and attractive tools for therapeutic applications. While conventional drugs generally target proteins and induce transient therapeutic effects, nucleic acid medicines can achieve long-lasting or curative effects by targeting the genetic bases of diseases. However, native oligonucleotides are characterized by low in vivo stability due to nuclease sensitivity and unfavourable physicochemical properties due to their polyanionic nature, which are obstacles to their therapeutic use. A myriad of synthetic oligonucleotides have been prepared in the last few decades and it has been shown that proper chemical modifications to either the nucleobase, the ribofuranose unit or the phosphate backbone can protect the nucleic acids from degradation, enable efficient cellular uptake and target localization ensuring the efficiency of the oligonucleotide-based therapy. In this review, we present a summary of structure and properties of artificial nucleic acids containing nucleobase, sugar or backbone modifications, and provide an overview of the structure and mechanism of action of approved oligonucleotide drugs including gene silencing agents, aptamers and mRNA vaccines.
      Citation: Pharmaceuticals
      PubDate: 2022-07-22
      DOI: 10.3390/ph15080909
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 910: Activation of Peripheral Cannabinoid
           Receptors Synergizes the Effect of Systemic Ibuprofen in a Pain Model in

    • Authors: M. Irene Díaz-Reval, Yolitzy Cárdenas, Miguel Huerta, Xóchitl Trujillo, Enrique Alejandro Sánchez-Pastor, María Eva González-Trujano, Adolfo Virgen-Ortíz, M. Gicela Pérez-Hernández
      First page: 910
      Abstract: Pharmacological synergism is a current strategy for the treatment of pain. However, few studies have been explored to provide evidence of the possible synergism between a non-steroidal anti-inflammatory drug (NSAID) and a cannabinoid agonist, in order to establish which combinations might be effective to manage pain. The aim of this study was to explore the synergism between ibuprofen (IBU) and the synthetic cannabinoid WIN 55,212-2 (WIN) to improve pain relief by analyzing the degree of participation of the CB1 and CB2 cannabinoid receptors in the possible antinociceptive synergism using an experimental model of pain in Wistar rats. First, the effective dose thirty (ED30) of IBU (10, 40, 80, and 160 mg/kg, subcutaneous) and WIN (3, 10, and 30 µg/p, intraplantar) were evaluated in the formalin test. Then, the constant ratio method was used to calculate the doses of IBU and WIN to be administered in combination (COMB) to determine the possible synergism using the isobolographic method. The participation of the CB1 and CB2 receptors was explored in the presence of the antagonists AM281 and AM630, respectively. The combination of these drugs produced a supra-additive response with an interaction index of 0.13. In addition, AM281 and AM630 antagonists reversed the synergistic effect in 45% and 76%, respectively, suggesting that both cannabinoid receptors are involved in this synergism, with peripheral receptors playing a relevant role. In conclusion, the combination of IBU + WIN synergism is mainly mediated by the participation of the CB2 receptor, which can be a good option for the better management of pain relief.
      Citation: Pharmaceuticals
      PubDate: 2022-07-23
      DOI: 10.3390/ph15080910
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 911: Immunogenicity of Current and New
           Therapies for Hemophilia A

    • Authors: Alessandra N. L. Prezotti, Jéssica O. Frade-Guanaes, Gabriela G. Yamaguti-Hayakawa, Margareth C. Ozelo
      First page: 911
      Abstract: Anti-drug antibody (ADA) development is a significant complication in the treatment of several conditions. For decades, the mainstay of hemophilia A treatment was the replacement of deficient coagulation factor VIII (FVIII) to restore hemostasis, control, and prevent bleeding events. Recently, new products have emerged for hemophilia A replacement therapy, including bioengineered FVIII molecules with enhanced pharmacokinetic profiles: the extended half-life (EHL) recombinant FVIII products. However, the main complication resulting from replacement treatment in hemophilia A is the development of anti-FVIII neutralizing alloantibodies, known as inhibitors, affecting approximately 25–30% of severe hemophilia A patients. Therefore, the immunogenicity of each FVIII product and the mechanisms that could help increase the tolerance to these products have become important research topics in hemophilia A. Furthermore, patients with inhibitors continue to require effective treatment for breakthrough bleedings and procedures, despite the availability of non-replacement therapy, such as emicizumab. Herein, we discuss the currently licensed treatments available for hemophilia A and the immunogenicity of new therapies, such as EHL-rFVIII products, compared to other products available.
      Citation: Pharmaceuticals
      PubDate: 2022-07-23
      DOI: 10.3390/ph15080911
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 912: Immunomodulatory and Antiaging
           Mechanisms of Resveratrol, Rapamycin, and Metformin: Focus on mTOR and
           AMPK Signaling Networks

    • Authors: Vincenzo Sorrenti, Francesca Benedetti, Alessandro Buriani, Stefano Fortinguerra, Giada Caudullo, Sergio Davinelli, Davide Zella, Giovanni Scapagnini
      First page: 912
      Abstract: Aging results from the progressive dysregulation of several molecular pathways and mTOR and AMPK signaling have been suggested to play a role in the complex changes in key biological networks involved in cellular senescence. Moreover, multiple factors, including poor nutritional balance, drive immunosenescence progression, one of the meaningful aspects of aging. Unsurprisingly, nutraceutical and pharmacological interventions could help maintain an optimal biological response by providing essential bioactive micronutrients required for the development, maintenance, and the expression of the immune response at all stages of life. In this regard, many studies have provided evidence of potential antiaging properties of resveratrol, as well as rapamycin and metformin. Indeed, in vitro and in vivo models have demonstrated for these molecules a number of positive effects associated with healthy aging. The current review focuses on the mechanisms of action of these three important compounds and their suggested use for the clinical treatment of immunosenescence and aging.
      Citation: Pharmaceuticals
      PubDate: 2022-07-23
      DOI: 10.3390/ph15080912
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 913: Discovery of Putative Dual Inhibitor
           of Tubulin and EGFR by Phenotypic Approach on LASSBio-1586 Homologs

    • Authors: Gisele Barbosa, Luis Gabriel Valdivieso Gelves, Caroline Marques Xavier Costa, Lucas Silva Franco, João Alberto Lins de Lima, Cristiane Aparecida-Silva, John Douglas Teixeira, Claudia dos Santos Mermelstein, Eliezer J. Barreiro, Lidia Moreira Lima
      First page: 913
      Abstract: Combretastatin A-4 (CA-4, 1) is an antimicrotubule agent used as a prototype for the design of several synthetic analogues with anti-tubulin activity, such as LASSBio-1586 (2). A series of branched and unbranched homologs of the lead-compound 2, and vinyl, ethinyl and benzyl analogues, were designed and synthesized. A comparison between the cytotoxic effect of these homologs and 2 on different human tumor cell lines was performed from a cell viability study using MTT with 48 h and 72 h incubations. In general, the compounds were less potent than CA-4, showing CC50 values ranging from 0.030 μM to 7.53 μM (MTT at 72 h) and 0.096 μM to 8.768 μM (MTT at 48 h). The antimitotic effect of the target compounds was demonstrated by cell cycle analysis through flow cytometry, and the cellular mechanism of cytotoxicity was determined by immunofluorescence. While the benzyl homolog 10 (LASSBio-2070) was shown to be a microtubule stabilizer, the lead-compound 2 (LASSBio-1586) and the methylated homolog 3 (LASSBio-1735) had microtubule destabilizing behavior. Molecular docking studies were performed on tubulin protein to investigate their binding mode on colchicine and taxane domain. Surprisingly, the benzyl homolog 10 was able to modulate EGFR phosphorylate activity in a phenotypic model. These data suggest LASSBio-2070 (10) as a putative dual inhibitor of tubulin and EGFR. Its binding mode with EGFR was determined by molecular docking and may be useful in lead-optimization initiatives.
      Citation: Pharmaceuticals
      PubDate: 2022-07-23
      DOI: 10.3390/ph15080913
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 914: Leukotriene Receptor Antagonist,
           Montelukast Ameliorates L-NAME-Induced Pre-eclampsia in Rats through
           Suppressing the IL-6/Jak2/STAT3 Signaling Pathway

    • Authors: Walaa Yehia Abdelzaher, Gomaa Mostafa-Hedeab, Haitham Ahmed Bahaa, Ahmad Mahran, Michael Atef Fawzy, Sara Mohamed Naguib Abdel Hafez, Nermeen N. Welson, Remon Roshdy Rofaeil
      First page: 914
      Abstract: Aims: To investigate the potential protective role of montelukast (Mont) in the pre-eclampsia rat model induced by L-NG-Nitro arginine methyl ester (L-NAME). Methods and materials: Thirty-two pregnant female albino Wistar rats were assigned to four groups: the control group: pregnant rats received vehicles; the Mont group: pregnant rats received Mont (10 mg/kg/day, p.o.) from the 6th to the 18th day of gestation; the L-NAME group: pregnant rats received L-NAME (50 mg/kg/day, i.p.) from the 9th to the 18th day of gestation; the Mont/L-NAME group: pregnant rats received Mont (10 mg/kg/day, p.o.) from the 6th to the 18th day of gestation and L-NAME (50 mg/kg/day, i.p.) from the 9th to the 18th day of gestation. Placental, hepatic, and renal malondialdehyde (MDA), total nitrites (NOx), interleukin 6 (IL-6), and tumor necrosis factor (TNF)-α were determined. Serum alanine transaminase (ALT), aspartate transaminase (AST), creatinine, urea, 24-h urinary protein, and the placental growth factor (PGF) were measured. Histopathological examinations of the placental, hepatic, and renal tissues were also performed. In addition, placental, hepatic, and renal Janus kinase 2 (Jak2) and signal transducer and activator of transcription 3 (STAT3) immunoblotting were performed. Key findings: Mont improves oxidative stress, IL-6, TNF-α, ALT, AST, creatinine, urea, 24-h urinary protein, PGF, Jak2, and STAT3 which were all affected by L-NAME. Moreover, the histopathological assessment indicated that Mont restored the normal architecture that was markedly disturbed by L-NAME. Significance: Mont exerted the biochemical and histopathological amelioration of L-NAME-caused pre-eclampsia through its anti-inflammatory, anti-oxidant function and suppression of the IL-6/Jak2/STAT3 signaling pathway.
      Citation: Pharmaceuticals
      PubDate: 2022-07-24
      DOI: 10.3390/ph15080914
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 915: Effect of Administration of
           Azithromycin and/or Probiotic Bacteria on Bones of Estrogen-Deficient Rats

    • Authors: Urszula Cegieła, Piotr Londzin, Aleksandra Janas, Maria Pytlik, Joanna Folwarczna
      First page: 915
      Abstract: The gut microbiota plays an important role in maintaining homeostasis, including that of the skeletal system. Antibiotics may affect the skeletal system directly or indirectly by influencing the microbiota. Probiotic bacteria have been reported to favorably affect bones in conditions of estrogen deficiency. The aim of this study was to investigate the effects of azithromycin (AZM) administered alone or with probiotic bacteria (Lactobacillus rhamnosus; LR) on bones in estrogen-deficient rats. The experiments were carried out on mature rats divided into five groups: non-ovariectomized (NOVX) control rats, ovariectomized (OVX) control rats, and OVX rats treated with: LR, AZM, or AZM with LR. The drugs were administered for 4 weeks. Serum biochemical parameters, bone mineralization, histomorphometric parameters, and mechanical properties were examined. Estrogen deficiency increased bone turnover and worsened cancellous bone microarchitecture and mechanical properties. The administration of LR or AZM slightly favorably affected some skeletal parameters of estrogen-deficient rats. The administration of AZM with LR did not lead to the addition of the effects observed for the separate treatments, indicating that the effects could be microbiota-mediated.
      Citation: Pharmaceuticals
      PubDate: 2022-07-24
      DOI: 10.3390/ph15080915
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 916: Etodolac Fortified Sodium
           Deoxycholate Stabilized Zein Nanoplatforms for Augmented Repositioning
           Profile in Human Hepatocellular Carcinoma: Assessment of Bioaccessibility,
           Anti-Proliferation, Pro-Apoptosis and Oxidant Potentials in HepG2 Cells

    • Authors: Ahmed K. Kammoun, Maha A. Hegazy, Alaa Khedr, Zuhier Ahmed Awan, Maan T. Khayat, Majid Mohammad Al-Sawahli
      First page: 916
      Abstract: This work aimed to enhance the purposing profile of Etodolac (ETD) in Human Hepatocellular Carcinoma (HCC) HepG2 cells using sodium deoxycholate stabilized zein nanospheres (ETD-SDZN NSs). ETD-SDZN NSs were formulated using the nan-precipitation method and were characterized, in particular, in terms of mean particle size, zeta potential, encapsulation efficiency, colloidal stability and bioaccessibility. Estimations of cytotoxicity, cellular uptake, cell cycle progression, Annexin-V staining, mRNA expression of apoptotic genes and oxidative stress evaluations were conducted. The ETD-SDZN NSs selected formula obtained an average particle size of 113.6 ± 7.4 nm, a zeta potential value of 32.7 ± 2.3 mV, an encapsulation efficiency of 93.3 ± 5.2%, enhanced bioaccessibility and significantly reduced IC50 against HepG2 cells, by approximately 13 times. There was also enhanced cellular uptake, accumulation in G2-M phase and elevated percentage cells in pre-G1 phase, significant elevated mRNA expression of P53, significant reduced expression of Cyclin-dependent kinase 1 (CDK1) and Cyclooxygenase-2 (COX-2) with enhanced oxidative stress by reducing glutathione reductase (GR) level, ameliorated reactive oxygen species (ROS) generation and lipid peroxidation outputs. ETD-SDZN NSs obtained a supreme cell death-inducing profile toward HepG2 cells compared to free ETD. The method of formulation was successful in acquiring the promising profile of ETD in HCC as a therapeutic molecule due to ameliorated cellular uptake, proapoptotic and oxidant potentials.
      Citation: Pharmaceuticals
      PubDate: 2022-07-24
      DOI: 10.3390/ph15080916
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 917: Antibladder Cancer Effects of
           Excavatolide C by Inducing Oxidative Stress, Apoptosis, and DNA Damage In

    • Authors: Che-Wei Yang, Tsu-Ming Chien, Chia-Hung Yen, Wen-Jeng Wu, Jyh-Horng Sheu, Hsueh-Wei Chang
      First page: 917
      Abstract: Excavatolide C (EXCC) is a bioactive compound derived from the gorgonian octocoral Briareum excavatum, and its anticancer effects are rarely addressed, particularly for bladder cancer. This investigation aimed to explore the potential impacts of EXCC on inhibiting the proliferation of three kinds of bladder cancer cells (5637, BFTC905, and T24). EXCC inhibits bladder cancer cell proliferation based on 48 h ATP assay. This antiproliferation function is validated to be oxidative stress dependent. Cellular and mitochondrial oxidative stresses were upregulated by EXCC, accompanied by depleting glutathione and mitochondrial membrane potential. These antiproliferation and oxidative stress events were suppressed by N-acetylcysteine (NAC), indicating that EXCC has an oxidative stress-regulating function for antiproliferation of bladder cancer cells. Oxidative stress-related responses such as apoptosis, caspase activation, and DNA damage were upregulated by EXCC and reverted by NAC. Taken together, the antiproliferation function of EXCC provides a potential treatment against bladder cancer cells via oxidative stress modulation.
      Citation: Pharmaceuticals
      PubDate: 2022-07-24
      DOI: 10.3390/ph15080917
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 918: Activation of SIRT-1 Pathway by
           Nanoceria Sheds Light on Its Ameliorative Effect on Doxorubicin-Induced
           Cognitive Impairment (Chemobrain): Restraining Its Neuroinflammation,
           Synaptic Dysplasticity and Apoptosis

    • Authors: Medhat Taha, Sara T. Elazab, Alaa. M. Badawy, Abdullah A. Saati, Naeem F. Qusty, Abdullah G. Al-Kushi, Anas Sarhan, Amira Osman, Amira E. Farage
      First page: 918
      Abstract: Chemo fog is one of the most serious health concerns encountered by cancer survivors receiving doxorubicin (DOX)-based chemotherapy. Oxidative stress, neuroinflammation, apoptosis and impairment of synaptic plasticity are regarded as the key factors implicated in DOX-induced cognitive impairment. This research aimed to assess the possible neuroprotective effect of cerium oxide nanoparticles (CeNPs) against DOX-induced neurotoxicity. Forty-eight rats were divided into four groups (12 rats/group): control group, CeNPs group (received oral CeNPs solution (35 mg/kg) daily for 4 weeks), and DOX group (were administered DOX intraperitoneally (2 mg/kg, once/week for 4 weeks)) and DOX+ CeNPs group. The findings revealed that CeNPs mitigated behavioral alterations in DOX-induced cognitive deficit. Additionally, CeNPs alleviated the histopathological abnormalities in hippocampus and ameliorated DOX-induced neuroinflammation by downregulating the expression of NF-κB, TNF-α, IL-1β and IL6. In addition, CeNPs antagonized the apoptosis through reducing the protein expression of cytochrome c and caspase 3. In addition, it stimulated the antioxidant defense, as indicated by upregulating the expression of the Nrf2, HO-1 and PGC-1α genes. CeNPs improved synaptic plasticity via acting on the BDNF. These actions were related through the modification of SIRT-1 expression. Based on the aforementioned results, CeNPs antagonized the doxorubicin-induced neurodegeneration by its antioxidant, anti-inflammatory and antiapoptotic effects, alongside its SIRT-1 mediated mechanisms.
      Citation: Pharmaceuticals
      PubDate: 2022-07-24
      DOI: 10.3390/ph15080918
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 919: Statin Use in Cancer Patients with
           Acute Myocardial Infarction and Its Impact on Long-Term Mortality

    • Authors: Konrad Stepien, Karol Nowak, Natalia Kachnic, Grzegorz Horosin, Piotr Walczak, Aleksandra Karcinska, Tomasz Schwarz, Mariusz Wojtas, Magdalena Zalewska, Maksymilian Pastuszak, Bogdan Wegrzyn, Jadwiga Nessler, Jarosław Zalewski
      First page: 919
      Abstract: Statin use and its impact on long-term clinical outcomes in active cancer patients following acute myocardial infarction (MI) remains insufficiently elucidated. Of the 1011 consecutive acute MI patients treated invasively between 2012 and 2017, cancer was identified in 134 (13.3%) subjects. All patients were observed within a median follow-up of 69.2 (37.8–79.9) months. On discharge, statins were prescribed less frequently in MI patients with cancer as compared to the non-cancer MI population (79.9% vs. 91.4%, p < 0.001). The most common statin in both groups was atorvastatin. The long-term mortality was higher in MI patients not treated vs. those treated with statins, both in non-cancer (29.5%/year vs. 6.7%/year, p < 0.001) and cancer groups (53.9%/year vs. 24.9%/year, p < 0.05), respectively. Patient’s age (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.03–1.05, p < 0.001, per year), an active cancer (HR 2.42, 95% CI 1.89–3.11, p < 0.001), hemoglobin level (HR 1.14, 95% CI 1.09–1.20, p < 0.001, per 1 g/dL decrease), and no statin on discharge (HR 2.13, 95% CI 1.61–2.78, p < 0.001) independently increased long-term mortality. In MI patients, simultaneous diagnosis of an active cancer was associated with less frequently prescribed statins on discharge. Irrespective of cancer diagnosis, no statin use was found as an independent predictor of increased long-term mortality.
      Citation: Pharmaceuticals
      PubDate: 2022-07-25
      DOI: 10.3390/ph15080919
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 920: Matrix Metalloproteinase 2 as a
           Pharmacological Target in Heart Failure

    • Authors: Pricila Rodrigues Gonçalves, Lisandra Duarte Nascimento, Raquel Fernanda Gerlach, Keuri Eleutério Rodrigues, Alejandro Ferraz Prado
      First page: 920
      Abstract: Heart failure (HF) is an acute or chronic clinical syndrome that results in a decrease in cardiac output and an increase in intracardiac pressure at rest or upon exertion. The pathophysiology of HF is heterogeneous and results from an initial harmful event in the heart that promotes neurohormonal changes such as autonomic dysfunction and activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, and inflammation. Cardiac remodeling occurs, which is associated with degradation and disorganized synthesis of extracellular matrix (ECM) components that are controlled by ECM metalloproteinases (MMPs). MMP-2 is part of this group of proteases, which are classified as gelatinases and are constituents of the heart. MMP-2 is considered a biomarker of patients with HF with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). The role of MMP-2 in the development of cardiac injury and dysfunction has clearly been demonstrated in animal models of cardiac ischemia, transgenic models that overexpress MMP-2, and knockout models for this protease. New research to minimize cardiac structural and functional alterations using non-selective and selective inhibitors for MMP-2 demonstrates that this protease could be used as a possible pharmacological target in the treatment of HF.
      Citation: Pharmaceuticals
      PubDate: 2022-07-25
      DOI: 10.3390/ph15080920
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 921: Copper (I)-Chloroquine Complexes:
           Interactions with DNA and Ferriprotoporphyrin, Inhibition of
           β-Hematin Formation and Relation to Antimalarial Activity

    • Authors: Wilmer Villarreal, William Castro, Sorenlis González, Marylin Madamet, Rémy Amalvict, Bruno Pradines, Maribel Navarro
      First page: 921
      Abstract: A new Cu(I)-chloroquine (CQ) complex [Cu(CQ)(PPh3)2]NO3 (1) was synthesized and characterized, and its mechanism of action studied concomitant with the previously reported complex [Cu(CQ)2]Cl (2). These copper (I) coordination compounds can be considered as potential antimalarial agents because they show better inhibition of the CQ-resistant strain in in vitro studies than CQ alone. In comparison with other metal-CQ complexes, only the gold complex was similar to (1), i.e., more active than CQ against both CQ-susceptible (3D7) and CQ-resistant strains (W2). These two copper (I)-compounds also demonstrated higher antiplasmodial activity against W2 than other copper complexes reported to date. This suggests that the incorporation of the copper metal center enhanced the biological activity of CQ. To better understand their significant growth inhibition of the Plasmodium falciparum parasite, the interaction with two essential molecular targets for the survival and proliferation of the malarial parasite were studied. These were the ferriprotoporphyrin group and the DNA, both important targets for current antimalarial drugs at the asexual erythrocytic stages. Both compounds (1,2) exhibited significant interactions with these targets. In particular, interactions with the DNA were dominated by the intercalator properties of the CQ ligand but may have also been affected by the presence of copper. Overall, these compounds were better parasitic inhibitors than chloroquine diphosphate (CQDP) alone or other previously reported metal-CQ complexes such as platinum, ruthenium and gold.
      Citation: Pharmaceuticals
      PubDate: 2022-07-25
      DOI: 10.3390/ph15080921
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 922: Discovery of Novel Dual Adenosine A2A
           and A1 Receptor Antagonists with 1H-Pyrazolo[3,4-d]pyrimidin-6-amine Core
           Scaffold as Anti-Parkinson’s Disease Agents

    • Authors: Juyoung Jung, Yoonsuk Lee, An-Na Moon, Jihyae Ann, Jin Ju Jeong, Nayeon Do, Jeewoo Lee
      First page: 922
      Abstract: New compounds with 1H-pyrazolo [3,4-d]pyrimidin-6-amine core scaffolds were synthesized and characterized in vitro to determine their affinity for human A2A and A1 receptors. Among the tested compounds, a few compounds displayed nanomolar binding affinities for both receptors. One particular compound, 11o, showed high binding activities (hA2A Ki = 13.3 nM; hA1 Ki = 55 nM) and full antagonism (hA2A IC50 = 136 nM; hA1 IC50 = 98.8 nM) toward both receptors. Further tests showed that 11o has low hepatic clearance and good pharmacokinetic properties in mice, along with high bioavailability and a high brain plasma ratio. In addition, 11o was associated with very low cardiovascular risk and mutagenic potential, and was well-tolerated in rats and dogs. When tested in an MPTP-induced mouse model of Parkinson’s disease, 11o tended to improve behavior. Moreover, 11o dose-dependently reversed haloperidol-induced catalepsy in female rats, with graded ED50 of between 3 and 10 mg/kg. Taken together, these results suggest that this potent dual A2A/A1 receptor antagonist, 11o, is a good candidate for the treatment of Parkinson’s disease with an excellent metabolic and safety profile.
      Citation: Pharmaceuticals
      PubDate: 2022-07-25
      DOI: 10.3390/ph15080922
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 923: Combined Cytotoxic Effect of
           Inhibitors of Proteostasis on Human Colon Cancer Cells

    • Authors: Alina D. Nikotina, Snezhana A. Vladimirova, Nadezhda E. Kokoreva, Elena Y. Komarova, Nikolay D. Aksenov, Sergey Efremov, Elizaveta Leonova, Rostislav Pavlov, Viktor G. Kartsev, Zhichao Zhang, Boris A. Margulis, Irina V. Guzhova
      First page: 923
      Abstract: Despite significant progress in the diagnosis and treatment of colorectal cancer, drug resistance continues to be a major limitation of therapy. In this regard, studies aimed at creating combination therapy are gaining popularity. One of the most promising adjuvants are inhibitors of the proteostasis system, chaperone machinery, and autophagy. The main HSP regulator, HSF1, is overactivated in cancer cells and autophagy sustains the survival of malignant cells. In this work, we focused on the selection of combination therapy for the treatment of rectal cancer cells obtained from patients after tumor biopsy without prior treatment. We characterized the migration, proliferation, and chaperone status in the resulting lines and also found them to be resistant to a number of drugs widely used in the clinic. However, these cells were sensitive to the autophagy inhibitor, chloroquine. For combination therapy, we used an HSF1 activity inhibitor discovered earlier in our laboratory, the cardenolide CL-43, which has already been proven as an auxiliary component of combined therapy in established cell lines. CL-43 effectively suppressed HSF1 activity and Hsp70 expression in all investigated cells. We tested the autophagy inhibitor, chloroquine, in combination with CL-43. Our results indicate that the use of an inhibitor of HSF1 activity in combination with an autophagy inhibitor results in effective cancer cell death, therefore, this therapeutic approach may be a promising treatment regimen for certain patients.
      Citation: Pharmaceuticals
      PubDate: 2022-07-25
      DOI: 10.3390/ph15080923
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 924: Clinical Efficacy and Safety of
           Antimicrobial Photodynamic Therapy in Residual Periodontal Pockets during
           the Maintenance Phase

    • Authors: Yamashita, Mae, Oohira, Ozaki, Ohba, Asahina, Yoshimura
      First page: 924
      Abstract: Antimicrobial photodynamic therapy (a-PDT) in combination with scaling root planing (SRP) is more effective at improving periodontal status than SRP alone. However, the effectiveness of a-PDT in combination with irrigation for patients undergoing periodontal maintenance has not been clarified. This study evaluated the efficacy and safety of a-PDT in the maintenance phase. Patients who had multiple sites with bleeding on probing (BOP) and periodontal probing depth (PPD) of 4–6 mm in the maintenance phase were treated with a split-mouth design. These sites were randomly assigned to one of two groups: the a-PDT group and the irrigation group. In the a-PDT group, the periodontal pockets were treated with light-sensitive toluidine blue and a light irradiator. In the irrigation group, the periodontal pockets were simply irrigated using an ultrasonic scaler. After 7 days, the safety and efficacy of a-PDT were assessed. The mean PPD of the a-PDT group had reduced from 4.50 mm to 4.13 mm, whereas negligible change was observed in the irrigation group. BOP significantly improved from 100% to 33% in the PDT group, whereas it hardly changed in the irrigation group. No adverse events were observed in any patients. a-PDT may be useful as a noninvasive treatment in the maintenance phase, especially in patients with relatively deep periodontal pocket.
      Citation: Pharmaceuticals
      PubDate: 2022-07-25
      DOI: 10.3390/ph15080924
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 925: Citicoline Modifies the Expression of
           Specific miRNAs Related to Cardioprotection in Patients with ST-Segment
           Elevation Myocardial Infarction Subjected to Coronary Angioplasty

    • Authors: Alejandro Silva-Palacios, Miguel Arroyo-Campuzano, Mirthala Flores-García, Mariana Patlán, Adrián Hernández-Díazcouder, Diego Alcántara, Ixchel Ramírez-Camacho, Dana Arana-Hidalgo, Elizabeth Soria-Castro, Fausto Sánchez, Héctor González-Pacheco, Cecilia Zazueta
      First page: 925
      Abstract: Extracellular vesicles are recognized as signaling mediators between cells both in physiological and pathological communication. In this work, we explored the potential effect of citicoline to modify relevant proteins or miRNAs for cardioprotection in the smallest population of such microvesicles; i.e., in exosomes from patients diagnosed with ST-segment elevation myocardial infarction (STEMI) undergoing coronary angioplasty. The plasma-exosome-enriched fraction from these patients was characterized. Their cellular origin was assessed by flow cytometry and Western blot, whereas miRNA expression was evaluated by real-time polymerase chain reaction (qRT-PCR). The content of caveolin-1, caveolin-3, and hnRNPA2B1, which play a relevant role in selective transport of miRNAs into microvesicles, along with the effect on cell viability of the exosomes obtained from citicoline-treated and untreated groups were also analyzed. Our results showed that hypoxic stress increases exosome release into the circulation. Moreover, we found that CD146+ increased in exosomes from citicoline-treated patients, while CD142+ decreased in these patients compared to the placebo group. No changes were detected in the protein levels of caveolin-1, caveolin-3, and hnRNPA2B1. Citicoline administration modified the expression of miR233-3p, miR92, and miR21-5p in exosomes. Cell viability decreased in the presence of exosomes from infarcted patients, while incubation of H9c2 cells with exosomes from patients reperfused with citicoline did not affect cell viability. In conclusion, citicoline administration modifies the expression of specific miRNAs related to cardioprotection in exosomes.
      Citation: Pharmaceuticals
      PubDate: 2022-07-27
      DOI: 10.3390/ph15080925
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 926: Three-Dimensional In Vitro Cell
           Culture Models for Efficient Drug Discovery: Progress So Far and Future

    • Authors: Shaimaa M. Badr-Eldin, Hibah M. Aldawsari, Sabna Kotta, Pran Kishore Deb, Katharigatta N. Venugopala
      First page: 926
      Abstract: Despite tremendous advancements in technologies and resources, drug discovery still remains a tedious and expensive process. Though most cells are cultured using 2D monolayer cultures, due to lack of specificity, biochemical incompatibility, and cell-to-cell/matrix communications, they often lag behind in the race of modern drug discovery. There exists compelling evidence that 3D cell culture models are quite promising and advantageous in mimicking in vivo conditions. It is anticipated that these 3D cell culture methods will bridge the translation of data from 2D cell culture to animal models. Although 3D technologies have been adopted widely these days, they still have certain challenges associated with them, such as the maintenance of a micro-tissue environment similar to in vivo models and a lack of reproducibility. However, newer 3D cell culture models are able to bypass these issues to a maximum extent. This review summarizes the basic principles of 3D cell culture approaches and emphasizes different 3D techniques such as hydrogels, spheroids, microfluidic devices, organoids, and 3D bioprinting methods. Besides the progress made so far in 3D cell culture systems, the article emphasizes the various challenges associated with these models and their potential role in drug repositioning, including perspectives from the COVID-19 pandemic.
      Citation: Pharmaceuticals
      PubDate: 2022-07-27
      DOI: 10.3390/ph15080926
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 927: Design, Synthesis, and Development of
           Pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective
           PI3Kδ Inhibitors: Part II—Benzimidazole Derivatives

    • Authors: Mariola Stypik, Stanisław Michałek, Nina Orłowska, Marcin Zagozda, Maciej Dziachan, Martyna Banach, Paweł Turowski, Paweł Gunerka, Daria Zdżalik-Bielecka, Aleksandra Stańczak, Urszula Kędzierska, Krzysztof Mulewski, Damian Smuga, Wioleta Maruszak, Lidia Gurba-Bryśkiewicz, Arkadiusz Leniak, Wojciech Pietruś, Zbigniew Ochal, Mateusz Mach, Beata Zygmunt, Jerzy Pieczykolan, Krzysztof Dubiel, Maciej Wieczorek
      First page: 927
      Abstract: Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: α, β, γ, δ) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis. In this work, we synthesized a library of benzimidazole derivatives of pyrazolo[1,5-a]pyrimidine representing a collection of new, potent, active, and selective inhibitors of PI3Kδ, displaying IC50 values ranging from 1.892 to 0.018 μM. Among all compounds obtained, CPL302415 (6) showed the highest activity (IC50 value of 18 nM for PI3Kδ), good selectivity (for PI3Kδ relative to other PI3K isoforms: PI3Kα/δ = 79; PI3Kβ/δ = 1415; PI3Kγ/δ = 939), and promising physicochemical properties. As a lead compound synthesized on a relatively large scale, this structure is considered a potential future candidate for clinical trials in SLE treatment.
      Citation: Pharmaceuticals
      PubDate: 2022-07-27
      DOI: 10.3390/ph15080927
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 928: Novel Antimicrobial Peptide
           “Octoprohibitin” against Multidrug Resistant Acinetobacter

    • Authors: E. H. T. Thulshan Jayathilaka, Dinusha C. Rajapaksha, Chamilani Nikapitiya, Joeun Lee, Mahanama De Zoysa, Ilson Whang
      First page: 928
      Abstract: Octoprohibitin is a synthetic antimicrobial peptide (AMP), derived from the prohibitin-2 gene of Octopus minor. It showed substantial activity against multidrug resistant (MDR) Acinetobacter baumannii with a minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of 200 and 400 µg/mL, respectively. Time-kill kinetics and bacterial viability assays confirmed the concentration-dependent antibacterial activity of octoprohibitin against A. baumannii. The morphology and ultrastructure of A. baumannii were altered by treatment with octoprohibitin at the MIC and MBC levels. Furthermore, propidium iodide-fluorescein diacetate (PI-FDA) staining and 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA) staining of octoprohibitin-treated A. baumannii revealed membrane permeability alterations and reactive oxygen species (ROS) generation, respectively. Agarose gel retardation results confirmed the DNA-binding ability of octoprohibitin to the genomic DNA of A. baumannii. Furthermore, octoprohibitin showed concentration-dependent inhibition of biofilm formation and eradication. The minimum biofilm inhibition concentration (MBIC) and minimum biofilm eradication concentration (MBEC) of octoprohibitin were 1000 and 1460 µg/mL, respectively. Octoprohibitin produced no significant cytotoxicity up to 800 µg/mL, and no hemolysis was observed up to 400 µg/mL. Furthermore, in vivo analysis in an A. baumannii-infected zebrafish model confirmed the effective bactericidal activity of octoprohibitin with higher cumulative survival percent (46.6%) and fewer pathological signs. Histological analysis showed reduced alterations in the gut, kidney, and gill tissues in the octoprohibitin-treated group compared with those in the phosphate-buffered saline (PBS)-treated group. In conclusion, our results suggest that octoprohibitin is a potential antibacterial and antibiofilm agent against MDR A. baumannii.
      Citation: Pharmaceuticals
      PubDate: 2022-07-27
      DOI: 10.3390/ph15080928
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 929: Experimental Studies Indicate That
           ST-2223, the Antagonist of Histamine H3 and Dopamine D2/D3 Receptors,
           Restores Social Deficits and Neurotransmission Dysregulation in Mouse
           Model of Autism

    • Authors: Nermin Eissa, Karthikkumar Venkatachalam, Petrilla Jayaprakash, Priya Yuvaraju, Markus Falkenstein, Holger Stark, Bassem Sadek
      First page: 929
      Abstract: Altered regulation of neurotransmitters may lead to many pathophysiological changes in brain disorders including autism spectrum disorder (ASD). Given the fact that there are no FDA-approved effective treatments for the social deficits in ASD, the present study determined the effects of chronic systemic treatment of the novel multiple-active H3R/D2R/D3R receptor antagonist ST-2223 on ASD-related social deficits in a male Black and Tan Brachyury (BTBR) mice. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly and dose-dependently mitigated social deficits and disturbed anxiety levels of BTBR mice (p < 0.05) in comparison to the effects of aripiprazole (1 mg/kg, i.p.). Moreover, levels of monoaminergic neurotransmitters quantified by LC-MS/MS in four brain regions including the prefrontal cortex, cerebellum, striatum, and hippocampus unveiled significant elevation of histamine (HA) in the cerebellum and striatum; dopamine (DA) in the prefrontal cortex and striatum; as well as acetylcholine (ACh) in the prefrontal cortex, striatum, and hippocampus following ST-2223 (5 mg/kg) administration (all p < 0.05). These in vivo findings demonstrate the mitigating effects of a multiple-active H3R/D2R/D3R antagonist on social deficits of assessed BTBR mice, signifying its pharmacological potential to rescue core ASD-related behaviors and altered monoaminergic neurotransmitters. Further studies on neurochemical alterations in ASD are crucial to elucidate the early neurodevelopmental variations behind the core symptoms and heterogeneity of ASD, leading to new approaches for the future therapeutic management of ASD.
      Citation: Pharmaceuticals
      PubDate: 2022-07-27
      DOI: 10.3390/ph15080929
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 930: Pumpkin Seed Oil-Loaded Niosomes for
           Topical Application: 5α-Reductase Inhibitory, Anti-Inflammatory, and
           In Vivo Anti-Hair Loss Effects

    • Authors: Veerawat Teeranachaideekul, Warisara Parichatikanond, Varaporn Buraphacheep Junyaprasert, Boontida Morakul
      First page: 930
      Abstract: Pumpkin seed oil (PSO)-loaded niosomes were prepared from Tween 20 and cholesterol by ethanol injection. Confocal microscopy showed better skin permeation and hair follicle accumulation of the niosomes compared to the PSO solution. The PSO-loaded niosomes inhibited 5α-reductase activity in DU-145 cells and hindered IL-6 activity in RAW 264.7 cells. These effects indicated the great potential of PSO-loaded niosomes to reduce hair loss. The hair scalp serum with PSO-loaded niosomes did not show irritation to reconstructed human skin. This formulation presented a significant decrease in the percentage of fallen hairs by 44.42% in the in vivo 60-second hair count experiment and a significant increase in the anagen to telogen (A/T) ratio (1.4-fold) in the TrichoScan® evaluation after 8 weeks of treatment compared to the initial conditions, indicating the promising efficacy of PSO-loaded niosomes as a natural alternative for anti-hair loss therapy.
      Citation: Pharmaceuticals
      PubDate: 2022-07-27
      DOI: 10.3390/ph15080930
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 931: The Occurrence of Hyperactivated
           Platelets and Fibrinaloid Microclots in Myalgic Encephalomyelitis/Chronic
           Fatigue Syndrome (ME/CFS)

    • Authors: Nunes, Kruger, Proal, Kell, Pretorius
      First page: 931
      Abstract: We have previously demonstrated that platelet-poor plasma (PPP) obtained from patients with Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is characterized by a hypercoagulable state and contains hyperactivated platelets and considerable numbers of already-formed amyloid fibrin(ogen) or fibrinaloid microclots. Due to the substantial overlap in symptoms and etiology between Long COVID/PASC and ME/CFS, we investigated whether coagulopathies reflected in Long COVID/PASC—hypercoagulability, platelet hyperactivation, and fibrinaloid microclot formation—were present in individuals with ME/CFS and gender- and age-matched healthy controls. ME/CFS samples showed significant hypercoagulability as judged by thromboelastography of both whole blood and platelet-poor plasma. The area of plasma images containing fibrinaloid microclots was commonly more than 10-fold greater in untreated PPP from individuals with ME/CFS than in that of healthy controls. A similar difference was found when the plasma samples were treated with thrombin. Using fluorescently labelled PAC-1, which recognizes glycoprotein IIb/IIIa, and CD62P, which binds P-selectin, we observed hyperactivation of platelets in ME/CFS hematocrit samples. Using a quantitative scoring system, the ME/CFS platelets were found to have a mean spreading score of 2.72 ± 1.24 vs. 1.00 (activation with pseudopodia formation) for healthy controls. We conclude that ME/CFS is accompanied by substantial and measurable changes in coagulability, platelet hyperactivation, and fibrinaloid microclot formation. However, the fibrinaloid microclot load was not as great as was previously noted in Long COVID/PASC. Fibrinaloid microclots, in particular, may contribute to many ME/CFS symptoms, such as fatigue, seen in patients with ME/CFS, via the (temporary) blockage of microcapillaries and hence ischemia. Furthermore, fibrinaloid microclots might damage the endothelium. The discovery of these biomarkers represents an important development in ME/CFS research. It also points to possible uses for treatment strategies using known drugs and/or nutraceuticals that target systemic vascular pathology and endothelial inflammation.
      Citation: Pharmaceuticals
      PubDate: 2022-07-27
      DOI: 10.3390/ph15080931
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 932: Therapeutic Potentials of
           Secoiridoids from the Fruits of Ligustrum lucidum Aiton against
           Inflammation-Related Skin Diseases

    • Authors: Sang Won Yeon, Su Ryeon Choi, Qing Liu, Yang Hee Jo, Da Hee Choi, Mi Ran Kim, Se Hwan Ryu, Solip Lee, Bang Yeon Hwang, Hyung Seo Hwang, Mi Kyeong Lee
      First page: 932
      Abstract: Ligustrum lucidum Aiton is a flowering plant of the Oleaceae family, and its fruits have been traditionally used for skin nourishment and the treatment of skin diseases. However, the anti-inflammatory constituents for skin disease are not well-characterized. Phytochemical investigation of L. lucidum fruits resulted in the isolation of a new secoiridoid, secoligulene (1), together with (E)-3-(1-oxobut-2-en-2-yl)pentanedioic acid (2) and trans-(E)-3-(1-oxobut-2-en-2-yl)glutaric acid (3). Secoligulene (1) displayed the potent inhibitory effect on NO production with an IC50 value of 12.0 μg/mL. Secoligulene (1) also downregulated mRNA transcriptional levels of pro-inflammatory cytokines such as IL-1 α, IL-1β, IL-6 and COX-2 in LPS-stimulated RAW264.7 cells. Further investigation showed that secoligulene (1) inhibited the phosphorylation of IκB and JNK activated by LPS. In addition, secoligulene (1) downregulated the expression of chemokines such as CXCL8 and CCL20 in the TNF-α/IL-17/IFN-γ induced HaCaT psoriasis model. Taken together, these findings support the beneficial effects of L. lucidum and its constituents on inflammation-related skin diseases and can be further developed as therapeutic treatments for related diseases.
      Citation: Pharmaceuticals
      PubDate: 2022-07-27
      DOI: 10.3390/ph15080932
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 933: Targeting Acne Bacteria and Wound
           Healing In Vitro Using Plectranthus aliciae, Rosmarinic Acid, and
           Tetracycline Gold Nanoparticles

    • Authors: Isa A. Lambrechts, Velaphi C. Thipe, Kattesh V. Katti, Vusani Mandiwana, Michel Lonji Kalombo, Suprakas Sinha Ray, Rirhandzu Rikhotso, Arno Janse van Vuuren, Tenille Esmear, Namrita Lall
      First page: 933
      Abstract: Gold nanoparticles from plant extracts and their bioactive compounds to treat various maladies have become an area of interest to many researchers. Acne vulgaris is an inflammatory disease of the pilosebaceous unit caused by the opportunistic bacteria Cutibacterium acnes and Staphylococcus epidermis. These bacteria are not only associated with inflammatory acne but also with prosthetic-implant-associated infections and wounds. Studies have hypothesised that these bacteria have a mutualistic relationship and act as a multispecies system. It is believed that these bacteria form a multispecies biofilm under various conditions and that these biofilms contribute to increased antibiotic resistance compared to single-species biofilms. This study aimed to investigate the antibacterial and wound healing potential of synthesised gold nanoparticles (AuNPs) from an endemic South African plant, Plectranthus aliciae (AuNPPAE), its major compound rosmarinic acid (AuNPRA) and a widely used antibiotic, tetracycline (AuNPTET). Synthesised gold nanoparticles were successfully formed and characterised using ultraviolet–visible spectroscopy (UV–vis), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), zeta potential (ζ-potential), high-resolution transmission electron microscopy (HRTEM), and selected area electron diffraction (SAED), and they were investigated for stability under various biological conditions. Stable nanoparticles were formed with ζ-potentials of −18.07 ± 0.95 mV (AuNPPAE), −21.5 ± 2.66 mV (AuNPRA), and −39.83 ± 1.6 mV (AuNPTET). The average diameter of the AuNPs was 71.26 ± 0.44 nm, 29.88 ± 3.30 nm, and 132.6 ± 99.5 nm for AuNPPAE, AuNPRA, and AuNPTET, respectively. In vitro, biological studies confirmed that although no antibacterial activity or biofilm inhibition was observed for the nanoparticles tested on the multispecies C. acnes and S. epidermis systems, these samples had potential wound closure activity. Gold nanoparticles formed with rosmarinic acid significantly increased wound closure by 21.4% at 25% v/v (≈29.2 µg/mL) compared to the negative cell control and the rosmarinic acid compound at the highest concentration tested of 500 µg/mL. This study concluded that green synthesised gold nanoparticles of rosmarinic acid could potentially be used for treating wounds.
      Citation: Pharmaceuticals
      PubDate: 2022-07-28
      DOI: 10.3390/ph15080933
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 934: Difelikefalin in the Treatment of
           Chronic Kidney Disease-Associated Pruritus: A Systematic Review

    • Authors: Kamila Wala, Jacek C. Szepietowski
      First page: 934
      Abstract: Chronic kidney disease-associated pruritus (CKD-aP) is a chronic condition that significantly reduces the quality of life of patients with end-stage renal disease. The etiology is not fully understood, but imbalance in the activity of the opioid pathways, including downregulation of the kappa-opioid receptor, may contribute to itching sensation. Difelikefalin is a selective, peripherally acting kappa-opioid receptor (KOR) agonist. Recently, difelikefalin has been approved as a first drug for the treatment of pruritus associated with chronic kidney disease (CKD) in adult hemodialysis patients. A systematic review of currently available clinical trials was performed to assess the efficacy and safety of difelikefalin in patients with uremic pruritus. A literature review was conducted in May 2022 based on the PRISMA 2020 guidelines. The analyzed clinical trials showed that difelikefalin was effective in reducing pruritus in patients as assessed by the Worst Itching Intensity Numerical Rating Scale. Improvement in quality of life assessed on the basis of the Skindex score and the 5-D itch scale was also noticed. The most commonly reported side effects were mild and included nausea, vomiting, dizziness, and diarrhea. Due to its proven efficacy and good safety profile, difelikefalin is a promising drug for the treatment of pruritus in patients with chronic kidney disease.
      Citation: Pharmaceuticals
      PubDate: 2022-07-28
      DOI: 10.3390/ph15080934
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 935: A Quantum Chemical Deep-Dive into the
           π-π Interactions of 3-Methylindole and Its Halogenated
           Derivatives—Towards an Improved Ligand Design and Tryptophan

    • Authors: Ruben Van Lommel, Tom Bettens, Thomas M. A. Barlow, Jolien Bertouille, Steven Ballet, Frank De Proft
      First page: 935
      Abstract: Non-covalent π-π stacking interactions often play a key role in the stability of the secondary and tertiary structures of peptides and proteins, respectively, and can be a means of ensuring the binding of ligands within protein and enzyme binding sites. It is generally accepted that minor structural changes to the aromatic ring, such as substitution, can have a large influence on these interactions. Nevertheless, a thorough understanding of underpinning phenomena guiding these key interactions is still limited. This is especially true for larger aromatic structures. To expand upon this knowledge, elaborate ab initio calculations were performed to investigate the effect of halogenation on the stability of 3-methylindole stacking. 3-Methylindole served as a representation of the tryptophan side chain, and is a frequently used motif in drug design and development. Moreover, an expression is derived that is able to accurately predict the interaction stability of stacked halogenated 3-methylindole dimers as well as halogenated toluene dimers, based on monomer level calculated DFT descriptors. We aim for this expression to provide the field with a straightforward and reliable method to assess the effect of halogenation on the π-π stacking interactions between aromatic scaffolds.
      Citation: Pharmaceuticals
      PubDate: 2022-07-28
      DOI: 10.3390/ph15080935
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 936: Jak Inhibitors for Treatment of
           Autoimmune Diseases: Lessons from Systemic Sclerosis and Systemic Lupus

    • Authors: Przemysław Kotyla, Olga Gumkowska-Sroka, Bartosz Wnuk, Kacper Kotyla
      First page: 936
      Abstract: Systemic sclerosis and systemic lupus erythematosus represent two distinct autoimmune diseases belonging to the group of connective tissue disorders. Despite the great progress in the basic science, this progress has not been translated to the development of novel therapeutic approaches that can radically change the face of these diseases. The discovery of JAK kinases, which are tyrosine kinases coupled with cytokine receptors, may open a new chapter in the treatment of so far untreatable diseases. Small synthetic compounds that can block Janus kinases and interact directly with cytokine signalling may provide therapeutic potential in these diseases. In this review, we discuss the therapeutic potential of Jak kinases in light of the cytokine network that JAK kinases are able to interact with. We also provide the theoretical background for the rationale of blocking cytokines with specific JAK inhibitors.
      Citation: Pharmaceuticals
      PubDate: 2022-07-28
      DOI: 10.3390/ph15080936
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 937: Benzothiazole Derivatives Endowed
           with Antiproliferative Activity in Paraganglioma and Pancreatic Cancer
           Cells: Structure–Activity Relationship Studies and Target Prediction

    • Authors: Rosa Amoroso, Laura De Lellis, Rosalba Florio, Nazaret Moreno, Mariangela Agamennone, Barbara De Filippis, Letizia Giampietro, Cristina Maccallini, Inmaculada Fernández, Rocío Recio, Alessandro Cama, Marialuigia Fantacuzzi, Alessandra Ammazzalorso
      First page: 937
      Abstract: The antiproliferative effects played by benzothiazoles in different cancers have aroused the interest for these molecules as promising antitumor agents. In this work, a library of phenylacetamide derivatives containing the benzothiazole nucleus was synthesized and compounds were tested for their antiproliferative activity in paraganglioma and pancreatic cancer cell lines. The novel synthesized compounds induced a marked viability reduction at low micromolar concentrations both in paraganglioma and pancreatic cancer cells. Derivative 4l showed a greater antiproliferative effect and higher selectivity index against cancer cells, as compared to other compounds. Notably, combinations of derivative 4l with gemcitabine at low concentrations induced enhanced and synergistic effects on pancreatic cancer cell viability, thus supporting the relevance of compound 4l in the perspective of clinical translation. A target prediction analysis was also carried out on 4l by using multiple computational tools, identifying cannabinoid receptors and sentrin-specific proteases as putative targets contributing to the observed antiproliferative activity.
      Citation: Pharmaceuticals
      PubDate: 2022-07-28
      DOI: 10.3390/ph15080937
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 938: A Density Functional Theory and
           Information-Theoretic Approach Study of Interaction Energy and
           Polarizability for Base Pairs and Peptides

    • Authors: Dongbo Zhao, Shubin Liu, Dahua Chen
      First page: 938
      Abstract: Using density functional theory (DFT) and the information-theoretic approach (ITA) quantities to appreciate the energetics and properties of biopolymers is still an unaccomplished and ongoing task. To this end, we studied the building blocks of nucleic acid base pairs and small peptides. For base pairs, we have dissected the relative importance of energetic components by using two energy partition schemes in DFT. Our results convincingly show that the exchange-correlation effect predominantly governs the molecular stability of base pairs while the electrostatic potential plays a minor but indispensable role, and the steric effect is trivial. Furthermore, we have revealed that simple density-based ITA functions are in good relationships with molecular polarizabilities for a series of 30 hydrogen-bonded base pairs and all 20 natural α-amino acids, 400 dipeptides, and 8000 tripeptides. Based on these lines, one can easily predict the molecular polarizabilities of larger peptides, even proteins as long as the total molecular wavefunction is available, rather than solving the computationally demanding coupled-perturbed Hartree–Fock (CPHF) equation or its DFT counterpart coupled-perturbed Kohn–Sham (CPKS) equation.
      Citation: Pharmaceuticals
      PubDate: 2022-07-28
      DOI: 10.3390/ph15080938
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 939: Methods Used for Enhancing the
           Bioavailability of Oral Curcumin in Randomized Controlled Trials: A
           Meta-Research Study

    • Authors: Mimica, Bučević Popović, Banjari, Jeličić Kadić, Puljak
      First page: 939
      Abstract: It is unknown how randomized controlled trials (RCTs) approach the problem related to curcumin bioavailability. We analyzed methods and reporting regarding the bioavailability of systemic oral curcumin used in RCTs. We searched PubMed on 12 September 2020, to find articles reporting RCTs that used curcumin as an intervention. We extracted data about trial characteristics, curcumin products used, methods for improving curcumin bioavailability, and mentions of curcumin bioavailability. We included 165 RCTs. The most common category of intervention was simply described as “curcumin” or “curcuminoids” without a commercial name. There were 107 (64%) manuscripts that reported that they used methods to enhance the oral bioavailability of curcuminoids used in their intervention; 25 different methods were reported. The most common method was the addition of piperine (23%). Phospholipidated curcumin, a combination of curcumin and turmeric oils, nanomicellar curcumin, and colloidal dispersion of curcumin were the next most common methods. Fourteen trials (8.4%) compared more than one different curcumin product; nine (7.9%) trials compared the bioavailability/pharmacokinetics of curcumin products. In conclusion, a high number of diverse methods were used, and very few trials compared different curcumin products. More studies are needed to explore the comparative bioavailability and efficacy of different curcumin products.
      Citation: Pharmaceuticals
      PubDate: 2022-07-28
      DOI: 10.3390/ph15080939
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 940: Central Composite Optimization of
           Glycerosomes for the Enhanced Oral Bioavailability and Brain Delivery of
           Quetiapine Fumarate

    • Authors: Randa Mohammed Zaki, Munerah M. Alfadhel, Manal A. Alossaimi, Lara Ayman Elsawaf, Vidya Devanathadesikan Seshadri, Alanood S. Almurshedi, Rehab mohammad Yusif, Mayada Said
      First page: 940
      Abstract: This study aimed to formulate and statistically optimize glycerosomal formulations of Quetiapine fumarate (QTF) to increase its oral bioavailability and enhance its brain delivery. The study was designed using a Central composite rotatable design using Design-Expert® software. The independent variables in the study were glycerol % w/v and cholesterol % w/v, while the dependent variables were vesicle size (VS), zeta potential (ZP), and entrapment efficiency percent (EE%). The numerical optimization process resulted in an optimum formula composed of 29.645 (w/v%) glycerol, 0.8 (w/v%) cholesterol, and 5 (w/v%) lecithin. It showed a vesicle size of 290.4 nm, zeta potential of −34.58, and entrapment efficiency of 80.85%. The optimum formula was further characterized for DSC, XRD, TEM, in-vitro release, the effect of aging, and pharmacokinetic study. DSC thermogram confirmed the compatibility of the drug with the ingredients. XRD revealed the encapsulation of the drug in the glycerosomal nanovesicles. TEM image revealed spherical vesicles with no aggregates. Additionally, it showed enhanced drug release when compared to a drug suspension and also exhibited good stability for one month. Moreover, it showed higher brain Cmax, AUC0–24, and AUC0–∞ and plasma AUC0–24 and AUC0–∞ in comparison to drug suspension. It showed brain and plasma bioavailability enhancement of 153.15 and 179.85%, respectively, compared to the drug suspension. So, the optimum glycerosomal formula may be regarded as a promising carrier to enhance the oral bioavailability and brain delivery of Quetiapine fumarate.
      Citation: Pharmaceuticals
      PubDate: 2022-07-29
      DOI: 10.3390/ph15080940
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 941: Interaction between Mesenchymal Stem
           Cells and the Immune System in Rheumatoid Arthritis

    • Authors: Darina Bačenková, Marianna Trebuňová, Radoslav Morochovič, Erik Dosedla, Alena Findrik Balogová, Petra Gašparová, Jozef Živčák
      First page: 941
      Abstract: Rheumatoid arthritis (RA) is an autoimmune disease that causes damage to joints. This review focuses on the possibility of influencing the disease through immunomodulation by mesenchymal stem cells (MSCs). There is an occurrence of rheumatoid factor and RA-specific autoantibodies to citrullinated proteins in most patients. Citrulline proteins have been identified in the joints of RA patients, and are considered to be the most suitable candidates for the stimulation of anti-citrulline protein antibodies production. Fibroblast-like proliferating active synoviocytes actively promote inflammation and destruction in the RA joint, in association with pro-inflammatory cells. The inflammatory process may be suppressed by MSCs, which are a population of adherent cells with the following characteristic phenotype: CD105+, CD73+, CD90+, CD45−, CD34− and HLA DR−. Following the stimulation process, MSCs are capable of immunomodulatory action through the release of bioactive molecules, as well as direct contact with the cells of the immune system. Furthermore, MSCs show the ability to suppress natural killer cell activation and dendritic cells maturation, inhibit T cell proliferation and function, and induce T regulatory cell formation. MSCs produce factors that suppress inflammatory processes, such as PGE2, TGF-β, HLA-G5, IDO, and IL-10. These properties suggest that MSCs may affect and suppress the excessive inflammation that occurs in RA. The effect of MSCs on rheumatoid arthritis has been proven to be a suitable alternative treatment thanks to successful experiments and clinical studies.
      Citation: Pharmaceuticals
      PubDate: 2022-07-28
      DOI: 10.3390/ph15080941
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 942: Antibiotics and
           Carbohydrate-Containing Drugs Targeting Bacterial Cell Envelopes: An

    • Authors: Federico Riu, Alessandro Ruda, Roberta Ibba, Simona Sestito, Ilenia Lupinu, Sandra Piras, Göran Widmalm, Antonio Carta
      First page: 942
      Abstract: Certain bacteria constitute a threat to humans due to their ability to escape host defenses as they easily develop drug resistance. Bacteria are classified into gram-positive and gram-negative according to the composition of the cell membrane structure. Gram-negative bacteria have an additional outer membrane (OM) that is not present in their gram-positive counterpart; the latter instead hold a thicker peptidoglycan (PG) layer. This review covers the main structural and functional properties of cell wall polysaccharides (CWPs) and PG. Drugs targeting CWPs are discussed, both noncarbohydrate-related (β-lactams, fosfomycin, and lipopeptides) and carbohydrate-related (glycopeptides and lipoglycopeptides). Bacterial resistance to these drugs continues to evolve, which calls for novel antibacterial approaches to be developed. The use of carbohydrate-based vaccines as a valid strategy to prevent bacterial infections is also addressed.
      Citation: Pharmaceuticals
      PubDate: 2022-07-29
      DOI: 10.3390/ph15080942
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 943: In Vivo and In Silico Study of the
           Antinociceptive and Toxicological Effect of the Extracts of Petiveria
           alliacea L. Leaves

    • Authors: Kelly del Carmen Cruz-Salomón, Rosa Isela Cruz-Rodríguez, Josué Vidal Espinosa-Juárez, Abumalé Cruz-Salomón, Alfredo Briones-Aranda, Nancy Ruiz-Lau, Víctor Manuel Ruíz-Valdiviezo
      First page: 943
      Abstract: Petiveria alliacea L. is an herb used in traditional medicine in Mexico and its roots have been studied to treat pain. However, until now, the antinociceptive properties of the leaves have not been investigated, being the main section used empirically for the treatment of diseases. For this reason, this study aimed to evaluate the antinociceptive and toxoicological activity of various extracts (aqueous, hexanic, and methanolic) from P. alliacea L. leaves in NIH mice and to perform an in silico analysis of the phytochemical compounds. Firstly, the antinociceptive effect was analyzed using the formalin model and the different doses of each of the extracts that were administered orally to obtain the dose–response curves. In addition, acute toxicity was determined by the up and down method and serum biochemical analysis. Later, the phytochemical study of extracts was carried out by thin layer chromatography (TLC) and visible light spectroscopy, and the volatile chemical components were analyzed by gas chromatography-mass spectrometry (GC/MS). Moreover, the most abundant compounds identified in the phytochemical study were analyzed in silico to predict their biological activity (PASSonline) and toxicology (OSIRIS Property Explorer). As a result, it was known that all extracts at doses from 10 to 316 mg/kg significantly reduced the pain response in both phases of the formalin model, with values of 50–60% for the inflammatory response. The toxicological studies (DL50) exhibited that all extracts did not cause any mortality up to the 2000 mg/kg dose level. This was corroborated by the values in the normal range of the biochemical parameters in the serum. Finally, the phytochemical screening of the presence of phenolic structures (coumarins, flavonoids) and terpenes (saponins and terpenes) was verified, and the highest content was of a lipid nature, 1.65 ± 0.54 meq diosgenin/mL in the methanolic extract. A total of 54 components were identified, 11 were the most abundant, and only four (Eicosane, Methyl oleate, 4-bis(1-phenylethyl) phenol, and Ethyl linolenate) of them showed a probability towards active antinociceptive activity in silico greater than 0.5. These results showed that the P. alliacea L. leaf extract possesses molecules with antinociceptive activity.
      Citation: Pharmaceuticals
      PubDate: 2022-07-29
      DOI: 10.3390/ph15080943
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 944: The Role of Myrrh Metabolites in
           Cancer, Inflammation, and Wound Healing: Prospects for a Multi-Targeted
           Drug Therapy

    • Authors: Rasha Saad Suliman, Sahar Saleh Alghamdi, Rizwan Ali, Dimah Aljatli, Norah Abdulaziz Aljammaz, Sarah U. Huwaizi, Rania Suliman, Khawla Mohammed Kahtani, Ghadeer M. Albadrani, Tlili Barhoumi, Abdulelah Altolayyan, Ishrat Rahman
      First page: 944
      Abstract: Background: Myrrh extract is a well-known medicinal plant with significant therapeutic benefits attributed to the activity of its diverse metabolites. It has promising activity against cancer and inflammatory diseases, and could serve as a potential therapeutic alternative since most therapeutic agents have severe side effects that impair quality of life. Method: The current study identified the active metabolites from the myrrh resin methanolic extract. Then, the extracts were tested for in vitro anti-inflammatory and anti-cancer activity using cancer cell lines and Tamm-Horsfall Protein 1 (Thp-1)-like macrophage cell lines. Furthermore, using an in vivo rat model, the extracts’ anti-inflammatory and wound-healing activity was investigated. In addition, in silico predictions of the myrrh constituents highlighted the pharmacokinetic properties, molecular targets, and safety profile, including cytochrome P 450 (CYP) inhibition and organ toxicity. Results: Nine secondary metabolites were identified, and computational predictions suggested a good absorption profile, anticancer, anti-inflammatory, and wound-healing effects. The myrrh extract had moderate cytotoxic activity against both HL60 and K562 leukemia cell lines and the KAIMRC1 breast cancer cell line. Myrrh caused a dose-dependent effect on macrophages to increase the reactive oxygen species (ROS) levels, promote their polarization to classically activated macrophages (M1) and alternatively activated macrophages (M2) phenotypes, and consequently induce apoptosis, highlighting its ability to modulate macrophage function, which could potentially aid in several desired therapeutic processes, including the resolution of inflammation, and autophagy which is an important aspect to consider in cancer treatment. The topical application of myrrh improved wound healing, with no delayed inflammatory response, and promoted complete re-epithelization of the skin, similar to the positive control. In conclusion, we provide evidence for the methanolic extract of myrrh having cytotoxic activity against cancer cells and anti-inflammatory wound-healing properties, which may be attributed to its role in modulating macrophage function. Furthermore, we suggest the active constituents responsible for these properties, which warrants further studies focusing on the precise roles of the active metabolites.
      Citation: Pharmaceuticals
      PubDate: 2022-07-29
      DOI: 10.3390/ph15080944
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 945: Impact of MnTBAP and Baricitinib
           Treatment on Hutchinson–Gilford Progeria Fibroblasts

    • Authors: Elena Vehns, Rouven Arnold, Karima Djabali
      First page: 945
      Abstract: Hutchinson–Gilford progeria syndrome (HGPS) is a rare premature aging disease. It is caused by a mutation in the LMNA gene, which results in a 50-amino-acid truncation of prelamin A. The resultant truncated prelamin A (progerin) lacks the cleavage site for the zinc-metallopeptidase ZMPSTE24. Progerin is permanently farnesylated, carboxymethylated, and strongly anchored to the nuclear envelope. This leads to abnormalities, such as altered nuclear shape, mitochondrial dysfunction, and inflammation. HGPS patients display symptoms of physiological aging, including atherosclerosis, alopecia, lipodystrophy, and arthritis. Currently, no cure for HGPS exists. Here we focus on a drug combination consisting of the superoxide dismutase mimetic MnTBAP and JAK1/2 inhibitor baricitinib (Bar) to restore phenotypic alterations in HGPS fibroblasts. Treating HGPS fibroblasts with the MnTBAP/Bar combination improved mitochondrial functions and sustained Bar’s positive effects on reducing progerin and pro-inflammatory factor levels. Collectively, MnTBAP/Bar combination treatment ameliorates the aberrant phenotype of HGPS fibroblasts and is a potential treatment strategy for patients with HGPS.
      Citation: Pharmaceuticals
      PubDate: 2022-07-29
      DOI: 10.3390/ph15080945
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 946: Optimization of Precursor Synthesis
           Conditions of (2S,4S)4–[18F]FPArg and Its Application in Glioma

    • Authors: Huang, Zhang, Wang, Li, Zheng, Chen, Liang, Wu
      First page: 946
      Abstract: Although the tracer (2S,4S)4–[18F]FPArg is expected to provide a powerful imaging method for the diagnosis and treatment of clinical tumors, it has not been realized due to the low yield of chemical synthesis and radiolabeling. A simple synthetic method for the radiolabeled precursor of (2S,4S)4–[18F]FPArg in stable yield was obtained by adjusting the sequence of the synthetic steps. Furthermore, the biodistribution experiments confirmed that (2S,4S)4–[18F]FPArg could be cleared out quickly in wild type mouse. Cell uptake experiments and U87MG tumor mouse microPET–CT imaging experiments showed that the tumor had high uptake of (2S,4S)4–[18F]FPArg and the clearance was slow, but (2S,4S)4–[18F]FPArg was rapidly cleared in normal brain tissue. MicroPET–CT imaging of nude mice bearing orthotopic HS683–Luc showed that (2S,4S)4–[18F]FPArg can penetrate blood–brain barrier and image gliomas with a high contrast. Therefore, (2S,4S)4–[18F]FPArg is expected to be further applied in the diagnosis and efficacy evaluation of clinical glioma.
      Citation: Pharmaceuticals
      PubDate: 2022-07-29
      DOI: 10.3390/ph15080946
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 947: Phosphodiesterase 10A Inhibition
           Modulates the Corticostriatal Activity and L-DOPA-Induced Dyskinesia

    • Authors: Rayanne Poletti Guimarães, Danilo Leandro Ribeiro, Keila Bariotto Dos Santos, Carlos Henrique Zanello Talarico, Lívea Dornela Godoy, Fernando E. Padovan-Neto
      First page: 947
      Abstract: The facilitation of corticostriatal transmission is modulated by the pharmacological inhibition of striatal phosphodiesterase 10A (PDE10A). Since L-DOPA-induced dyskinesia is associated with abnormal corticostriatal transmission, we hypothesized that inhibition of PDE10A would modulate L-DOPA-induced dyskinesia (LID) by regulating corticostriatal activity. 6-OHDA-lesioned rats were chronically treated with L-DOPA for one week. After that, for two additional weeks, animals were treated with the PDE10A inhibitor PDM-042 (1 and 3 mg/kg) one hour before L-DOPA. Behavioral analyses were performed to quantify abnormal involuntary movements (AIMs) and to assess the antiparkinsonian effects of L-DOPA. Single-unit extracellular electrophysiological recordings were performed in vivo to characterize the responsiveness of MSNs to cortical stimulation. The low dose of PDM-042 had an antidyskinetic effect (i.e., attenuated peak-dose dyskinesia) and did not interfere with cortically evoked spike activity. Conversely, the high dose of PDM-042 did not affect peak-dose dyskinesia, prolonged AIMs, and increased cortically evoked spike activity. These data suggest that the facilitation of corticostriatal transmission is likely to contribute to the expression of AIMs. Therefore, cyclic nucleotide manipulation is an essential target in controlling LID.
      Citation: Pharmaceuticals
      PubDate: 2022-07-30
      DOI: 10.3390/ph15080947
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 948: Synthesis of
           3,4-Dihydropyrimidin(thio)one Containing Scaffold: Biginelli-like

    • Authors: Francisco Sánchez-Sancho, Marcos Escolano, Daniel Gaviña, Aurelio G. Csáky, María Sánchez-Roselló, Santiago Díaz-Oltra, Carlos del Pozo
      First page: 948
      Abstract: The interest in 3,4-dihydropyrimidine-2(1H)-(thio)ones is increasing every day, mainly due to their paramount biological relevance. The Biginelli reaction is the classical approach to reaching these scaffolds, although the product diversity suffers from some limitations. In order to overcome these restrictions, two main approaches have been devised. The first one involves the modification of the conventional components of the Biginelli reaction and the second one refers to the postmodification of the Biginelli products. Both strategies have been extensively revised in this manuscript. Regarding the first one, initially, the modification of one of the components was covered. Although examples of modifications of the three of them were described, by far the modification of the keto ester counterpart was the most popular approach, and a wide variety of different enolizable carbonylic compounds were used; moreover, changes in two or the three components were also described, broadening the substitution of the final dihydropyrimidines. Together with these modifications, the use of Biginelli adducts as a starting point for further modification was also a very useful strategy to decorate the final heterocyclic structure.
      Citation: Pharmaceuticals
      PubDate: 2022-07-30
      DOI: 10.3390/ph15080948
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 949: Design, Synthesis, and Development of
           pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective
           PI3Kδ Inhibitors: Part I—Indole Derivatives

    • Authors: Mariola Stypik, Marcin Zagozda, Stanisław Michałek, Barbara Dymek, Daria Zdżalik-Bielecka, Maciej Dziachan, Nina Orłowska, Paweł Gunerka, Paweł Turowski, Joanna Hucz-Kalitowska, Aleksandra Stańczak, Paulina Stańczak, Krzysztof Mulewski, Damian Smuga, Filip Stefaniak, Lidia Gurba-Bryśkiewicz, Arkadiusz Leniak, Zbigniew Ochal, Mateusz Mach, Karolina Dzwonek, Monika Lamparska-Przybysz, Krzysztof Dubiel, Maciej Wieczorek
      First page: 949
      Abstract: Phosphoinositide 3-kinase δ (PI3Kδ), a member of the class I PI3K family, is an essential signaling biomolecule that regulates the differentiation, proliferation, migration, and survival of immune cells. The overactivity of this protein causes cellular dysfunctions in many human disorders, for example, inflammatory and autoimmune diseases, including asthma or chronic obstructive pulmonary disease (COPD). In this work, we designed and synthesized a new library of small-molecule inhibitors based on indol-4-yl-pyrazolo[1,5-a]pyrimidine with IC50 values in the low nanomolar range and high selectivity against the PI3Kδ isoform. CPL302253 (54), the most potent compound of all the structures obtained, with IC50 = 2.8 nM, is a potential future candidate for clinical development as an inhaled drug to prevent asthma.
      Citation: Pharmaceuticals
      PubDate: 2022-07-30
      DOI: 10.3390/ph15080949
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 950: Design, Synthesis, and Antitumor
           Evaluation of Novel Mono-Carbonyl Curcumin Analogs in Hepatocellular
           Carcinoma Cell

    • Authors: Pan Yu, Weiya Cao, Linguo Zhao, Qing Han, Shilong Yang, Kepeng Yang, Xiaolei Pan, Qianyun Wang, Yuan Wang
      First page: 950
      Abstract: Curcumin is a polyphenolic natural product that has promising anticancer properties. However, its clinical utility is limited by its chemical instability and poor metabolic properties. In this paper, a series of new curcumin analogs were synthesized and found to be potent antiproliferative agents against the HepG2 cell line by MTT assay. In general, Group B with single ketone and group C with chalcone were markedly more cytotoxic than group A with diketone. Compound B5 was found as the most potent analog (IC50 = 11.33 μM) compared to curcumin (IC50 = 32.83 μM) and the mechanism of its cytotoxicity was investigated. The result of the wound healing assay indicated B5 strong potential to suppress HepG2 cell migration in a dose- and time-dependent manner. Subsequent assays (including JC-1 staining, Bcl-2, and caspase 3 protein levels by Western blotting) confirmed that B5 exposure induced apoptosis in HepG2 cells. Curcumin-induced comprehensive transcriptomes profile, Western blotting, molecular docking, and molecular dynamics analysis showed that the mechanism may relate to the regulation of cellular metabolic process and the expression of AKT protein. Taken together, we could conclude that curcumin and its analogs induced HepG2 cell proliferation, migration, and apoptosis via AKT signaling pathway and the mitochondrial death pathway. This study could lay the foundation for optimizing curcumin and provide valuable information for finding novel anti-HCC drugs.
      Citation: Pharmaceuticals
      PubDate: 2022-07-30
      DOI: 10.3390/ph15080950
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 951: Investigation into the
           Antihypertensive Effects of Diosmetin and Its Underlying Vascular
           Mechanisms Using Rat Model

    • Authors: Taseer Ahmad, Adil Javed, Taous Khan, Yusuf S. Althobaiti, Aman Ullah, Farooq M. Almutairi, Abdul Jabbar Shah
      First page: 951
      Abstract: Objective: Diosmetin is a flavonoid that is found in many important medicinal plants that have antihypertensive therapeutic potential. Diosmetin has been shown to have antiplatelet, anti-inflammatory and antioxidant properties, which suggests that it could be a potential candidate for use in antihypertensive therapy. Methods: In vivo and in vitro methods were used for our investigation into the antihypertensive effects of diosmetin. Results: Diosmetin significantly decreased the mean arterial pressure (MAP). The effects of diosmetin on the MAP and heart rate were more pronounced in hypertensive rats. To explore the involvement of the muscarinic receptors-linked NO pathway, Nω-nitro-L-arginine methyl ester (L-NAME) and atropine were pre-administered in vivo. The pretreatment with L-NAME did not significantly change the effects of diosmetin on the MAP by excluding the involvement of NO. Unlike L-NAME, the atropine pretreatment reduced the effects of diosmetin on the MAP, which demonstrated the role of the muscarinic receptors. In the in vitro study, diosmetin at lower concentrations produced endothelium-dependent and -independent (at higher concentrations) vasorelaxation, which was attenuated significantly by the presence of atropine and indomethacin but not L-NAME. Diosmetin was also tested for high K+-induced contractions. Diosmetin induced significant relaxation (similar to verapamil), which indicated its Ca2+ antagonistic effects. This was further confirmed by diosmetin shifting the CaCl2 CRCs toward the right due to its suppression of the maximum response. Diosmetin also suppressed phenylephrine peak formation, which indicated its antagonist effects on the release of Ca2+. Moreover, BaCl2 significantly inhibited the effects of diosmetin, followed by 4-AP and TEA, which suggested that the K+ channels had a role as well. Conclusions: The obtained data showed the Ca2+ channel antagonism, potassium channel activation and antimuscarinic receptor-linked vasodilatory effects of diosmetin, which demonstrated its antihypertensive potential.
      Citation: Pharmaceuticals
      PubDate: 2022-07-30
      DOI: 10.3390/ph15080951
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 952: Role of Calcimimetics in Treating
           Bone and Mineral Disorders Related to Chronic Kidney Disease

    • Authors: Yi-Chou Hou, Cai-Mei Zheng, Hui-Wen Chiu, Wen-Chih Liu, Kuo-Cheng Lu, Chien-Lin Lu
      First page: 952
      Abstract: Renal osteodystrophy is common in patients with chronic kidney disease and end-stage renal disease and leads to the risks of fracture and extraosseous vascular calcification. Secondary hyperparathyroidism (SHPT) is characterized by a compensatory increase in parathyroid hormone (PTH) secretion in response to decreased renal phosphate excretion, resulting in potentiating bone resorption and decreased bone quantity and quality. Calcium-sensing receptors (CaSRs) are group C G-proteins and negatively regulate the parathyroid glands through (1) increasing CaSR insertion within the plasma membrane, (2) increasing 1,25-dihydroxy vitamin D3 within the kidney and parathyroid glands, (3) inhibiting fibroblast growth factor 23 (FGF23) in osteocytes, and (4) attenuating intestinal calcium absorption through Transient Receptor Potential Vanilloid subfamily member 6 (TRPV6). Calcimimetics (CaMs) decrease PTH concentrations without elevating the serum calcium levels or extraosseous calcification through direct interaction with cell membrane CaSRs. CaMs reduce osteoclast activity by reducing stress-induced oxidative autophagy and improving Wnt-10b release, which promotes the growth of osteoblasts and subsequent mineralization. CaMs also directly promote osteoblast proliferation and survival. Consequently, bone quality may improve due to decreased bone resorption and improved bone formation. CaMs modulate cardiovascular fibrosis, calcification, and renal fibrosis through different mechanisms. Therefore, CaMs assist in treating SHPT. This narrative review focuses on the role of CaMs in renal osteodystrophy, including their mechanisms and clinical efficacy.
      Citation: Pharmaceuticals
      PubDate: 2022-07-31
      DOI: 10.3390/ph15080952
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 953: Continuous Subcutaneous Insulin
           Infusion (CSII) Combined with Oral Glucose-Lowering Drugs in Type 2
           Diabetes: A Systematic Review and Network Meta-Analysis of Randomized,
           Controlled Trials

    • Authors: Hui Li, Aimin Yang, Shi Zhao, Elaine Y. K. Chow, Mohammad Javanbakht, Yinhui Li, Dandan Lin, Lijuan Xu, Deng Zang, Kai Wang, Li Ma
      First page: 953
      Abstract: The clinical efficacy of continuous subcutaneous insulin infusion (CSII) therapy combined with six classes of oral glucose-lowering drugs (GLDs) (TZDs/metformin/acarbose/GLP-1 receptor agonist/SGLT-2 inhibitor/DPP-4 inhibitor) was evaluated by a network meta-analysis to provide an evidence-based reference in making a clinical decision on CSII combined with drugs in the treatment of type 2 diabetes. Data were retrieved from eight databases: the Chinese Journal Full-Text Database (CNKI), VIP Chinese Science and Technology Periodicals Full-Text Database (VP-CSFD), Wanfang Data Journal Paper Resource (WANFANG), China Biomedical Database (CBM), PubMed, Embase, Cochrane Library, and Web of Science. The retrieval period dated from the library’s construction to 27 June 2021. The search was for randomized, controlled trial studies (RCT) on insulin infusion (CSII) combined with oral hypoglycemic drugs (TZDs/metformin/acarbose/GLP-1 receptor agonist/SGLT-2 inhibitor/DPP-4 inhibitor) in the treatment of type 2 diabetes. Quality evaluation and data extraction were performed on the studies included, and network meta-analysis was performed with R4.0.1 software. A total of 56 publications was included in the final network meta-analysis, with a total sample size of 4395. Results based on the network meta-analysis were that CSII combined with a metformin works best on fasting blood glucose (FBG) and 2 h postprandial blood glucose (2hPG) and improves insulin resistance (lower HOMA-IR levels). CSII combined with a DPP-4 inhibitor had the best clinical effect in reducing glycosylated hemoglobin levels. Treatment with CSII combined with a DPP-4 inhibitor was the fastest way to achieve the blood glucose standard. In terms of insulin dosage, an insulin pump (CSII) combined with the GLP-1 receptor agonist can significantly reduce insulin dosage. Network meta-analysis evidence suggests that an insulin infusion (CSII) combined with oral hypoglycemic drugs can improve clinical efficacy in controlling blood sugar and improving insulin resistance, insulin dosage, and standard time. However, the most outstanding performance was that of insulin infusion (CSII) combined with metformin, which had the best clinical effect in controlling blood sugar and improving insulin resistance.
      Citation: Pharmaceuticals
      PubDate: 2022-07-30
      DOI: 10.3390/ph15080953
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 954: Molecular Targets of Pinocembrin
           Underlying Its Regenerative Activities in Human Keratinocytes

    • Authors: Jirapak Ruttanapattanakul, Nitwara Wikan, Saranyapin Potikanond, Wutigri Nimlamool
      First page: 954
      Abstract: Pinocembrin is one of the well-known compounds in the group of flavonoids. The pharmacological activities of pinocembrin in association with wound-healing activities have been reported. However, its effects on the aspect of cellular interaction underlying growth and survival are still unidentified in human keratinocytes. Our previous study reported that Boesenbergia rotunda potently stimulated survival and proliferation of a human keratinocyte cell line (HaCaT). On the basis that pinocembrin is revealed to be one of the major constituents of this plant, we aimed to define the survival- and proliferation-enhancing effects of this compound at the cellular level. Results from the current study confirmed that pinocembrin induced an increase in HaCaT cell number. At the signaling perspective, we identified that pinocembrin significantly triggered ERK1/2 and Akt activation. The stimulating effects of pinocembrin were clearly inhibited by MEK and PI3K inhibitors authenticating that proliferation- and survival-promoting activities of pinocembrin were mainly acted on these two signaling cascades. Altogether, we successfully identified that pinocembrin functions to induce keratinocyte proliferation and survival, at least by provoking MAPK and PI3K pathways. Our study encourages the fact that pinocembrin is one of the interesting natural flavonoid compounds to be developed as a wound closure-promoting agent.
      Citation: Pharmaceuticals
      PubDate: 2022-07-31
      DOI: 10.3390/ph15080954
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 955: Cholesterol-Lowering Effects of
           Asperidine B, a Pyrrolidine Derivative from the Soil-Derived Fungus
           Aspergillus Sclerotiorum PSU-RSPG178: A Potential Cholesterol Absorption

    • Authors: Atcharaporn Ontawong, Acharaporn Duangjai, Yaowapa Sukpondma, Kwanruthai Tadpetch, Chatchai Muanprasat, Vatcharin Rukachaisirikul, Jakkapong Inchai, Chutima S. Vaddhanaphuti
      First page: 955
      Abstract: Isolated secondary metabolites asperidine B (preussin) and asperidine C, produced by the soil-derived fungus Aspergillus Sclerotiorum PSU-RSPG178, were found to exhibit inhibitory effects against 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and oxidative stress in an in vitro assay. Whether or not the known pyrrolidine asperidine B and the recently isolated piperidine asperidine C have lipid-lowering effects remains unknown. Thus, this study aimed to investigate the hypocholesterolemic effects of asperidines B and C and identify the mechanisms involved in using in vitro, ex vivo, and in vivo models. The results show that both compounds interfered with cholesterol micelle formation by increasing bile acid binding capacity, similar to the action of the bile acid sequestrant drug cholestyramine. However, only asperidine B, but not asperidine C, was found to inhibit cholesterol uptake in Caco-2 cells by up-regulating LXRα without changing cholesterol transporter NPC1L1 protein expression. Likewise, reduced cholesterol absorption via asperidine-B-mediated activation of LXRα was also observed in isolated rat jejunal loops. Asperidine B consistently decreases plasma cholesterol absorption, similar to the effect of ezetimibe in rats. Therefore, asperidine B, the pyrrolidine derivative, has therapeutic potential to be developed into a type of cholesterol absorption inhibitor for the treatment of hypercholesterolemia.
      Citation: Pharmaceuticals
      PubDate: 2022-07-31
      DOI: 10.3390/ph15080955
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 956: Efficacy and Safety of Trametinib in
           Neurofibromatosis Type 1-Associated Plexiform Neurofibroma and Low-Grade
           Glioma: A Systematic Review and Meta-Analysis

    • Authors: Dun Wang, Lingling Ge, Zizhen Guo, Yuehua Li, Beiyao Zhu, Wei Wang, Chengjiang Wei, Qingfeng Li, Zhichao Wang
      First page: 956
      Abstract: Trametinib has been used in neurofibromatosis type 1 (NF1) patients, especially those with unresectable nerve tumors, but no systematic review based on the latest studies has been published. We conducted this meta-analysis to evaluate the effectiveness and safety of trametinib in treating NF1-related nerve tumors. Original articles reporting the efficacy and safety of trametinib in NF1 patents were identified in PubMed, EMBASE, and Web of Science up to 1 June 2022. Using R software and the ‘meta’ package, the objective response rates (ORRs) and disease control rates (DCRs) were calculated to evaluate the efficacy, and the pooled proportion of adverse events (AEs) was calculated. The Grading of Recommendations, Assessment, Development and Evaluation system was used to assess the quality of evidence. Eight studies involving 92 patients were included, which had a very low to moderate quality of evidence. The pooled ORR was 45.3% (95% CI: 28.9–62.1%, I2 = 0%), and the DCR was 99.8% (95% CI: 95.5–100%, I2 = 0%). The most common AEs was paronychia, with a pooled rate of 60.7% (95% CI: 48.8–72.7%, I2 = 0%). Our results indicate the satisfactory ability to stabilize tumor progression but a more limited ability to shrink tumors of trametinib in NF1-related nerve tumors. The safety profile of trametinib is satisfactory.
      Citation: Pharmaceuticals
      PubDate: 2022-07-31
      DOI: 10.3390/ph15080956
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 957: Resveratrol from Dietary Supplement
           to a Drug Candidate: An Assessment of Potential

    • Authors: Shivani Khattar, Sauban Ahmed Khan, Syed Amir Azam Zaidi, Mahdi Darvishikolour, Uzma Farooq, Punnoth Poonkuzhi Naseef, Mohamed Saheer Kurunian, Mohammed Zaafar Khan, Athar Shamim, Mohd Masih Uzzaman Khan, Zeenat Iqbal, Mohd. Aamir Mirza
      First page: 957
      Abstract: Resveratrol (RVT) is a well known phyto-chemical and is widely used in dietary supplements and botanical products. It shows a wide range of pharmacological/beneficial effects. Therefore, it can be a potential candidate to be developed as phyto-pharmaceutical. Multiple diseases are reported to be treated by the therapeutic effect of RVT since it has antioxidant, anti-cancer activity and anti-inflammatory activities. It also has a major role in diabetes, arthritis, cardiac disorder and platelet aggregation etc. The major requirements are establishments regarding safety, efficacy profile and physicochemical characterization. As it is already being consumed in variable maximum daily dose, there should not be a major safety concern but the dose needs to be established for different indications. Clinical trials are also being reported in different parts of the world. Physicochemical properties of the moiety are also well reported. Moreover, due to its beneficial effect on health it leads to the development of some intellectual property in the form of patents.
      Citation: Pharmaceuticals
      PubDate: 2022-08-01
      DOI: 10.3390/ph15080957
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 958: Automated Radiosynthesis, Preliminary
           In Vitro/In Vivo Characterization of OncoFAP-Based Radiopharmaceuticals
           for Cancer Imaging and Therapy

    • Authors: Francesco Bartoli, Philip Elsinga, Luiza Reali Nazario, Aureliano Zana, Andrea Galbiati, Jacopo Millul, Francesca Migliorini, Samuele Cazzamalli, Dario Neri, Riemer H. J. A. Slart, Paola Anna Erba
      First page: 958
      Abstract: FAP-targeted radiopharmaceuticals represent a breakthrough in cancer imaging and a viable option for therapeutic applications. OncoFAP is an ultra-high-affinity ligand of FAP with a dissociation constant of 680 pM. OncoFAP has been recently discovered and clinically validated for PET imaging procedures in patients with solid malignancies. While more and more clinical validation is becoming available, the need for scalable and robust procedures for the preparation of this new class of radiopharmaceuticals continues to increase. In this article, we present the development of automated radiolabeling procedures for the preparation of OncoFAP-based radiopharmaceuticals for cancer imaging and therapy. A new series of [68Ga]Ga-OncoFAP, [177Lu]Lu-OncoFAP and [18F]AlF-OncoFAP was produced with high radiochemical yields. Chemical and biochemical characterization after radiolabeling confirmed its excellent stability, retention of high affinity for FAP and absence of radiolysis by-products. The in vivo biodistribution of [18F]AlF-NOTA-OncoFAP, a candidate for PET imaging procedures in patients, was assessed in mice bearing FAP-positive solid tumors. The product showed rapid accumulation in solid tumors, with an average of 6.6% ID/g one hour after systemic administration and excellent tumor-to-healthy organs ratio. We have developed simple, quick, safe and robust synthetic procedures for the preparation of theranostic OncoFAP-compounds based on Gallium-68, Lutetium-177 and Fluorine-18 using the commercially available FASTlab synthesis module.
      Citation: Pharmaceuticals
      PubDate: 2022-08-02
      DOI: 10.3390/ph15080958
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 959: Activating SIRT-1 Signalling with the
           Mitochondrial-CoQ10 Activator Solanesol Improves Neurobehavioral and
           Neurochemical Defects in Ouabain-Induced Experimental Model of Bipolar

    • Authors: Bidisha Rajkhowa, Sidharth Mehan, Pranshul Sethi, Aradhana Prajapati, Manisha Suri, Sumit Kumar, Sonalika Bhalla, Acharan S. Narula, Abdulrahman Alshammari, Metab Alharbi, Nora Alkahtani, Saeed Alghamdi, Reni Kalfin
      First page: 959
      Abstract: Bipolar disorder (BD) is a chronic mental illness characterized by mood fluctuations that range from depressive lows to manic highs. Several studies have linked the downregulation of SIRT-1 (silent mating type information regulation-2 homologs) signaling to the onset of BD and other neurological dysfunctions. This research aimed to look into the neuroprotective potential of Solanesol (SNL) in rats given ICV-Ouabain injections, focusing on its effect on SIRT-1 signaling activation in the brain. Ouabain, found in hypothalamic and medullary neurons, is an endogenous inhibitor of brain Na+/K+ ATPase. The inhibition of brain Na+/K+ ATPase by Ouabain may also result in changes in neurotransmission within the central nervous system. SNL is a Solanaceae family active phytoconstituent produced from the plant Nicotiana tabacum. SNL is used as a precursor for the production of CoQ10 (Coenzyme Q10), a powerful antioxidant and neuroprotective compound. In the current study, lithium (Li), an important mood stabilizer drug, was used as a control. This study looked at the neuroprotective potential of SNL at dosages of 40 and 80 mg/kg in ICV-OUA injections that caused BD-like neurobehavioral and neurochemical defects in Wistar rats. Wistar rats were placed into eight groups (n = 6) and administered 1 mM/0.5 µL ICV-OUA injections for three days. Neurochemical assessments were done in rat brain homogenates, CSF, and blood plasma samples at the end of the experiment protocol schedule. Long-term SNL and lithium administration have been shown to decrease the number of rearing and crossings and reduce time spent in the center, locomotor activities, and immobility time. Solansesol treatment gradually raises the amount of Na+/K+ ATPase, limiting the severity of behavioural symptoms. These findings also revealed that SNL increases the levels of SIRT-1 in CSF, blood plasma, and brain homogenate samples. Moreover, in rat brain homogenates and blood plasma samples, SNL modulates apoptotic markers such as Caspase-3, Bax (pro-apoptotic), and Bcl-2 (anti-apoptotic). Mitochondrial-ETC complex enzymes, including complex-I, II, IV, V, and CoQ10, were also restored following long-term SNL treatment. Furthermore, SNL lowered inflammatory cytokines (TNF-α, IL-1β) levels while restoring neurotransmitter levels (serotonin, dopamine, glutamate, and acetylcholine) and decreasing oxidative stress markers. Histological examinations also validated Solanesol’s protective effect. As a result, our findings suggest that SNL, as a SIRT-1 signalling activator, may be a promising therapeutic approach for BD-like neurological dysfunctions.
      Citation: Pharmaceuticals
      PubDate: 2022-08-02
      DOI: 10.3390/ph15080959
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 960: Development and Validation of
           [3H]OF-NB1 for Preclinical Assessment of GluN1/2B Candidate Drugs

    • Authors: Hazem Ahmed, Livio Gisler, Nehal H. Elghazawy, Claudia Keller, Wolfgang Sippl, Steven H. Liang, Ahmed Haider, Simon M. Ametamey
      First page: 960
      Abstract: GluN2B-enriched N-methyl-D-aspartate receptors (NMDARs) are implicated in several neurodegenerative and psychiatric diseases, such as Alzheimer’s disease. No clinically valid GluN1/2B therapeutic exists due to a lack of selective GluN2B imaging tools, and the state-of-the-art [3H]ifenprodil shows poor selectivity in drug screening. To this end, we developed a tritium-labeled form of OF-NB1, a recently reported selective GluN1/2B positron emission tomography imaging (PET) agent, with a molar activity of 1.79 GBq/µmol. The performance of [3H]OF-NB1 and [3H]ifenprodil was compared through head-to-head competitive binding experiments, using the GluN1/2B ligand CP-101,606 and the sigma-1 receptor (σ1R) ligand SA-4503. Contrary to [3H]ifenprodil, the usage of [3H]OF-NB1 differentiated between GluN1/2B and σ1R binding components. These results were corroborated by observations from PET imaging experiments in Wistar rats using the σ1R radioligand [18F]fluspidine. To unravel the binding modes of OF-NB1 and ifenprodil in GluN1/2B and σ1Rs, we performed a retrospective in silico study using a molecular operating environment. OF-NB1 maintained similar interactions to GluN1/2B as ifenprodil, but only ifenprodil successfully fitted in the σ1R pocket, thereby explaining the high GluN1/2B selectivity of OF-NB1 compared to ifenprodil. We successfully showed in a proof-of-concept study the superiority of [3H]OF-NB1 over the gold standard [3H]ifenprodil in the screening of potential GluN1/2B drug candidates.
      Citation: Pharmaceuticals
      PubDate: 2022-08-02
      DOI: 10.3390/ph15080960
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 961: Identification of a Dual Inhibitor of
           Secreted Phospholipase A2 (GIIA sPLA2) and SARS-CoV-2 Main Protease

    • Authors: Maria A. Theodoropoulou, Giorgos S. Koutoulogenis, Linlin Zhang, Ifigeneia Akrani, Emmanuel Mikros, Rolf Hilgenfeld, George Kokotos
      First page: 961
      Abstract: The development of novel agents to combat COVID-19 is of high importance. SARS-CoV-2 main protease (Mpro) is a highly attractive target for the development of novel antivirals and a variety of inhibitors have already been developed. Accumulating evidence on the pathobiology of COVID-19 has shown that lipids and lipid metabolizing enzymes are critically involved in the severity of the infection. The purpose of the present study was to identify an inhibitor able to simultaneously inhibit both SARS-CoV-2 Mpro and phospholipase A2 (PLA2), an enzyme which plays a significant role in inflammatory diseases. Evaluating several PLA2 inhibitors, we demonstrate that the previously known potent inhibitor of Group IIA secretory PLA2, GK241, may also weakly inhibit SARS-CoV-2 Mpro. Molecular mechanics docking and molecular dynamics calculations shed light on the interactions between GK241 and SARS-CoV-2 Mpro. 2-Oxoamide GK241 may represent a lead molecular structure for the development of dual PLA2 and SARS-CoV-2 Mpro inhibitors.
      Citation: Pharmaceuticals
      PubDate: 2022-08-03
      DOI: 10.3390/ph15080961
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 962: Pharmacokinetic Interaction between
           Atorvastatin and Omega-3 Fatty Acid in Healthy Volunteers

    • Authors: Jae Hoon Kim, Jung Sunwoo, Ji Hye Song, Yu-Bin Seo, Won Tae Jung, Kyu-Yeol Nam, YeSeul Kim, Hye Jung Lee, JungHa Moon, Jin-Gyu Jung, Jang Hee Hong
      First page: 962
      Abstract: The interaction between statins and omega-3 fatty acids remains controversial. The aim of this phase 1 trial was to evaluate the pharmacokinetics of drug-drug interaction between atorvastatin and omega-3 fatty acids. Treatments were once-daily oral administrations of omega-3 (4 g), atorvastatin (40 mg), and both for 14 days, 7 days, and 14 days, respectively, with washout periods. The concentrations of atorvastatin, 2-OH-atorvastatin, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) were determined with LC-MS/MS. Parameters of DHA and EPA were analyzed after baseline correction. A total of 37 subjects completed the study without any major violations. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the co-administration of a single drug for the area under the concentration–time curve during the dosing interval at steady state of atorvastatin, 2-OH-atorvastatin, DHA, and EPA were 1.042 (0.971–1.118), 1.185 (1.113–1.262), 0.157 (0.091–0.271), and 0.557 (0.396–0.784), respectively. The GMRs (90% Cis) for the co-administration at steady state of atorvastatin, 2-OH-atorvastatin, DHA, and EPA were 1.150 (0.990–1.335), 1.301 (1.2707–1.1401), 0.320 (0.243–0.422), and 0.589 (0.487–0.712), respectively. The 90% CIs for most primary endpoints were outside the range of typical bioequivalence, indicating a pharmacokinetic interaction between atorvastatin and omega-3.
      Citation: Pharmaceuticals
      PubDate: 2022-08-03
      DOI: 10.3390/ph15080962
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 963: Optimization of Long-Acting
           Bronchodilator Dose Ratios Using Isolated Guinea Pig Tracheal Rings for
           Synergistic Combination Therapy in Asthma and COPD

    • Authors: Elena Menchi, Charaf El Khattabi, Stéphanie Pochet, Olivier Denis, Karim Amighi, Nathalie Wauthoz
      First page: 963
      Abstract: The co-administration of a long-acting β2-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), has been shown to be beneficial in the management of non-communicable chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). The resulting relaxation of the airways can be synergistically enhanced, reducing symptoms and optimizing lung function. This provides an insight into more effective treatments. In this study, the LABAs formoterol fumarate dihydrate (FOR) and indacaterol maleate (IND) were each associated with tiotropium bromide monohydrate (TIO) to assess their synergistic potential. This was done using an appropriate ex vivo model of isolated perfused guinea pig tracheal rings, and pharmacological models of drug interaction. Among the dose ratios studied for both types of combination, a higher synergistic potential was highlighted for FOR/TIO 2:1 (w/w). This was done through three steps by using multiple additions of drugs to the organ baths based on a non-constant dose ratio and then on a constant dose ratio, and by a single addition to the organ baths of specific amounts of drugs. In this way, the synergistic improvement of the relaxant effect on the airways was confirmed, providing a basis for improving therapeutic approaches in asthma and COPD. The synergy found at this dose ratio should now be confirmed on a preclinical model of asthma and COPD by assessing lung function.
      Citation: Pharmaceuticals
      PubDate: 2022-08-03
      DOI: 10.3390/ph15080963
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 964: Biotransformation of
           (–)-Isopulegol by Rhodococcus rhodochrous

    • Authors: Irina B. Ivshina, Natalia A. Luchnikova, Polina Yu. Maltseva, Irina V. Ilyina, Konstantin P. Volcho, Yurii V. Gatilov, Dina V. Korchagina, Nadezhda A. Kostrikina, Vladimir V. Sorokin, Andrey L. Mulyukin, Nariman F. Salakhutdinov
      First page: 964
      Abstract: The ability of actinobacteria of the genus Rhodococcus to biotransform the monoterpenoid (–)-isopulegol has been established for the first time. R. rhodochrous strain IEGM 1362 was selected as a bacterium capable of metabolizing (–)-isopulegol to form new, previously unknown, 10-hydroxy (2) and 10-carboxy (3) derivatives, which may presumably have antitumor activity and act as respiratory stimulants and cancer prevention agents. In the experiments, optimal conditions were selected to provide the maximum target catalytic activity of rhodococci. Using up-to-date (TEM, AFM-CLSM, and EDX) and traditional (cell size, roughness, and zeta potential measurements) biophysical and microbiological methods, it was shown that (–)-isopulegol and halloysite nanotubes did not negatively affect the bacterial cells. The data obtained expand our knowledge of the biocatalytic potential of rhodococci and their possible involvement in the synthesis of pharmacologically active compounds from plant derivatives.
      Citation: Pharmaceuticals
      PubDate: 2022-08-03
      DOI: 10.3390/ph15080964
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 965: Accessing Lipophilicity and
           Biomimetic Chromatography Profile of Biologically Active Ingredients of
           Botanicals Used in the Treatment of Inflammatory Bowel Disease

    • Authors: Mario-Livio Jeličić, Daniela Amidžić Klarić, Jelena Kovačić, Donatella Verbanac, Ana Mornar
      First page: 965
      Abstract: In the present study, various procedures have been compared for the determination of lipophilicity, hydrophobicity, and plasma protein binding of curcuminoids, boswellic acids, andrographolides, and piperine as biologically active ingredients of botanicals used in IBD treatment. Our results have shown that IAM-HPLC assay is the most suitable one for lipophilicity determination of all analytes regardless of their class and botanical source. HSA-HPAC and AGP-HPAC assays revealed that all investigated compounds have a higher affinity for HSA which is the most abundant protein in human plasma. The high affinity of biologically active compounds to all biological structures (phospholipids and proteins) admonishes that their small portion is available for therapeutic effects in IBD patients. Our experimental research is complemented by various theoretical approaches based on different algorithms for pharmacokinetic properties prediction. The similarities between experimental and calculated values were evaluated using PCA and CA as a statistical tool. The statistical analysis implies that plasma protein binding is a complex process, and theoretical approaches still cannot fully replace experimental ones.
      Citation: Pharmaceuticals
      PubDate: 2022-08-04
      DOI: 10.3390/ph15080965
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 966: Immunomodulatory Effects of
           (R)-Sulforaphane on LPS-Activated Murine Immune Cells: Molecular Signaling
           Pathways and Epigenetic Changes in Histone Markers

    • Authors: Manuel Alcarranza, Isabel Villegas, Rocío Muñoz-García, Rocío Recio, Inmaculada Fernández, Catalina Alarcón-de-la-Lastra
      First page: 966
      Abstract: The aim of this study was to explore the immunomodulatory effects of the natural enantiomer (R)-Sulforaphane (SFN) and the possible signaling pathways involved in an ex vivo model of LPS-stimulated murine peritoneal macrophages. Furthermore, we studied the epigenetic changes induced by (R)-SFN as well as the post-translational modifications of histone H3 (H3K9me3 and H3K18ac) in relation to the production of cytokines in murine splenocytes after LPS stimulation. (R)-SFN was able to modulate the inflammatory response and oxidative stress induced by LPS stimulation in murine peritoneal macrophages through the inhibition of reactive oxygen species (ROS), nitric oxide (NO) and cytokine (IL-1β, IL-6, IL-17, IL-18 and TNF-α) production by down-regulating the expression of pro-inflammatory enzymes (iNOS, COX-2 and mPGES-1). We also found that activation of the Nrf-2/HO-1 axis and inhibition of the JAK2/STAT-3, MAPK, canonical and non-canonical inflammasome signaling pathways could have been responsible for the immunomodulatory effects of (R)-SFN. Furthermore, (R)-SFN modulated epigenetic modifications through histone methylation (H3K9me3) and deacetylation (H3K18ac) in LPS-activated spleen cells. Collectively, our results suggest that (R)-SFN could be a promising epinutraceutical compound for the management of immunoinflammatory diseases.
      Citation: Pharmaceuticals
      PubDate: 2022-08-04
      DOI: 10.3390/ph15080966
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 967: Antibacterial, Antiparasitic, and
           Cytotoxic Activities of Chemical Characterized Essential Oil of
           Chrysopogon zizanioides Roots

    • Authors: Thaís A. S. Oliveira, Tatiana M. Vieira, Viviane R. Esperandim, Carlos H. G. Martins, Lizandra G. Magalhães, Mayker L. D. Miranda, Antônio E. M. Crotti
      First page: 967
      Abstract: This study aimed to investigate the chemical composition as well as the antibacterial, antiparasitic, and cytotoxic potentialities of the Brazilian Chrysopogon zizanioides root essential oil (CZ-EO) In addition, CZ-EO cytotoxicity to LLCMK2 adherent epithelial cells was assessed. The major compounds identified in CZ-EO were khusimol (30.0 ± 0.3%), β-eudesmol (10.8 ± 0.3%), α-muurolene (6.0 ± 0.1%), and patchouli alcohol (5.6 ± 0.2%). CZ-EO displayed optimal antibacterial activity against Prevotella nigrescens, Fusobacterium nucleatum, Prevotella melaninogenica, and Aggregatibacter actinomycetemcomitans, with Minimum Inhibitory Concentration (MIC) values between 22 and 62.5 µg/mL and Minimum Bactericidal Concentration (MBC) values between 22 and 400 µg/mL. CZ-EO was highly active against the L. amazonensis promastigote and amastigote forms (IC50 = 7.20 and 16.21 µg/mL, respectively) and the T. cruzi trypomastigote form (IC50 = 11.2 µg/mL). Moreover, CZ-EO showed moderate cytotoxicity to LLCMK2 cells, with CC50 = 565.4 µg/mL. These results revealed an interesting in vitro selectivity of CZ-EO toward the L. amazonensis promastigote and amastigote forms (Selectivity Index, SI = 78.5 and 34.8, respectively) and the T. cruzi trypomastigote form (SI = 50.5) compared to LLCMK2 cells. These results showed the promising potential of CZ-EO for developing new antimicrobial, antileishmanial, and antitrypanosomal drugs.
      Citation: Pharmaceuticals
      PubDate: 2022-08-05
      DOI: 10.3390/ph15080967
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 968: Ag2O Nanoparticles as a Candidate for
           Antimicrobial Compounds of the New Generation

    • Authors: Sergey V. Gudkov, Dmitriy A. Serov, Maxim E. Astashev, Anastasia A. Semenova, Andrey B. Lisitsyn
      First page: 968
      Abstract: Antibiotic resistance in microorganisms is an important problem of modern medicine which can be solved by searching for antimicrobial preparations of the new generation. Nanoparticles (NPs) of metals and their oxides are the most promising candidates for the role of such preparations. In the last few years, the number of studies devoted to the antimicrobial properties of silver oxide NPs have been actively growing. Although the total number of such studies is still not very high, it is quickly increasing. Advantages of silver oxide NPs are the relative easiness of production, low cost, high antibacterial and antifungal activities and low cytotoxicity to eukaryotic cells. This review intends to provide readers with the latest information about the antimicrobial properties of silver oxide NPs: sensitive organisms, mechanisms of action on microorganisms and further prospects for improving the antimicrobial properties.
      Citation: Pharmaceuticals
      PubDate: 2022-08-05
      DOI: 10.3390/ph15080968
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 969: Skin Anti-Aging Potential of Ipomoea
           pes-caprae Ethanolic Extracts on Promoting Cell Proliferation and Collagen
           Production in Human Fibroblasts (CCD-986sk Cells)

    • Authors: Tasanee Panichakul, Saranyoo Ponnikorn, Wipa Tupchiangmai, Woraphot Haritakun, Kitima Srisanga
      First page: 969
      Abstract: Collagen loss in the skin dermis is a major cause of age-related changes to the skin. Natural phytochemical substances are desirable for the prevention of skin aging and the formation of wrinkles. Ipomoea pes-caprae (IPC) has been utilized for nutritional and therapeutic purposes, and its extract contains collagenase inhibitory activity while causing no cytotoxicity. The purpose of this study was to examine the impact of IPC extracts on cell proliferation and collagen production in human fibroblasts (CCD-986sk cells). IPC leaves were macerated in 70% and 95% ethanol and the chemical composition of the resulting extracts (IPC70 and IPC95) were determined using high performance liquid chromatography (HPLC). The bioactivity of IPC extracts was examined in CCD-986sk cells, including antioxidant capacity, inhibition of collagenase, effects on cell proliferation and collagen production, as well as wound healing using an in vitro scratch test. Changes in expression of collagen type I (COL1A1), tumor growth factor beta 1 (TGFB1), and beta-fibroblast growth factor (FGF2) genes were also evaluated. The antioxidant and collagenase inhibitory properties of IPC extracts were associated with 3,5-di-caffeoylquinic acid, chlorogenic acid, and ferulic acid. IPC extracts at noncytotoxic concentrations significantly increased cell proliferation, collagen production, and wound healing. These effects appear linked to the upregulation of COL1A1, TGFB1, and FGF2 genes. The bioactivity of the IPC70 extract was greater than that for IPC95. This is useful in cosmeceutical applications for human skin aging. Our findings indicate that IPC extracts have the potential for use in skin anti-aging cosmeceutical preparations.
      Citation: Pharmaceuticals
      PubDate: 2022-08-06
      DOI: 10.3390/ph15080969
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 970: Synthesis and Biological Activity
           Characterization of Novel 5-Oxopyrrolidine Derivatives with Promising
           Anticancer and Antimicrobial Activity

    • Authors: Karolina Kairytė, Birutė Grybaitė, Rita Vaickelionienė, Birutė Sapijanskaitė-Banevič, Povilas Kavaliauskas, Vytautas Mickevičius
      First page: 970
      Abstract: The 1-(4-acetamidophenyl)-5-oxopyrrolidine carboxylic acid was applied for synthesizing derivatives bearing azole, diazole, and hydrazone moieties in the molecule. Modification of an acetamide fragment to the free amino group afforded compounds with two functional groups, which enabled to provide a series of 4-substituted-1-(4-substituted phenyl)pyrrolidine-2-ones. The resulted compounds 2 and 4–22 were subjected to the in vitro anticancer and antimicrobial activity determination. The compounds 18–22 exerted the most potent anticancer activity against A549 cells. Furthermore, compound 21 bearing 5-nitrothiophene substituents demonstrated promising and selective antimicrobial activity against multidrug-resistant Staphylococcus aureus strains, including linezolid and tedizolid-resistant S. aureus. These results demonstrate that 5-oxopyrolidine derivatives are attractive scaffolds for the further development of anticancer and antimicrobial compounds targeting multidrug-resistant Gram-positive pathogens.
      Citation: Pharmaceuticals
      PubDate: 2022-08-06
      DOI: 10.3390/ph15080970
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 971: The Effect of Various Poly
           (N-vinylpyrrolidone) (PVP) Polymers on the Crystallization of Flutamide

    • Authors: Dawid Heczko, Barbara Hachuła, Paulina Maksym, Kamil Kamiński, Andrzej Zięba, Luiza Orszulak, Marian Paluch, Ewa Kamińska
      First page: 971
      Abstract: In this study, several experimental techniques were applied to probe thermal properties, molecular dynamics, crystallization kinetics and intermolecular interactions in binary mixtures (BMs) composed of flutamide (FL) and various poly(N-vinylpyrrolidone) (PVP) polymers, including a commercial product and, importantly, samples obtained from high-pressure syntheses, which differ in microstructure (defined by the tacticity of the macromolecule) from the commercial PVP. Differential Scanning Calorimetry (DSC) studies revealed a particularly large difference between the glass transition temperature (Tg) of FL+PVPsynth. mixtures with 10 and 30 wt% of the excipient. In the case of the FL+PVPcomm. system, this effect was significantly lower. Such unexpected findings for the former mixtures were strictly connected to the variation of the microstructure of the polymer. Moreover, combined DSC and dielectric measurements showed that the onset of FL crystallization is significantly suppressed in the BM composed of the synthesized polymers. Further non-isothermal DSC investigations carried out on various FL+10 wt% PVP mixtures revealed a slowing down of FL crystallization in all FL-based systems (the best inhibitor of this process was PVP Mn = 190 kg/mol). Our research indicated a significant contribution of the microstructure of the polymer on the physical stability of the pharmaceutical—an issue completely overlooked in the literature.
      Citation: Pharmaceuticals
      PubDate: 2022-08-06
      DOI: 10.3390/ph15080971
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 972: Anticariogenic Activity of Three
           Essential Oils from Brazilian Piperaceae

    • Authors: Êni S. Carvalho, Vanessa F. S. Ayres, Midiã R. Oliveira, Geone M. Corrêa, Renata Takeara, Anderson C. Guimarães, Mariana B. Santiago, Thaís A. S. Oliveira, Carlos H. G. Martins, Antônio E. M. Crotti, Eliane O. Silva
      First page: 972
      Abstract: The current trend toward using natural food additives, cosmetics, and medicines has motivated industries to substitute synthetic compounds for natural products. Essential oils (EOs) from medicinal plants are a well-known source of chemical compounds that display several interesting biological activities, including antimicrobial action. In this study, we investigated the antibacterial activity of EOs extracted from three Piperaceae species collected in the Brazilian Amazon region against a representative panel of cariogenic bacteria. The minimum inhibitory concentration (MIC) of the essential oils extracted from Peperomia pellucida (PP-EO), Piper marginatum (PM-EO), and Piper callosum (PC-EO) was determined against Streptococcus mutans, S. mitis, S. sanguinis, S. salivarius, S. sobrinus, Enterococcus faecalis, and Lactobacillus casei by using the microplate microdilution method. PM-EO, PC-EO, and PP-EO displayed antibacterial activity against all the tested cariogenic bacteria. PM-EO displayed the best inhibitory activity, with MIC values ranging from 50 to 500 µg/mL. The lowest MIC values were obtained for PM-EO against S. mitis (MIC = 75 μg/mL), Lactobacillus casei (MIC = 50 μg/mL), and S. mutans (MIC = 50 μg/mL). Gas chromatography mass spectrometry (GC-MS) analysis allowed the chemical composition of all the EOs to be identified. The main constituents of PM-EO, PC-EO, and PP-EO were 3,4-(methylenedioxy)propiophenone, α-pinene, and dillapiole, respectively. Finally, the compounds that were exclusively detected in PM-EO are highlighted. Our results suggest that PM-EO may be used in products for treating dental caries and periodontal diseases.
      Citation: Pharmaceuticals
      PubDate: 2022-08-06
      DOI: 10.3390/ph15080972
      Issue No: Vol. 15, No. 8 (2022)
  • Pharmaceuticals, Vol. 15, Pages 872: New Life of an Old Drug: Caffeine as
           a Modulator of Antibacterial Activity of Commonly Used Antibiotics

    • Authors: Anna Woziwodzka, Marta Krychowiak-Maśnicka, Grzegorz Gołuński, Anna Łosiewska, Agnieszka Borowik, Dariusz Wyrzykowski, Jacek Piosik
      First page: 872
      Abstract: With the rapid and continuous emergence of antimicrobial resistance, bacterial infections became a significant global healthcare concern. One of the proposed strategies to combat multidrug-resistant pathogens is to use additional compounds, such as natural biologically active substances, as adjuvants for existing antibiotics. In this study, we investigated the potential of caffeine, the widely consumed alkaloid, to modulate the antibacterial effects of antibiotics commonly used in clinical practice. We used disc diffusion assay to evaluate the effects of caffeine on 40 antibiotics in two Staphylococcus aureus strains (methicillin-resistant and methicillin-sensitive). Based on the results of this step, we selected five antibiotics for which the greatest caffeine-induced improvements in antibacterial activity were observed, and further analyzed their interactions with caffeine using a checkerboard approach. Caffeine at concentrations of 250 µg/mL or higher halved the MIC values of ticarcillin, cefepime, gentamycin, azithromycin, and novobiocin for all gram-negative species investigated (Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii). At the highest caffeine concentrations tested (up to 16 mg/mL), decreases in MIC values were 8- to 16-fold. The obtained results prove that caffeine modulates the activity of structurally diverse antibiotics, with the most promising synergistic effects observed for cefepime and azithromycin toward gram-negative pathogens.
      Citation: Pharmaceuticals
      PubDate: 2022-07-15
      DOI: 10.3390/ph15070872
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 873: Opportunities and Challenges for In
           Silico Drug Discovery at Delta Opioid Receptors

    • Authors: Yazan J. Meqbil, Richard M. van Rijn
      First page: 873
      Abstract: The delta opioid receptor is a Gi-protein-coupled receptor (GPCR) with a broad expression pattern both in the central nervous system and the body. The receptor has been investigated as a potential target for a multitude of significant diseases including migraine, alcohol use disorder, ischemia, and neurodegenerative diseases. Despite multiple attempts, delta opioid receptor-selective molecules have not been translated into the clinic. Yet, the therapeutic promise of the delta opioid receptor remains and thus there is a need to identify novel delta opioid receptor ligands to be optimized and selected for clinical trials. Here, we highlight recent developments involving the delta opioid receptor, the closely related mu and kappa opioid receptors, and in the broader area of the GPCR drug discovery research. We focus on the validity and utility of the available delta opioid receptor structures. We also discuss the increased ability to perform ultra-large-scale docking studies on GPCRs, the rise in high-resolution cryo-EM structures, and the increased prevalence of machine learning and artificial intelligence in drug discovery. Overall, we pose that there are multiple opportunities to enable in silico drug discovery at the delta opioid receptor to identify novel delta opioid modulators potentially with unique pharmacological properties, such as biased signaling.
      Citation: Pharmaceuticals
      PubDate: 2022-07-15
      DOI: 10.3390/ph15070873
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 874: ZLM-7 Blocks Breast Cancer
           Progression by Inhibiting MDM2 via Upregulation of 14-3-3 Sigma

    • Authors: Min Wen, Zi-Zheng Zou, Tiao Luo, Xuan Li, Su-You Liu, Ji-Jia Li, Zhi-Yong Luo
      First page: 874
      Abstract: Breast cancer is one of the most prevalent malignancies with poor prognosis. Inhibition of angiogenesis is becoming a valid and evident therapeutic strategy to treat cancer. Recent studies uncovered the antiangiogenic activity of ZLM-7 (a combretastain A-4 derivative), but the regulatory mechanism is unclear. ZLM-7 treatment was applied in estrogen receptor-positive cell MCF-7, triple-negative breast cancer cell MDA-MB-231 and xenograft models. Transfections were conducted to overexpress or knockdown targeted genes. The gene and protein expressions were measured by qPCR and Western blotting assay, respectively. Cell proliferation and apoptosis were evaluated using the CCK8 method, clone formation assay and flow cytometry. We found that ZLM-7 upregulated 14-3-3 sigma expression but downregulated MDM2 expression in breast cancer cells. ZLM-7 delayed cell proliferation, promoted apoptosis and blocked cell-cycle progression in human breast cancer cells in vitro, while those effects were abolished by 14-3-3 sigma knockdown; overexpression of 14-3-3 sigma reproduced the actions of ZLM-7 on the cell cycle, which could be reversed by MDM2 overexpression. In xenograft models, ZLM-7 treatment significantly inhibited tumor growth while the inhibition was attenuated when 14-3-3 sigma was silenced. Collectively, ZLM-7 could inhibit MDM2 via upregulating 14-3-3 sigma expression, thereby blocking the breast cancer progression.
      Citation: Pharmaceuticals
      PubDate: 2022-07-15
      DOI: 10.3390/ph15070874
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 876: Tumor-Derived Membrane Vesicles: A
           Promising Tool for Personalized Immunotherapy

    • Authors: Jiabin Xu, Wenqiang Cao, Penglai Wang, Hong Liu
      First page: 876
      Abstract: Tumor-derived membrane vesicles (TDMVs) are non-invasive, chemotactic, easily obtained characteristics and contain various tumor-borne substances, such as nucleic acid and proteins. The unique properties of tumor cells and membranes make them widely used in drug loading, membrane fusion and vaccines. In particular, personalized vectors prepared using the editable properties of cells can help in the design of personalized vaccines. This review focuses on recent research on TDMV technology and its application in personalized immunotherapy. We elucidate the strengths and challenges of TDMVs to promote their application from theory to clinical practice.
      Citation: Pharmaceuticals
      PubDate: 2022-07-16
      DOI: 10.3390/ph15070876
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 877: Novel Pharmaceutical Strategies for
           Enhancing Skin Penetration of Biomacromolecules

    • Authors: Luyu Zhang, Zirong Dong, Wenjuan Liu, Xiying Wu, Haisheng He, Yi Lu, Wei Wu, Jianping Qi
      First page: 877
      Abstract: Skin delivery of biomacromolecules holds great advantages in the systemic and local treatment of multiple diseases. However, the densely packed stratum corneum and the tight junctions between keratinocytes stand as formidable skin barriers against the penetration of most drug molecules. The large molecular weight, high hydrophilicity, and lability nature of biomacromolecules pose further challenges to their skin penetration. Recently, novel penetration enhancers, nano vesicles, and microneedles have emerged as efficient strategies to deliver biomacromolecules deep into the skin to exert their therapeutic action. This paper reviews the potential application and mechanisms of novel skin delivery strategies with emphasis on the pharmaceutical formulations.
      Citation: Pharmaceuticals
      PubDate: 2022-07-16
      DOI: 10.3390/ph15070877
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 878: Dexamethasone Increases the
           Anesthetic Success in Patients with Symptomatic Irreversible Pulpitis: A

    • Authors: Lorenzo Franco-de la Torre, Eduardo Gómez-Sánchez, Nicolás Addiel Serafín-Higuera, Ángel Josabad Alonso-Castro, Sandra López-Verdín, Nelly Molina-Frechero, Vinicio Granados-Soto, Mario Alberto Isiordia-Espinoza
      First page: 878
      Abstract: Inferior alveolar nerve block (IANB) has a high failure rate in subjects with symptomatic irreversible pulpitis (SIP). It has been suggested that drugs with anti-inflammatory activity could improve the efficacy of the anesthetic used for IANB. The aim of this study was to assess the effect of dexamethasone on the success of dental anesthesia in patients with SIP. An information search was performed using PubMed and Google Scholar. The risk of bias of the included studies was evaluated with the Cochrane Collaboration’s risk-of-bias tool. The anesthetic success rate, pain intensity (VAS), and adverse effects were extracted. Data were analyzed using the Mantel–Haenszel test and odds ratio or the inverse variance and standardized mean difference. Dexamethasone increased the anesthetic success in comparison with placebo (n = 502; p < 0.001; OR = 2.59; 95% CIs: 1.46 to 4.59). Moreover, patients who were given dexamethasone had lower pain scores at 6 h (n = 302; p < 0.001; MD= −1.43; 95% CIs: −2.28 to −0.58), 12 h (n = 302; p < 0.0001; MD = −1.65; 95% CIs: −2.39 to −0.92), and 24 h (n = 302; p < 0.0008; MD = −1.27; 95% CIs: −2.01 to −0.53) when compared with placebo. In conclusion, the systemic administration of dexamethasone increases the anesthetic success rate and improves pain management in patients with SIP.
      Citation: Pharmaceuticals
      PubDate: 2022-07-16
      DOI: 10.3390/ph15070878
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 879: Bone Tissue Engineering in the
           Treatment of Bone Defects

    • Authors: Nannan Xue, Xiaofeng Ding, Rizhong Huang, Ruihan Jiang, Heyan Huang, Xin Pan, Wen Min, Jun Chen, Jin-Ao Duan, Pei Liu, Yiwei Wang
      First page: 879
      Abstract: Bones play an important role in maintaining exercise and protecting organs. Bone defect, as a common orthopedic disease in clinics, can cause tremendous damage with long treatment cycles. Therefore, the treatment of bone defect remains as one of the main challenges in clinical practice. Today, with increased incidence of bone disease in the aging population, demand for bone repair material is high. At present, the method of clinical treatment for bone defects including non-invasive therapy and invasive therapy. Surgical treatment is the most effective way to treat bone defects, such as using bone grafts, Masquelet technique, Ilizarov technique etc. In recent years, the rapid development of tissue engineering technology provides a new treatment strategy for bone repair. This review paper introduces the current situation and challenges of clinical treatment of bone defect repair in detail. The advantages and disadvantages of bone tissue engineering scaffolds are comprehensively discussed from the aspect of material, preparation technology, and function of bone tissue engineering scaffolds. This paper also summarizes the 3D printing technology based on computer technology, aiming at designing personalized artificial scaffolds that can accurately fit bone defects.
      Citation: Pharmaceuticals
      PubDate: 2022-07-17
      DOI: 10.3390/ph15070879
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 880: The Pivotal Role of Quantum
           Dots-Based Biomarkers Integrated with Ultra-Sensitive Probes for Multiplex
           Detection of Human Viral Infections

    • Authors: Seyyed Mojtaba Mousavi, Seyyed Alireza Hashemi, Masoomeh Yari Kalashgrani, Navid Omidifar, Chin Wei Lai, Neralla Vijayakameswara Rao, Ahmad Gholami, Wei-Hung Chiang
      First page: 880
      Abstract: The spread of viral diseases has caused global concern in recent years. Detecting viral infections has become challenging in medical research due to their high infectivity and mutation. A rapid and accurate detection method in biomedical and healthcare segments is essential for the effective treatment of pathogenic viruses and early detection of these viruses. Biosensors are used worldwide to detect viral infections associated with the molecular detection of biomarkers. Thus, detecting viruses based on quantum dots biomarkers is inexpensive and has great potential. To detect the ultrasensitive biomarkers of viral infections, QDs appear to be a promising option as biological probes, while physiological components have been used directly to detect multiple biomarkers simultaneously. The simultaneous measurement of numerous clinical parameters of the same sample volume is possible through multiplex detection of human viral infections, which reduces the time and cost required to record any data point. The purpose of this paper is to review recent studies on the effectiveness of the quantum dot as a detection tool for human pandemic viruses. In this review study, different types of quantum dots and their valuable properties in the structure of biomarkers were investigated. Finally, a vision for recent advances in quantum dot-based biomarkers was presented, whereby they can be integrated into super-sensitive probes for the multiplex detection of human viral infections.
      Citation: Pharmaceuticals
      PubDate: 2022-07-17
      DOI: 10.3390/ph15070880
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 881: Co-Delivery of 5-Fluorouracil and
           Paclitaxel in Mitochondria-Targeted KLA-Modified Liposomes to Improve
           Triple-Negative Breast Cancer Treatment

    • Authors: Tianyu Chen, Hui Chen, Yichun Jiang, Qi Yan, Shuling Zheng, Min Wu
      First page: 881
      Abstract: In this research, KLA-modified liposomes co-loaded with 5-fluorouracil and paclitaxel (KLA-5-FU/PTX Lps) were developed, and their antitumor activity against triple-negative breast cancer (TNBC) was evaluated. KLA-5-FU/PTX Lps were prepared using the thin-film dispersion method, and their in vitro anticancer efficacy was assessed in human breast cancer cells (MDA-MB-231). An MDA-MB-231 tumor-bearing mouse model was also established to evaluate their antitumor efficacy in vivo. KLA-5-FU/PTX Lps showed enhanced cytotoxicity against MDA-MB-231 cells, improved drug delivery to mitochondria, and induced mitochondria-mediated apoptosis. The modified liposomes also showed favorable antitumor activity in vivo due to their strong ability to target tumors and mitochondria. The liposomes showed no obvious systemic toxicity. Our results suggest that KLA-5-FU/PTX Lps are a promising system with which to target the delivery of antitumor drugs to mitochondria as a treatment for TNBC.
      Citation: Pharmaceuticals
      PubDate: 2022-07-17
      DOI: 10.3390/ph15070881
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 882: The N-Methyl-D-Aspartate Receptor
           Blocker REL-1017 (Esmethadone) Reduces Calcium Influx Induced by
           Glutamate, Quinolinic Acid, and Gentamicin

    • Authors: Ezio Bettini, Sara De Martin, Andrea Mattarei, Marco Pappagallo, Stephen M. Stahl, Francesco Bifari, Charles E. Inturrisi, Franco Folli, Sergio Traversa, Paolo L. Manfredi
      First page: 882
      Abstract: REL-1017 (esmethadone) is a novel N-methyl-D-aspartate receptor (NMDAR) antagonist and promising rapid antidepressant candidate. Using fluorometric imaging plate reader (FLIPR) assays, we studied the effects of quinolinic acid (QA) and gentamicin, with or without L-glutamate and REL-1017, on intracellular calcium ([Ca2+]in) in recombinant cell lines expressing human GluN1-GluN2A, GluN1-GluN2B, GluN1-GluN2C, and GluN1-GluN2D NMDAR subtypes. There were no effects of QA on [Ca2+]in in cells expressing GluN1-GluN2C subtypes. QA acted as a low-potency, subtype-selective, NMDAR partial agonist in GluN1-GluN2A, GluN1-GluN2B, and GluN1-GluN2D subtypes. REL-1017 reduced [Ca2+]in induced by QA. In cells expressing the GluN1-GluN2D subtype, QA acted as an agonist in the presence of 0.04 μM L-glutamate and as an antagonist in the presence of 0.2 μM L-glutamate. REL-1017 reduced [Ca2+]in induced by L-glutamate alone and with QA in all cell lines. In the absence of L-glutamate, gentamicin had no effect. Gentamicin was a positive modulator for GluN1-GluN2B subtypes at 10 μM L-glutamate, for GluN1-GluN2A at 0.2 μM L-glutamate, and for GluN1-GluN2A, GluN1-GluN2B, and GluN1-GluN2D at 0.04 μM L-glutamate. No significant changes were observed with GluN1-GluN2C NMDARs. REL-1017 reduced [Ca2+]in induced by the addition of L-glutamate in all NMDAR cell lines in the presence or absence of gentamicin. In conclusion, REL-1017 reduced [Ca2+]in induced by L-glutamate alone and when increased by QA and gentamicin. REL-1017 may protect cells from excessive calcium entry via NMDARs hyperactivated by endogenous and exogenous molecules.
      Citation: Pharmaceuticals
      PubDate: 2022-07-17
      DOI: 10.3390/ph15070882
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 883: Chronic Pruritus in Atopic Patients
           Treated with Dupilumab: Real Life Response and Related Parameters in 354

    • Authors: Luca Mastorino, François Rosset, Federica Gelato, Michela Ortoncelli, Giovanni Cavaliere, Pietro Quaglino, Simone Ribero
      First page: 883
      Abstract: Chronic pruritus is a major symptom of atopic dermatitis (AD). Its etiopathogenesis is complex, and an understanding of the driving factors of its pathogenesis allows for the development of new molecule-targeted therapies. Dupilumab, targeting and blocking interleukin-4 (IL-4) and interleukin-13 (IL-13) molecules, has shown great efficacy in treating AD symptoms such chronic itching. We performed a retrospective observational study to evaluate possible chronic-itch-related characteristics and parameters in 356 AD patients who received dupilumab. The objective of the study was to evaluate the factors associated with the level of pruritus reported by patients at each of the 1575 detections in the form of the peak pruritus numerical rating scale (NRSpp) and sleep disturbance numerical rating scale (NRSsd). We focused on: the eczema area and severity index (EASI), dermatology life quality index (DLQI), patient-oriented eczema measure (POEMS), eosinophilia, L-lactate dehydrogenase (LDH), immunoglobulin E (IgE) and the time from the start of dupilumab therapy. NRSpp fell from 8.6 (sd 1.7) at baseline to 1.7 (sd 2.3) at 36 months and NRSsd from 7 (sd 3) to 0. Regarding the parameters that correlate with NRSpp, all the parameters analysed were significantly correlated except for eosinophils (p = 0.136). In the multivariate analysis, both considering and not considering treatment duration, the parameters were correlated (p < 0.001); EASI, DLQI, POEM, and LDH significantly correlated with NRSpp (p < 0.001 for each, except for LDH p = 0.003); while IgE tot lost significance (p = 0.337). Similar results were obtained for the parameters correlating with NRSsd. Our results confirm the efficacy of dupilumab on pruritus. The use of questionnaires such as DLQI and POEM is advisable in clinical practice and is adequate for assessing the impact of itching on AD. The low correlation of IgE and eosinophils, the ambiguity of LDH levels with the level of pruritus, and a poor clinical validity and unclear correlation with disease severity suggest a progressive abandonment of monitoring of these values.
      Citation: Pharmaceuticals
      PubDate: 2022-07-17
      DOI: 10.3390/ph15070883
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 884: Hybrid Nanosystems Based on
           Nicotinate-Functionalized Mesoporous Silica and Silver Chloride
           Nanoparticles Loaded with Phenytoin for Preventing Pseudomonas aeruginosa
           Biofilm Development

    • Authors: Maider Ugalde-Arbizu, John Jairo Aguilera-Correa, Aranzazu Mediero, Jaime Esteban, Paulina L. Páez, Eider San Sebastian, Santiago Gómez-Ruiz
      First page: 884
      Abstract: Pseudomonas aeruginosa (PA) is one of the most common bacteria isolated from chronic wounds and burns. Its treatment is a challenge due to antimicrobial drug resistance and biofilm formation. In this context, this study aimed to perform the synthesis and full characterization of hybrid nanosystems based on mesoporous silica nanoparticles (MSNs) functionalized with a nicotinic ligand and silver chloride nanoparticles, both phenytoin sodium (Ph)-loaded and unloaded, to evaluate the antibacterial properties against three different strains of PA (including two clinical strains) in a planktonic state and as biofilms. Ph is a well-known proliferative agent, which was incorporated into the hybrid nanomaterials to obtain an effective material for tissue healing and prevention of infection caused by PA. The Ph-loaded materials promoted a quasi-complete inhibition of bacterial growth in wound-like medium and biofilm development, with values of 99% and 96%, respectively, with selectivity indices above the requirements for drugs to become promising agents for the topic preventive treatment of chronic wounds and burns.
      Citation: Pharmaceuticals
      PubDate: 2022-07-18
      DOI: 10.3390/ph15070884
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 885: Morphological Changes, Antibacterial
           Activity, and Cytotoxicity Characterization of Hydrothermally Synthesized
           Metal Ions-Incorporated Nanoapatites for Biomedical Application

    • Authors: Ssu-Meng Huang, Shih-Ming Liu, Wen-Cheng Chen, Chia-Ling Ko, Chi-Jen Shih, Jian-Chih Chen
      First page: 885
      Abstract: The objective of this study was to prepare hydroxyapatite (HA) with potential antibacterial activity against gram-negative and gram-positive bacteria by incorporating different atomic ratios of Cu2+ (0.1–1.0%), Mg2+ (1.0–7.0%), and Zn2+ (1.0–7.0%) to theoretically replace Ca2+ ions during the hydrothermal synthesis of grown precipitated HA nanorods. This study highlights the role of comparing different metal ions on synthetic nanoapatite in regulating the antibacterial properties and toxicity. The comparisons between infrared spectra and between diffractograms have confirmed that metal ions do not affect the formation of HA phases. The results show that after doped Cu2+, Mg2+, and Zn2+ ions replace Ca2+, the ionic radius is almost the same, but significantly smaller than that of the original Ca2+ ions, and the substitution effect causes the lattice distance to change, resulting in crystal structure distortion and reducing crystallinity. The reduction in the length of the nanopatites after the incorporation of Cu2+, Mg2+, and Zn2+ ions confirmed that the metal ions were mainly substituted during the growth of the rod-shape nanoapatite Ca2+ distributed along the longitudinal site. The antibacterial results show that nanoapatite containing Cu2+ (0.1%), Mg2+ (3%), and Zn2+ (5–7%) has obvious and higher antibacterial activity against gram-positive bacteria Staphylococcus aureus within 2 days. The antibacterial effect against the gram-negative bacillus Escherichia coli is not as pronounced as against Staphylococcus aureus. The antibacterial effect of Cu2+ substituted Ca2+ with an atomic ratio of 0.1~1.0% is even better than that of Mg2+- and Zn2+- doped with 1~7% groups. In terms of cytotoxicity, nanoapatites with Cu2+ (~0.2%) exhibit cytotoxicity, whereas Mg2+- (1–5%) and Zn2+- (~1%) doped nanoapatites are biocompatible at low concentrations but become cytotoxic as ionic concentration increases. The results show that the hydrothermally synthesized nanoapatite combined with Cu2+ (0.2%), Mg2+ (3%), and Zn2+ (3%) exhibits low toxicity and high antibacterial activity, which provides a good prospect for bypassing antibiotics for future biomedical applications.
      Citation: Pharmaceuticals
      PubDate: 2022-07-18
      DOI: 10.3390/ph15070885
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 886: Palladium(II) Complexes of
           Substituted Salicylaldehydes: Synthesis, Characterization and
           Investigation of Their Biological Profile

    • Authors: Ariadni Zianna, George Geromichalos, Augusta-Maria Fiotaki, Antonios G. Hatzidimitriou, Stavros Kalogiannis, George Psomas
      First page: 886
      Abstract: Five palladium(II) complexes of substituted salicylaldehydes (X-saloH, X = 4-Et2N (for 1), 3,5-diBr (for 2), 3,5-diCl (for 3), 5-F (for 4) or 4-OMe (for 5)) bearing the general formula [Pd(X-salo)2] were synthesized and structurally characterized. The crystal structure of complex [Pd(4-Et2N-salo)2] was determined by single-crystal X-ray crystallography. The complexes can scavenge 1,1-diphenyl-picrylhydrazyl and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radicals and reduce H2O2. They are active against two Gram-positive (Staphylococcus aureus and Bacillus subtilis) and two Gram-negative (Escherichia coli and Xanthomonas campestris) bacterial strains. The complexes interact strongly with calf-thymus DNA via intercalation, as deduced by diverse techniques and via the determination of their binding constants. Complexes interact reversibly with bovine and human serum albumin. Complementary insights into their possible mechanisms of bioactivity at the molecular level were provided by molecular docking calculations, exploring in silico their ability to bind to calf-thymus DNA, Escherichia coli and Staphylococcus aureus DNA-gyrase, 5-lipoxygenase, and membrane transport lipid protein 5-lipoxygenase-activating protein, contributing to the understanding of the role complexes 1–5 can play both as antioxidant and antibacterial agents. Furthermore, in silico predictive tools have been employed to study the chemical reactivity, molecular properties and drug-likeness of the complexes, and also the drug-induced changes of gene expression profile (as protein- and mRNA-based prediction results), the sites of metabolism, the substrate/metabolite specificity, the cytotoxicity for cancer and non-cancer cell lines, the acute rat toxicity, the rodent organ-specific carcinogenicity, the anti-target interaction profiles, the environmental ecotoxicity, and finally the activity spectra profile of the compounds.
      Citation: Pharmaceuticals
      PubDate: 2022-07-18
      DOI: 10.3390/ph15070886
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 887: Assessing the Immunomodulatory Effect
           of Size on the Uptake and Immunogenicity of Influenza- and Hepatitis B
           Subunit Vaccines In Vitro

    • Authors: Rick Heida, Philip A. Born, Gabriela Tapia-Calle, Henderik W. Frijlink, Anna Salvati, Anke L. W. Huckriede, Wouter L. J. Hinrichs
      First page: 887
      Abstract: Viral subunit vaccines are a safer and more tolerable alternative to whole inactivated virus vaccines. However, they often come with limited efficacy, necessitating the use of adjuvants. Using free and particle-bound viral antigens, we assessed whether size affects the uptake of those antigens by human monocyte-derived dendritic cells (Mo-DCs) and whether differences in uptake affect their capacity to stimulate cytokine production by T cells. To this end, influenza antigens and hepatitis B surface antigen (HBsAg) were covalently conjugated to polystyrene particles of 500 nm and 3 μm. Cellular uptake of the antigens, either unconjugated or conjugated, and their capacity to stimulate T cells within a population of human peripheral blood mononuclear cells (PBMCs) were measured by flow cytometry. Conjugation of both antigens to particles significantly increased their uptake by Mo-DCs. Moreover, both the 500 nm and 3 μm influenza conjugates induced significantly higher numbers of cytokine-producing CD4+ T cells and induced increased production of the pro-inflammatory cytokines IFNγ and TNFα. In contrast, conjugation of HBsAg to particles did not notably affect the T cell response. In conclusion, conjugation of antigen to 500 nm and 3 μm particles leads to increased antigen uptake by human Mo-DCs, although the capacity of such conjugates to induce T cell stimulation likely depends on the immunological status of the PBMC donor.
      Citation: Pharmaceuticals
      PubDate: 2022-07-18
      DOI: 10.3390/ph15070887
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 888: Application of Plackett–Burman
           Design for Spectrochemical Determination of the Last-Resort Antibiotic,
           Tigecycline, in Pure Form and in Pharmaceuticals: Investigation of
           Thermodynamics and Kinetics

    • Authors: Ahmed S. El-Shafie, Aseel Yousef, Marwa El-Azazy
      First page: 888
      Abstract: Tigecycline (TIGC) reacts with 7,7,8,8-tetracyanoquinodimethane (TCNQ) to form a bright green charge transfer complex (CTC). The spectrum of the CTC showed multiple charge transfer bands with a major peak at 843 nm. The Plackett–Burman design (PBD) was used to investigate the process variables with the objective being set to obtaining the maximum absorbance and thus sensitivity. Four variables, three of which were numerical (temperature—Temp; reagent volume—RV; reaction time—RT) and one non-numerical (diluting solvent—DS), were studied. The maximum absorbance was achieved using a factorial blend of Temp: 25 °C, RV: 0.50 mL, RT: 60 min, and acetonitrile (ACN) as a DS. The molecular composition that was investigated using Job’s method showed a 1:1 CTC. The method’s validation was performed following the International Conference of Harmonization (ICH) guidelines. The linearity was achieved over a range of 0.5–10 µg mL−1 with the limits of detection (LOD) and quantification (LOQ) of 166 and 504 ng mL−1, respectively. The method was applicable to TIGC per se and in formulations without interferences from common additives. The application of the Benesi–Hildebrand equation revealed the formation of a stable complex with a standard Gibbs free energy change (∆G°) value of −26.42 to −27.95 kJ/mol. A study of the reaction kinetics revealed that the CTC formation could be best described using a pseudo-first-order reaction.
      Citation: Pharmaceuticals
      PubDate: 2022-07-19
      DOI: 10.3390/ph15070888
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 889: Good Response of Advanced Thymic
           Carcinoma with Low PD-L1 Expression to Chemotherapy plus Pembrolizumab as
           First-Line Therapy and to Pembrolizumab as Maintenance Therapy: A Case

    • Authors: Yoichi Nishii, Kazuki Furuhashi, Kentaro Ito, Tadashi Sakaguchi, Yuta Suzuki, Kentaro Fujiwara, Taro Yasuma, Tetsu Kobayashi, Corina N. D’Alessandro-Gabazza, Esteban C. Gabazza, Osamu Taguchi, Osamu Hataji
      First page: 889
      Abstract: Thymic carcinoma is a rare malignant tumor with a poor prognosis. No standard treatment is currently available. The present case was a 64-year-old male smoker with no symptoms referred to our hospital because of abnormal chest radiological findings. The CT study showed a tumor between the anterior mediastinum and the right lung upper lobe, multiple nodular shadows along the right pleura, and pleural effusion. A CT-guided needle biopsy revealed squamous cell carcinoma. However, the differential diagnosis between thymic carcinoma and primary lung cancer was difficult. Treatment with carboplatin, nanoparticle albumin-bound paclitaxel, and pembrolizumab was initiated. The CT scan showed tumor shrinkage and good clinical response after four treatment cycles. Therapy was switched to maintenance therapy with pembrolizumab alone. Imaging studies showed further tumor shrinkage after twelve cycles of maintenance therapy with pembrolizumab. Sixteen cycles of maintenance therapy were continued without performance status deterioration. An abnormal radiological finding was detected after a twelve-month exacerbation-free period. The diagnosis was thymic carcinoma. Treatment with lenvatinib was initiated, and tumor-size reduction was observed. This is the first report of a case showing a successful maintenance therapy with pembrolizumab after effective first-line therapy with a combination of carboplatin-based chemotherapy plus pembrolizumab in advanced thymic carcinoma.
      Citation: Pharmaceuticals
      PubDate: 2022-07-19
      DOI: 10.3390/ph15070889
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 890: C-Myc Expression in Oral Squamous
           Cell Carcinoma: Molecular Mechanisms in Cell Survival and Cancer

    • Authors: Guya Diletta Marconi, Ylenia Della Rocca, Luigia Fonticoli, Francesco Melfi, Thangavelu Soundara Rajan, Simone Carradori, Jacopo Pizzicannella, Oriana Trubiani, Francesca Diomede
      First page: 890
      Abstract: Oral squamous cell carcinoma (OSCC) represents 90% of malignant epithelial cancer that occurs in the oral cavity. The c-Myc factor is expressed in multiple types of cancer, comprising head and neck squamous cell carcinoma (HNSCC), where it plays a fundamental role in tumor prognosis and in the self-renewal of tumor stem cells. However, the role of c-Myc in controlling OSCC cells is not well-known. The aim of the present study is the evaluation of the biological roles and regulatory mechanism of c-Myc in the pathogenesis of OSCC. Results indicated that c-Myc, c-Jun, Bcl-2, hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), ERK 1/2 and pERK1/2 were overexpressed in a cellular model of squamous cell carcinoma, Cal-27. Doxorubicin (Doxo), a common chemotherapeutic agent, inhibited cell invasion, hypoxia, angiogenesis and inflammation in a cellular model of Cal-27 cells as indicated by downregulation of MMP-9, VEGF, ERK 1/2 and pERK 1/2 as well as promoted apoptosis as evidenced by the downregulation of Bcl-2 protein. This work aimed at underlying the functional relevance of c-Myc in OSCC and the HIF-Myc collaboration by integrating the knowledge on this molecular link in an OSCC tumor microenvironment. The results obtained showed for the first time the vital role of c-Myc in Cal-27 in cell survival/proliferation and tumor growth as well as the negative regulatory effect of Doxo against c-Myc signaling pathway.
      Citation: Pharmaceuticals
      PubDate: 2022-07-19
      DOI: 10.3390/ph15070890
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 891: Synthesis and Evaluation of Some New
           4H-Pyran Derivatives as Antioxidant, Antibacterial and Anti-HCT-116 Cells
           of CRC, with Molecular Docking, Antiproliferative, Apoptotic and ADME

    • Authors: Nahed N. E. El-Sayed, Magdi E. A. Zaki, Sami A. Al-Hussain, Abir Ben Bacha, Malika Berredjem, Vijay H. Masand, Zainab M. Almarhoon, Hanaa S. Omar
      First page: 891
      Abstract: Colorectal cancer oncogenesis is linked to dysbiosis, oxidative stress and overexpression of CDK2. The 4H-pyran scaffold is considered an antitumoral, antibacterial and antioxidant lead as well as a CDK2 inhibitor. Herein, certain 4H-pyran derivatives were evaluated as antibacterial, antioxidant and cytotoxic agents against HCT-116 cells. Derivatives 4g and 4j inhibited all the tested Gram-positive isolates, except for B. cereus (ATCC 14579), with lower IC50 values (µM) than ampicillin. In addition, 4g and 4j demonstrated the strongest DPPH scavenging and reducing potencies, with 4j being more efficient than BHT. In cell viability assays, 4d and 4k suppressed the proliferation of HCT-116 cells, with the lowest IC50 values being 75.1 and 85.88 µM, respectively. The results of molecular docking simulations of 4d and 4k, inhibitory kinase assays against CDK2, along with determination of CDK2 protein concentration and the expression level of CDK2 gene in the lysates of HCT-116 treated cells, suggested that these analogues blocked the proliferation of HCT-116 cells by inhibiting kinase activity and downregulating expression levels of CDK2 protein and gene. Moreover, 4d and 4k were found to induce apoptosis in HCT-116 cells via activation of the caspase-3 gene. Lastly, compounds 4g, 4j, 4d and 4k were predicted to comply with Lipinski’s rule of five, and they are expected to possess excellent physiochemical and pharmacokinetic properties suitable for in vivo bioavailability, as predicted by the SwissADME web tool.
      Citation: Pharmaceuticals
      PubDate: 2022-07-19
      DOI: 10.3390/ph15070891
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 892: Druggable Targets and Compounds with
           Both Antinociceptive and Antipruritic Effects

    • Authors: Hao-Jui Weng, Quoc Thao Trang Pham, Chia-Wei Chang, Tsen-Fang Tsai
      First page: 892
      Abstract: Pain and itch are both important manifestations of various disorders, such as herpes zoster, atopic dermatitis, and psoriasis. Growing evidence suggests that both sensations have shared mediators, overlapping neural circuitry, and similarities in sensitization processes. In fact, pain and itch coexist in some disorders. Determining pharmaceutical agents and targets for treating pain and itch concurrently is of scientific and clinical relevance. Here we review the neurobiology of pain and itch and discuss the pharmaceutical targets as well as novel compounds effective for the concurrent treatment of these sensations.
      Citation: Pharmaceuticals
      PubDate: 2022-07-19
      DOI: 10.3390/ph15070892
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 893:
           (Spiroconazol A) Isolated from Dioscorea bulbifera L. var. sativa Induces
           Autophagic Cell Death by p38 MAPK Activation in NSCLC Cells

    • Authors: Yo Sook Ki, Kyung-Sook Chung, Heon-Woo Lee, Jung-Hye Choi, Léon Azefack Tapondjou, Eungyeong Jang, Kyung-Tae Lee
      First page: 893
      Abstract: In our previous study, we reported the isolation of pennogenin-3-O-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→3)]-β-D-glucopyranoside (spiroconazol A), a steroidal saponin, from the flowers of Dioscorea bulbifera L. var. sativa. In the present study, we aimed to investigate the effects of spiroconazol A on autophagy and its underlying mechanisms in A549 and NCI-H358 human non-small cell lung cancer (NSCLC) cells. Spiroconazol A inhibited the proliferation of NSCLC cells in a concentration- and time-dependent manner. To determine the type of programmed cell death induced by spiroconazol A, we performed a characterization of apoptosis in spiroconazol A-treated A549 cells. Our results showed that spiroconazol A significantly suppressed A549 cell viability but did not influence cell apoptosis because phosphatidylserine and caspase activation were not detected. Furthermore, spiroconazol A treatment upregulated the expression of LC3-II and autophagy-related Beclin-1 protein, suggesting that spiroconazol A induces autophagy in A549 cells. Moreover, spiroconazol A activated the phosphorylation of p38 mitogen-activated protein kinase (MAPK) but did not affect the phosphorylation of Janus kinase or ERK1/2. Notably, SB203580, a p38 MAPK inhibitor, had a significant inhibitory effect on spiroconazol A-induced autophagic cell death in A549 cells. Our results indicated that spiroconazol A-induced autophagy is dependent on p38 MAPK signaling and has potential as a therapeutic target in NSCLC.
      Citation: Pharmaceuticals
      PubDate: 2022-07-19
      DOI: 10.3390/ph15070893
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 894: Analgesic and Anesthetic Efficacy of
           Rocuronium/Sugammadex in Otorhinolaryngologic Surgery: A Propensity
           Score-Matched Analysis

    • Authors: Wu, Hung, Luo, Wu, Lee, Chin, Tsai, Yang
      First page: 894
      Abstract: The use of rocuronium/sugammadex in otorhinolaryngologic surgery improves intubation conditions and surgical rating scales. This study primarily aimed to evaluate the effect of the combination of rocuronium and sugammadex on intraoperative anesthetic consumption. The secondary outcomes were the intraoperative and postoperative morphine milligram equivalent (MME) consumption, duration of intraoperative hypertension, extubation time, incidence of delayed extubation and postoperative nausea and vomiting, pain score, and length of stay. A total of 2848 patients underwent otorhinolaryngologic surgery at a tertiary medical center in southern Taiwan. After applying the exclusion criteria, 2648 of these cases were included, with 167 and 2481 in the rocuronium/sugammadex and cisatracurium/neostigmine groups, respectively. To reduce potential bias, 119 patients in each group were matched by propensity scores for sex, age, body weight, and type of surgery. We found that the rocuronium/sugammadex group was associated with significant preservation of the intraoperative sevoflurane and MME consumption, with reductions of 14.2% (p = 0.009) and 11.8% (p = 0.035), respectively. The use of the combination of rocuronium and sugammadex also significantly increased the dose of intraoperative labetalol (p = 0.002), although there was no significant difference in intraoperative hypertensive events between both groups. In conclusion, our results may encourage the use of the combination of rocuronium and sugammadex as part of volatile-sparing and opioid-sparing anesthesia in otorhinolaryngologic surgery.
      Citation: Pharmaceuticals
      PubDate: 2022-07-19
      DOI: 10.3390/ph15070894
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 895: Investigation of Patient-Centric
           3D-Printed Orodispersible Films Containing Amorphous Aripiprazole

    • Authors: Lee, Park, Song, Lee, Kang, Park
      First page: 895
      Abstract: The objective of this study was to design and evaluate an orodispersible film (ODF) composed of aripiprazole (ARP), prepared using a conventional solvent casting technique, and to fuse a three-dimensional (3D) printing technique with a hot-melt extrusion (HME) filament. Klucel® LF (hydroxypropyl cellulose, HPC) and PE-05JPS® (polyvinyl alcohol, PVA) were used as backbone polymers for 3D printing and solvent casting. HPC-, PVA-, and ARP-loaded filaments were applied for 3D printing using HME. The physicochemical and mechanical properties of the 3D printing filaments and films were optimized based on the composition of the polymers and the processing parameters. The crystalline states of drug and drug-loaded formulations were investigated using differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD). The dissolution and disintegration of the 3D-printed films were faster than those of solvent-cast films. HPC-3D printed film was fully disintegrated within 45 ± 3.5 s. The dissolution rate of HPC films reached 80% within 30 min at pH 1.2 and pH 4.0 USP buffer. There was a difference in the dissolution rate of about 5 to 10% compared to PVA films at the same sampling time. The root mean square of the roughness (Rq) values of each sample were evaluated using atomic force microscopy. The higher the Rq value, the rougher the surface, and the larger the surface area, the more salivary fluid penetrated the film, resulting in faster drug release and disintegration. Specifically, The HPC 3D-printed film showed the highest Rq value (102.868 nm) and average surface roughness (85.007 nm). The puncture strength of 3D-printed films had desirable strength with HPC (0.65 ± 0.27 N/mm2) and PVA (0.93 ± 0.15 N/mm2) to prevent deformation compared to those of marketed film products (over 0.34 N/mm2). In conclusion, combining polymer selection and 3D printing technology could innovatively design ODFs composed of ARP to solve the unmet medical needs of psychiatric patients.
      Citation: Pharmaceuticals
      PubDate: 2022-07-19
      DOI: 10.3390/ph15070895
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 896: Phloridzin Reveals New Treatment
           Strategies for Liver Fibrosis

    • Authors: Yahong Shi, Tun Yan, Xi Lu, Kai Li, Yifeng Nie, Chuqiao Jiao, Huizhen Sun, Tingting Li, Xiang Li, Dong Han
      First page: 896
      Abstract: Liver fibrosis is an urgent public health problem which is difficult to resolve. However, various drugs for the treatment of liver fibrosis in clinical practice have their own problems during use. In this study, we used phloridzin to treat hepatic fibrosis in the CCl4-induced C57/BL6N mouse model, which was extracted from lychee core, a traditional Chinese medicine. The therapeutic effect was evaluated by biochemical index detections and ultrasound detection. Furthermore, in order to determine the mechanism of phloridzin in the treatment of liver fibrosis, we performed high-throughput sequencing of mRNA and lncRNA in different groups of liver tissues. The results showed that compared with the model group, the phloridzin-treated groups revealed a significant decrease in collagen deposition and decreased levels of serum alanine aminotransferase, aspartate aminotransferase, laminin, and hyaluronic acid. GO and KEGG pathway enrichment analysis of the differential mRNAs was performed and revealed that phloridzin mainly affects cell ferroptosis. Gene co-expression analysis showed that the target genes of lncRNA were obvious in cell components such as focal adhesions, intercellular adhesion, and cell–substrate junctions and in metabolic pathways such as carbon metabolism. These results showed that phloridizin can effectively treat liver fibrosis, and the mechanism may involve ferroptosis, carbon metabolism, and related changes in biomechanics.
      Citation: Pharmaceuticals
      PubDate: 2022-07-20
      DOI: 10.3390/ph15070896
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 897: The Future of Tissue-Targeted Lipid
           Nanoparticle-Mediated Nucleic Acid Delivery

    • Authors: Ruvanthi N. Kularatne, Rachael M. Crist, Stephan T. Stern
      First page: 897
      Abstract: The earliest example of in vivo expression of exogenous mRNA is by direct intramuscular injection in mice without the aid of a delivery vehicle. The current state of the art for therapeutic nucleic acid delivery is lipid nanoparticles (LNP), which are composed of cholesterol, a helper lipid, a PEGylated lipid and an ionizable amine-containing lipid. The liver is the primary organ of LNP accumulation following intravenous administration and is also observed to varying degrees following intramuscular and subcutaneous routes. Delivery of nucleic acid to hepatocytes by LNP has therapeutic potential, but there are many disease indications that would benefit from non-hepatic LNP tissue and cell population targeting, such as cancer, and neurological, cardiovascular and infectious diseases. This review will concentrate on the current efforts to develop the next generation of tissue-targeted LNP constructs for therapeutic nucleic acids.
      Citation: Pharmaceuticals
      PubDate: 2022-07-20
      DOI: 10.3390/ph15070897
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 898: Nutraceutical Interventions for
           Post-Traumatic Stress Disorder in Animal Models: A Focus on the
           Hypothalamic–Pituitary–Adrenal Axis

    • Authors: Mudan Cai, Hee Ra Park, Eun Jin Yang
      First page: 898
      Abstract: Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic events and is characterized by overwhelming fear and anxiety. Disturbances in the hypothalamic–pituitary–adrenal (HPA) axis are involved in the pathogenesis of mood disorders, including anxiety, PTSD, and major depressive disorders. Studies have demonstrated the relationship between the HPA axis response and stress vulnerability, indicating that the HPA axis regulates the immune system, fear memory, and neurotransmission. The selective serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, are the only drugs that have been approved by the United States Food and Drug Administration for the treatment of PTSD. However, SSRIs require long treatment times and are associated with lower response and remission rates; therefore, additional pharmacological interventions are required. Complementary and alternative medicine therapies ameliorate HPA axis disturbances through regulation of gut dysbiosis, insomnia, chronic stress, and depression. We have described the cellular and molecular mechanisms through which the HPA axis is involved in PTSD pathogenesis and have evaluated the potential of herbal medicines for PTSD treatment. Herbal medicines could comprise a good therapeutic strategy for HPA axis regulation and can simultaneously improve PTSD-related symptoms. Finally, herbal medicines may lead to novel biologically driven approaches for the treatment and prevention of PTSD.
      Citation: Pharmaceuticals
      PubDate: 2022-07-20
      DOI: 10.3390/ph15070898
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 899: Phosphodiesterase-4 Inhibitor
           Roflumilast-Mediated Protective Effect in Sepsis-Induced Late-Phase Event
           of Acute Kidney Injury: A Narrative Review

    • Authors: Imran Kazmi, Fahad A. Al-Abbasi, Muhammad Afzal, Muhammad Shahid Nadeem, Hisham N. Altayb, Gaurav Gupta
      First page: 899
      Abstract: Severe infections such as viral, bacterial, or fungal sepsis can cause an inflammatory response in the host, leading to organ failure and septic shock—phosphodiesterase-4 (PDE-4) inhibiting related agents from suppressing cyclic adenosine monophosphate (cAMP) degradation. Regulatory organisations have approved some substances in this category to reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with chronic bronchitis and a history of COPD exacerbations. Roflumilast has been shown to alleviate inflammatory responses, thus regulating airway inflammation. Additionally, roflumilast therapy dramatically enhanced B-cell lymphoma 2 (Bcl-2) expression, an anti-apoptotic marker lowered in septic animals. Previous research has indicated that roflumilast may help reverse sepsis-induced liver and lung harm, but whether it is also effective in reversing sepsis-induced renal impairment remains unknown. Therefore, this review determines whether roflumilast protects against renal dysfunction, inflammatory response, and apoptosis in sepsis-induced kidney damage. Additionally, we discussed the molecular mechanism through which roflumilast exerts its protective effect to uncover a possible treatment agent for sepsis-induced renal impairment.
      Citation: Pharmaceuticals
      PubDate: 2022-07-20
      DOI: 10.3390/ph15070899
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 900: Novel p38 Mitogen-Activated Protein
           Kinase Inhibitor Reverses Hypoxia-Induced Pulmonary Arterial Hypertension
           in Rats

    • Authors: Grazielle Fernandes Silva, Jaqueline Soares da Silva, Allan Kardec Nogueira de Alencar, Marina de Moraes Carvalho da Silva, Tadeu Lima Montagnoli, Bruna de Souza Rocha, Rosana Helena Coimbra Nogueira de Freitas, Roberto Takashi Sudo, Carlos Alberto Manssour Fraga, Gisele Zapata-Sudo
      First page: 900
      Abstract: Mitogen-activated protein kinase (MAPK) signaling is strongly implicated in cardiovascular remodeling in pulmonary hypertension (PH) and right ventricle (RV) failure. The effects of a newly designed p38 inhibitor, LASSBio-1824, were investigated in experimentally induced PH. Male Wistar rats were exposed to hypoxia and SU5416 (SuHx), and normoxic rats were used as controls. Oral treatment was performed for 14 days with either vehicle or LASSBio-1824 (50 mg/kg). Pulmonary vascular resistance and RV structure and function were assessed by echocardiography and catheterization. Histological, immunohistochemical and Western blot analysis of lung and RV were performed to investigate cardiovascular remodeling and inflammation. Treatment with LASSBio-1824 normalized vascular resistance by attenuating vessel muscularization and endothelial dysfunction. In the heart, treatment decreased RV systolic pressure, hypertrophy and collagen content, improving cardiac function. Protein content of TNF-α, iNOS, phosphorylated p38 and caspase-3 were reduced both in lung vessels and RV tissues after treatment and a reduced activation of transcription factor c-fos was found in cardiomyocytes of treated SuHx rats. Therefore, LASSBio-1824 represents a potential candidate for remodeling-targeted treatment of PH.
      Citation: Pharmaceuticals
      PubDate: 2022-07-21
      DOI: 10.3390/ph15070900
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 901: Sensitive Detection of Pharmaceutical
           Drugs and Metabolites in Serum Using Data-Independent Acquisition Mass
           Spectrometry and Open-Access Data Acquisition Tools

    • Authors: Syed Muhammad Zaki Shah, Arslan Ali, Muhammad Noman Khan, Adeeba Khadim, Mufarreh Asmari, Jalal Uddin, Syed Ghulam Musharraf
      First page: 901
      Abstract: Data-independent acquisition (DIA) based strategies have been explored in recent years for improving quantitative analysis of metabolites. However, the data analysis is challenging for DIA methods as the resulting spectra are highly multiplexed. Thus, the DIA mode requires advanced software analysis to facilitate the data deconvolution process. We proposed a pipeline for quantitative profiling of pharmaceutical drugs and serum metabolites in DIA mode after comparing the results obtained from full-scan, Data-dependent acquisition (DDA) and DIA modes. using open-access software. Pharmaceutical drugs (10) were pooled in healthy human serum and analysed by LC-ESI-QTOF-MS. MS1 full-scan and Data-dependent (MS2) results were used for identification using MS-DIAL software while deconvolution of MS1/MS2 spectra in DIA mode was achieved by using Skyline software. The results of acquisition methods for quantitative analysis validated the remarkable analytical performance of the constructed workflow, proving it to be a sensitive and reproducible pipeline for biological complex fluids.
      Citation: Pharmaceuticals
      PubDate: 2022-07-21
      DOI: 10.3390/ph15070901
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 902: Naturally Occurring
           8ß,13ß-kaur-15-en-17-al and Anti-Malarial Activity from
           Podocarpus polystachyus Leaves

    • Authors: Mira Syahfriena Amir Rawa, Mohammad G. Al-Thiabat, Toshihiko Nogawa, Yushi Futamura, Akiko Okano, Habibah A. Wahab
      First page: 902
      Abstract: Despite much interest and studies toward the genus Podocarpus, the anti-malarial evaluation of Podocarpus polystachyus’s phytoconstituents remains lacking. Herein, the phytoconstituents of P. polystachyus leaves and their anti-malarial effect against Plasmodium falciparum were investigated for the first time. One new natural product, 8ß,13ß-kaur-15-en-17-al (1), along with three known compounds, 8ß,13ß-kaur-15-en-17-ol (2) and 13ß-kaur-16-ene (3), and α-tocopherol hydroquinone (4) were isolated via HR-ESI-MS and NMR analyses. Compounds 1 and 2 inhibited P. falciparum growth at 12 and 52 µM of IC50, respectively. Their anti-malarial activity was associated with the in silico P. falciparum lactate dehydrogenase (PfLDH) inhibition. Molecular docking of ligands 1 and 2 with the putative target PfLDH revealed ~−2 kcal/mol of binding energies more negative than the control. Molecular dynamic simulations (100 ns) showed equal or smaller deviation values (RMSD, RMSF, Rg) and stronger interactions of PfLDH-1 and PfLDH-2 complexes via at least one consistent H-bond than the control. Additionally, a slightly increased PfLDH H-bond profile in their interactions improved the PfLDH dynamic and structural stabilities. Overall, this study supports the relevance of 1 and 2 as plasmodial growth inhibitors with their putative anti-PfLDH activity, which could be a potential scaffold for developing anti-malarial drugs.
      Citation: Pharmaceuticals
      PubDate: 2022-07-21
      DOI: 10.3390/ph15070902
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 903: Siccanin Is a Dual-Target Inhibitor
           of Plasmodium falciparum Mitochondrial Complex II and Complex III

    • Authors: Keisuke Komatsuya, Takaya Sakura, Kazuro Shiomi, Satoshi Ōmura, Kenji Hikosaka, Tomoyoshi Nozaki, Kiyoshi Kita, Daniel Ken Inaoka
      First page: 903
      Abstract: Plasmodium falciparum contains several mitochondrial electron transport chain (ETC) dehydrogenases shuttling electrons from the respective substrates to the ubiquinone pool, from which electrons are consecutively transferred to complex III, complex IV, and finally to the molecular oxygen. The antimalarial drug atovaquone inhibits complex III and validates this parasite’s ETC as an attractive target for chemotherapy. Among the ETC dehydrogenases from P. falciparum, dihydroorotate dehydrogenase, an essential enzyme used in de novo pyrimidine biosynthesis, and complex III are the two enzymes that have been characterized and validated as drug targets in the blood-stage parasite, while complex II has been shown to be essential for parasite survival in the mosquito stage; therefore, these enzymes and complex II are considered candidate drug targets for blocking parasite transmission. In this study, we identified siccanin as the first (to our knowledge) nanomolar inhibitor of the P. falciparum complex II. Moreover, we demonstrated that siccanin also inhibits complex III in the low-micromolar range. Siccanin did not inhibit the corresponding complexes from mammalian mitochondria even at high concentrations. Siccanin inhibited the growth of P. falciparum with IC50 of 8.4 μM. However, the growth inhibition of the P. falciparum blood stage did not correlate with ETC inhibition, as demonstrated by lack of resistance to siccanin in the yDHODH-3D7 (EC50 = 10.26 μM) and Dd2-ELQ300 strains (EC50 = 18.70 μM), suggesting a third mechanism of action that is unrelated to mitochondrial ETC inhibition. Hence, siccanin has at least a dual mechanism of action, being the first potent and selective inhibitor of P. falciparum complexes II and III over mammalian enzymes and so is a potential candidate for the development of a new class of antimalarial drugs.
      Citation: Pharmaceuticals
      PubDate: 2022-07-21
      DOI: 10.3390/ph15070903
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 904: Bolus Injection of Liraglutide Raises
           Plasma Glucose in Normal Rats by Activating Glucagon-like Peptide 1
           Receptor in the Brain

    • Authors: Chia-Chen Hsu, Juei-Tang Cheng, Ping Hao Hsu, Yingxiao Li, Kai-Chun Cheng
      First page: 904
      Abstract: Diabetes is commonly treated with glucagon-like peptide-1 receptor (GLP-1R) agonists including liraglutide and others. However, liraglutide was found to raise plasma glucose levels in normal rats. The current study aims to determine how liraglutide causes this contentious condition in rats, both normal and diabetic. An adrenalectomy was performed to investigate the relationship between steroid hormone and liraglutide. To investigate the effect of central liraglutide infusion on blood glucose in rats, rats were intracerebroventricularly administrated with liraglutide with or without HPA axis inhibitors such as berberine and dexamethasone. The results showed that a single injection of liraglutide caused a temporary increase in blood glucose in healthy rats. Another GLP-1R agonist, Exendin-4 (Ex-4), increased blood sugar in a manner similar to that of liraglutide. The effects of liraglutide were also blocked by guanethidine pretreatment and vanished in normal rats with adrenalectomy. Additionally, central infusion of liraglutide via intracerebroventricular (icv) injection into normal rats also causes a temporary increase in blood glucose that was blocked by GLP-1R antagonists or the inhibitors such as berberine and dexamethasone. Similarly, central liraglutide treatment causes temporary increases in plasma glucose, adrenocorticotropic hormone (ACTH), and cortisol levels, which were reversed by inhibitors for the hypothalamic-pituitary-adrenal (HPA) axis. In normal rats, the temporary glucose-increasing effect of liraglutide was gradually eliminated during consecutive daily treatments, indicating tolerance formation. Additionally, liraglutide and Ex-4 cross-tolerance was also discovered in normal rats. Liraglutide was more effective in diabetic rats than in normal rats in activating GLP-1R gene expression in the isolated adrenal gland. Interestingly, the effect of liraglutide on glycemic control varied depending on whether the rats were diabetic or not. In normal rats, bolus injection of liraglutide, such as Ex-4, may stimulate the HPA axis, resulting in hyperglycemia. The cross-tolerance of liraglutide and Ex-4 provided a novel perspective on GLP-1R activation.
      Citation: Pharmaceuticals
      PubDate: 2022-07-21
      DOI: 10.3390/ph15070904
      Issue No: Vol. 15, No. 7 (2022)
  • Pharmaceuticals, Vol. 15, Pages 905: Traditional Uses, Phytochemistry, and

    • Authors: Emmanuel Nyongesa Waswa, Felix Wambua Muema, Wyclif Ochieng Odago, Elizabeth Syowai Mutinda, Consolata Nanjala, Elijah Mbandi Mkala, Sarah Getachew Amenu, Shi-Xiong Ding, Jing Li, Guang-Wan Hu
      First page: 905
      Abstract: Blechnum L. is a genus belonging to the Blechnaceae family with 236 accepted species that grow in intertropical, subtropical, and southern temperate regions. Several species of the genus have long been used in folk medicines to treat a broad spectrum of ailments, including typhoid, urinary infections, influenza, wounds, pulmonary complaints, blisters, boils, and antihelmintic-related complications. So far, about 91 chemical compounds have been isolated from different parts of 20 Blechnum species. Among these metabolites, phenolic compounds, sterols, and fatty acids are the main constituents. Modern pharmacological investigations revealed several isolated compounds and extracts to exhibit exceptional biological properties including the antioxidant, antimicrobial, anti-inflammatory, anticancer, insecticidal, antitrematocidal and wound healing. In various tests, both quercetin-7′,3′,4′-trimethoxy and phytol metabolites showed potential antioxidant and antitrematocidal properties, while ponasterone exhibited insecticidal activity. Despite having a broad range of traditional medicinal benefits and biological properties, understanding the scientific connotations based on the available data is still challenging. This article presents a comprehensive review of the traditional uses, phytochemical compounds, and pharmacological aspects of the Blechnum species.
      Citation: Pharmaceuticals
      PubDate: 2022-07-21
      DOI: 10.3390/ph15070905
      Issue No: Vol. 15, No. 7 (2022)
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