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

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

Showing 201 - 400 of 735 Journals sorted alphabetically
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 11)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 13)
Computational Chemistry     Open Access   (Followers: 3)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 12)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 6)
Corrosion Communications     Open Access  
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 17)
Croatica Chemica Acta     Open Access  
CrystEngComm     Hybrid Journal   (Followers: 10)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 8)
Current Opinion in Green and Sustainable Chemistry     Hybrid Journal  
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 8)
Current Protocols in Nucleic Acid Chemistry     Hybrid Journal  
Current Protocols in Protein Science     Hybrid Journal   (Followers: 1)
Current Research in Chemical Biology     Open Access  
Current Research in Chemistry     Open Access   (Followers: 7)
Current Research in Green and Sustainable Chemistry     Open Access  
Current Science     Open Access   (Followers: 117)
Current Topics in Medicinal Chemistry     Hybrid Journal   (Followers: 7)
Dalton Transactions     Hybrid Journal   (Followers: 23)
Detection     Open Access   (Followers: 3)
Diamond and Related Materials     Hybrid Journal   (Followers: 10)
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 4)
Ecological Chemistry and Engineering S     Open Access   (Followers: 2)
Educação Química en Punto de Vista     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 5)
EDUSAINS     Open Access  
EJNMMI Radiopharmacy and Chemistry     Open Access  
Elements     Full-text available via subscription   (Followers: 3)
Energetic Materials Frontiers     Open Access  
EnergyChem     Hybrid Journal   (Followers: 1)
Environmental Chemistry     Hybrid Journal   (Followers: 9)
Environmental Chemistry and Ecotoxicology     Open Access  
Environmental Chemistry Letters     Hybrid Journal   (Followers: 4)
Environmental Science & Technology Letters     Hybrid Journal   (Followers: 8)
Environmental Science : Nano     Hybrid Journal   (Followers: 2)
Environmental Toxicology & Chemistry     Hybrid Journal   (Followers: 22)
Enzyme Research     Open Access   (Followers: 4)
Eurasian Chemico-Technological Journal     Open Access  
European Journal of Chemistry     Open Access   (Followers: 25)
European Journal of Histochemistry     Open Access   (Followers: 4)
European Journal of Medicinal Chemistry     Hybrid Journal   (Followers: 20)
European Journal of Medicinal Chemistry Reports     Open Access  
European Online Journal of Natural and Social Sciences     Open Access   (Followers: 4)
Faraday Discussions     Hybrid Journal   (Followers: 3)
Fine Chemical Technologies / Тонкие химические технологии     Open Access  
FirePhysChem     Open Access  
Fitoterapia     Hybrid Journal   (Followers: 4)
FlatChem : Chemistry of Flat Materials     Hybrid Journal  
Fluid Phase Equilibria     Hybrid Journal   (Followers: 4)
Folia Histochemica et Cytobiologica     Open Access  
Folia Microbiologica     Hybrid Journal   (Followers: 2)
Food Chemistry : Molecular Sciences     Open Access   (Followers: 1)
Food Digestion     Hybrid Journal   (Followers: 5)
Food Security     Open Access   (Followers: 11)
Food Structure     Hybrid Journal   (Followers: 3)
Forensic Chemistry     Hybrid Journal   (Followers: 9)
Foundations of Chemistry     Hybrid Journal   (Followers: 4)
Frontiers in Chemistry     Open Access   (Followers: 4)
Frontiers in Soil Science     Open Access  
Frontiers of Chemical Science and Engineering     Hybrid Journal   (Followers: 5)
Fullerenes, Nanotubes and Carbon Nanostructures     Hybrid Journal   (Followers: 9)
Future Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Gases     Open Access   (Followers: 1)
Gels     Open Access  
Geochemical Transactions     Open Access   (Followers: 2)
Geofluids     Open Access   (Followers: 5)
Giant     Open Access   (Followers: 1)
Graphene     Open Access   (Followers: 7)
Graphene     Full-text available via subscription   (Followers: 3)
Graphene Technology     Hybrid Journal  
Green Analytical Chemistry     Open Access   (Followers: 6)
Green and Sustainable Chemistry     Open Access   (Followers: 4)
Green Chemistry Letters and Reviews     Open Access   (Followers: 6)
Green Synthesis and Catalysis     Open Access  
GSTF Journal of Chemical Sciences (JChem)     Open Access  
Helvetica Chimica Acta     Hybrid Journal   (Followers: 30)
Heritage Science     Open Access   (Followers: 5)
Heteroatom Chemistry     Open Access   (Followers: 3)
High Energy Chemistry     Hybrid Journal  
Indian Chemical Engineer     Hybrid Journal   (Followers: 4)
Indian Journal of Chemical Technology (IJCT)     Open Access   (Followers: 9)
Indian Journal of Chemistry - Section B (IJC-B)     Open Access   (Followers: 10)
Indian Journal of Natural Products and Resources (IJNPR)     Open Access   (Followers: 1)
Indonesian Journal of Chemical Science     Open Access  
Indonesian Journal of Chemistry     Open Access   (Followers: 1)
Indonesian Journal of Pure and Applied Chemistry     Partially Free  
Industrial & Engineering Chemistry     Full-text available via subscription   (Followers: 10)
InfoMat     Open Access  
Inorganic Chemistry     Hybrid Journal   (Followers: 31)
Inorganic Chemistry Communications     Hybrid Journal   (Followers: 13)
Inorganic Materials     Hybrid Journal   (Followers: 5)
Inorganica Chimica Acta     Hybrid Journal   (Followers: 6)
Instrumentation Science & Technology     Hybrid Journal   (Followers: 7)
International Archives of Science and Technology     Open Access  
International Journal for Ion Mobility Spectrometry     Hybrid Journal   (Followers: 1)
International Journal of Adhesion and Adhesives     Hybrid Journal   (Followers: 18)
International Journal of Advanced Chemistry     Open Access   (Followers: 1)
International Journal of Agrochemistry     Full-text available via subscription  
International Journal of Analytical Mass Spectrometry and Chromatography     Open Access   (Followers: 7)
International Journal of Biological and Chemical Sciences     Open Access   (Followers: 4)
International Journal of Biological Chemistry     Open Access   (Followers: 2)
International Journal of Biological, Physical and Chemical Studies     Open Access  
International Journal of Chemical Kinetics     Hybrid Journal   (Followers: 7)
International Journal of Chemical Technology     Open Access   (Followers: 7)
International Journal of Chemistry     Open Access   (Followers: 10)
International Journal of Chemistry and Technology     Open Access   (Followers: 1)
International Journal of Chemoinformatics and Chemical Engineering     Full-text available via subscription   (Followers: 2)
International Journal of Corrosion     Open Access   (Followers: 10)
International Journal of Energetic Materials     Full-text available via subscription  
International Journal of Environmental Chemistry     Full-text available via subscription  
International Journal of Materials and Chemistry     Open Access   (Followers: 7)
International Journal of Medicinal Chemistry     Open Access   (Followers: 4)
International Journal of Minerals, Metallurgy, and Materials     Hybrid Journal   (Followers: 9)
International Journal of Molecular Sciences     Open Access   (Followers: 2)
International Journal of Nano Dimension     Open Access   (Followers: 2)
International Journal of Photoenergy     Open Access   (Followers: 3)
International Journal of Spray and Combustion Dynamics     Full-text available via subscription   (Followers: 15)
International Journal of Thermodynamics and Chemical Kinetics     Full-text available via subscription   (Followers: 2)
International Journal of Tryptophan Research     Open Access  
International Letters of Chemistry, Physics and Astronomy     Open Access   (Followers: 9)
International Research Journal of Pure and Applied Chemistry     Open Access  
Iranian Journal of Chemistry and Chemical Engineering (IJCCE)     Open Access   (Followers: 1)
Iranian Polymer Journal     Hybrid Journal   (Followers: 3)
Iraqi Journal of Pharmacy     Open Access  
Israel Journal of Chemistry     Full-text available via subscription   (Followers: 4)
IUCrData     Open Access   (Followers: 1)
JACS Au     Open Access  
JBIC Journal of Biological Inorganic Chemistry     Hybrid Journal   (Followers: 2)
JCIS Open     Open Access   (Followers: 1)
JOT Journal für Oberflächentechnik     Hybrid Journal   (Followers: 1)
JOT-International Surface Technology     Hybrid Journal   (Followers: 1)
Journal of Adhesion     Hybrid Journal   (Followers: 7)
Journal of Adhesion Science and Technology     Hybrid Journal   (Followers: 10)
Journal of Advances in Chemistry     Open Access   (Followers: 4)
Journal of Agricultural and Food Chemistry     Hybrid Journal   (Followers: 9)
Journal of Agricultural Chemistry and Environment     Open Access   (Followers: 3)
Journal of Al-Qadisiyah for Pure Science     Open Access  
Journal of Amino Acids     Open Access   (Followers: 1)
Journal of Analytical Methods in Chemistry     Open Access   (Followers: 1)
Journal of Analytical Sciences, Methods and Instrumentation     Open Access   (Followers: 4)
Journal of AOAC International     Hybrid Journal   (Followers: 4)
Journal of Applied Chemistry     Open Access   (Followers: 6)
Journal of Applied Solution Chemistry and Modeling     Hybrid Journal   (Followers: 1)
Journal of Applied Spectroscopy     Hybrid Journal   (Followers: 9)
Journal of Biomaterials and Nanobiotechnology     Open Access   (Followers: 6)
Journal of Boron     Open Access  
Journal of Carbohydrate Chemistry     Hybrid Journal   (Followers: 4)
Journal of Catalysis     Hybrid Journal   (Followers: 11)
Journal of Catalyst & Catalysis     Full-text available via subscription   (Followers: 2)
Journal of Chemical & Engineering Data     Hybrid Journal   (Followers: 10)
Journal of Chemical Education     Hybrid Journal   (Followers: 20)
Journal of Chemical Information and Modeling     Hybrid Journal   (Followers: 18)
Journal of Chemical Research     Open Access   (Followers: 6)
Journal of Chemical Reviews     Open Access  
Journal of Chemical Sciences     Partially Free   (Followers: 22)
Journal of Chemical Theory and Computation     Hybrid Journal   (Followers: 21)
Journal of Chemical Thermodynamics     Hybrid Journal   (Followers: 7)
Journal of Cheminformatics     Open Access   (Followers: 7)
Journal of Chemistry     Open Access   (Followers: 6)
Journal of Chemistry, Environmental Sciences and its Applications     Open Access   (Followers: 2)
Journal of Chemometrics     Hybrid Journal   (Followers: 9)
Journal of Chromatography A     Hybrid Journal   (Followers: 61)
Journal of Chromatography Open     Open Access   (Followers: 1)
Journal of Coating Science and Technology     Hybrid Journal  
Journal of Colloid and Interface Science     Hybrid Journal   (Followers: 16)
Journal of Computational Chemistry     Hybrid Journal   (Followers: 21)
Journal of Coordination Chemistry     Hybrid Journal   (Followers: 5)
Journal of Dispersion Science and Technology     Hybrid Journal  
Journal of Education and Science     Open Access   (Followers: 2)
Journal of Encapsulation and Adsorption Sciences     Open Access   (Followers: 1)
Journal of Energy Chemistry     Full-text available via subscription   (Followers: 3)
Journal of Flow Chemistry     Full-text available via subscription   (Followers: 1)
Journal of Fluorescence     Hybrid Journal   (Followers: 3)
Journal of Fluorine Chemistry     Hybrid Journal   (Followers: 7)
Journal of Fuel Chemistry and Technology     Full-text available via subscription   (Followers: 1)
Journal of Great Lakes Research     Hybrid Journal   (Followers: 5)
Journal of Heterocyclic Chemistry     Hybrid Journal   (Followers: 9)
Journal of Immunoassay and Immunochemistry     Hybrid Journal   (Followers: 8)
Journal of Inclusion Phenomena and Macrocyclic Chemistry     Hybrid Journal   (Followers: 1)
Journal of Inorganic Biochemistry     Hybrid Journal   (Followers: 4)
Journal of Ionic Liquids     Open Access  
Journal of Labelled Compounds and Radiopharmaceuticals     Hybrid Journal   (Followers: 4)
Journal of Macromolecular Science, Part A: Pure and Applied Chemistry     Hybrid Journal   (Followers: 1)
Journal of Mass Spectrometry     Hybrid Journal   (Followers: 39)
Journal of Materials Chemistry A : Materials for Energy and Sustainability     Hybrid Journal   (Followers: 40)
Journal of Materials Chemistry B : Materials for Biology and Medicine     Hybrid Journal   (Followers: 11)
Journal of Materials Chemistry C : Materials for Optical, Magnetic and Electronic Devices     Hybrid Journal   (Followers: 17)
Journal of Materials Physics and Chemistry     Open Access   (Followers: 7)
Journal of Materials Research     Full-text available via subscription   (Followers: 13)
Journal of Materials Science and Chemical Engineering     Open Access   (Followers: 1)
Journal of Mathematical Chemistry     Hybrid Journal   (Followers: 5)
Journal of Medicinal Chemistry     Hybrid Journal   (Followers: 134)
Journal of Membrane Science     Hybrid Journal   (Followers: 22)
Journal of Metastable and Nanocrystalline Materials     Full-text available via subscription   (Followers: 1)
Journal of Modern Chemistry & Chemical Technology     Open Access   (Followers: 2)
Journal of Molecular Graphics and Modelling     Hybrid Journal   (Followers: 1)

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Journal Cover
International Journal of Molecular Sciences
Journal Prestige (SJR): 1.26
Citation Impact (citeScore): 4
Number of Followers: 2  

  This is an Open Access Journal Open Access journal
ISSN (Print) 1661-6596 - ISSN (Online) 1422-0067
Published by MDPI Homepage  [84 journals]
  • IJMS, Vol. 23, Pages 7047: Human Mesenchymal Stem Cell-Derived
           Extracellular Vesicles Promote Neural Differentiation of Neural Progenitor

    • Authors: So-Yeon Park, Da-Seul Kim, Hyun-Mun Kim, Jun-Kyu Lee, Dong-Youn Hwang, Tae-Hyung Kim, Seungkwon You, Dong Keun Han
      First page: 7047
      Abstract: Mesenchymal stem cells (MSCs) have been adopted in various preclinical and clinical studies because of their multipotency and low immunogenicity. However, numerous obstacles relating to safety issues remain. Therefore, MSC-derived extracellular vesicles (EVs) have been recently employed. EVs are nano-sized endoplasmic reticulum particles generated and released in cells that have similar biological functions to their origin cells. EVs act as cargo for bioactive molecules such as proteins and genetic materials and facilitate tissue regeneration. EVs obtained from adipose-derived MSC (ADMSC) also have neuroprotective and neurogenesis effects. On the basis of the versatile effects of EVs, we aimed to enhance the neural differentiation ability of ADMSC-derived EVs by elucidating the neurogenic-differentiation process. ADMSC-derived EVs isolated from neurogenesis conditioned media (differentiated EVs, dEVs) increased neurogenic ability by altering innate microRNA expression and cytokine composition. Consequently, dEVs promoted neuronal differentiation of neural progenitor cells in vitro, suggesting that dEVs are a prospective candidate for EV-based neurological disorder regeneration therapy.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-24
      DOI: 10.3390/ijms23137047
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7048: The Interplay between cGMP and Calcium
           Signaling in Alzheimer’s Disease

    • Authors: Aileen Jehle, Olga Garaschuk
      First page: 7048
      Abstract: Cyclic guanosine monophosphate (cGMP) is a ubiquitous second messenger and a key molecule in many important signaling cascades in the body and brain, including phototransduction, olfaction, vasodilation, and functional hyperemia. Additionally, cGMP is involved in long-term potentiation (LTP), a cellular correlate of learning and memory, and recent studies have identified the cGMP-increasing drug Sildenafil as a potential risk modifier in Alzheimer’s disease (AD). AD development is accompanied by a net increase in the expression of nitric oxide (NO) synthases but a decreased activity of soluble guanylate cyclases, so the exact sign and extent of AD-mediated imbalance remain unclear. Moreover, human patients and mouse models of the disease present with entangled deregulation of both cGMP and Ca2+ signaling, e.g., causing changes in cGMP-mediated Ca2+ release from the intracellular stores as well as Ca2+-mediated cGMP production. Still, the mechanisms governing such interplay are poorly understood. Here, we review the recent data on mechanisms underlying the brain cGMP signaling and its interconnection with Ca2+ signaling. We also discuss the recent evidence stressing the importance of such interplay for normal brain function as well as in Alzheimer’s disease.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-24
      DOI: 10.3390/ijms23137048
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7050: Candida Worsens Klebsiella pneumoniae
           Induced-Sepsis in a Mouse Model with Low Dose Dextran Sulfate Solution
           through Gut Dysbiosis and Enhanced Inflammation

    • Authors: Wimonrat Panpetch, Pornpimol Phuengmaung, Pratsanee Hiengrach, Jiraphorn Issara-Amphorn, Thanya Cheibchalard, Naraporn Somboonna, Somying Tumwasorn, Asada Leelahavanichkul
      First page: 7050
      Abstract: Klebsiella pneumoniae is an opportunistic pathogen and a commensal organism that is possibly enhanced in several conditions with gut dysbiosis, and frequently detectable together with Candida overgrowth. Here, K. pneumoniae with or without Candida albicans was daily orally administered for 3 months in 0.8% dextran sulfate solution-induced mucositis mice and also tested in vitro. As such, Candida worsened Klebsiella-DSS-colitis as demonstrated by mortality, leaky gut (FITC-dextran assay, bacteremia, endotoxemia, and serum beta-glucan), gut dysbiosis (increased Deferribacteres from fecal microbiome analysis), liver pathology (histopathology), liver apoptosis (activated caspase 3), and cytokines (in serum and in the internal organs) when compared with Klebsiella-administered DSS mice. The combination of heat-killed Candida plus Klebsiella mildly facilitated inflammation in enterocytes (Caco-2), hepatocytes (HepG2), and THP-1-derived macrophages as indicated by supernatant cytokines or the gene expression. The addition of heat-killed Candida into Klebsiella preparations upregulated TLR-2, reduced Occludin (an intestinal tight junction molecule), and worsened enterocyte integrity (transepithelial electrical resistance) in Caco-2 and enhanced casp8 and casp9 (apoptosis genes) in HepG2 when compared with heat-killed Klebsiella alone. In conclusion, Candida enhanced enterocyte inflammation (partly through TLR-2 upregulation and gut dysbiosis) that induced gut translocation of endotoxin and beta-glucan causing hyper-inflammatory responses, especially in hepatocytes and macrophages.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-24
      DOI: 10.3390/ijms23137050
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7051: Chronically Radiation-Exposed Survivor

    • Authors: Nareg Pinarbasi-Degirmenci, Ilknur Sur-Erdem, Vuslat Akcay, Yasemin Bolukbasi, Ugur Selek, Ihsan Solaroglu, Tugba Bagci-Onder
      First page: 7051
      Abstract: Glioblastoma is the most malignant primary brain tumor, and a cornerstone in its treatment is radiotherapy. However, tumor cells surviving after irradiation indicates treatment failure; therefore, better understanding of the mechanisms regulating radiotherapy response is of utmost importance. In this study, we generated clinically relevant irradiation-exposed models by applying fractionated radiotherapy over a long time and selecting irradiation-survivor (IR-Surv) glioblastoma cells. We examined the transcriptomic alterations, cell cycle and growth rate changes and responses to secondary radiotherapy and DNA damage response (DDR) modulators. Accordingly, IR-Surv cells exhibited slower growth and partly retained their ability to resist secondary irradiation. Concomitantly, IR-Surv cells upregulated the expression of DDR-related genes, such as CHK1, ATM, ATR, and MGMT, and had better DNA repair capacity. IR-Surv cells displayed downregulation of hypoxic signature and lower induction of hypoxia target genes, compared to naïve glioblastoma cells. Moreover, Chk1 inhibition alone or in combination with irradiation significantly reduced cell viability in both naïve and IR-Surv cells. However, IR-Surv cells’ response to Chk1 inhibition markedly decreased under hypoxic conditions. Taken together, we demonstrate the utility of combining DDR inhibitors and irradiation as a successful approach for both naïve and IR-Surv glioblastoma cells as long as cells are refrained from hypoxic conditions.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-24
      DOI: 10.3390/ijms23137051
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7053: Involvement of the PI3K/AKT Intracellular
           Signaling Pathway in the AntiCancer Activity of Hydroxytyrosol, a
           Polyphenol from Olea europaea, in Hematological Cells and Implication of
           HSP60 Levels in Its Anti-Inflammatory Activity

    • Authors: Alberto Parra-Perez, Amalia Pérez-Jiménez, Isabel Gris-Cárdenas, Gloria Bonel-Pérez, Luis Carrasco-Díaz, Khalida Mokhtari, Leticia García-Salguero, José Lupiáñez, Eva Rufino-Palomares
      First page: 7053
      Abstract: Hydroxytyrosol (HT), the main representative of polyphenols of olive oil, has been described as one of the most powerful natural antioxidants, also showing anti-inflammatory, antimicrobial, cardioprotective and anticancer activity in different type of cancers, but has been little studied in hematological neoplasms. The objective of this work was to evaluate the anticancer potential of HT in acute human leukemia T cells (Jurkat and HL60) and the anti-inflammatory potential in murine macrophages (Raw264.7). For this, cytotoxicity tests were performed for HT, showing IC50 values, at 24 h, for Jurkat, HL60 and Raw264.7 cells, of 27.3 µg·mL−1, 109.8 µg·mL−1 and 45.7 µg·mL−1, respectively. At the same time, HT caused cell arrest in G0/G1 phase in both Jurkat and HL60 cells by increasing G0/G1 phase and significantly decreasing S phase. Apoptosis and cell cycle assays revealed an antiproliferative effect of HT, decreasing the percentage of dividing cells and increasing apoptosis. Furthermore, HT inhibited the PI3K signaling pathway and, consequently, the MAPK pathway was activated. Inflammation tests revealed that HT acts as an anti-inflammatory agent, reducing NO levels in Raw264.7 cells previously stimulated by lipopolysaccharide (LPS). These processes were confirmed by the changes in the expression of the main markers of inflammation and cancer. In conclusion, HT has an anticancer and anti-inflammatory effect in the cell lines studied, which were Raw264.7, Jurkat, and HL60, and could be used as a natural drug in the treatment of liquid cancers, leukemias, myelomas and lymphomas.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-24
      DOI: 10.3390/ijms23137053
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7054: Comparative Genomic Analysis of SAUR Gene
           Family, Cloning and Functional Characterization of Two Genes (PbrSAUR13
           and PbrSAUR52) in Pyrus bretschneideri

    • Authors: Mengna Wang, Muhammad Aamir Manzoor, Xinya Wang, Xiaofeng Feng, Yu Zhao, Jinling He, Yongping Cai
      First page: 7054
      Abstract: The SAUR (small auxin-up RNA) gene family is the biggest family of early auxin response genes in higher plants and has been associated with the control of a variety of biological processes. Although SAUR genes had been identified in several genomes, no systematic analysis of the SAUR gene family has been reported in Chinese white pear. In this study, comparative and systematic genomic analysis has been performed in the SAUR gene family and identified a total of 116 genes from the Chinese white pear. A phylogeny analysis revealed that the SAUR family could be classified into four groups. Further analysis of gene structure (introns/exons) and conserved motifs showed that they are diverse functions and SAUR-specific domains. The most frequent mechanisms are whole-genome duplication (WGD) and dispersed duplication (DSD), both of which may be important in the growth of the SAUR gene family in Chinese white pear. Moreover, cis-acting elements of the PbrSAUR genes were found in promoter regions associated with the auxin-responsive elements that existed in most of the upstream sequences. Remarkably, the qRT-PCR and transcriptomic data indicated that PbrSAUR13 and PbrSAUR52 were significantly expressed in fruit ripening. Subsequently, subcellular localization experiments revealed that PbrSAUR13 and PbrSAUR52 were localized in the nucleus. Moreover, PbrSAUR13 and PbrSAUR52 were screened for functional verification, and Dangshan pear and frandi strawberry were transiently transformed. Finally, the effects of these two genes on stone cells and lignin were analyzed by phloroglucinol staining, Fourier infrared spectroscopy, and qRT-PCR. It was found that PbrSAUR13 promoted the synthesis and accumulation of stone cells and lignin, PbrSAUR52 inhibited the synthesis and accumulation of stone cells and lignin. In conclusion, these results indicate that PbrSAUR13 and PbrSAUR52 are predominantly responsible for lignin inhibit synthesis, which provides a basic mechanism for further study of PbrSAUR gene functions.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-24
      DOI: 10.3390/ijms23137054
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7055: Drug-Resistant Stem Cells: Novel Approach for
           Colon Cancer Therapy

    • Authors: Nitin Telang
      First page: 7055
      Abstract: Background: Next to breast cancer, advanced stage metastatic colon cancer represents a major cause for mortality in women. Germline or somatic mutations in tumor suppressor genes or in DNA mismatch repair genes represent risk factors for genetic predisposition of colon cancer that are also detectable in sporadic colon cancer. Conventional chemotherapy for colon cancer includes combination of 5-fluoro-uracil with oxaliplatin and irinotecan or targeted therapy with non-steroid anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors. Major limitations of these therapeutic interventions are associated with systemic toxicity, acquired tumor resistance and the emergence of drug resistant stem cells that favor initiation, progression and metastasis of therapy-resistant disease. These limitations emphasize an unmet need to identify tumor stem cell selective testable alternatives. Drug-resistant stem cell models facilitate the identification of new testable alternatives from natural phytochemicals and herbal formulations. The goal of this review is to provide an overview relevant to the current status of conventional/targeted therapy, the role of cancer stem cells and the status of testable alternatives for therapy-resistant colon cancer. Experimental models: Hyper-proliferative and tumorigenic cell lines from genetically predisposed colonic tissues of female mice represent experimental models. Chemotherapeutic agents select drug-resistant phenotypes that exhibit upregulated expressions of cellular and molecular stem cell markers. Mechanistically distinct natural phytochemicals effectively inhibit stem cell growth and downregulate the expressions of stem cell markers. Conclusions: The present review discusses the status of colon cancer therapy and inherent limitations, cancer stem cell biology, potential lead compounds and their advantages over chemotherapy. The present experimental approaches will facilitate the identification of pharmacological and naturally-occurring agents as lead compounds for stem cell targeted therapy of colon cancer.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-24
      DOI: 10.3390/ijms23137055
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7056: Development and Molecular Cytogenetic
           Identification of Two Wheat-Aegilops geniculata Roth 7Mg Chromosome
           Substitution Lines with Resistance to Fusarium Head Blight, Powdery Mildew
           and Stripe Rust

    • Authors: Xiaoying Yang, Maoru Xu, Yongfu Wang, Xiaofang Cheng, Chenxi Huang, Hong Zhang, Tingdong Li, Changyou Wang, Chunhuan Chen, Yajuan Wang, Wanquan Ji
      First page: 7056
      Abstract: Fusarium head blight (Fhb), powdery mildew, and stripe rust are major wheat diseases globally. Aegilops geniculata Roth (UgUgMgMg, 2n = 4x = 28), a wild relative of common wheat, is valuable germplasm of disease resistance for wheat improvement and breeding. Here, we report the development and characterization of two substitution accessions with high resistance to powdery mildew, stripe rust and Fhb (W623 and W637) derived from hybrid progenies between Ae. geniculata and hexaploid wheat Chinese Spring (CS). Fluorescence in situ hybridization (FISH), Genomic in situ hybridizations (GISH), and sequential FISH-GISH studies indicated that the two substitution lines possess 40 wheat chromosomes and 2 Ae. geniculata chromosomes. Furthermore, compared that the wheat addition line parent W166, the 2 alien chromosomes from W623 and W637 belong to the 7Mg chromosomes of Ae. geniculata via sequential FISH-GISH and molecular marker analysis. Nullisomic-tetrasomic analysis for homoeologous group-7 of wheat and FISH revealed that the common wheat chromosomes 7A and 7B were replaced in W623 and W637, respectively. Consequently, lines W623, in which wheat chromosomes 7A were replaced by a pair of Ae. geniculata 7Mg chromosomes, and W637, which chromosomes 7B were substituted by chromosomes 7Mg, with resistance to Fhb, powdery mildew, and stripe rust. This study has determined that the chromosome 7Mg from Ae. geniculata exists genes resistant to Fhb and powdery mildew.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-24
      DOI: 10.3390/ijms23137056
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7057: Computational Analysis Identifies Novel
           Biomarkers for High-Risk Bladder Cancer Patients

    • Authors: Radosław Piliszek, Anna A. Brożyna, Witold R. Rudnicki
      First page: 7057
      Abstract: In the case of bladder cancer, carcinoma in situ (CIS) is known to have poor diagnosis. However, there are not enough studies that examine the biomarkers relevant to CIS development. Omics experiments generate data with tens of thousands of descriptive variables, e.g., gene expression levels. Often, many of these descriptive variables are identified as somehow relevant, resulting in hundreds or thousands of relevant variables for building models or for further data analysis. We analyze one such dataset describing patients with bladder cancer, mostly non-muscle-invasive (NMIBC), and propose a novel approach to feature selection. This approach returns high-quality features for prediction and yet allows interpretability as well as a certain level of insight into the analyzed data. As a result, we obtain a small set of seven of the most-useful biomarkers for diagnostics. They can also be used to build tests that avoid the costly and time-consuming existing methods. We summarize the current biological knowledge of the chosen biomarkers and contrast it with our findings.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-24
      DOI: 10.3390/ijms23137057
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7058: Revisiting the Function of p21CDKN1A in DNA
           Repair: The Influence of Protein Interactions and Stability

    • Authors: Ticli, Cazzalini, Stivala, Prosperi
      First page: 7058
      Abstract: The p21CDKN1A protein is an important player in the maintenance of genome stability through its function as a cyclin-dependent kinase inhibitor, leading to cell-cycle arrest after genotoxic damage. In the DNA damage response, p21 interacts with specific proteins to integrate cell-cycle arrest with processes such as transcription, apoptosis, DNA repair, and cell motility. By associating with Proliferating Cell Nuclear Antigen (PCNA), the master of DNA replication, p21 is able to inhibit DNA synthesis. However, to avoid conflicts with this process, p21 protein levels are finely regulated by pathways of proteasomal degradation during the S phase, and in all the phases of the cell cycle, after DNA damage. Several lines of evidence have indicated that p21 is required for the efficient repair of different types of genotoxic lesions and, more recently, that p21 regulates DNA replication fork speed. Therefore, whether p21 is an inhibitor, or rather a regulator, of DNA replication and repair needs to be re-evaluated in light of these findings. In this review, we will discuss the lines of evidence describing how p21 is involved in DNA repair and will focus on the influence of protein interactions and p21 stability on the efficiency of DNA repair mechanisms.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-24
      DOI: 10.3390/ijms23137058
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7059: Dynamics of Protein Phosphorylation during
           Arabidopsis Seed Germination

    • Authors: Emmanuel Baudouin, Juliette Puyaubert, Patrice Meimoun, Mélisande Blein-Nicolas, Marlène Davanture, Michel Zivy, Christophe Bailly
      First page: 7059
      Abstract: Seed germination is critical for early plantlet development and is tightly controlled by environmental factors. Nevertheless, the signaling networks underlying germination control remain elusive. In this study, the remodeling of Arabidopsis seed phosphoproteome during imbibition was investigated using stable isotope dimethyl labeling and nanoLC-MS/MS analysis. Freshly harvested seeds were imbibed under dark or constant light to restrict or promote germination, respectively. For each light regime, phosphoproteins were extracted and identified from dry and imbibed (6 h, 16 h, and 24 h) seeds. A large repertoire of 10,244 phosphopeptides from 2546 phosphoproteins, including 110 protein kinases and key regulators of seed germination such as Delay Of Germination 1 (DOG1), was established. Most phosphoproteins were only identified in dry seeds. Early imbibition led to a similar massive downregulation in dormant and non-dormant seeds. After 24 h, 411 phosphoproteins were specifically identified in non-dormant seeds. Gene ontology analyses revealed their involvement in RNA and protein metabolism, transport, and signaling. In addition, 489 phosphopeptides were quantified, and 234 exhibited up or downregulation during imbibition. Interaction networks and motif analyses revealed their association with potential signaling modules involved in germination control. Our study provides evidence of a major role of phosphosignaling in the regulation of Arabidopsis seed germination.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-24
      DOI: 10.3390/ijms23137059
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7060: Biochemical, Enzymatic, and Computational
           Characterization of Recurrent Somatic Mutations of the Human Protein
           Tyrosine Phosphatase PTP1B in Primary Mediastinal B Cell Lymphoma

    • Authors: Rongxing Liu, Yujie Sun, Jérémy Berthelet, Linh-Chi Bui, Ximing Xu, Mireille Viguier, Jean-Marie Dupret, Frédérique Deshayes, Fernando Rodrigues Lima
      First page: 7060
      Abstract: Human protein tyrosine phosphatase 1B (PTP1B) is a ubiquitous non-receptor tyrosine phosphatase that serves as a major negative regulator of tyrosine phosphorylation cascades of metabolic and oncogenic importance such as the insulin, epidermal growth factor receptor (EGFR), and JAK/STAT pathways. Increasing evidence point to a key role of PTP1B-dependent signaling in cancer. Interestingly, genetic defects in PTP1B have been found in different human malignancies. Notably, recurrent somatic mutations and splice variants of PTP1B were identified in human B cell and Hodgkin lymphomas. In this work, we analyzed the molecular and functional levels of three PTP1B mutations identified in primary mediastinal B cell lymphoma (PMBCL) patients and located in the WPD-loop (V184D), P-loop (R221G), and Q-loop (G259V). Using biochemical, enzymatic, and molecular dynamics approaches, we show that these mutations lead to PTP1B mutants with extremely low intrinsic tyrosine phosphatase activity that display alterations in overall protein stability and in the flexibility of the active site loops of the enzyme. This is in agreement with the key role of the active site loop regions, which are preorganized to interact with the substrate and to enable catalysis. Our study provides molecular and enzymatic evidence for the loss of protein tyrosine phosphatase activity of PTP1B active-site loop mutants identified in human lymphoma.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-24
      DOI: 10.3390/ijms23137060
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7061: A New Bistable Switch Model of
           Alzheimer’s Disease Pathogenesis

    • Authors: Bruno Burlando, Serena Losacco, Viviana Villa, Ernesto Fedele, Roberta Ricciarelli
      First page: 7061
      Abstract: We propose a model to explain the pathogenesis of Alzheimer’s disease (AD) based on the theory that any disease affecting a healthy organism originates from a bistable feedback loop that shifts the system from a physiological to a pathological condition. We focused on the known double inhibitory loop involving the cellular prion protein (PrPC) and the enzyme BACE1 that produces amyloid-beta (Aβ) peptides. BACE1 is inhibited by PrPC, but its inhibitory activity is lost when PrPC binds to Aβ oligomers (Aβo). Excessive Aβo formation would switch the loop to a pathogenic condition involving the Aβo-PrPC-mGluR5 complex, Fyn kinase activation, tau, and NMDAR phosphorylation, ultimately leading to neurodegeneration. Based on the emerging role of cyclic nucleotides in Aβ production, and thereby in synaptic plasticity and cognitive processes, cAMP and cGMP can be considered as modulatory factors capable of inducing the transition from a physiological steady state to a pathogenic one. This would imply that critical pharmacological targets for AD treatment lie within pathways that lead to an imbalance of cyclic nucleotides in neurons. If this hypothesis is confirmed, it will provide precise indications for the development of preventive or therapeutic treatments for the disease.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137061
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7062: Microsatellite Instability in Russian Patients
           with Colorectal Cancer

    • Authors: Vitaly Shubin, Yury Shelygin, Sergey Achkasov, Oleg Sushkov, Ilya Nazarov, Alexey Ponomarenko, Iuliia Alimova, Anna Loginova, Aleksey Tsukanov
      First page: 7062
      Abstract: The aim of this study was to determine the characteristics of Russian patients with microsatellite instability (MSI) tumors. MSI in the tumor was determined in 514 patients with colon cancer using PCR and subsequent fragment analysis for five markers (NR21, NR24, BAT25, BAT26, and NR27). In the presence of microsatellite instability, the mismatch repair (MMR) system genes were examined using the NGS and MLPA methods to establish the diagnosis of Lynch syndrome. The overall frequency of MSI tumors was 15%: at stage I—19% (9/48), at stage II—21% (44/213), at stage III—16% (26/160), and at stage IV—2% (2/93). Patients with MSI tumors differed in the age of diagnosis, tumor localization, time of cancer recurrence, and stage of the disease. The overall and disease-free survival of patients whose tumors had MSI status was higher than that of patients with microsatellite-stable status, p = 0.04 and p = 0.02, respectively. Analysis of overall and disease-free survival of patients with Lynch syndrome and patients with sporadic colon cancer, but with MSI status, did not reveal significant differences, p = 0.52 and p = 0.24, respectively. The age of patients with Lynch syndrome was significantly younger than that of patients with sporadic colon cancer whose tumors had MSI status (p < 0.001).
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137062
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7063: Genome Wide Identification and Annotation of
           NGATHA Transcription Factor Family in Crop Plants

    • Authors: Hymavathi Salava, Sravankumar Thula, Adrià Sans Sánchez, Tomasz Nodzyński, Fatemeh Maghuly
      First page: 7063
      Abstract: The NGATHA (NGA) transcription factor (TF) belongs to the ABI3/VP1 (RAV) transcriptional subfamily, a subgroup of the B3 superfamily, which is relatively well-studied in Arabidopsis. However, limited data are available on the contributions of NGA TF in other plant species. In this study, 207 NGA gene family members were identified from a genome-wide search against Arabidopsis thaliana in the genome data of 18 dicots and seven monocots. The phylogenetic and sequence alignment analyses divided NGA genes into different clusters and revealed that the numbers of genes varied depending on the species. The phylogeny was followed by the characterization of the Solanaceae (tomato, potato, capsicum, tobacco) and Poaceae (Brachypodium distachyon, Oryza sativa L. japonica, and Sorghum bicolor) family members in comparison with A. thaliana. The gene and protein structures revealed a similar pattern for NGA and NGA-like sequences, suggesting that both are conserved during evolution. Promoter cis-element analysis showed that phytohormones such as abscisic acid, auxin, and gibberellins play a crucial role in regulating the NGA gene family. Gene ontology analysis revealed that the NGA gene family participates in diverse biological processes such as flower development, leaf morphogenesis, and the regulation of transcription. The gene duplication analysis indicates that most of the genes are evolved due to segmental duplications and have undergone purifying selection pressure. Finally, the gene expression analysis implicated that the NGA genes are abundantly expressed in lateral organs and flowers. This analysis has presented a detailed and comprehensive study of the NGA gene family, providing basic knowledge of the gene, protein structure, function, and evolution. These results will lay the foundation for further understanding of the role of the NGA gene family in various plant developmental processes.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137063
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7064: Synthesis of Shape-Memory Polyurethanes:
           Combined Experimental and Simulation Studies

    • Authors: Karolina Rolińska, Magdalena Mazurek-Budzyńska, Paweł G. Parzuchowski, Dominik Wołosz, Maria Balk, Krzysztof Gorący, Miroslawa El Fray, Piotr Polanowski, Andrzej Sikorski
      First page: 7064
      Abstract: The presented research focuses on the synthesis and structure–properties relationship of poly(carbonate-urea-urethane) (PCUU) systems including investigations on shape memory effect capability. Furthermore, we approached the topic from a broader perspective by conducting extensive analysis of the relationship between the synthesized compounds and the results of computer simulations by means of the Monte Carlo method. For the first time, by using a unique simulation tool, the dynamic lattice liquid model (DLL), all steps of multi-step synthesis of these materials were covered by the simulations. Furthermore, broad thermal, mechanical, and thermomechanical characterization of synthesized PCUUs was performed, as well as determining the shape memory properties. PCUUs exhibited good mechanical properties with a tensile strength above 20 MPa, elongation at break around 800%, and an exhibited shape memory effect with shape fixity and shape recovery ratios above 94% and 99%, respectively. The dynamic lattice liquid model was employed to show the products and their molar mass distribution, as well as monomer conversion or the dispersity index for individual reaction steps. The results obtained in the following manuscript allow the planning of syntheses for the PCUUs of various structures, including crosslinked and soluble systems, which can provide a broad variety of applications of these materials, as well as a better understanding of the composition–properties relationship.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137064
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7065: Scorpion Neurotoxin Syb-prII-1 Exerts Analgesic
           Effect through Nav1.8 Channel and MAPKs Pathway

    • Authors: Fei Bai, Yongbo Song, Yi Cao, Mengqi Ban, Zhenyu Zhang, Yang Sun, Yuan Feng, Chunli Li
      First page: 7065
      Abstract: Trigeminal neuralgia (TN) is a common type of peripheral neuralgia in clinical practice, which is usually difficult to cure. Common analgesic drugs are difficult for achieving the desired analgesic effect. Syb-prII-1 is a β-type scorpion neurotoxin isolated from the scorpion venom of Buthus martensi Karsch (BmK). It has an important influence on the voltage-gated sodium channel (VGSCs), especially closely related to Nav1.8 and Nav1.9. To explore whether Syb-prII-1 has a good analgesic effect on TN, we established the Sprague Dawley (SD) rats’ chronic constriction injury of the infraorbital nerve (IoN-CCI) model. Behavioral, electrophysiological, Western blot, and other methods were used to verify the model. It was found that Syb-prII-1 could significantly relieve the pain behavior of IoN-CCI rats. After Syb-prII-1 was given, the phosphorylation level of the mitogen-activated protein kinases (MAPKs) pathway showed a dose-dependent decrease after IoN-CCI injury. Moreover, Syb-prII-1(4.0 mg/kg) could significantly change the steady-state activation and inactivation curves of Nav1.8. The steady-state activation and inactivation curves of Nav1.9 were similar to those of Nav1.8, but there was no significant difference. It was speculated that it might play an auxiliary role. The binding mode, critical residues, and specific interaction type of Syb-prII-1 and VSD2rNav1.8 were clarified with computational simulation methods. Our results indicated that Syb-prII-1 could provide a potential treatment for TN by acting on the Nav1.8 target.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137065
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7066: The Neonatal Fc Receptor Is Elevated in
           Monocyte-Derived Immune Cells in Pancreatic Cancer

    • Authors: Justin Thomas, Molly A. Torok, Kriti Agrawal, Timothy Pfau, Trang T. Vu, Justin Lyberger, Hsiaochi Chang, Alyssa Marie M. Castillo, Min Chen, Bryan Remaily, Kyeongmin Kim, Zhiliang Xie, Mary E. Dillhoff, Samuel K. Kulp, Gregory K. Behbehani, Zobeida Cruz-Monserrate, Latha P. Ganesan, Dwight H. Owen, Mitch A. Phelps, Christopher C. Coss, Thomas A. Mace
      First page: 7066
      Abstract: The neonatal Fc receptor (FcRn) is responsible for recycling of IgG antibodies and albumin throughout the body. This mechanism has been exploited for pharmaceutic delivery across an array of diseases to either enhance or diminish this function. Monoclonal antibodies and albumin-bound nanoparticles are examples of FcRn-dependent anti-cancer therapeutics. Despite its importance in drug delivery, little is known about FcRn expression in circulating immune cells. Through time-of-flight mass cytometry (CyTOF) we were able to characterize FcRn expression in peripheral blood mononuclear cell (PBMC) populations of pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer donors. Furthermore, we were able to replicate these findings in an orthotopic murine model of PDAC. Altogether, we found that in both patients and mice with PDAC, FcRn was elevated in migratory and resident classical dendritic cell type 2 (cDC2) as well as monocytic and granulocytic myeloid-derived suppressor cell (MDSC) populations compared to tumor-free controls. Furthermore, PBMCs from PDAC patients had elevated monocyte, dendritic cells and MDSCs relative to non-cancer donor PBMCs. Future investigations into FcRn activity may further elucidate possible mechanisms of poor efficacy of antibody immunotherapies in patients with PDAC.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137066
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7067: Transcriptome Profiling of the Dorsomedial
           Prefrontal Cortex in Suicide Victims

    • Authors: Fanni Dóra, Éva Renner, Dávid Keller, Miklós Palkovits, Árpád Dobolyi
      First page: 7067
      Abstract: The default mode network (DMN) plays an outstanding role in psychiatric disorders. Still, gene expressional changes in its major component, the dorsomedial prefrontal cortex (DMPFC), have not been characterized. We used RNA sequencing in postmortem DMPFC samples to investigate suicide victims compared to control subjects. 1400 genes differed using log2FC > ±1 and adjusted p-value < 0.05 criteria between groups. Genes associated with depressive disorder, schizophrenia and impaired cognition were strongly overexpressed in top differentially expressed genes. Protein–protein interaction and co-expressional networks coupled with gene set enrichment analysis revealed that pathways related to cytokine receptor signaling were enriched in downregulated, while glutamatergic synaptic signaling upregulated genes in suicidal individuals. A validated differentially expressed gene, which is known to be associated with mGluR5, was the N-terminal EF-hand calcium-binding protein 2 (NECAB2). In situ hybridization histochemistry and immunohistochemistry proved that NECAB2 is expressed in two different types of inhibitory neurons located in layers II-IV and VI, respectively. Our results imply extensive gene expressional alterations in the DMPFC related to suicidal behavior. Some of these genes may contribute to the altered mental state and behavior of suicide victims.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137067
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7068: Immunotherapy in NSCLC Patients with Brain

    • Authors: Silvia Buriolla, Giacomo Pelizzari, Carla Corvaja, Martina Alberti, Giada Targato, Martina Bortolot, Sara Torresan, Francesco Cortiula, Gianpiero Fasola, Alessandro Follador
      First page: 7068
      Abstract: Approximately 40% of unselected non-small cell lung cancer (NSCLC) patients develop brain metastases (BMs) during their disease, with considerable morbidity and mortality. The management of BMs in patients with NSCLC is a clinical challenge and requires a multidisciplinary approach to gain effective intracranial disease control. Over the last decade, immune checkpoint inhibitors (ICIs) have emerged as a game-changer in the treatment landscape of advanced NSCLC, with significant improvements in survival outcomes, although patients with BMs are mostly underrepresented in randomized clinical trials. Moreover, the safety and activity of ICIs and radiotherapy combinations compared with single-agent or sequential modalities is still under evaluation to establish the optimal management of these patients. The aim of this review is to summarize the state-of-the-art of clinical evidence of ICIs intracranial activity and the main challenges of incorporating these agents in the treatment armamentarium of NSCLC patients with BMs.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137068
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7069: Exopolysaccharide ID1 Improves Post-Warming
           Outcomes after Vitrification of In Vitro-Produced Bovine Embryos

    • Authors: Erika Alina Ordóñez-León, Iris Martínez-Rodero, Tania García-Martínez, Manel López-Béjar, Marc Yeste, Elena Mercade, Teresa Mogas
      First page: 7069
      Abstract: This study aimed to assess the cryoprotectant role of exopolysaccharide (EPS) ID1, produced by Antarctic Pseudomonas sp., in the vitrification of in vitro-produced (IVP) bovine embryos. IVP day 7 (D7) and day 8 (D8) expanded blastocysts derived from cow or calf oocytes were vitrified without supplementation (EPS0) or supplemented with 10 µg/mL (EPS10) or 100 µg/mL (EPS100) EPS ID1. The effect of EPS ID1 was assessed in post-warming re-expansion and hatching rates, differential cell count, apoptosis rate, and gene expression. EPS100 re-expansion rates were significantly higher than those observed for the EPS0 and EPS10 treatments, regardless of culture length or oocyte source. EPS100 hatching rate was similar to the one of the fresh blastocysts except for those D7 blastocysts derived from calf oocytes. No differences were observed among EPS ID1 treatments when the inner cell mass, trophectoderm, and total cell number were assessed. Although apoptosis rates were higher (p ≤ 0.05) in vitrified groups compared to fresh embryos, EPS100 blastocysts had a lower number (p ≤ 0.05) of apoptotic nuclei than the EPS0 or EPS10 groups. No differences in the expression of BCL2, AQP3, CX43, and SOD1 genes between treatments were observed. Vitrification without EPS ID1 supplementation produced blastocysts with significantly higher BAX gene expression, whereas treatment with 100 µg/mL EPS ID1 returned BAX levels to those observed in non-vitrified blastocysts. Our results suggest that 100 µg/mL EPS ID1 added to the vitrification media is beneficial for embryo cryopreservation because it results in higher re-expansion and hatching ability and it positively modulates apoptosis.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137069
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7070: Early Osteogenic Marker Expression in hMSCs
           Cultured onto Acid Etching-Derived Micro- and Nanotopography 3D-Printed
           Titanium Surfaces

    • Authors: Nora Bloise, Erik I. Waldorff, Giulia Montagna, Giovanna Bruni, Lorenzo Fassina, Samuel Fang, Nianli Zhang, Jiechao Jiang, James T. Ryaby, Livia Visai
      First page: 7070
      Abstract: Polyetheretherketone (PEEK) titanium composite (PTC) is a novel interbody fusion device that combines a PEEK core with titanium alloy (Ti6Al4V) endplates. The present study aimed to investigate the in vitro biological reactivity of human bone-marrow-derived mesenchymal stem cells (hBM-MSCs) to micro- and nanotopographies produced by an acid-etching process on the surface of 3D-printed PTC endplates. Optical profilometer and scanning electron microscopy were used to assess the surface roughness and identify the nano-features of etched or unetched PTC endplates, respectively. The viability, morphology and the expression of specific osteogenic markers were examined after 7 days of culture in the seeded cells. Haralick texture analysis was carried out on the unseeded endplates to correlate surface texture features to the biological data. The acid-etching process modified the surface roughness of the 3D-printed PTC endplates, creating micro- and nano-scale structures that significantly contributed to sustaining the viability of hBM-MSCs and triggering the expression of early osteogenic markers, such as alkaline phosphatase activity and bone-ECM protein production. Finally, the topography of 3D-printed PTC endplates influenced Haralick’s features, which in turn correlated with the expression of two osteogenic markers, osteopontin and osteocalcin. Overall, these data demonstrate that the acid-etching process of PTC endplates created a favourable environment for osteogenic differentiation of hBM-MSCs and may potentially have clinical benefit.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137070
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7071: Systematic Review: Targeted Molecular Imaging
           of Angiogenesis and Its Mediators in Rheumatoid Arthritis

    • Authors: Fatemeh Khodadust, Aiarpi Ezdoglian, Maarten M. Steinz, Judy R. van van Beijnum, Gerben J. C. Zwezerijnen, Gerrit Jansen, Sander W. Tas, Conny J. van der van der Laken
      First page: 7071
      Abstract: Extensive angiogenesis is a characteristic feature in the synovial tissue of rheumatoid arthritis (RA) from a very early stage of the disease onward and constitutes a crucial event for the development of the proliferative synovium. This process is markedly intensified in patients with prolonged disease duration, high disease activity, disease severity, and significant inflammatory cell infiltration. Angiogenesis is therefore an interesting target for the development of new therapeutic approaches as well as disease monitoring strategies in RA. To this end, nuclear imaging modalities represent valuable non-invasive tools that can selectively target molecular markers of angiogenesis and accurately and quantitatively track molecular changes in multiple joints simultaneously. This systematic review summarizes the imaging markers used for single photon emission computed tomography (SPECT) and/or positron emission tomography (PET) approaches, targeting pathways and mediators involved in synovial neo-angiogenesis in RA.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137071
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7072: Investigation of Structural Features of Two
           Related Lipases and the Impact on Fatty Acid Specificity in Vegetable Fats

    • Authors: Zehui Dong, Kim Olofsson, Javier A. Linares-Pastén, Eva Nordberg Nordberg Karlsson
      First page: 7072
      Abstract: One of the indispensable applications of lipases in modification of oils and fats is the possibility to tailor the fatty acid content of triacylglycerols (TAGs), to meet specific requirements from various applications in food, nutrition, and cosmetic industries. Oleic acid (C18:1) and stearic acid (C18:0) are two common long fatty acids in the side chain of triglycerides in plant fats and oils that have similar chemical composition and structures, except for an unsaturated bond between C9 and C10 in oleic acid. Two lipases from Rhizomucor miehei (RML) and Rhizopus oryzae (ROL), show activity in reactions involving oleate and stearate, and share high sequence and structural identity. In this research, the preference for one of these two similar fatty acid side chains was investigated for the two lipases and was related to the respective enzyme structure. From transesterification reactions with 1:1 (molar ratio) mixed ethyl stearate (ES) and ethyl oleate (EO), both RML and ROL showed a higher activity towards EO than ES, but RML showed around 10% higher preference for ES compared with ROL. In silico results showed that stearate has a less stable interaction with the substrate binding crevice in both RML and ROL and higher tendency to freely move out of the substrate binding region, compared with oleate whose structure is more rigid due to the existence of the double bond. However, Trp88 from RML which is an Ala at the identical position in ROL shows a significant stabilization effect in the substrate interaction in RML, especially with stearate as a ligand.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137072
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7073: Glucose Stimulates Glial Cell Line-Derived
           Neurotrophic Factor Gene Expression in Microglia through a
           GLUT5-Independent Mechanism

    • Authors: Muhammad S. Aldhshan, Gursagar Jhanji, Nicole J. Poritsanos, Tooru M. Mizuno
      First page: 7073
      Abstract: Feeding-regulating neurotrophic factors are expressed in both neurons and glial cells. However, nutritional regulation of anorexigenic glial cell line-derived neurotrophic factor (GDNF) and orexigenic mesencephalic astrocyte-derived neurotrophic factor (MANF) expression in specific cell types remains poorly understood. Hypothalamic glucose sensing plays a critical role in the regulation of food intake. It has been theorized that local glucose concentration modulates microglial activity partially via glucose transporter 5 (GLUT5). We hypothesized that an increased local glucose concentration stimulates GDNF expression while inhibiting MANF expression in the hypothalamus and microglia via GLUT5. The present study investigated the effect of glucose on Gdnf and Manf mRNA expression in the mouse hypothalamus and murine microglial cell line SIM-A9. Intracerebroventricular glucose treatment significantly increased Gdnf mRNA levels in the hypothalamus without altering Manf mRNA levels. Exposure to high glucose caused a significant increase in Gdnf mRNA expression and a time-dependent change in Manf mRNA expression in SIM-A9 cells. GLUT5 inhibitor treatment did not block glucose-induced Gdnf mRNA expression in these cells. These findings suggest that microglia are responsive to changes in the local glucose concentration and increased local glucose availability stimulates the expression of microglial GNDF through a GLUT5-independent mechanism, contributing to glucose-induced feeding suppression.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137073
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7074: Relaxin Inhibits the Cardiac Myofibroblast
           NLRP3 Inflammasome as Part of Its Anti-Fibrotic Actions via the
           Angiotensin Type 2 and ATP (P2X7) Receptors

    • Authors: Felipe Tapia Cáceres, Tracey A. Gaspari, Mohammed Akhter Hossain, Chrishan S. Samuel
      First page: 7074
      Abstract: Chronic NLRP3 inflammasome activation can promote fibrosis through its production of interleukin (IL)-1β and IL-18. Conversely, recombinant human relaxin (RLX) can inhibit the pro-fibrotic interactions between IL-1β, IL-18 and transforming growth factor (TGF)-β1. Here, the broader extent by which RLX targeted the myofibroblast NLRP3 inflammasome to mediate its anti-fibrotic effects was elucidated. Primary human cardiac fibroblasts (HCFs), stimulated with TGF-β1 (to promote myofibroblast (HCMF) differentiation), LPS (to prime the NLRP3 inflammasome) and ATP (to activate the NLRP3 inflammasome) (T+L+A) or benzoylbenzoyl-ATP (to activate the ATP receptor; P2X7R) (T+L+Bz), co-expressed relaxin family peptide receptor-1 (RXFP1), the angiotensin II type 2 receptor (AT2R) and P2X7R, and underwent increased protein expression of toll-like receptor (TLR)-4, NLRP3, caspase-1, IL-1β and IL-18. Whilst RLX co-administration to HCMFs significantly prevented the T+L+A- or T+L+Bz-stimulated increase in these end points, the inhibitory effects of RLX were annulled by the pharmacological antagonism of either RXFP1, AT2R, P2X7R, TLR-4, reactive oxygen species (ROS) or caspase-1. The RLX-induced amelioration of left ventricular inflammation, cardiomyocyte hypertrophy and fibrosis in isoproterenol (ISO)-injured mice, was also attenuated by P2X7R antagonism. Thus, the ability of RLX to ameliorate the myofibroblast NLRP3 inflammasome as part of its anti-fibrotic effects, appeared to involve RXFP1, AT2R, P2X7R and the inhibition of TLR-4, ROS and caspase-1.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137074
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7075: Th17 Activation and Th17/Treg Imbalance in
           Prolonged Anterior Intraocular Inflammation after Ocular Alkali Burn

    • Authors: Miner Yuan, Xiaobing Qian, Yanqiao Huang, Xinqi Ma, Fang Duan, Yao Yang, Bingsheng Lou, Xiaofeng Lin
      First page: 7075
      Abstract: Ocular alkali burn (OAB) is a sight-threatening disease with refractory ocular inflammation causing various blinding complications. Th17 lymphocytes account for the pathogeneses of the autoimmune disease and chronic inflammation, but their role in prolonged anterior intraocular inflammation after OAB is still unknown. A rat OAB model was established for this purpose. Anterior intraocular inflammation was observed in both the acute and late phases of OAB, and histological examination confirmed the presence of inflammatory cell infiltration and fibrin exudation in the anterior segment. Luminex xMAP technology and qPCR were used to evaluate the intraocular levels of cytokines. The levels of IL-1β, IL-6, and TNF-α were significantly elevated during the acute phase. The expression of IL-17A gradually increased from day 7 onwards and remained at a relatively high level. Immunofluorescence was performed to identify Th17 cells. CD4 and IL-17A double positive cells were detected in the anterior chamber from days 7 to 28. Flow cytometry showed that the frequency of Th17 cells increased in both lymph nodes and spleen, while the frequency of Treg cells remained unchanged, resulting in an elevated Th17/Treg ratio. The present study suggests that Th17 activation and Th17/Treg imbalance account for prolonged anterior intraocular inflammation after OAB.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137075
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7076: Longitudinal Proteomic Analysis of Plasma
           across Healthy Pregnancies Reveals Indicators of Gestational Age

    • Authors: Elizabeth Yohannes, Danielle L. Ippolito, Jennifer R. Damicis, Elisabeth M. Dornisch, Katherine M. Leonard, Peter G. Napolitano, Nicholas Ieronimakis
      First page: 7076
      Abstract: Longitudinal changes in the blood proteome during gestation relate to fetal development and maternal homeostasis. Charting the maternal blood proteome in normal pregnancies is critical for establishing a baseline reference when assessing complications and disease. Using mass spectrometry-based shotgun proteomics, we surveyed the maternal plasma proteome across uncomplicated pregnancies. Results indicate a significant rise in proteins that govern placentation and are vital to the development and health of the fetus. Importantly, we uncovered proteome signatures that strongly correlated with gestational age. Fold increases and correlations between the plasma concentrations of ADAM12 (ρ = 0.973), PSG1 (ρ = 0.936), and/or CSH1/2 (ρ = 0.928) with gestational age were validated with ELISA. Proteomic and validation analyses demonstrate that the maternal plasma concentration of ADAM12, either independently or in combination with either PSG1 or CSH1/2, correlates with gestational age within ±8 days throughout pregnancy. These findings suggest that the gestational age in healthy pregnancies may be determined by referencing the concentration of select plasma proteins.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137076
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7077: Molecular Basis Underlying the Therapeutic
           Potential of Vitamin D for the Treatment of Depression and Anxiety

    • Authors: Bruna R. Kouba, Anderson Camargo, Joana Gil-Mohapel, Ana Lúcia S. Rodrigues
      First page: 7077
      Abstract: Major depressive disorder and anxiety disorders are common and disabling conditions that affect millions of people worldwide. Despite being different disorders, symptoms of depression and anxiety frequently overlap in individuals, making them difficult to diagnose and treat adequately. Therefore, compounds capable of exerting beneficial effects against both disorders are of special interest. Noteworthily, vitamin D deficiency has been associated with an increased risk of developing depression and anxiety, and individuals with these psychiatric conditions have low serum levels of this vitamin. Indeed, in the last few years, vitamin D has gained attention for its many functions that go beyond its effects on calcium–phosphorus metabolism. Particularly, antioxidant, anti-inflammatory, pro-neurogenic, and neuromodulatory properties seem to contribute to its antidepressant and anxiolytic effects. Therefore, in this review, we highlight the main mechanisms that may underlie the potential antidepressant and anxiolytic effects of vitamin D. In addition, we discuss preclinical and clinical studies that support the therapeutic potential of this vitamin for the management of these disorders.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137077
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7078: Transcriptome Analysis Reveals the Response
           Mechanism of Frl-Mediated Resistance to Fusarium oxysporum f. sp.
           radicis-lycopersici (FORL) Infection in Tomato

    • Authors: Yuqing Sun, Huanhuan Yang, Jingfu Li
      First page: 7078
      Abstract: Tomato Fusarium crown and root rot (FCRR) is an extremely destructive soil-borne disease. To date, studies have shown that only plants with tomato mosaic virus (TMV) resistance exhibit similar resistance to tomato Fusarium oxysporum f. sp. radicis-lycopersici (FORL) and have identified a single relevant gene, Frl, in Peruvian tomato. Due to the relative lack of research on FCRR disease-resistance genes in China and elsewhere, transcriptome data for FORL-resistant (cv. ‘19912’) and FORL-susceptible (cv. ‘Moneymaker’) tomato cultivars were analysed for the first time in this study. The number of differentially expressed genes (DEGs) was higher in Moneymaker than in 19912, and 189 DEGs in the ‘plant–pathogen interaction’ pathway were subjected to GO and KEGG enrichment analyses. MAPK and WRKY genes were enriched in major metabolic pathways related to plant disease resistance; thus, we focused on these two gene families. In the early stage of tomato infection, the content of JA and SA increased, but the change in JA was more obvious. Fourteen genes were selected for confirmation of their differential expression levels by qRT-PCR. This study provides a series of novel disease resistance resources for tomato breeding and genetic resources for screening and cloning FORL resistance genes.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137078
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7079: Role of Intrinsic Subtype Analysis with PAM50
           in Hormone Receptors Positive HER2 Negative Metastatic Breast Cancer: A
           Systematic Review

    • Authors: Fabio Canino, Federico Piacentini, Claudia Omarini, Angela Toss, Monica Barbolini, Patrizia Vici, Massimo Dominici, Luca Moscetti
      First page: 7079
      Abstract: Endocrine therapy (ET), associated with CDK 4/6 inhibitors, represents the first choice of treatment for HR+/HER2- metastatic breast cancer (mBC). Primary or secondary endocrine resistance could develop; however validated biomarkers capable of predicting such a conditions are not available. Several studies have shown that HR+/HER2- mBC comprises five intrinsic subtypes. The purpose of this systematic review was to analyze the potential correlations between intrinsic subtype, efficacy of treatment, and patient outcome. Five papers that analyzed the intrinsic subtype with PAM50 assay in patients (pts) with HR+/HER2- mBC treated with ET (alone or in combination) within seven phase III clinical trials (EGF30008, BOLERO-2, PALOMA-2,3, MONALEESA-2,3,7) were identified. Non-luminal subtypes are more frequent in endocrine-resistant pts and in metastatic sites (vs. primary tumors), have less benefit from ET, and worse prognosis. Among these, HER2-enriched subtypes are similar to HER2+ tumors and benefit from the addition of anti-HER2 agents (lapatinib) and, for less clear reasons, of ribociclib (unconfirmed data for palbociclib and everolimus). Basal-like subtypes are similar to triple-negative tumors, making them more sensitive to chemotherapy. The intrinsic subtype is also not static but can vary over time with the evolution of the disease. Currently, the intrinsic subtype does not play a decisive role in the choice of treatment in clinical practice, but has potential prognostic and predictive value that should be further investigated.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137079
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7080: Risk Factors from Pregnancy to Adulthood in
           Multiple Sclerosis Outcome

    • Authors: Enrique González-Madrid, Ma. Andreina Rangel-Ramírez, María José Mendoza-León, Oscar Álvarez-Mardones, Pablo A. González, Alexis M. Kalergis, Ma. Cecilia Opazo, Claudia A. Riedel
      First page: 7080
      Abstract: Multiple sclerosis (MS) is an autoimmune disease characterized by a robust inflammatory response against myelin sheath antigens, which causes astrocyte and microglial activation and demyelination of the central nervous system (CNS). Multiple genetic predispositions and environmental factors are known to influence the immune response in autoimmune diseases, such as MS, and in the experimental autoimmune encephalomyelitis (EAE) model. Although the predisposition to suffer from MS seems to be a multifactorial process, a highly sensitive period is pregnancy due to factors that alter the development and differentiation of the CNS and the immune system, which increases the offspring’s susceptibility to develop MS. In this regard, there is evidence that thyroid hormone deficiency during gestation, such as hypothyroidism or hypothyroxinemia, may increase susceptibility to autoimmune diseases such as MS. In this review, we discuss the relevance of the gestational period for the development of MS in adulthood.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137080
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7081: Improvement of Kiteplatin Efficacy by a
           Benzoato Pt(IV) Prodrug Suitable for Oral Administration

    • Authors: Alessandra Barbanente, Valentina Gandin, Cecilia Ceresa, Cristina Marzano, Nicoletta Ditaranto, James D. Hoeschele, Giovanni Natile, Fabio Arnesano, Concetta Pacifico, Francesco P. Intini, Nicola Margiotta
      First page: 7081
      Abstract: Kiteplatin, [PtCl2(cis-1,4-DACH)] (DACH = diaminocyclohexane), contains an isomeric form of the oxaliplatin diamine ligand trans-1R,2R-DACH and has been proposed as a valuable drug candidate against cisplatin- and oxaliplatin-resistant tumors, in particular, colorectal cancer. To further improve the activity of kiteplatin, it has been transformed into a Pt(IV) prodrug by the addition of two benzoato groups in the axial positions. The new compound, cis,trans,cis-[PtCl2(OBz)2(cis-1,4-DACH)] (1; OBz = benzoate), showed cytotoxic activity at nanomolar concentration against a wide panel of human cancer cell lines. Based on these very promising results, the investigation has been extended to the in vivo activity of compound 1 in a Lewis Lung Carcinoma (LLC) model and its suitability for oral administration. Compound 1 resulted to be remarkably stable in acidic conditions (pH 1.5 to mimic the stomach environment) undergoing a drop of the initial concentration to ~60% of the initial one only after 72 h incubation at 37 °C; thus resulting amenable for oral administration. Interestingly, in a murine model (2·106 LLC cells implanted i.m. into the right hind leg of 8-week old male and female C57BL mice), a comparable reduction of tumor mass (~75%) was observed by administering compound 1 by oral gavage and the standard drug cisplatin by intraperitoneal injection, thus indicating that, indeed, there is the possibility of oral administration for this dibenzoato prodrug of kiteplatin. Moreover, since the mechanism of action of Pt(IV) prodrugs involves an initial activation by chemical reduction to cytotoxic Pt(II) species, the reduction of 1 by two bioreductants (ascorbic acid/sodium ascorbate and glutathione) was investigated resulting to be rather slow (not complete after 120 h incubation at 37 °C). Finally, the neurotoxicity of 1 was evaluated using an in vitro assay.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137081
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7082: Molecular Evolution and Functional Divergence
           of Stress-Responsive Cu/Zn Superoxide Dismutases in Plants

    • Authors: Guozhi Zhou, Chaochao Liu, Yuan Cheng, Meiying Ruan, Qingjing Ye, Rongqing Wang, Zhuping Yao, Hongjian Wan
      First page: 7082
      Abstract: Superoxide dismutases (SODs), a family of antioxidant enzymes, are the first line of defense against oxidative damage and are ubiquitous in every cell of all plant types. The Cu/Zn SOD, one of three types of SODs present in plant species, is involved in many of the biological functions of plants in response to abiotic and biotic stresses. Here, we carried out a comprehensive analysis of the Cu/Zn SOD gene family in different plant species, ranging from lower plants to higher plants, and further investigated their organization, sequence features, and expression patterns in response to biotic and abiotic stresses. Our results show that plant Cu/Zn SODs can be divided into two subfamilies (group I and group II). Group II appeared to be conserved only as single- or low-copy genes in all lineages, whereas group I genes underwent at least two duplication events, resulting in multiple gene copies and forming three different subgroups (group Ia, group Ib, and group Ic). We also found that, among these genes, two important events—the loss of introns and the loss of and variation in signal peptides—occurred over the long course of their evolution, indicating that they were involved in shifts in subcellular localization from the chloroplast to cytosol or peroxisome and underwent functional divergence. In addition, expression patterns of Cu/Zn SOD genes from Arabidopsis thaliana and Solanum lycopersicum were tested in different tissues/organs and developmental stages and under different abiotic stresses. The results indicate that the Cu/Zn SOD gene family possesses potential functional divergence and may play vital roles in ROS scavenging in response to various stresses in plants. This study will help establish a foundation for further understanding these genes’ function during stress responses.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137082
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7083: Dried Blood Spots as Matrix for Evaluation of
           Valproate Levels and the Immediate and Delayed Metabolomic Changes Induced
           by Single Valproate Dose Treatment

    • Authors: Sing Teang Kong, Hai-Shu Lin, Jianhong Ching, Huiqing Xie, Paul C. Ho
      First page: 7083
      Abstract: The immediate and delayed metabolic changes in rats treated with valproate (VPA), a drug used for the treatment of epilepsy, were profiled. An established approach using dried blood spots (DBS) as sample matrices for gas chromatography/mass spectrometry-based metabolomics profiling was modified using double solvents in the extraction of analytes. With the modified method, some of the previously undetectable metabolites were recovered and subtle differences in the metabolic changes upon exposure to a single dose of VPA between males and female rats were identified. In male rats, changes in 2-hydroxybutyric acid, pipecolic acid, tetratriacontane and stearic acid were found between the control and treatment groups at various time points from 2.5 h up to 24 h. In contrast, such differences were not observed in female rats, which could be caused by the vast inter-individual variations in metabolite levels within the female group. Based on the measured DBS drug concentrations, clearance and apparent volume of distribution of VPA were estimated and the values were found to be comparable to those estimated previously from full blood drug concentrations. The current study indicated that DBS is a powerful tool to monitor drug levels and metabolic changes in response to drug treatment.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137083
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7084: Flagellotropic Bacteriophages: Opportunities
           and Challenges for Antimicrobial Applications

    • Authors: Nathaniel C. Esteves, Birgit E. Scharf
      First page: 7084
      Abstract: Bacteriophages (phages) are the most abundant biological entities in the biosphere. As viruses that solely infect bacteria, phages have myriad healthcare and agricultural applications including phage therapy and antibacterial treatments in the foodservice industry. Phage therapy has been explored since the turn of the twentieth century but was no longer prioritized following the invention of antibiotics. As we approach a post-antibiotic society, phage therapy research has experienced a significant resurgence for the use of phages against antibiotic-resistant bacteria, a growing concern in modern medicine. Phages are extraordinarily diverse, as are their host receptor targets. Flagellotropic (flagellum-dependent) phages begin their infection cycle by attaching to the flagellum of their motile host, although the later stages of the infection process of most of these phages remain elusive. Flagella are helical appendages required for swimming and swarming motility and are also of great importance for virulence in many pathogenic bacteria of clinical relevance. Not only is bacterial motility itself frequently important for virulence, as it allows pathogenic bacteria to move toward their host and find nutrients more effectively, but flagella can also serve additional functions including mediating bacterial adhesion to surfaces. Flagella are also a potent antigen recognized by the human immune system. Phages utilizing the flagellum for infections are of particular interest due to the unique evolutionary tradeoff they force upon their hosts: by downregulating or abolishing motility to escape infection by a flagellotropic phage, a pathogenic bacterium would also likely attenuate its virulence. This factor may lead to flagellotropic phages becoming especially potent antibacterial agents. This review outlines past, present, and future research of flagellotropic phages, including their molecular mechanisms of infection and potential future applications.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137084
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7085: Regulation and Release of Vasoactive Endoglin
           by Brain Endothelium in Response to Hypoxia/Reoxygenation in Stroke

    • Authors: Axel Haarmann, Lena Zimmermann, Michael Bieber, Christine Silwedel, Guido Stoll, Michael K. Schuhmann
      First page: 7085
      Abstract: In large vessel occlusion stroke, recanalization to restore cerebral perfusion is essential but not necessarily sufficient for a favorable outcome. Paradoxically, in some patients, reperfusion carries the risk of increased tissue damage and cerebral hemorrhage. Experimental and clinical data suggest that endothelial cells, representing the interface for detrimental platelet and leukocyte responses, likely play a crucial role in the phenomenon referred to as ischemia/reperfusion (I/R)-injury, but the mechanisms are unknown. We aimed to determine the role of endoglin in cerebral I/R-injury; endoglin is a membrane-bound protein abundantly expressed by endothelial cells that has previously been shown to be involved in the maintenance of vascular homeostasis. We investigated the expression of membranous endoglin (using Western blotting and RT-PCR) and the generation of soluble endoglin (using an enzyme-linked immunosorbent assay of cell culture supernatants) after hypoxia and subsequent reoxygenation in human non-immortalized brain endothelial cells. To validate these in vitro data, we additionally examined endoglin expression in an intraluminal monofilament model of permanent and transient middle cerebral artery occlusion in mice. Subsequently, the effects of recombinant human soluble endoglin were assessed by label-free impedance-based measurement of endothelial monolayer integrity (using the xCELLigence DP system) and immunocytochemistry. Endoglin expression is highly inducible by hypoxia in human brain endothelial monolayers in vitro, and subsequent reoxygenation induced its shedding. These findings were corroborated in mice during MCAO; an upregulation of endoglin was displayed in the infarcted hemispheres under occlusion, whereas endoglin expression was significantly diminished after transient MCAO, which is indicative of shedding. Of note is the finding that soluble endoglin induced an inflammatory phenotype in endothelial monolayers. The treatment of HBMEC with endoglin resulted in a decrease in transendothelial resistance and the downregulation of VE-cadherin. Our data establish a novel mechanism in which hypoxia triggers the initial endothelial upregulation of endoglin and subsequent reoxygenation triggers its release as a vasoactive mediator that, when rinsed into adjacent vascular beds after recanalization, can contribute to cerebral reperfusion injury.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137085
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7086: Cathepsin B p.Gly284Val Variant in
           Parkinson’s Disease Pathogenesis

    • Authors: Lukasz M. Milanowski, Xu Hou, Jenny M. Bredenberg, Fabienne C. Fiesel, Liam T. Cocker, Alexandra I. Soto-Beasley, Ronald L. Walton, Audrey J. Strongosky, Ayman H. Faroqi, Maria Barcikowska, Magdalena Boczarska-Jedynak, Jaroslaw Dulski, Lyuda Fedoryshyn, Piotr Janik, Anna Potulska-Chromik, Katherine Karpinsky, Anna Krygowska-Wajs, Tim Lynch, Diana A. Olszewska, Grzegorz Opala, Aleksander Pulyk, Irena Rektorova, Yanosh Sanotsky, Joanna Siuda, Mariusz Widlak, Jaroslaw Slawek, Monika Rudzinska-Bar, Ryan Uitti, Monika Figura, Stanislaw Szlufik, Sylwia Rzonca-Niewczas, Elzbieta Podgorska, Pamela J. McLean, Dariusz Koziorowski, Owen A. Ross, Dorota Hoffman-Zacharska, Wolfdieter Springer, Zbigniew K. Wszolek
      First page: 7086
      Abstract: Parkinson’s disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137086
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7087: Fibroblast Growth Factor 7 Suppresses Fibrosis
           and Promotes Epithelialization during Wound Healing in Mouse Fetuses

    • Authors: Kento Takaya, Noriko Aramaki-Hattori, Shigeki Sakai, Keisuke Okabe, Toru Asou, Kazuo Kishi
      First page: 7087
      Abstract: Adult mammalian wounds leave visible scars, whereas skin wounds in developing mouse fetuses are scarless until a certain point in development when complete regeneration occurs, including the structure of the dermis and skin appendages. Analysis of the molecular mechanisms at this transition will provide clues for achieving scarless wound healing. The fibroblast growth factor (FGF) family is a key regulator of inflammation and fibrosis during wound healing. We aimed to determine the expression and role of FGF family members in fetal wound healing. ICR mouse fetuses were surgically wounded at embryonic day 13 (E13), E15, and E17. Expression of FGF family members and FGF receptor (FGFR) in tissue samples from these fetuses was evaluated using in situ hybridization and reverse transcription-quantitative polymerase chain reaction. Fgfr1 was downregulated in E15 and E17 wounds, and its ligand Fgf7 was upregulated in E13 and downregulated in E15 and E17. Recombinant FGF7 administration in E15 wounds suppressed fibrosis and promoted epithelialization at the wound site. Therefore, the expression level of Fgf7 may correlate with scar formation in late mouse embryos, and external administration of FGF7 may represent a therapeutic option to suppress fibrosis and reduce scarring.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137087
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7088: Comparison of the Response to the CXCR4
           Antagonist AMD3100 during the Development of Retinal Organoids Derived
           from ES Cells and Zebrafish Retina

    • Authors: Yihui Wu, Jin Qiu, Shuilian Chen, Xi Chen, Jing Zhang, Jiejie Zhuang, Sian Liu, Meng Yang, Pan Zhou, Haoting Chen, Keming Yu, Jian Ge, Jing Zhuang
      First page: 7088
      Abstract: Retinal organoids generated from human embryonic stem cells or iPSCs recreate the key structural and functional features of mammalian retinal tissue in vitro. However, the differences in the development of retinal organoids and normal retina in vivo are not well defined. Thus, in the present study, we analyzed the development of retinal organoids and zebrafish retina after inhibition of CXCR4, a key role in neurogenesis and optic nerve development, with the antagonist AMD3100. Our data indicated that CXCR4 was mainly expressed in ganglion cells in retinal organoids and was rarely expressed in amacrine or photoreceptor cells. AMD3100 treatment reduced the retinal organoid generation ratio, impaired differentiation, and induced morphological changes. Ganglion cells, amacrine cells, and photoreceptors were decreased and abnormal locations were observed in organoids treated with AMD3100. Neuronal axon outgrowth was also damaged in retinal organoids. Similarly, a decrease of ganglion cells, amacrine cells, and photoreceptors and the distribution of neural outgrowth was induced by AMD3100 treatment in zebrafish retina. However, abnormal photoreceptor ensembles induced by AMD3100 treatment in the organoids were not detected in zebrafish retina. Therefore, our study suggests that although retinal organoids might provide a reliable model for reproducing a retinal developmental model, there is a difference between the organoids and the retina in vivo.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137088
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7089: Hepatocyte Specific gp130 Signalling Underlies
           APAP Induced Liver Injury

    • Authors: Jinrui Dong, Wei-Wen Lim, Shamini G. Shekeran, Jessie Tan, Sze Yun Lim, Joyce Wei Ting Goh, Benjamin L. George, Sebastian Schafer, Stuart A. Cook, Anissa A. Widjaja
      First page: 7089
      Abstract: N-acetyl-p-aminophenol (APAP)-induced liver damage is associated with upregulation of Interleukin-11 (IL11), which is thought to stimulate IL6ST (gp130)-mediated STAT3 activity in hepatocytes, as a compensatory response. However, recent studies have found IL11/IL11RA/gp130 signaling to be hepatotoxic. To investigate further the role of IL11 and gp130 in APAP liver injury, we generated two new mouse strains with conditional knockout (CKO) of either Il11 (CKOIl11) or gp130 (CKOgp130) in adult hepatocytes. Following APAP, as compared to controls, CKOgp130 mice had lesser liver damage with lower serum Alanine Transaminase (ALT) and Aspartate Aminotrasnferase (AST), greatly reduced serum IL11 levels (90% lower), and lesser centrilobular necrosis. Livers from APAP-injured CKOgp130 mice had lesser ERK, JNK, NOX4 activation and increased markers of regeneration (PCNA, Cyclin D1, Ki67). Experiments were repeated in CKOIl11 mice that, as compared to wild-type mice, had lower APAP-induced ALT/AST, reduced centrilobular necrosis and undetectable IL11 in serum. As seen with CKOgp130 mice, APAP-treated CKOIl11 mice had lesser ERK/JNK/NOX4 activation and greater features of regeneration. Both CKOgp130 and CKOIl11 mice had normal APAP metabolism. After APAP, CKOgp130 and CKOIl11 mice had reduced Il6, Ccl2, Ccl5, Il1β, and Tnfɑ expression. These studies exclude IL11 upregulation as compensatory and establish autocrine, self-amplifying, gp130-dependent IL11 secretion from damaged hepatocytes as toxic and anti-regenerative.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137089
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7090: New Perspectives for Whole Genome Amplification
           in Forensic STR Analysis

    • Authors: Jäger
      First page: 7090
      Abstract: Modern PCR-based analytical techniques have reached sensitivity levels that allow for obtaining complete forensic DNA profiles from even tiny traces containing genomic DNA amounts as small as 125 pg. Yet these techniques have reached their limits when it comes to the analysis of traces such as fingerprints or single cells. One suggestion to overcome these limits has been the usage of whole genome amplification (WGA) methods. These methods aim at increasing the copy number of genomic DNA and by this means generate more template DNA for subsequent analyses. Their application in forensic contexts has so far remained mostly an academic exercise, and results have not shown significant improvements and even have raised additional analytical problems. Until very recently, based on these disappointments, the forensic application of WGA seems to have largely been abandoned. In the meantime, however, novel improved methods are pointing towards a perspective for WGA in specific forensic applications. This review article tries to summarize current knowledge about WGA in forensics and suggests the forensic analysis of single-donor bioparticles and of single cells as promising applications.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137090
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7091: Effect of Compressive Stress in Tumor
           Microenvironment on Malignant Tumor Spheroid Invasion Process

    • Authors: Ryota Nishi, Yudai Oda, Takashi Morikura, Shogo Miyata
      First page: 7091
      Abstract: In this study, we proposed an in vitro tumor model to simulate the mechanical microenvironment and investigate the effect of compressive stress on the invasion process of malignant tumors. It has been pointed out that the biomechanical environment, as well as the biochemical environment, could affect the transformation of cancer cell migration, invasion, and metastasis. We hypothesized that the solid stress caused by the exclusion of surrounding tissue could transform tumor cells from noninvasive to invasive phenotypes. Colorectal cell spheroids were embedded and cultured in agarose gels of varying concentrations to simulate the earliest stages of tumor formation and invasion. The spheroids embedded in gels at higher concentrations showed peculiar growth after 72 h of culture, and the external compressive loading imposed on them caused peculiar growth even in the gels at lower concentrations. In conclusion, the mechanical microenvironment caused the transformation of tumor cell phenotypes, promoting the growth and invasion of tumor cell spheroids.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137091
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7092: Crosstalk between Schizophrenia and Metabolic
           Syndrome: The Role of Oxytocinergic Dysfunction

    • Authors: Kah Kheng Goh, Cynthia Yi-An Chen, Tzu-Hua Wu, Chun-Hsin Chen, Mong-Liang Lu
      First page: 7092
      Abstract: The high prevalence of metabolic syndrome in persons with schizophrenia has spurred investigational efforts to study the mechanism beneath its pathophysiology. Early psychosis dysfunction is present across multiple organ systems. On this account, schizophrenia may be a multisystem disorder in which one organ system is predominantly affected and where other organ systems are also concurrently involved. Growing evidence of the overlapping neurobiological profiles of metabolic risk factors and psychiatric symptoms, such as an association with cognitive dysfunction, altered autonomic nervous system regulation, desynchrony in the resting-state default mode network, and shared genetic liability, suggest that metabolic syndrome and schizophrenia are connected via common pathways that are central to schizophrenia pathogenesis, which may be underpinned by oxytocin system dysfunction. Oxytocin, a hormone that involves in the mechanisms of food intake and metabolic homeostasis, may partly explain this piece of the puzzle in the mechanism underlying this association. Given its prosocial and anorexigenic properties, oxytocin has been administered intranasally to investigate its therapeutic potential in schizophrenia and obesity. Although the pathophysiology and mechanisms of oxytocinergic dysfunction in metabolic syndrome and schizophrenia are both complex and it is still too early to draw a conclusion upon, oxytocinergic dysfunction may yield a new mechanistic insight into schizophrenia pathogenesis and treatment.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137092
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7093: Arabinoxylan and Pectin Metabolism in
           Crohn’s Disease Microbiota: An In Silico Study

    • Authors: Carlos Sabater, Inés Calvete-Torre, Lorena Ruiz, Abelardo Margolles
      First page: 7093
      Abstract: Inflammatory bowel disease is a chronic disorder including ulcerative colitis and Crohn’s disease (CD). Gut dysbiosis is often associated with CD, and metagenomics allows a better understanding of the microbial communities involved. The objective of this study was to reconstruct in silico carbohydrate metabolic capabilities from metagenome-assembled genomes (MAGs) obtained from healthy and CD individuals. This computational method was developed as a mean to aid rationally designed prebiotic interventions to rebalance CD dysbiosis, with a focus on metabolism of emergent prebiotics derived from arabinoxylan and pectin. Up to 1196 and 1577 MAGs were recovered from CD and healthy people, respectively. MAGs of Akkermansia muciniphila, Barnesiella viscericola DSM 18177 and Paraprevotella xylaniphila YIT 11841 showed a wide range of unique and specific enzymes acting on arabinoxylan and pectin. These glycosidases were also found in MAGs recovered from CD patients. Interestingly, these arabinoxylan and pectin degraders are predicted to exhibit metabolic interactions with other gut microbes reduced in CD. Thus, administration of arabinoxylan and pectin may ameliorate dysbiosis in CD by promoting species with key metabolic functions, capable of cross-feeding other beneficial species. These computational methods may be of special interest for the rational design of prebiotic ingredients targeting at CD.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137093
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7094: Melatonin and the Brain–Heart Crosstalk
           in Neurocritically Ill Patients—From Molecular Action to Clinical

    • Authors: Artur Bekała, Włodzimierz Płotek, Dorota Siwicka-Gieroba, Joanna Sołek-Pastuszka, Romuald Bohatyrewicz, Jowita Biernawska, Katarzyna Kotfis, Magdalena Bielacz, Andrzej Jaroszyński, Wojciech Dabrowski
      First page: 7094
      Abstract: Brain injury, especially traumatic brain injury (TBI), may induce severe dysfunction of extracerebral organs. Cardiac dysfunction associated with TBI is common and well known as the brain–heart crosstalk, which broadly refers to different cardiac disorders such as cardiac arrhythmias, ischemia, hemodynamic insufficiency, and sudden cardiac death, which corresponds to acute disorders of brain function. TBI-related cardiac dysfunction can both worsen the brain damage and increase the risk of death. TBI-related cardiac disorders have been mainly treated symptomatically. However, the analysis of pathomechanisms of TBI-related cardiac dysfunction has highlighted an important role of melatonin in the prevention and treatment of such disorders. Melatonin is a neurohormone released by the pineal gland. It plays a crucial role in the coordination of the circadian rhythm. Additionally, melatonin possesses strong anti-inflammatory, antioxidative, and antiapoptotic properties and can modulate sympathetic and parasympathetic activities. Melatonin has a protective effect not only on the brain, by attenuating its injury, but on extracranial organs, including the heart. The aim of this study was to analyze the molecular activity of melatonin in terms of TBI-related cardiac disorders. Our article describes the benefits resulting from using melatonin as an adjuvant in protection and treatment of brain injury-induced cardiac dysfunction.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-25
      DOI: 10.3390/ijms23137094
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7095: Thermal Shift Assay for Small GTPase Stability
           Screening: Evaluation and Suitability

    • Authors: Kari Kopra, Salla Valtonen, Randa Mahran, Jonas N. Kapp, Nazia Hassan, William Gillette, Bryce Dennis, Lianbo Li, Kenneth D. Westover, Andreas Plückthun, Harri Härmä
      First page: 7095
      Abstract: Thermal unfolding methods are commonly used as a predictive technique by tracking the protein’s physical properties. Inherent protein thermal stability and unfolding profiles of biotherapeutics can help to screen or study potential drugs and to find stabilizing or destabilizing conditions. Differential scanning calorimetry (DSC) is a ‘Gold Standard’ for thermal stability assays (TSA), but there are also a multitude of other methodologies, such as differential scanning fluorimetry (DSF). The use of an external probe increases the assay throughput, making it more suitable for screening studies, but the current methodologies suffer from relatively low sensitivity. While DSF is an effective tool for screening, interpretation and comparison of the results is often complicated. To overcome these challenges, we compared three thermal stability probes in small GTPase stability studies: SYPRO Orange, 8-anilino-1-naphthalenesulfonic acid (ANS), and the Protein-Probe. We studied mainly KRAS, as a proof of principle to obtain biochemical knowledge through TSA profiles. We showed that the Protein-Probe can work at lower concentration than the other dyes, and its sensitivity enables effective studies with non-covalent and covalent drugs at the nanomolar level. Using examples, we describe the parameters, which must be taken into account when characterizing the effect of drug candidates, of both small molecules and Designed Ankyrin Repeat Proteins.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137095
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7096: Effects of Non-Opioid Analgesics on the Cell
           Membrane of Skin and Gastrointestinal Cancers

    • Authors: Natalia Janicka, Agnieszka Sałek, Magdalena Sawińska, Ernest Kuchar, Anna Wiela-Hojeńska, Katarzyna Karłowicz-Bodalska
      First page: 7096
      Abstract: Skin and gastrointestinal cancer cells are the target of research by many scientists due to the increasing morbidity and mortality rates around the world. New indications for drugs used in various conditions are being discovered. Non-opioid analgesics are worth noting as very popular, widely available, relatively cheap medications. They also have the ability to modulate the membrane components of tumor cells. The aim of this review is to analyze the impact of diclofenac, ibuprofen, naproxen, acetylsalicylic acid and paracetamol on skin and gastrointestinal cancers cell membrane. These drugs may affect the membrane through topical application, at the in vitro and in vivo level after oral or parenteral administration. They can lead to up- or downregulated expression of receptors, transporters and other molecules associated with plasma membrane. Medications may also alter the lipid bilayer composition of membrane, resulting in changes in its integrity and fluidity. Described modulations can cause the visualization of cancer cells, enhanced response of the immune system and the initiation of cell death. The outcome of this is inhibition of progression or reduction of tumor mass and supports chemotherapy. In conclusion, non-opioid analgesics may be used in the future as adjunctive therapy for the treatment of these cancers.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137096
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7097: Recent Advances in Renal Medullary Carcinoma

    • Authors: Yongdong Su, Andrew L. Hong
      First page: 7097
      Abstract: Renal medullary carcinoma (RMC) is a rare renal malignancy that has been associated with sickle hemoglobinopathies. RMC is aggressive, difficult to treat, and occurs primarily in adolescents and young adults of African ancestry. This cancer is driven by the loss of SMARCB1, a tumor suppressor seen in a number of primarily rare childhood cancers (e.g., rhabdoid tumor of the kidney and atypical teratoid rhabdoid tumor). Treatment options remain limited due in part to the limited knowledge of RMC biology. However, significant advances have been made in unraveling the biology of RMC, from genomics to therapeutic targets, over the past 5 years. In this review, we will present these advances and discuss what new questions exist in the field.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137097
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7098: Molecular Research on Muscle Protein and

    • Authors: Olga Karpicheva
      First page: 7098
      Abstract: This Special Issue highlights new data on the molecular mechanisms of muscle functioning under normal conditions and cellular dysfunctions [...]
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137098
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7099: Methylphenidate Restores Behavioral and
           Neuroplasticity Impairments in the Prenatal Nicotine Exposure Mouse Model
           of ADHD: Evidence for Involvement of AMPA Receptor Subunit Composition and
           Synaptic Spine Morphology in the Hippocampus

    • Authors: Darwin Contreras, Ricardo Piña, Claudia Carvallo, Felipe Godoy, Gonzalo Ugarte, Marc Zeise, Carlos Rozas, Bernardo Morales
      First page: 7099
      Abstract: In ADHD treatment, methylphenidate (MPH) is the most frequently used medication. The present work provides evidence that MPH restored behavioral impairments and neuroplasticity due to changes in AMPAR subunit composition and distribution, as well as maturation of dendritic spines, in a prenatal nicotine exposure (PNE) ADHD mouse model. PNE animals and controls were given a single oral dose of MPH (1 mg/kg), and their behavior was tested for attention, hyperactivity, and working memory. Long-term potentiation (LTP) was induced and analyzed at the CA3/CA1 synapse in hippocampal slices taken from the same animals tested behaviorally, measuring fEPSPs and whole-cell patch-clamp EPSCs. By applying crosslinking and Western blots, we estimated the LTP effects on AMPAR subunit composition and distribution. The density and types of dendritic spines were quantified by using the Golgi staining method. MPH completely restored the behavioral impairments of PNE mice. Reduced LTP and AMPA-receptor-mediated EPSCs were also restored. EPSC amplitudes were tightly correlated with numbers of GluA1/GluA1 AMPA receptors at the cell surface. Finally, we found a lower density of dendritic spines in hippocampal pyramidal neurons in PNE mice, with a higher fraction of thin-type immature spines and a lower fraction of mushroom mature spines; the latter effect was also reversed by MPH.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137099
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7100: Systemic Dietary Hesperidin Modulation of
           Osteoclastogenesis, Bone Homeostasis and Periodontal Disease in Mice

    • Authors: Vinícius de Paiva Gonçalves, Marta Liliana Musskopf, Angeliz Rivera-Concepcion, Christina Yu, Sing Wai Wong, Stephen A. Tuin, Yizu Jiao, Cristiano Susin, Luís Carlos Spolidorio, Patricia Almeida Miguez
      First page: 7100
      Abstract: This study aimed to evaluate the effects of hesperidin (HE) on in vitro osteoclastogenesis and dietary supplem entation on mouse periodontal disease and femoral bone phenotype. RAW 264.7 cells were stimulated with RANKL in the presence or absence of HE (1, 100 or 500 µM) for 5 days, and evaluated by TRAP, TUNEL and Western Blot (WB) analyses. In vivo, C57BL/6 mice were given HE via oral gavage (125, 250 and 500 mg/kg) for 4 weeks. A sterile silk ligature was placed between the first and second right maxillary molars for 10 days and microcomputed tomography (μCT), histopathological and immunohistochemical evaluation were performed. Femoral bones subjected or not to dietary HE (500 mg/kg) for 6 and 12 weeks were evaluated using μCT. In vitro, HE 500 µM reduced formation of RANKL-stimulated TRAP-positive(+) multinucleated cells (500 µM) as well as c-Fos and NFATc1 protein expression (p < 0.05), markers of osteoclasts. In vivo, dietary HE 500 mg/kg increased the alveolar bone resorption in ligated teeth (p < 0.05) and resulted in a significant increase in TRAP+ cells (p < 0.05). Gingival inflammatory infiltrate was greater in the HE 500 mg/kg group even in the absence of ligature. In femurs, HE 500 mg/kg protected trabecular and cortical bone mass at 6 weeks of treatment. In conclusion, HE impaired in vitro osteoclastogenesis, but on the contrary, oral administration of a high concentration of dietary HE increased osteoclast numbers and promoted inflammation-induced alveolar bone loss. However, HE at 500 mg/kg can promote a bone-sparing effect on skeletal bone under physiological conditions.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137100
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7101: Porous Carbon Spheres Derived from
           Hemicelluloses for Supercapacitor Application

    • Authors: Yuanyuan Wang, Chengshuai Lu, Xuefei Cao, Qiang Wang, Guihua Yang, Jiachuan Chen
      First page: 7101
      Abstract: With the increasing demand for dissolving pulp, large quantities of hemicelluloses were generated and abandoned. These hemicelluloses are very promising biomass resources for preparing carbon spheres. However, the pore structures of the carbon spheres obtained from biomass are usually poor, which extensively limits their utilization. Herein, the carbon microspheres derived from hemicelluloses were prepared using hydrothermal carbonization and further activated with different activators (KOH, K2CO3, Na2CO3, and ZnCl2) to improve their electrochemical performance as supercapacitors. After activation, the specific surface areas of these carbon spheres were improved significantly, which were in the order of ZnCl2 > K2CO3 > KOH > Na2CO3. The carbon spheres with high surface area of 2025 m2/g and remarkable pore volume of 1.07 cm3/g were achieved, as the carbon spheres were activated by ZnCl2. The supercapacitor electrode fabricated from the ZnCl2-activated carbon spheres demonstrated high specific capacitance of 218 F/g at 0.2 A/g in 6 M KOH in a three-electrode system. A symmetric supercapacitor was assembled in 2 M Li2SO4 electrolyte, and the carbon spheres activated by ZnCl2 showed excellent electrochemical performance with high specific capacitance (137 F/g at 0.5 A/g), energy densities (15.4 Wh/kg), and good cyclic stability (95% capacitance retention over 2000 cycles).
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137101
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7102: Antibacterial and Cytotoxicity Evaluation of
           New Hydroxyapatite-Based Granules Containing Silver or Gallium Ions with
           Potential Use as Bone Substitutes

    • Authors: Kamil Pajor, Anna Michalicha, Anna Belcarz, Lukasz Pajchel, Anna Zgadzaj, Filip Wojas, Joanna Kolmas
      First page: 7102
      Abstract: The aim of the current work was to study the physicochemical properties and biological activity of different types of porous granules containing silver or gallium ions. Firstly, hydroxyapatites powders doped with Ga3+ or Ag+ were synthesized by the standard wet method. Then, the obtained powders were used to fabricate ceramic microgranules (AgM and GaM) and alginate/hydroxyapatite composite granules (AgT and GaT). The ceramic microgranules were also used to prepare a third type of granules (AgMT and GaMT) containing silver or gallium, respectively. All the granules turned out to be porous, except that the AgT and GaT granules were characterized by higher porosity and a better developed specific surface, whereas the microgranules had very fine, numerous micropores. The granules revealed a slow release of the substituted ions. All the granules except AgT were classified as non-cytotoxic according to the neutral red uptake (NRU) test and the MTT assay. The obtained powders and granules were subjected to various antibacterial test towards the following four different bacterial strains: Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa and Escherichia coli. The Ag-containing materials revealed high antibacterial activity.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137102
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7103: miRNA and mRNA Expression Profiles Associated
           with Lymph Node Metastasis and Prognosis in Penile Carcinoma

    • Authors: Claudio B. Murta, Tatiane K. Furuya, Alexis G. M. Carrasco, Miyuki Uno, Laura Sichero, Luisa L. Villa, Sheila F. Faraj, Rafael F. Coelho, Giuliano B. Guglielmetti, Mauricio D. Cordeiro, Katia R. M. Leite, William C. Nahas, Roger Chammas, José Pontes
      First page: 7103
      Abstract: Penile cancer (PeC) is a rare disease, and no prognostic biomarkers have been adopted in clinical practice yet. The objective of the present study was to identify differentially expressed miRNAs (DEmiRs) and genes (DEGs) as potential biomarkers for lymph node metastasis and other prognostic factors in PeC. Tumor samples were prospectively obtained from 24 patients with squamous cell carcinoma of the penis. miRNA microarray analysis was performed comparing tumors from patients with inguinal lymph node metastatic and localized disease, and the results were validated by qRT-PCR. Eighty-three gene expression levels were also compared between groups through qRT-PCR. Moreover, DEmiRs and DEGs expression levels were correlated with clinicopathological variables, cancer-specific (CSS), and overall survival (OS). TAC software, TM4 MeV 4.9 software, SPSS v.25.0, and R software v.4.0.2 were used for statistical analyses. We identified 21 DEmiRs in microarray analysis, and seven were selected for validation. miR-744-5p and miR-421 were overexpressed in tissue samples of metastatic patients, and high expression of miR-421 was also associated with lower OS. We found seven DEGs (CCND1, EGFR, ENTPD5, HOXA10, IGF1R, MYC, and SNAI2) related to metastatic disease. A significant association was found between increased MMP1 expression and tumor size, grade, pathological T stage, and perineural invasion. Other genes were also associated with clinicopathological variables, CSS and OS. Finally, we found changes in mRNA–miRNA regulation that contribute to understanding the mechanisms involved in tumor progression. Therefore, we identified miRNA and mRNA expression profiles as potential biomarkers associated with lymph node metastasis and prognosis in PeC, in addition to disruption in mRNA–miRNA regulation during disease progression.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137103
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7104: Development of Novel Ecto-Nucleotide
           Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Tumor

    • Authors: Xiang Wang, Xing Lu, Daojing Yan, Yajun Zhou, Xiangshi Tan
      First page: 7104
      Abstract: The cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes–TANK-binding kinase 1–interferon regulating factor 3 (cGAS-STING-TBK1-IRF3) axis is now acknowledged as the major signaling pathway in innate immune responses. However, 2′,3′-cGAMP as a STING stimulator is easily recognized and degraded by ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which reduces the effect of tumor immunotherapy and promotes metastatic progression. In this investigation, the structure-based virtual screening strategy was adopted to discover eight candidate compounds containing zinc-binding quinazolin-4(3H)-one scaffold as ENPP1 inhibitors. Subsequently, these novel inhibitors targeting ENPP1 were synthesized and characterized by NMR and high-resolution mass spectra (HRMS). In bioassays, 7-fluoro-2-(((5-methoxy-1H-imidazo[4,5-b]pyridin-2-yl)thio)methyl)quina-zolin-4(3H)-one(compound 4e) showed excellent activity against the ENPP1 at the molecular and cellular levels, with IC50 values of 0.188 μM and 0.732 μM, respectively. Additionally, compound 4e had superior selectivity towards metastatic breast cancer cells (4T1) than towards normal cells (LO2 and 293T) in comparison with cisplatin, indicating that compound 4e can potentially be used in metastatic breast cancer therapy. On the other hand, compound 4e upgraded the expression levels of IFN-β in vivo by preventing the ENPP1 from hydrolyzing the cGAMP to stimulate a more potent innate immune response. Therefore, this compound might be applied to boost antitumor immunity for cancer immunotherapy. Overall, our work provides a strategy for the development of a promising drug candidate targeting ENPP1 for tumor immunotherapy.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137104
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7105: Centipede Venom: A Potential Source of Ion
           Channel Modulators

    • Authors: Anna Luo, Aili Wang, Peter Muiruri Kamau, Ren Lai, Lei Luo
      First page: 7105
      Abstract: Centipedes are one of the most ancient and successful living venomous animals. They have evolved spooky venoms to deter predators or hunt prey, and are widely distributed throughout the world besides Antarctica. Neurotoxins are the most important virulence factor affecting the function of the nervous system. Ion channels and receptors expressed in the nervous system, including NaV, KV, CaV, and TRP families, are the major targets of peptide neurotoxins. Insight into the mechanism of neurotoxins acting on ion channels contributes to our understanding of the function of both channels and centipede venoms. Meanwhile, the novel structure and selective activities give them the enormous potential to be modified and exploited as research tools and biological drugs. Here, we review the centipede venom peptides that act on ion channels.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137105
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7106: Vascular Dysfunction Is Central to
           Alzheimer’s Disease Pathogenesis in APOE e4 Carriers

    • Authors: Andrew N. McCorkindale, Hamish D. Mundell, Boris Guennewig, Greg T. Sutherland
      First page: 7106
      Abstract: Alzheimer’s disease (AD) is the most common form of dementia and the leading risk factor, after age, is possession of the apolipoprotein E epsilon 4 allele (APOE4). Approximately 50% of AD patients carry one or two copies of APOE4 but the mechanisms by which it confers risk are still unknown. APOE4 carriers are reported to demonstrate changes in brain structure, cognition, and neuropathology, but findings have been inconsistent across studies. In the present study, we used multi-modal data to characterise the effects of APOE4 on the brain, to investigate whether AD pathology manifests differently in APOE4 carriers, and to determine if AD pathomechanisms are different between carriers and non-carriers. Brain structural differences in APOE4 carriers were characterised by applying machine learning to over 2000 brain MRI measurements from 33,384 non-demented UK biobank study participants. APOE4 carriers showed brain changes consistent with vascular dysfunction, such as reduced white matter integrity in posterior brain regions. The relationship between APOE4 and AD pathology was explored among the 1260 individuals from the Religious Orders Study and Memory and Aging Project (ROSMAP). APOE4 status had a greater effect on amyloid than tau load, particularly amyloid in the posterior cortical regions. APOE status was also highly correlated with cerebral amyloid angiopathy (CAA). Bulk tissue brain transcriptomic data from ROSMAP and a similar dataset from the Mount Sinai Brain Bank showed that differentially expressed genes between the dementia and non-dementia groups were enriched for vascular-related processes (e.g., “angiogenesis”) in APOE4 carriers only. Immune-related transcripts were more strongly correlated with AD pathology in APOE4 carriers with some transcripts such as TREM2 and positively correlated with pathology severity in APOE4 carriers, but negatively in non-carriers. Overall, cumulative evidence from the largest neuroimaging, pathology, and transcriptomic studies available suggests that vascular dysfunction is key to the development of AD in APOE4 carriers. However, further studies are required to tease out non-APOE4-specific mechanisms.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137106
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7107: Human PARP1 Facilitates Transcription through a
           Nucleosome and Histone Displacement by Pol II In Vitro

    • Authors: Elena Y. Kotova, Fu-Kai Hsieh, Han-Wen Chang, Natalia V. Maluchenko, Marie-France Langelier, John M. Pascal, Donal S. Luse, Alexey V. Feofanov, Vasily M. Studitsky
      First page: 7107
      Abstract: Human poly(ADP)-ribose polymerase-1 (PARP1) is a global regulator of various cellular processes, from DNA repair to gene expression. The underlying mechanism of PARP1 action during transcription remains unclear. Herein, we have studied the role of human PARP1 during transcription through nucleosomes by RNA polymerase II (Pol II) in vitro. PARP1 strongly facilitates transcription through mononucleosomes by Pol II and displacement of core histones in the presence of NAD+ during transcription, and its NAD+-dependent catalytic activity is essential for this process. Kinetic analysis suggests that PARP1 facilitates formation of “open” complexes containing nucleosomal DNA partially uncoiled from the octamer and allowing Pol II progression along nucleosomal DNA. Anti-cancer drug and PARP1 catalytic inhibitor olaparib strongly represses PARP1-dependent transcription. The data suggest that the negative charge on protein(s) poly(ADP)-ribosylated by PARP1 interact with positively charged DNA-binding surfaces of histones transiently exposed during transcription, facilitating transcription through chromatin and transcription-dependent histone displacement/exchange.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137107
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7108: Are Alterations in DNA Methylation Related to
           CKD Development'

    • Authors: Jacek Rysz, Beata Franczyk, Magdalena Rysz-Górzyńska, Anna Gluba-Brzózka
      First page: 7108
      Abstract: The modifications in genomic DNA methylation are involved in the regulation of normal and pathological cellular processes. The epigenetic regulation stimulates biological plasticity as an adaptive response to variations in environmental factors. The role of epigenetic changes is vital for the development of some diseases, including atherogenesis, cancers, and chronic kidney disease (CKD). The results of studies presented in this review have suggested that altered DNA methylation can modulate the expression of pro-inflammatory and pro-fibrotic genes, as well those essential for kidney development and function, thus stimulating renal disease progression. Abnormally increased homocysteine, hypoxia, and inflammation have been suggested to alter epigenetic regulation of gene expression in CKD. Studies of renal samples have demonstrated the relationship between variations in DNA methylation and fibrosis and variations in estimated glomerular filtration rate (eGFR) in human CKD. The unravelling of the genetic–epigenetic profile would enhance our understanding of processes underlying the development of CKD. The understanding of multifaceted relationship between DNA methylation, genes expression, and disease development and progression could improve the ability to identify individuals at risk of CKD and enable the choice of appropriate disease management.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137108
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7109: New Peptide Functionalized Nanostructured Lipid
           Carriers with CNS Drugs and Evaluation Anti-proliferative Activity

    • Authors: Sara Silva, Joana Marto, Lídia M. Gonçalves, Diana Duarte, O. Salomé G. P. Soares, Francisco Vasques-Nóvoa, António J. Almeida, Nuno Vale
      First page: 7109
      Abstract: Nanoparticulate systems have been widely investigated as delivery vectors for efficient drug delivery in different diseases. Nanostructured lipid carriers (NLC) are composed of both solid and liquid lipids (glyceryl dibehenate and diethylene glycol monoethyl ether) and have demonstrated enhanced biological compatibility and increased drug loading capability. Furthermore, the use of peptides, in particular cell-penetrating peptides, to functionalize nanoparticles and enhance cell membrane permeation was explored in this paper. In this paper, we described the synthesis of a new conjugated of tranylcypromine with MAP. In addition, taking into consideration our previous results, this study developed different NLCs loaded with three central nervous system (CNS) drugs (tacrine (TAC), rasagiline (RAS), and tranylcypromine (TCP)) functionalized with model amphipathic peptide (MAP) and evaluated their activity against cancer cells. Particle size analysis demonstrated NLC presented less than 200 nm and a polydispersity index less than 0.3. Moreover, in vitro results showed that conjugation of MAP with drugs led to a higher decrease in cell viability of a neuroblastoma cell line and Caco-2 cell line, more than MAP alone. Furthermore, NLC encapsulation contributed to higher cellular delivery and enhanced toxic activity at lower concentrations when compared with free or co-administration drug-MAP conjugate.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137109
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7110: Bacterial Quorum-Sensing Signal DSF Inhibits
           LPS-Induced Inflammations by Suppressing Toll-like Receptor Signaling and
           Preventing Lysosome-Mediated Apoptosis in Zebrafish

    • Authors: Hongjie Zhu, Zhihao Wang, Wenxin Wang, Yongbo Lu, Ya-Wen He, Jing Tian
      First page: 7110
      Abstract: Bacteria and their eukaryotic hosts have co-evolved for millions of years, and the former can intercept eukaryotic signaling systems for the successful colonization of the host. The diffusible signal factor (DSF) family represents a type of quorum-sensing signals found in diverse Gram-negative bacterial pathogens. Recent evidence shows that the DSF is involved in interkingdom communications between the bacterial pathogen and the host plant. In this study, we explored the anti-inflammatory effect of the DSF and its underlying molecular mechanism in a zebrafish model. We found that the DSF treatment exhibited a strong protective effect on the inflammatory response of zebrafish induced by lipopolysaccharide (LPS). In the LPS-induced inflammation zebrafish model, the DSF could significantly ameliorate the intestinal pathological injury, reduce abnormal migration and the aggregation of inflammatory cells, inhibit the excessive production of inflammatory mediator reactive oxygen species (ROS) content, and prevent apoptosis. Through an RNA-Seq analysis, a total of 938 differentially expressed genes (DEGs) was screened between LPS and LPS + DSF treatment zebrafish embryos. A further bioinformatics analysis and validation revealed that the DSF might inhibit the LPS-induced zebrafish inflammatory response by preventing the activation of signaling in the Toll-like receptor pathway, attenuating the expression of pro-inflammatory cytokines and chemokines, and regulating the activation of the caspase cascade through restoring the expression of lysosomal cathepsins and apoptosis signaling. This study, for the first time, demonstrates the anti-inflammatory role and a potential pharmaceutical application of the bacterial signal DSF. These findings also suggest that the interkingdom communication between DSF-producing bacteria and zebrafish might occur in nature.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137110
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7111: Recent Development in Nanoconfined Hydrides for
           Energy Storage

    • Authors: Cezar Comanescu
      First page: 7111
      Abstract: Hydrogen is the ultimate vector for a carbon-free, sustainable green-energy. While being the most promising candidate to serve this purpose, hydrogen inherits a series of characteristics making it particularly difficult to handle, store, transport and use in a safe manner. The researchers’ attention has thus shifted to storing hydrogen in its more manageable forms: the light metal hydrides and related derivatives (ammonia-borane, tetrahydridoborates/borohydrides, tetrahydridoaluminates/alanates or reactive hydride composites). Even then, the thermodynamic and kinetic behavior faces either too high energy barriers or sluggish kinetics (or both), and an efficient tool to overcome these issues is through nanoconfinement. Nanoconfined energy storage materials are the current state-of-the-art approach regarding hydrogen storage field, and the current review aims to summarize the most recent progress in this intriguing field. The latest reviews concerning H2 production and storage are discussed, and the shift from bulk to nanomaterials is described in the context of physical and chemical aspects of nanoconfinement effects in the obtained nanocomposites. The types of hosts used for hydrogen materials are divided in classes of substances, the mean of hydride inclusion in said hosts and the classes of hydrogen storage materials are presented with their most recent trends and future prospects.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137111
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7112: Synthesis, Physicochemical Characterization,
           and Antibacterial Performance of Silver–Lactoferrin Complexes

    • Authors: Oleksandra Pryshchepa, Paweł Pomastowski, Katarzyna Rafińska, Adrian Gołębiowski, Agnieszka Rogowska, Maciej Monedeiro-Milanowski, Gulyaim Sagandykova, Bernhard Michalke, Philippe Schmitt-Kopplin, Michał Gloc, Renata Dobrucka, Krzysztof Kurzydłowski, Bogusław Buszewski
      First page: 7112
      Abstract: Antibiotic-resistant bacteria pose one of the major threats to human health worldwide. The issue is fundamental in the case of chronic wound treatment. One of the latest trends to overcome the problem is the search for new antibacterial agents based on silver. Thus, the aim of this research was to synthesize the silver-lactoferrin complex as a new generation of substances for the treatment of infected wounds. Moreover, one of the tasks was to investigate the formation mechanisms of the respective complexes and the influence of different synthesis conditions on the features of final product. The batch-sorption study was performed by applying the Langmuir and Freundlich isotherm models for the process description. Characterization of the complexes was carried out by spectroscopy, spectrometry, and separation techniques, as well as with electron microscopy. Additionally, the biological properties of the complex were evaluated, i.e., the antibacterial activity against selected bacteria and the impact on L929 cell-line viability. The results indicate the formation of a heterogeneous silver–lactoferrin complex that comprises silver nanoparticles. The complex has higher antibacterial strength than both native bovine lactoferrin and Ag+, while being comparable to silver toxicity.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137112
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7113: Multi-Modal and Molecular Imaging of Cellular
           Microenvironment and Tissue Development

    • Authors: Francesco Pampaloni
      First page: 7113
      Abstract: Imaging the interaction of individual cells with their surrounding tissue microenvironment is essential to advance in bioprinting, tissue engineering and cancer biology, to mention just three highly relevant fields in the life sciences [...]
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137113
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7114: Human Sarcopenic Myoblasts Can Be Rescued by
           Pharmacological Reactivation of HIF-1α

    • Authors: Federica Cirillo, Laura Mangiavini, Paolo La Rocca, Marco Piccoli, Andrea Ghiroldi, Paola Rota, Adriana Tarantino, Barbara Canciani, Simona Coviello, Carmelo Messina, Giuseppe Ciconte, Carlo Pappone, Giuseppe Maria Peretti, Luigi Anastasia
      First page: 7114
      Abstract: Sarcopenia, an age-related decline in muscle mass and strength, is associated with metabolic disease and increased risk of cardiovascular morbidity and mortality. It is associated with decreased tissue vascularization and muscle atrophy. In this work, we investigated the role of the hypoxia inducible factor HIF-1α in sarcopenia. To this end, we obtained skeletal muscle biopsies from elderly sarcopenic patients and compared them with those from young individuals. We found a decrease in the expression of HIF-1α and its target genes in sarcopenia, as well as of PAX7, the major stem cell marker of satellite cells, whereas the atrophy marker MURF1 was increased. We also isolated satellite cells from muscle biopsies and cultured them in vitro. We found that a pharmacological activation of HIF-1α and its target genes caused a reduction in skeletal muscle atrophy and activation of PAX7 gene expression. In conclusion, in this work we found that HIF-1α plays a role in sarcopenia and is involved in satellite cell homeostasis. These results support further studies to test whether pharmacological reactivation of HIF-1α could prevent and counteract sarcopenia.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137114
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7115: Deoxyshikonin Mediates Heme Oxygenase-1
           Induction and Apoptotic Response via p38 Signaling in Tongue Cancer Cell

    • Authors: Chun-Yi Chuang, Chiao-Wen Lin, Chun-Wen Su, Yi-Tzu Chen, Wei-En Yang, Shun-Fa Yang, Shih-Chi Su
      First page: 7115
      Abstract: Deoxyshikonin (DSK), a phytochemical constituent, has been documented to elicit various oncostatic properties alone or in combination with established therapeutics. However, its role in restraining oral squamous cell carcinoma (OSCC) is mostly unclear. Here, we examined the tumor-suppressive effect of DSK and explored the molecular mechanisms underlying DSK’s activities on controlling oral cancer. Our results showed that DSK dose-dependently lessened the cell viability of tongue cancer cell lines, involving induction of cell cycle arrest at the sub-G1 phase and apoptotic cell death. Moreover, a unique signature of apoptosis-related proteins, including augmented nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) expression and caspase activation, was observed in DSK-treated tongue cancer cell lines. Furthermore, DSK-mediated upregulation of HO-1 and cleavage of caspase-9 and -3 were significantly inhibited by pharmacological blockage of p38 kinase. Collectively, these data revealed that DSK halted cell cycle progression and elicited cell apoptosis in tongue cancer cell lines, reshaping a p38-dependent profile of apoptotic proteome. Our findings provided novel insights into the therapeutic implications of a natural compound on the management of OSCC.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-26
      DOI: 10.3390/ijms23137115
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7116: Transcriptome and Quasi-Targeted Metabolome
           Analyze Overexpression of 4-Hydroxyphenylpyruvate Dioxygenase Alleviates
           Fungal Toxicity of 9-Phenanthrol in Magnaporthe oryzae

    • Authors: Yi Wang, Ziyi Wang, Sauban Musa Jibril, Mian Wei, Xin Pu, Chao Yang, Chan Ma, Qi Wu, Lina Liu, Yiji Quan, Chengyun Li
      First page: 7116
      Abstract: Magnaporthe oryzae, the causal agent of rice blast disease, produces devastating damage to global rice production. It is urgent to explore novel strategies to overcome the losses caused by this disease. 9-phenanthrol is often used as a transient receptor potential melastatin 4 (TRPM4) channel inhibitor for animals, but we found its fungal toxicity to M. oryzae. Thus, we explored the antimicrobial mechanism through transcriptome and metabolome analyses. Moreover, we found that overexpression of a gene encoding 4-hydroxyphenylpyruvate dioxygenase involved in the tyrosine degradative pathway enhanced the tolerance of 9-phenanthrol in M. oryzae. Thus, our results highlight the potential fungal toxicity mechanism of 9-phenanthrol at metabolic and transcriptomic levels and identify a gene involving 9-phenanthrol alleviation. Importantly, our results demonstrate the novel mechanism of 9-phenanthrol on fungal toxicity that will provide new insights of 9-phenanthrol for application on other organisms.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137116
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7117: Sera of Neuromyelitis Optica Patients Increase
           BID-Mediated Apoptosis in Astrocytes

    • Authors: Omri Zveik, Ariel Rechtman, Nitzan Haham, Irit Adini, Tamar Canello, Iris Lavon, Livnat Brill, Adi Vaknin-Dembinsky
      First page: 7117
      Abstract: Neuromyelitis optica (NMO) is a rare disease usually presenting with bilateral or unilateral optic neuritis with simultaneous or sequential transverse myelitis. Autoantibodies directed against aquaporin-4 (AQP4-IgG) are found in most patients. They are believed to cross the blood–brain barrier, target astrocytes, activate complement, and eventually lead to astrocyte destruction, demyelination, and axonal damage. However, it is still not clear what the primary pathological event is. We hypothesize that the interaction of AQP4-IgG and astrocytes leads to DNA damage and apoptosis. We studied the effect of sera from seropositive NMO patients and healthy controls (HCs) on astrocytes’ immune gene expression and viability. We found that sera from seropositive NMO patients led to higher expression of apoptosis-related genes, including BH3-interacting domain death agonist (BID), which is the most significant differentiating gene (p < 0.0001), and triggered more apoptosis in astrocytes compared to sera from HCs. Furthermore, NMO sera increased DNA damage and led to a higher expression of immunological genes that interact with BID (TLR4 and NOD-1). Our findings suggest that sera of seropositive NMO patients might cause astrocytic DNA damage and apoptosis. It may be one of the mechanisms implicated in the primary pathological event in NMO and provide new avenues for therapeutic intervention.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137117
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7118: A Combination of the Natural Molecules Gallic

    • Authors: Maxime Gobin, Richard Proust, Stéphane Lack, Laura Duciel, Céline Des Courtils, Emmanuel Pauthe, Adeline Gand, Damien Seyer
      First page: 7118
      Abstract: Wound infection, especially the development of bacterial biofilms, delays wound healing and is a major public health concern. Bacteria in biofilms are more tolerant to antimicrobial agents, and new treatments to eradicate mature biofilms are needed. Combining antimicrobial molecules with different mechanisms of action is an attractive strategy to tackle the heterogeneous nature of microbial communities in biofilms. This study focused on three molecules of natural origin: gallic acid (G), carvacrol (K) and curcumin (Q). Their abilities, individually or in combination, to eradicate biofilms were quantified on mono- and dual-species mature biofilms of Pseudomonas aeruginosa and Staphylococcus aureus, the strains most commonly found in infected wounds. G presented biofilm eradicating activity on P. aeruginosa, whereas K had biofilm eradicating activity on S. aureus and P. aeruginosa. Q had no potent biofilm eradicating activity. The combination of G and K increased the effects previously observed on P. aeruginosa biofilm and led to complete eradication of S. aureus biofilm. This combination was also efficient in eradicating a dual-species biofilm of S. aureus and P. aeruginosa. This work demonstrates that K and G used in combination have a strong and synergistic eradicating activity on both mono- and dual-species mature biofilms of S. aureus and P. aeruginosa and may therefore represent an efficient alternative for the treatment of biofilms in wounds.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137118
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7119: Shear Stress Enhances the Paracrine-Mediated
           Immunoregulatory Function of Human Periodontal Ligament Stem Cells via the
           ERK Signalling Pathway

    • Authors: Ravipha Suwittayarak, Nuttha Klincumhom, Utapin Ngaokrajang, Worachat Namangkalakul, João N. Ferreira, Prasit Pavasant, Thanaphum Osathanon
      First page: 7119
      Abstract: Relevant immunomodulatory effects have been proposed following allogeneic cell-based therapy with human periodontal ligament stem cells (hPDLSCs). This study aimed to examine the influence of shear stress on the immunosuppressive capacity of hPDLSCs. Cells were subjected to shear stress at different magnitudes (0.5, 5 and 10 dyn/cm2). The expression of immunosuppressive markers was evaluated in shear stress-induced hPDLSCs using qRT-PCR, western blot, enzyme activity and enzyme-linked immunosorbent assays. The effects of a shear stress-derived condition medium (SS-CM) on T cell proliferation were examined using a resazurin assay. Treg differentiation was investigated using qRT-PCR and flow cytometry analysis. Our results revealed that shear stress increased mRNA expression of IDO and COX2 but not TGF-β1 and IFN-γ. IDO activity, kynurenine and active TGF-β1 increased in SS-CM when compared to the non-shear stress-derived conditioned medium (CTL-CM). The amount of kynurenine in SS-CM was reduced in the presence of cycloheximide and ERK inhibitor. Subsequently, T cell proliferation decreased in SS-CM compared to CTL-CM. Treg differentiation was promoted in SS-CM, indicated by FOXP3, IL-10 expression and CD4+CD25hiCD127lo/− subpopulation. In conclusion, shear stress promotes kynurenine production through ERK signalling in hPDLSC, leading to the inhibition of T cell proliferation and the promotion of Treg cell differentiation.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137119
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7120: Relaxin and Erythropoietin Significantly Reduce
           Uterine Tissue Damage during Experimental Ischemia–Reperfusion

    • Authors: Lina Jakubauskiene, Matas Jakubauskas, Gintare Razanskiene, Bettina Leber, Jennifer Weber, Lisa Rohrhofer, Diana Ramasauskaite, Kestutis Strupas, Philipp Stiegler, Peter Schemmer
      First page: 7120
      Abstract: Successful uterus transplantation, a potential treatment method for women suffering from absolute uterine infertility, is negatively affected by ischemia–reperfusion injury (IRI). The aim of this study is to investigate the protective effect of relaxin (RLX) or/and erythropoietin (EPO) on experimental uterus IRI. Eighty rats, randomly assigned into eight groups (n = 10/group), were pretreated with either saline, 5 μg/kg human relaxin-2, 4000 IU/kg recombinant human erythropoietin or their combination. Ischemia was achieved by clamping the aorta and ovarian arteries for 60 min, following 120 min of reperfusion and tissue sampling. For sham animals, clamping was omitted during surgery. There were no differences in tissue histological score, malondialdehyde (MDA) and superoxide dismutase (SOD) levels, myeloperoxidase (MPO) and TUNEL-positive cell count between all sham-operated rats. Pretreatment with RLX preserved normal tissue morphology, reduced MDA levels, MPO and TUNEL-positive cell count, preserved SOD activity and upregulated NICD and HES1 gene expression when compared to the control group. Pretreatment with EPO reduced MDA levels. In conclusion, pretreatment with RLX, EPO or a combination of both EPO and RLX significantly alleviates uterine tissue damage caused by IRI.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137120
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7121: Photoresponsive Metal-Organic Frameworks as
           Adjustable Scaffolds in Reticular Chemistry

    • Authors: Adrian Saura-Sanmartin
      First page: 7121
      Abstract: The easy and remote switching of light makes this stimulus an ideal candidate for a large number of applications, among which the preparation of photoresponsive materials stands out. The interest of several scientists in this area in order to achieve improved functionalities has increase parallel to the growth of the structural complexity of these materials. Thus, metal-organic frameworks (MOFs) turned out to be ideal scaffolds for light-responsive ligands. This review is focused on the integration of photoresponsive organic ligands inside MOF crystalline arrays to prepare enhanced functional materials. Besides the summary of the preparation, properties and applications of these materials, an overview of the future outlook of this research area is provided.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137121
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7122: Effects of Compounds Isolated from Lindera
           erythrocarpa on Anti-Inflammatory and Anti-Neuroinflammatory Action in BV2
           Microglia and RAW264.7 Macrophage

    • Authors: Chi-Su Yoon, Hwan Lee, Zhiming Liu, Hyeong-Kyu Lee, Dong-Sung Lee
      First page: 7122
      Abstract: Lindera erythrocarpa contains various constituents such as cyclopentenedione-, flavonoid-, and chalcone-type components. In this study, a novel bi-linderone derivative and 17 known compounds were isolated from the leaves of L. erythrocarpa by using various chromatographic methods. The structures of the components were determined from nuclear magnetic resonance and mass spectrometry data. All isolated compounds were tested for anti-inflammatory and anti-neuroinflammatory activities in lipopolysaccharide (LPS)-induced BV2 and RAW264.7 cells. Some of these compounds showed anti-inflammatory effects by inhibiting the nitric oxide (NO) produced by LPS. In particular, linderaspirone A (16), bi-linderone (17) and novel compound demethoxy-bi-linderone (18) showed significant inhibitory effects on the production of prostaglandin E2 (PGE2), tumor necrosis factor-α, and interleukin-6. The three compounds also inhibited the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), which are pro-inflammatory proteins, and the activation of nuclear factor κB (NF-κB). Therefore, linderaspirone A (16), bi-linderone (17), and demethoxy-bi-linderone (18) isolated from the leaves of L. erythrocarpa have therapeutic potential in neuroinflammatory diseases.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137122
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7123: Catalase Inhibition by Aminoalkanol Derivatives
           with Potential Anti-Cancer Activity—In Vitro and In Silico Studies
           Using Capillary Electrophoresis Method

    • Authors: Błażej Grodner, Mariola Napiórkowska, Dariusz Maciej Pisklak
      First page: 7123
      Abstract: In this work, the investigation of type and inhibitory strength of catalase by two pairs of aminoalkanol derivatives (1,7 diEthyl- and 1,7-diMethyl-8,9-diphenyl-4-azatricyclo ( dec-8-ene- 3,5,10-trione) has been presented. The obtained results allowed for the determination of all kinetic parameters (Km, Vmax, slope angles of Lineweaver–Burk plots, Ki and IC50) on the basis of which it was shown that all four aminoalkanol derivatives are competitive inhibitors of catalase. However, the strength of action of each of them depends on the type of substituents present in the main structure of the molecule. Subtle differences in the potency of individual derivatives were possible to detect thanks to the developed, sensitive method of capillary electrophoresis, which allowed simultaneous monitoring of the mutual changes in the concentrations of substrates and products of the reaction catalyzed by the enzyme. Detailed values of kinetic parameters showed that all derivatives are weak inhibitors of catalase, which in this case is a big advantage because each inhibition of catalase activity is associated with a greater amount of accumulated, harmful reactive oxygen species. The results of docking studies also show the convergence of the binding energies values of individual inhibitors with all kinetic parameters of the investigated catalase inhibition and thus additionally confirm the weak inhibitory strength of all four aminoalkanol derivatives.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137123
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7124: Modeling of the Senescence-Associated Phenotype
           in Human Skin Fibroblasts

    • Authors: Marta Gerasymchuk, Gregory Ian Robinson, Olga Kovalchuk, Igor Kovalchuk
      First page: 7124
      Abstract: Modern understanding of aging is based on the accumulation of cellular damage during one’s life span due to the gradual deterioration of regenerative mechanisms in response to the continuous effect of stress, lifestyle, and environmental factors, followed by increased morbidity and mortality. Simultaneously, the number of senescent cells accumulate exponentially as organisms age. Cell culture models are valuable tools to investigate the mechanisms of aging by inducing cellular senescence in stress-induced premature senescence (SIPS) models. Here, we explain the three-step and one-step H2O2-induced senescence models of SIPS designed and reproduced on different human dermal fibroblast cell lines (CCD-1064Sk, CCD-1135Sk, and BJ-5ta). In both SIPS models, it was evident that the fibroblasts developed similar aging characteristics as cells with replicative senescence. Among the most noticeable senescent biomarkers were increased β-Gal expression, high levels of the p21 protein, altered levels of cell-cycle regulators (i.e., CDK2 and c-Jun), compromised extracellular matrix (ECM) composition, reduced cellular viability, and delayed wound healing properties. Based on the significant increase in senescence biomarkers in fibroblast cultures, reduced functional activity, and metabolic dysfunction, the one-step senescence model was chosen as a feasible and reliable method for future testing of anti-aging compounds.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137124
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7125: Changes in the Expression of Smooth Muscle
           Cell–Related Genes in Human Dermal Sheath Cup Cells Associated with
           the Treatment Outcome of Autologous Cell–Based Therapy for Male and
           Female Pattern Hair Loss

    • Authors: Yuzo Yoshida, Miki Takahashi, Haruyo Yamanishi, Yosuke Nakazawa, Jiro Kishimoto, Manabu Ohyama
      First page: 7125
      Abstract: In a clinical study of autologous cell–based therapy using dermal sheath cup (DSC) cells, the treatment of hair loss showed improvements. However, the outcomes were variable. Here, correlations between marker gene expression in DSC cells and treatment outcomes were assessed to predict therapeutic efficacy. Overall, 32 DSC cell lines were used to evaluate correlations between marker gene expression and treatment outcomes. Correlations between vascular pericyte and preadipocyte marker expression and treatment outcomes were inconsistent. As smooth muscle cell markers, MYOCD correlated negatively with treatment outcomes and SRF consistently demonstrated an inverse correlation. Additionally, CALD1 correlated negatively and ACTA2 correlated inversely with treatment outcomes. DSC cell lines were divided into good and moderate/poor responders to further investigate the correlations. SRF and CALD1 were lower in a good responder compared with a moderate responder. Next, DSC cells were differentiated toward dermal papilla cells. Dermal papilla markers SOX2 and LEF1 before differentiation had moderate positive and inverse correlations with the treatment outcome, respectively. SOX2 after differentiation more consistently demonstrated a positive correlation. Significant downregulation of smooth muscle–related genes was also observed after differentiation. These findings revealed putative markers for preclinical evaluation of DSC cells to improve hair loss.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137125
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7126: The Dysregulation of MicroRNAs in the
           Development of Cervical Pre-Cancer—An Update

    • Authors: Pui-Wah Choi, Tin Lun Liu, Chun Wai Wong, Sze Kei Liu, Yick-Liang Lum, Wai-Kit Ming
      First page: 7126
      Abstract: Globally in 2020, an estimated ~600,000 women were diagnosed with and 340,000 women died from cervical cancer. Compared to 2012, the number of cases increased by 7.5% and the number of deaths increased by 17%. MiRNAs are involved in multiple processes in the pathogenesis of cervical cancer. Dysregulation of miRNAs in the pre-stage of cervical cancer is the focus of this review. Here we summarize the dysregulated miRNAs in clinical samples from cervical pre-cancer patients and relate them to the early transformation process owing to human papillomavirus (HPV) infection in the cervical cells. When HPV infects the normal cervical cells, the DNA damage response is initiated with the involvement of HPV’s E1 and E2 proteins. Later, cell proliferation and cell death are affected by the E6 and E7 proteins. We find that the expressions of miRNAs in cervical pre-cancerous tissue revealed by different studies seldom agreed with each other. The discrepancy in sample types, samples’ HPV status, expression measurement, and methods for analysis contributed to the non-aligned results across studies. However, several miRNAs (miR-34a, miR-9, miR-21, miR-145, and miR-375) were found to be dysregulated across multiple studies. In addition, there are hints that the DNA damage response and cell growth response induced by HPV during the early transformation of the cervical cells are related to these miRNAs. Currently, no review articles analyse the relationship between the dysregulated miRNAs in cervical pre-cancerous tissue and their possible roles in the early processes involving HPV’s protein encoded by the early genes and DNA damage response during normal cell transformation. Our review provides insight on spotting miRNAs involved in the early pathogenic processes and pointing out their potential as biomarker targets of cervical pre-cancer.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137126
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7127: ErbB3-Targeting Oncolytic Adenovirus Causes
           Potent Tumor Suppression by Induction of Apoptosis in Cancer Cells

    • Authors: Bo-Kyeong Jung, Young Jun Kim, JinWoo Hong, Han-Gyu Chang, A-Rum Yoon, Chae-Ok Yun
      First page: 7127
      Abstract: Cancer is a multifactorial and deadly disease. Despite major advancements in cancer therapy in the last two decades, cancer incidence is on the rise and disease prognosis still remains poor. Furthermore, molecular mechanisms of cancer invasiveness, metastasis, and drug resistance remain largely elusive. Targeted cancer therapy involving the silencing of specific cancer-enriched proteins by small interfering RNA (siRNA) offers a powerful tool. However, its application in clinic is limited by the short half-life of siRNA and warrants the development of efficient and stable siRNA delivery systems. Oncolytic adenovirus-mediated therapy offers an attractive alternative to the chemical drugs that often suffer from innate and acquired drug resistance. In continuation to our reports on the development of oncolytic adenovirus-mediated delivery of shRNA, we report here the replication-incompetent (dAd/shErbB3) and replication-competent (oAd/shErbB3) oncolytic adenovirus systems that caused efficient and persistent targeting of ErbB3. We demonstrate that the E1A coded by oAd/shErbB, in contrast to dAd/shErbB, caused downregulation of ErbB2 and ErbB3, yielding stronger downregulation of the ErbB3-oncogenic signaling axis in in vitro models of lung and breast cancer. These results were validated by in vivo antitumor efficacy of dAd/shErbB3 and oAd/shErbB3.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137127
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7128: K+-Dependent Na+/Ca2+ Exchanger Isoform 2,
           Nckx2, Takes Part in the Neuroprotection Elicited by Ischemic
           Preconditioning in Brain Ischemia

    • Authors: Ornella Cuomo, Rossana Sirabella, Francesca Boscia, Antonella Casamassa, Jonathan Lytton, Lucio Annunziato, Giuseppe Pignataro
      First page: 7128
      Abstract: Sodium/Calcium exchangers are neuronal plasma membrane antiporters which, by coupling Ca2+ and Na+ fluxes across neuronal membranes, play a relevant role in brain ischemia. The most brain-expressed isoform among the members of the K+-dependent Na+/Ca2+ exchanger family, NCKX2, is involved in the progression of the ischemic lesion, since both its knocking-down and its knocking-out worsens ischemic damage. The aim of this study was to elucidate whether NCKX2 functions as an effector in the neuroprotection evoked by ischemic preconditioning. For this purpose, we investigated: (1) brain NCKX2 expression after preconditioning and preconditioning + ischemia; (2) the contribution of AKT and calpain to modulating NCKX2 expression during preconditioning; and (3) the effect of NCKX2 knocking-out on the neuroprotection mediated by ischemic preconditioning. Our results showed that NCKX2 expression increased in those brain regions protected by ischemic preconditioning. These changes were p-AKT-mediated since its inhibition prevented NCKX2 up-regulation. More interestingly, NCKX2 knocking-out significantly prevented the protection exerted by ischemic preconditioning. Overall, our results suggest that NCKX2 plays a fundamental role in the neuroprotective effect mediated by ischemic preconditioning and support the idea that the enhancement of its expression and activity might represent a reasonable strategy to reduce infarct extension after stroke.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137128
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7129: Advancements in Activating Transcription Factor
           5 Function in Regulating Cell Stress and Survival

    • Authors: Pameila Paerhati, Jin Liu, Zhedong Jin, Tanja Jakoš, Shunyin Zhu, Lan Qian, Jianwei Zhu, Yunsheng Yuan
      First page: 7129
      Abstract: Activating transcription factor 5 (ATF5) belongs to the activating transcription factor/cyclic adenosine monophosphate (cAMP) response element-binding protein family of basic region leucine zipper transcription factors. ATF5 plays an important role in cell stress regulation and is involved in cell differentiation and survival, as well as centrosome maintenance and development. Accumulating evidence demonstrates that ATF5 plays an oncogenic role in cancer by regulating gene expressions involved in tumorigenesis and tumor survival. Recent studies have indicated that ATF5 may also modify the gene expressions involved in other diseases. This review explores in detail the regulation of ATF5 expression and signaling pathways and elucidates the role of ATF5 in cancer biology. Furthermore, an overview of putative therapeutic strategies that can be used for restoring aberrant ATF5 activity in different cancer types is provided.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137129
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7130: Cucurbitacin B Down-Regulates TNF Receptor 1
           Expression and Inhibits the TNF-α-Dependent Nuclear Factor κB
           Signaling Pathway in Human Lung Adenocarcinoma A549 Cells

    • Authors: Eiichi Kusagawa, Chiharu Okuda, Rikako Yamaguchi, Kaori Nakano, Yasunobu Miyake, Takao Kataoka
      First page: 7130
      Abstract: Pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), induce the expression of intracellular adhesion molecule-1 (ICAM-1) by activating the nuclear factor κB (NF-κB) signaling pathway. In the present study, we found that cucurbitacin B decreased the expression of ICAM-1 in human lung adenocarcinoma A549 cells stimulated with TNF-α or interleukin-1α. We further investigated the mechanisms by which cucurbitacin B down-regulates TNF-α-induced ICAM-1 expression. Cucurbitacin B inhibited the nuclear translocation of the NF-κB subunit RelA and the phosphorylation of IκBα in A549 cells stimulated with TNF-α. Cucurbitacin B selectively down-regulated the expression of TNF receptor 1 (TNF-R1) without affecting three adaptor proteins (i.e., TRADD, RIPK1, and TRAF2). The TNF-α-converting enzyme inhibitor suppressed the down-regulation of TNF-R1 expression by cucurbitacin B. Glutathione, N-acetyl-L-cysteine, and, to a lesser extent, L-cysteine attenuated the inhibitory effects of cucurbitacin B on the TNF-α-induced expression of ICAM-1, suggesting that an α,β-unsaturated carbonyl moiety is essential for anti-inflammatory activity. The present results revealed that cucurbitacin B down-regulated the expression of TNF-R1 at the initial step in the TNF-α-dependent NF-κB signaling pathway.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137130
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7131: Cisplatin-Resistant CD44+ Lung Cancer Cells Are
           Sensitive to Auger Electrons

    • Authors: Karina Lindbøg Madsen, Oke Gerke, Poul F. Høilund-Carlsen, Birgitte Brinkmann Olsen
      First page: 7131
      Abstract: Cancer stem cells (CSCs) are resistant to conventional therapy and present a major clinical challenge since they are responsible for the relapse of many cancers, including non-small cell lung cancer (NSCLC). Hence, future successful therapy should also eradicate CSCs. Auger electrons have demonstrated promising therapeutic potential and can induce DNA damage while sparing surrounding cells. Here, we sort primary patient-derived NSCLC cells based on their expression of the CSC-marker CD44 and investigate the effects of cisplatin and a thymidine analog (deoxyuridine) labeled with an Auger electron emitter (125I). We show that the CD44+ populations are more resistant to cisplatin than the CD44− populations. Interestingly, incubation with the thymidine analog 5-[125I]iodo-2′-deoxyuridine ([125I]I-UdR) induces equal DNA damage, G2/M cell cycle arrest, and apoptosis in the CD44− and CD44+ populations. Our results suggest that Auger electron emitters can also eradicate resistant lung cancer CD44+ populations.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137131
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7132: Outcome Prediction in Critically Ill Patients
           with Venous Thromboembolism and/or Cancer Using Machine Learning
           Algorithms: External Validation and Comparison with Scoring Systems

    • Authors: Vasiliki Danilatou, Stylianos Nikolakakis, Despoina Antonakaki, Christos Tzagkarakis, Dimitrios Mavroidis, Theodoros Kostoulas, Sotirios Ioannidis
      First page: 7132
      Abstract: Intensive care unit (ICU) patients with venous thromboembolism (VTE) and/or cancer suffer from high mortality rates. Mortality prediction in the ICU has been a major medical challenge for which several scoring systems exist but lack in specificity. This study focuses on two target groups, namely patients with thrombosis or cancer. The main goal is to develop and validate interpretable machine learning (ML) models to predict early and late mortality, while exploiting all available data stored in the medical record. To this end, retrospective data from two freely accessible databases, MIMIC-III and eICU, were used. Well-established ML algorithms were implemented utilizing automated and purposely built ML frameworks for addressing class imbalance. Prediction of early mortality showed excellent performance in both disease categories, in terms of the area under the receiver operating characteristic curve (AUC−ROC): VTE-MIMIC-III 0.93, eICU 0.87, cancer-MIMIC-III 0.94. On the other hand, late mortality prediction showed lower performance, i.e., AUC−ROC: VTE 0.82, cancer 0.74–0.88. The predictive model of early mortality developed from 1651 VTE patients (MIMIC-III) ended up with a signature of 35 features and was externally validated in 2659 patients from the eICU dataset. Our model outperformed traditional scoring systems in predicting early as well as late mortality. Novel biomarkers, such as red cell distribution width, were identified.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137132
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7133: Chronic Hypergravity Induces a Modification of
           Histone H3 Lysine 27 Trimethylation at TCRβ Locus in Murine

    • Authors: Gaetano Calcagno, Nassima Ouzren, Sandra Kaminski, Stéphanie Ghislin, Jean-Pol Frippiat
      First page: 7133
      Abstract: Gravity changes are major stressors encountered during spaceflight that affect the immune system. We previously evidenced that hypergravity exposure during gestation affects the TCRβ repertoire of newborn pups. To identify the mechanisms underlying this observation, we studied post-translational histone modifications. We first showed that among the four studied post-translational histone H3 modifications, only lysine 27 trimethylation (H3K27me3) is downregulated in the thymus of mice exposed to 2xg for 21 days. We then asked whether the TCRβ locus chromatin structure is altered by hypergravity exposure. ChIP studies performed on four Vβ segments of the murine double-negative SCIET27 thymic cell line, which corresponds to the last maturation stage before V(D)J recombination, revealed increases in H3K27me3 after 2xg exposure. Finally, we evaluated the implication for the EZH2 methyltransferase in the regulation of the H3K27me3 level at these Vβ segments by treating SCIET27 cells with the GSK126-specific inhibitor. These experiments showed that the downregulation of H3K27me3 contributes to the regulation of the Vβ germline transcript expression that precedes V(D)J recombination. These data show that modifications of H3K27me3 at the TCRβ locus likely contribute to an explanation of why the TCR repertoire is affected by gravity changes and imply, for the first time, EZH2 in the regulation of the TCRβ locus chromatin structure.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137133
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7134: Isolation and Characterization of Urinary
           Extracellular Vesicles from Healthy Donors and Patients with
           Castration-Resistant Prostate Cancer

    • Authors: Haneul Lee, Su Jin Kang, Jimin Lee, Kyong Hwa Park, Won Jong Rhee
      First page: 7134
      Abstract: Prostate cancer (PCa) is the most commonly diagnosed malignancy among men in developed countries. The five-year survival rate for men diagnosed with early-stage PCa is approximately 100%, while it is less than 30% for castration-resistant PCa (CRPC). Currently, the detection of prostate-specific antigens as biomarkers for the prognosis of CRPC is criticized because of its low accuracy, high invasiveness, and high false-positive rate. Therefore, it is important to identify new biomarkers for prediction of CRPC progression. Extracellular vesicles (EVs) derived from tumors have been highlighted as potential markers for cancer diagnosis and prognosis. Specifically, urinary EVs directly reflect changes in the pathophysiological conditions of the urogenital system because it is exposed to prostatic secretions. Thus, detecting biomarkers in urinary EVs provides a promising approach for performing an accurate and non-invasive liquid biopsy for CPRC. In this study, we effectively isolated urinary EVs with low protein impurities using size-exclusion chromatography combined with ultrafiltration. After EV isolation and characterization, we evaluated the miRNAs in urinary EVs from healthy donors and patients with CRPC. The results indicated that miRNAs (miR-21-5p, miR-574-3p, and miR-6880-5p) could be used as potential biomarkers for the prognosis of CRPC. This analysis of urinary EVs contributes to the fast and convenient prognosis of diseases, including CRPC, in the clinical setting.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137134
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7135: Ciliary Proteins Repurposed by the Synaptic
           Ribbon: Trafficking Myristoylated Proteins at Rod Photoreceptor Synapses

    • Authors: Shweta Suiwal, Mayur Dembla, Karin Schwarz, Rashmi Katiyar, Martin Jung, Yvonne Carius, Stephan Maxeiner, Marcel A. Lauterbach, C. Roy D. Lancaster, Frank Schmitz
      First page: 7135
      Abstract: The Unc119 protein mediates transport of myristoylated proteins to the photoreceptor outer segment, a specialized primary cilium. This transport activity is regulated by the GTPase Arl3 as well as by Arl13b and Rp2 that control Arl3 activation/inactivation. Interestingly, Unc119 is also enriched in photoreceptor synapses and can bind to RIBEYE, the main component of synaptic ribbons. In the present study, we analyzed whether the known regulatory proteins, that control the Unc119-dependent myristoylated protein transport at the primary cilium, are also present at the photoreceptor synaptic ribbon complex by using high-resolution immunofluorescence and immunogold electron microscopy. We found Arl3 and Arl13b to be enriched at the synaptic ribbon whereas Rp2 was predominantly found on vesicles distributed within the entire terminal. These findings indicate that the synaptic ribbon could be involved in the discharge of Unc119-bound lipid-modified proteins. In agreement with this hypothesis, we found Nphp3 (Nephrocystin-3), a myristoylated, Unc119-dependent cargo protein enriched at the basal portion of the ribbon in close vicinity to the active zone. Mutations in Nphp3 are known to be associated with Senior–Løken Syndrome 3 (SLS3). Visual impairment and blindness in SLS3 might thus not only result from ciliary dysfunctions but also from malfunctions of the photoreceptor synapse.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137135
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7136: The Role of Immunosenescence in Cerebral Small
           Vessel Disease: A Review

    • Authors: Alessandro Del Cuore, Gaetano Pacinella, Renata Riolo, Antonino Tuttolomondo
      First page: 7136
      Abstract: Cerebral small vessel disease (CSVD) is one of the most important causes of vascular dementia. Immunosenescence and inflammatory response, with the involvement of the cerebrovascular system, constitute the basis of this disease. Immunosenescence identifies a condition of deterioration of the immune organs and consequent dysregulation of the immune response caused by cellular senescence, which exposes older adults to a greater vulnerability. A low-grade chronic inflammation status also accompanies it without overt infections, an “inflammaging” condition. The correlation between immunosenescence and inflammaging is fundamental in understanding the pathogenesis of age-related CSVD (ArCSVD). The production of inflammatory mediators caused by inflammaging promotes cellular senescence and the decrease of the adaptive immune response. Vice versa, the depletion of the adaptive immune mechanisms favours the stimulation of the innate immune system and the production of inflammatory mediators leading to inflammaging. Furthermore, endothelial dysfunction, chronic inflammation promoted by senescent innate immune cells, oxidative stress and impairment of microglia functions constitute, therefore, the framework within which small vessel disease develops: it is a concatenation of molecular events that promotes the decline of the central nervous system and cognitive functions slowly and progressively. Because the causative molecular mechanisms have not yet been fully elucidated, the road of scientific research is stretched in this direction, seeking to discover other aberrant processes and ensure therapeutic tools able to enhance the life expectancy of people affected by ArCSVD. Although the concept of CSVD is broader, this manuscript focuses on describing the neurobiological basis and immune system alterations behind cerebral aging. Furthermore, the purpose of our work is to detect patients with CSVD at an early stage, through the evaluation of precocious MRI changes and serum markers of inflammation, to treat untimely risk factors that influence the burden and the worsening of the cerebral disease.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137136
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7137: Glycation of Tie-2 Inhibits Angiopoietin-1
           Signaling Activation and Angiopoietin-1-Induced Angiogenesis

    • Authors: Haiyan Zhou, Tangting Chen, Yongjie Li, Jingcan You, Xin Deng, Ni Chen, Tian Li, Youkun Zheng, Rong Li, Mao Luo, Jianbo Wu, Liqun Wang
      First page: 7137
      Abstract: The impairment of the angiopoietin-1 (Ang-1)/Tie-2 signaling pathway has been thought to play a critical role in diabetic complications. However, the underlying mechanisms remain unclear. The present study aims to investigate the effects of Tie-2 glycation on Ang-1 signaling activation and Ang-1-induced angiogenesis. We identified that Tie-2 was modified by advanced glycation end products (AGEs) in aortae derived from high fat diet (HFD)-fed mice and in methylglyoxal (MGO)-treated human umbilical vein endothelial cells (HUVECs). MGO-induced Tie-2 glycation significantly inhibited Ang-1-evoked Tie-2 and Akt phosphorylation and Ang-1-regulated endothelial cell migration and tube formation, whereas the blockade of AGE formation by aminoguanidine remarkably rescued Ang-1 signaling activation and Ang-1-induced angiogenesis in vitro. Furthermore, MGO treatment markedly increased AGE cross-linking of Tie-2 in cultured aortae ex vivo and MGO-induced Tie-2 glycation also significantly decreased Ang-1-induced vessel outgrow from aortic rings. Collectively, these data suggest that Tie-2 may be modified by AGEs in diabetes mellitus and that Tie-2 glycation inhibits Ang-1 signaling activation and Ang-1-induced angiogenesis. This may provide a novel mechanism for Ang-1/Tie-2 signal dysfunction and angiogenesis failure in diabetic ischaemic diseases.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137137
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7138: Characterization of the MicroRNA Cargo of
           Extracellular Vesicles Isolated from a Pulmonary Tumor-Draining Vein
           Identifies miR-203a-3p as a Relapse Biomarker for Resected Non-Small Cell
           Lung Cancer

    • Authors: Bing Han, Laureano Molins, Yangyi He, Nuria Viñolas, David Sánchez-Lorente, Marc Boada, Angela Guirao, Tania Díaz, Daniel Martinez, Jose Ramirez, Jorge Moisés, Melissa Acosta-Plasencia, Mariano Monzo, Ramón M. Marrades, Alfons Navarro
      First page: 7138
      Abstract: In resected non-small cell lung cancer (NSCLC), post-surgical recurrence occurs in around 40% of patients, highlighting the necessity to identify relapse biomarkers. An analysis of the extracellular vesicle (EV) cargo from a pulmonary tumor-draining vein (TDV) can grant biomarker identification. We studied the pulmonary TDV EV-miRNAome to identify relapse biomarkers in a two-phase study (screening and validation). In the screening phase, a 17-miRNA relapse signature was identified in 18 selected patients by small RNAseq. The most expressed miRNA from the signature (EV-miR-203a-3p) was chosen for further validation. Pulmonary TDV EV-miR-203a-3p was studied by qRT-PCR in a validation cohort of 70 patients, where it was found to be upregulated in relapsed patients (p = 0.0194) and in patients with cancer spread to nearby lymph nodes (N+ patients) (p = 0.0396). The ROC curve analysis showed that TDV EV-miR-203a-3p was able to predict relapses with a sensitivity of 88% (AUC: 0.67; p = 0.022). Moreover, patients with high TDV EV-miR-203a-3p had a shorter time to relapse than patients with low levels (43.6 vs. 97.6 months; p = 0.00703). The multivariate analysis showed that EV-miR-203a-3p was an independent, predictive and prognostic post-surgical relapse biomarker. In conclusion, pulmonary TDV EV-miR-203a-3p is a promising new relapse biomarker for resected NSCLC patients.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137138
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7139: Effects of Ferroptosis on Male Reproduction

    • Authors: Yang Liu, Xuanhong Cao, Chen He, Xinrui Guo, Hui Cai, Aili Aierken, Jinlian Hua, Sha Peng
      First page: 7139
      Abstract: Ferroptosis is a relatively novel form of regulated cell death that was discovered in 2012. With the increasing research related to the mechanisms of ferroptosis, previous studies have demonstrated that the inactive of the intracellular antioxidant system and iron overload can result in the accumulation of reactive oxygen species (ROS), which can ultimately cause lipid peroxidation in the various cell types of the body. ROS accumulation can cause sperm damage by attacking the plasma membrane and damaging DNA. Acute ferroptosis causes oxidative damage to sperm DNA and testicular oxidative stress, thereby causing male reproductive dysfunction. This review aims to discuss the metabolic network of ferroptosis, summarize and analyze the relationship between male reproductive diseases caused by iron overload as well as lipid peroxidation, and provide a novel direction for the research and prevention of various male reproductive diseases.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137139
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7140: Promising Strategies for the Development of
           Advanced In Vitro Models with High Predictive Power in Ischaemic Stroke

    • Authors: Elise Van Breedam, Peter Ponsaerts
      First page: 7140
      Abstract: Although stroke is one of the world’s leading causes of death and disability, and more than a thousand candidate neuroprotective drugs have been proposed based on extensive in vitro and animal-based research, an effective neuroprotective/restorative therapy for ischaemic stroke patients is still missing. In particular, the high attrition rate of neuroprotective compounds in clinical studies should make us question the ability of in vitro models currently used for ischaemic stroke research to recapitulate human ischaemic responses with sufficient fidelity. The ischaemic stroke field would greatly benefit from the implementation of more complex in vitro models with improved physiological relevance, next to traditional in vitro and in vivo models in preclinical studies, to more accurately predict clinical outcomes. In this review, we discuss current in vitro models used in ischaemic stroke research and describe the main factors determining the predictive value of in vitro models for modelling human ischaemic stroke. In light of this, human-based 3D models consisting of multiple cell types, either with or without the use of microfluidics technology, may better recapitulate human ischaemic responses and possess the potential to bridge the translational gap between animal-based in vitro and in vivo models, and human patients in clinical trials.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137140
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7141: Changes of Sensory Quality, Flavor-Related
           Metabolites and Gene Expression in Peach Fruit Treated by Controlled
           Atmosphere (CA) under Cold Storage

    • Authors: Hongru Liu, Hui He, Chenxia Liu, Chunfang Wang, Yongjin Qiao, Bo Zhang
      First page: 7141
      Abstract: Controlled atmosphere (CA) has been used to alleviate chilling injury (CI) of horticultural crops caused by cold storage. However, the effects of CA treatment on peach fruit sensory quality and flavor-related chemicals suffering from CI remain largely unknown. Here, we stored peach fruit under CA with 5% O2 and 10% CO2 at 0 ℃ up to 28 d followed by a subsequent 3 d shelf-life at 20 ℃ (28S3). CA significantly reduced flesh browning and improved sensory quality at 28S3. Though total volatiles declined during extended cold storage, CA accumulated higher content of volatile esters and lactones than control at 28S3. A total of 14 volatiles were positively correlated with consumer acceptability, mainly including three C6 compounds, three esters and four lactones derived from the fatty acid lipoxygenase (LOX)pathway. Correspondingly, the expression levels of genes including PpLOX1, hyperoxide lyase PpHPL1 and alcohol acyltransferase PpAAT1 were positively correlated with the change of esters and lactones. CA elevated the sucrose content and the degree of fatty acids unsaturation under cold storage, which gave us clues to clarify the mechanism of resistance to cold stress. The results suggested that CA treatment improved sensory quality by alleviating CI of peach fruits under cold storage.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137141
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7142: Blocking of SGLT2 to Eliminate NADPH-Induced
           Oxidative Stress in Lenses of Animals with Fructose-Induced Diabetes

    • Authors: Ying-Ying Chen, Tsung-Tien Wu, Chiu-Yi Ho, Tung-Chen Yeh, Gwo-Ching Sun, Ching-Jiunn Tseng, Pei-Wen Cheng
      First page: 7142
      Abstract: Chronic hyperglycemia triggers an abnormal rise in reactive oxygen species (ROS) that leads to blindness in patients with diabetes mellitus (DM) and cataracts. In this study, the effects of dapagliflozin, metformin and resveratrol on ROS production were investigated in lens epithelial cells (LECs) of animals with fructose-induced DM. LECs were isolated from patients without DM, or with DM devoid of diabetic retinopathy. Animals were treated with 10% fructose for 8 weeks to induce DM, which was verified by monitoring blood pressure and serum parameters. For drug treatments, 1.2 mg/day of dapagliflozin was given for 2 weeks, 500 mg/kg/day of metformin was given, and 10 mg/kg/day of resveratrol was given. Dihydroethidium was used to stain endogenous O2˙− production in vivo of the LECs. Superoxide production was expressed in the cataract of DM, or patients without DM. Sodium–glucose cotransporter 2 (SGLT2), glucose transporter 1 (GLUT1), GLUT5, the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47/p67-phox, NOX4 and RAGE were significantly increased in LECs with DM. In addition, the dapagliflozin treatment reduced GLUT5, p47/p67-phox, NADPH oxidase 4 (NOX4) and receptor for advanced glycation end products (RAGE) expressions. On the contrary, metformin or resveratrol inhibited p47-phox, GLUT5, and SGLT2 expressions, but not nuclear factor erythroid 2–related factor 2 (NRF2). In summary, dapagliflozin, metformin or resveratrol down-regulated p47-phox expression through SGLT2 inactivation and ROS reduction. These important findings imply that SGLT2 can be blocked to ameliorate oxidative stress in the cataracts of DM patients.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137142
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7143: Erythropoietin in Optic Neuropathies: Current
           Future Strategies for Optic Nerve Protection and Repair

    • Authors: Yi-Fen Lai, Ting-Yi Lin, Pin-Kuan Ho, Yi-Hao Chen, Yu-Chuan Huang, Da-Wen Lu
      First page: 7143
      Abstract: Erythropoietin (EPO) is known as a hormone for erythropoiesis in response to anemia and hypoxia. However, the effect of EPO is not only limited to hematopoietic tissue. Several studies have highlighted the neuroprotective function of EPO in extra-hematopoietic tissues, especially the retina. EPO could interact with its heterodimer receptor (EPOR/βcR) to exert its anti-apoptosis, anti-inflammation and anti-oxidation effects in preventing retinal ganglion cells death through different intracellular signaling pathways. In this review, we summarized the available pre-clinical studies of EPO in treating glaucomatous optic neuropathy, optic neuritis, non-arteritic anterior ischemic optic neuropathy and traumatic optic neuropathy. In addition, we explore the future strategies of EPO for optic nerve protection and repair, including advances in EPO derivates, and EPO deliveries. These strategies will lead to a new chapter in the treatment of optic neuropathy.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137143
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7144: An Altered Sphingolipid Profile as a Risk
           Factor for Progressive Neurodegeneration in Long-Chain 3-Hydroxyacyl-CoA
           Deficiency (LCHADD)

    • Authors: Sara Tucci
      First page: 7144
      Abstract: Long-chain 3-hydroxyacyl-CoA deficiency (LCHADD) and mitochondrial trifunctional protein (MTPD) belong to a group of inherited metabolic diseases affecting the degradation of long-chain chain fatty acids. During metabolic decompensation the incomplete degradation of fatty acids results in life-threatening episodes, coma and death. Despite fast identification at neonatal screening, LCHADD/MTPD present with progressive neurodegenerative symptoms originally attributed to the accumulation of toxic hydroxyl acylcarnitines and energy deficiency. Recently, it has been shown that LCHADD human fibroblasts display a disease-specific alteration of complex lipids. Accumulating fatty acids, due to defective β-oxidation, contribute to a remodeling of several lipid classes including mitochondrial cardiolipins and sphingolipids. In the last years the face of LCHADD/MTPD has changed. The reported dysregulation of complex lipids other than the simple acylcarnitines represents a novel aspect of disease development. Indeed, aberrant lipid profiles have already been associated with other neurodegenerative diseases such as Parkinson’s Disease, Alzheimer’s Disease, amyotrophic lateral sclerosis and retinopathy. Today, the physiopathology that underlies the development of the progressive neuropathic symptoms in LCHADD/MTPD is not fully understood. Here, we hypothesize an alternative disease-causing mechanism that contemplates the interaction of several factors that acting in concert contribute to the heterogeneous clinical phenotype.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137144
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7145: Cannabidiol Antiproliferative Effect in
           Triple-Negative Breast Cancer MDA-MB-231 Cells Is Modulated by Its
           Physical State and by IGF-1

    • Authors: Alessia D’Aloia, Michela Ceriani, Renata Tisi, Simone Stucchi, Elena Sacco, Barbara Costa
      First page: 7145
      Abstract: Cannabidiol (CBD) is a non-psychoactive phytocannabinoid that has been discussed for its safety and efficacy in cancer treatments. For this reason, we have inquired into its use on triple-negative human breast cancer. Analyzing the biological effects of CBD on MDA-MB-231, we have demonstrated that both CBD dosage and serum concentrations in the culture medium influence its outcomes; furthermore, light scattering studies demonstrated that serum impacts the CBD aggregation state by acting as a surfactant agent. Pharmacological studies on CBD in combination with chemotherapeutic agents reveal that CBD possesses a protective action against the cytotoxic effect exerted by cisplatin on MDA-MB-231 grown in standard conditions. Furthermore, in a low serum condition (0.5%), starting from a threshold concentration (5 µM), CBD forms aggregates, exerts cytostatic antiproliferative outcomes, and promotes cell cycle arrest activating autophagy. At doses above the threshold, CBD exerts a highly cytotoxic effect inducing bubbling cell death. Finally, IGF-1 and EGF antagonize the antiproliferative effect of CBD protecting cells from harmful consequences of CBD aggregates. In conclusion, CBD effect is strongly associated with the physical state and concentration that reaches the treated cells, parameters not taken into account in most of the research papers.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137145
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7146: Broad Spectrum Functional Activity of
           Structurally Related Monoanionic Au(III) Bis(Dithiolene) Complexes

    • Authors: Le Gal, Filatre-Furcate, Lorcy, Jeannin, Roisnel, Dorcet, Fontinha, Francisco, Prudêncio, Martins, Soeiro, Sousa, Leitão, Morais, Bártolo, Taveira, Guerreiro, Marques
      First page: 7146
      Abstract: The biological properties of sixteen structurally related monoanionic gold (III) bis(dithiolene/diselenolene) complexes were evaluated. The complexes differ in the nature of the heteroatom connected to the gold atom (AuS for dithiolene, AuSe for diselenolene), the substituent on the nitrogen atom of the thiazoline ring (Me, Et, Pr, iPr and Bu), the nature of the exocyclic atom or group of atoms (O, S, Se, C(CN)2) and the counter-ion (Ph4P+ or Et4N+). The anticancer and antimicrobial activities of all the complexes were investigated, while the anti-HIV activity was evaluated only for selected complexes. Most complexes showed relevant anticancer activities against Cisplatin-sensitive and Cisplatin-resistant ovarian cancer cells A2780 and OVCAR8, respectively. After 48 h of incubation, the IC50 values ranged from 0.1–8 µM (A2780) and 0.8–29 µM (OVCAR8). The complexes with the Ph4P+ ([P]) counter-ion are in general more active than their Et4N+ ([N]) analogues, presenting IC50 values in the same order of magnitude or even lower than Auranofin. Studies in the zebrafish embryo model further showed that, despite their marked anticancer effect, the complexes with [P] counter-ion exhibited low in vivo toxicity. In general, the exocyclic exchange of sulfur by oxygen or ylidenemalononitrile (C(CN)2) enhanced the compounds toxicity. Most complexes containing the [P] counter ion exhibited exceptional antiplasmodial activity against the Plasmodium berghei parasite liver stages, with submicromolar IC50 values ranging from 400–700 nM. In contrast, antibacterial/fungi activities were highest for most complexes with the [N] counter-ion. Auranofin and two selected complexes [P][AuSBu(=S)] and [P][AuSEt(=S)] did not present anti-HIV activity in TZM-bl cells. Mechanistic studies for selected complexes support the idea that thioredoxin reductase, but not DNA, is a possible target for some of these complexes. The complexes [P] [AuSBu(=S)], [P] [AuSEt(=S)], [P] [AuSEt(=Se)] and [P] [AuSeiPr(=S)] displayed a strong quenching of the fluorescence intensity of human serum albumin (HSA), which indicates a strong interaction with this protein. Overall, the results highlight the promising biological activities of these complexes, warranting their further evaluation as future drug candidates with clinical applicability.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137146
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7147: Electrospun Membranes Designed for Burst
           Release of New Gold-Complexes Inducing Apoptosis of Melanoma Cells

    • Authors: Liberata Guadagno, Marialuigia Raimondo, Luigi Vertuccio, Erwin Pavel Lamparelli, Maria Camilla Ciardulli, Pasquale Longo, Annaluisa Mariconda, Giovanna Porta, Raffaele Longo
      First page: 7147
      Abstract: Two non-commercial metallic Au-based complexes were tested against one of the most aggressive malignant melanomas of the skin (MeWo cells), through cell viability and time-lapse live-cell imaging system assays. The tests with the complexes were carried out both in the form of free metallic complexes, directly in contact with the MeWo cell line culture, and embedded in fibers of Polycaprolactone (PCL) membranes produced by the electrospinning technique. Membranes functionalized with complexes were prepared to evaluate the efficiency of the membranes against the melanoma cells and therefore their feasibility in the application as an antitumoral patch for topical use. Both series of tests highlighted a very effective antitumoral activity, manifesting a very relevant cell viability inhibition after both 24 h and 48 h. In the case of the AuM1 complex at the concentration of 20 mM, melanoma cells completely died in this short period of time. A mortality of around 70% was detected from the tests performed using the membranes functionalized with AuM1 complex at a very low concentration (3 wt.%), even after 24 h of the contact period. The synthesized complexes also manifest high selectivity with respect to the MeWo cells. The peculiar structural and morphological organization of the nanofibers constituting the membranes allows for a very effective antitumoral activity in the first 3 h of treatment. Experimental points of the release profiles were perfectly fitted with theoretical curves, which easily allow interpretation of the kinetic phenomena occurring in the release of the synthesized complexes in the chosen medium.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137147
      Issue No: Vol. 23, No. 13 (2022)
  • IJMS, Vol. 23, Pages 7148: MGMT and Whole-Genome DNA Methylation Impacts
           on Diagnosis, Prognosis and Therapy of Glioblastoma Multiforme

    • Authors: Rosa Della Monica, Mariella Cuomo, Michela Buonaiuto, Davide Costabile, Raduan Ahmed Franca, Marialaura Del Basso De Caro, Giuseppe Catapano, Lorenzo Chiariotti, Roberta Visconti
      First page: 7148
      Abstract: Epigenetic changes in DNA methylation contribute to the development of many diseases, including cancer. In glioblastoma multiforme, the most prevalent primary brain cancer and an incurable tumor with a median survival time of 15 months, a single epigenetic modification, the methylation of the O6-Methylguanine-DNA Methyltransferase (MGMT) gene, is a valid biomarker for predicting response to therapy with alkylating agents and also, independently, prognosis. More recently, the progress from single gene to whole-genome analysis of DNA methylation has allowed a better subclassification of glioblastomas. Here, we review the clinically relevant information that can be obtained by studying MGMT gene and whole-genome DNA methylation changes in glioblastomas, also highlighting benefits, including those of liquid biopsy, and pitfalls of the different detection methods. Finally, we discuss how changes in DNA methylation, especially in glioblastomas bearing mutations in the Isocitrate Dehydrogenase (IDH) 1 and 2 genes, can be exploited as targets for tailoring therapy.
      Citation: International Journal of Molecular Sciences
      PubDate: 2022-06-27
      DOI: 10.3390/ijms23137148
      Issue No: Vol. 23, No. 13 (2022)
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