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Resveratrol and Vitamin D: Eclectic Molecules Promoting Mitochondrial Health in Sarcopenia
Hematopoietic Stem Cells and Their Niche in Bone Marrow
Amelioration of Fibrosis via S1P Inhibition Is Regulated by Inactivation of TGF-β and SPL Pathways in the Human Cornea
Modulation of Gut Microbial Biomarkers and Metabolites in Cancer Management by Tea Compounds
Molecular Pathogenesis of Ischemic and Hemorrhagic Strokes: Background and Therapeutic Approaches

Journal Description

International Journal of Molecular Sciences

International Journal of Molecular Sciences is an international, peer-reviewed, open access journal providing an advanced forum for biochemistry, molecular and cell biology, molecular biophysics, molecular medicine, and all aspects of molecular research in chemistry, and is published semimonthly online by MDPI. The Australian Society of Plant Scientists (ASPS), Epigenetics Society, European Calcium Society (ECS), European Chitin Society (EUCHIS), Spanish Society for Cell Biology (SEBC) and others are affiliated with IJMS and their members receive a discount on the article processing charges.

Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, MEDLINE, Embase, CAPlus / SciFinder, and other databases.
Journal Rank: JCR - Q1 (Biochemistry and Molecular Biology) / CiteScore - Q1 (Inorganic Chemistry)
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 18.1 days after submission; acceptance to publication is undertaken in 2.8 days (median values for papers published in this journal in the first half of 2024).
Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Testimonials: See what our editors and authors say about the IJMS.
Companion journals for IJMS include: Biophysica, Stresses, Lymphatics and SynBio.

Impact Factor: 4.9 (2023); 5-Year Impact Factor: 5.6 (2023)

Imprint Information Journal Flyer Open Access ISSN: 1422-0067

Latest Articles

18 pages, 5185 KiB

Open AccessArticle

TOPAS-Tissue: A Framework for the Simulation of the Biological Response to Ionizing Radiation at the Multi-Cellular Level

by Omar Rodrigo García García, Ramon Ortiz, Eduardo Moreno-Barbosa, Naoki D-Kondo, Bruce Faddegon and Jose Ramos-Méndez

Int. J. Mol. Sci. 2024, 25(18), 10061; https://doi.org/10.3390/ijms251810061 (registering DOI) - 19 Sep 2024

This work aims to develop and validate a framework for the multiscale simulation of the biological response to ionizing radiation in a population of cells forming a tissue. We present TOPAS-Tissue, a framework to allow coupling two Monte Carlo (MC) codes: TOPAS with [...] Read more.

This work aims to develop and validate a framework for the multiscale simulation of the biological response to ionizing radiation in a population of cells forming a tissue. We present TOPAS-Tissue, a framework to allow coupling two Monte Carlo (MC) codes: TOPAS with the TOPAS-nBio extension, capable of handling the track-structure simulation and subsequent chemistry, and CompuCell3D, an agent-based model simulator for biological and environmental behavior of a population of cells. We verified the implementation by simulating the experimental conditions for a clonogenic survival assay of a 2-D PC-3 cell culture model (10 cells in 10,000 µm²) irradiated by MV X-rays at several absorbed dose values from 0–8 Gy. The simulation considered cell growth and division, irradiation, DSB induction, DNA repair, and cellular response. The survival was obtained by counting the number of colonies, defined as a surviving primary (or seeded) cell with progeny, at 2.7 simulated days after irradiation. DNA repair was simulated with an MC implementation of the two-lesion kinetic model and the cell response with a p53 protein-pulse model. The simulated survival curve followed the theoretical linear–quadratic response with dose. The fitted coefficients α = 0.280 ± 0.025/Gy and β = 0.042 ± 0.006/Gy² agreed with published experimental data within two standard deviations. TOPAS-Tissue extends previous works by simulating in an end-to-end way the effects of radiation in a cell population, from irradiation and DNA damage leading to the cell fate. In conclusion, TOPAS-Tissue offers an extensible all-in-one simulation framework that successfully couples Compucell3D and TOPAS for multiscale simulation of the biological response to radiation. Full article

(This article belongs to the Special Issue Radiation-Induced DNA Damage, Repair and Responses)

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16 pages, 3796 KiB

Open AccessArticle

HRS Facilitates Newcastle Disease Virus Replication in Tumor Cells by Promoting Viral Budding

by Yu Chen, Chunxuan Wang, Shunlin Hu and Xiufan Liu

Int. J. Mol. Sci. 2024, 25(18), 10060; https://doi.org/10.3390/ijms251810060 (registering DOI) - 19 Sep 2024

Newcastle disease virus (NDV) is a highly pathogenic avian infectious disease agent and also a promising oncolytic virus with broad application prospects. The Endosomal Sorting Complex Required for Transport (ESCRT) machinery has been increasingly recognized for its crucial role in the life cycles [...] Read more.

Newcastle disease virus (NDV) is a highly pathogenic avian infectious disease agent and also a promising oncolytic virus with broad application prospects. The Endosomal Sorting Complex Required for Transport (ESCRT) machinery has been increasingly recognized for its crucial role in the life cycles of enveloped viruses, influencing processes such as viral entry, replication, and budding. In this study, we employed an RNA interference screening approach to identify key ESCRT components that regulate NDV replication in tumor cells. qPCR, immunofluorescence, and Western blot assays demonstrated that knockdown of HRS, CHMP4A, CHMP4B, and CHMP4C significantly impaired NDV replication in HeLa cells, with HRS exhibiting the most pronounced inhibitory effect. Additionally, HRS knockout significantly inhibited viral budding and suppressed NDV-induced cell death in HeLa cells. Notably, NDV infection was shown to significantly upregulate HRS gene and protein expression in a time-dependent manner. In conclusion, this study systematically identifies critical ESCRT components involved in NDV replication within tumor cells, with a particular focus on the role of HRS in promoting NDV’s replication by promoting viral budding, offering new insights for the development of NDV-based oncolytic therapies. Full article

(This article belongs to the Section Molecular Microbiology)

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19 pages, 6356 KiB

Open AccessArticle

Acidocin A and Acidocin 8912 Belong to a Distinct Subfamily of Class II Bacteriocins with a Broad Spectrum of Antimicrobial Activity

by Daria V. Antoshina, Sergey V. Balandin, Ekaterina I. Finkina, Ivan V. Bogdanov, Sofia I. Eremchuk, Daria V. Kononova, Alena A. Kovrizhnykh and Tatiana V. Ovchinnikova

Int. J. Mol. Sci. 2024, 25(18), 10059; https://doi.org/10.3390/ijms251810059 (registering DOI) - 19 Sep 2024

Within class II bacteriocins, we assume the presence of a separate subfamily of antimicrobial peptides possessing a broad spectrum of antimicrobial activity. Although these peptides are structurally related to the subclass IIa (pediocin-like) bacteriocins, they have significant differences in biological activities and, probably, [...] Read more.

Within class II bacteriocins, we assume the presence of a separate subfamily of antimicrobial peptides possessing a broad spectrum of antimicrobial activity. Although these peptides are structurally related to the subclass IIa (pediocin-like) bacteriocins, they have significant differences in biological activities and, probably, a mechanism of their antimicrobial action. A representative of this subfamily is acidocin A from Lactobacillus acidophilus TK9201. We discovered the similarity between acidocin A and acidocin 8912 from Lactobacillus acidophilus TK8912 when analyzing plasmids from lactic acid bacteria and suggested the presence of a single evolutionary predecessor of these peptides. We obtained the C-terminally extended homolog of acidocin 8912, named acidocin 8912A, a possible intermediate form in the evolution of the former. The study of secondary structures and biological activities of these peptides showed their structural similarity to acidocin A; however, the antimicrobial activities of acidocin 8912 and acidocin 8912A were lower than that of acidocin A. In addition, these peptides demonstrated stronger cytotoxic and membranotropic effects. Building upon what we previously discovered about the immunomodulatory properties of acidocin A, we studied its proteolytic stability under conditions simulating those in the digestive tract and also assessed its ability to permeate intestinal epithelium using the Caco-2 cells monolayer model. In addition, we found a pronounced effect of acidocin A against fungi of the genus Candida, which might also expand the therapeutic potential of this bacterial antimicrobial peptide. Full article

(This article belongs to the Special Issue Drug Treatment for Bacterial Infections)

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13 pages, 1570 KiB

Open AccessReview

The Impact of Developmental and Metabolic Cues on Cytoophidium Formation

by Yuanbing Zhang and Ji-Long Liu

Int. J. Mol. Sci. 2024, 25(18), 10058; https://doi.org/10.3390/ijms251810058 (registering DOI) - 19 Sep 2024

The cytoophidium, composed mainly of CTP synthase (CTPS), is a newly discovered dynamic filamentous structure in various organisms such as archaea, bacteria, and humans. These filamentous structures represent a fascinating example of intracellular compartmentation and dynamic regulation of metabolic enzymes. Currently, cytoophidia have [...] Read more.

The cytoophidium, composed mainly of CTP synthase (CTPS), is a newly discovered dynamic filamentous structure in various organisms such as archaea, bacteria, and humans. These filamentous structures represent a fascinating example of intracellular compartmentation and dynamic regulation of metabolic enzymes. Currently, cytoophidia have been proven to be tightly regulated and highly dynamic, responding rapidly to developmental and metabolic cues and playing a critical role in maintaining cellular homeostasis. In this review, we would like to discuss in detail the characteristics, mechanisms, functions, and potential applications of this conservative but promising organelle. Full article

(This article belongs to the Special Issue Cytoophidia in the Molecular Sciences: Structure, Function, and Regulation)

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11 pages, 2872 KiB

Open AccessCommunication

Enzymatic Methoxycarbonylation of Tyrosol and Hydroxytyrosol

by Lucia Černáková, Michaela Macková, Tatiana Klempová, Peter Haluz, Vladimír Mastihuba and Mária Mastihubová

Int. J. Mol. Sci. 2024, 25(18), 10057; https://doi.org/10.3390/ijms251810057 (registering DOI) - 19 Sep 2024

Tyrosol and hydroxytyrosol are powerful phenolic antioxidants occurring in olive oil and in by-products from olive processing. Due to their high polarity, esterification or other lipophilization is necessary to make them compatible with lipid matrices. Hydroxytyrosol methyl carbonate is a more effective antioxidant [...] Read more.

Tyrosol and hydroxytyrosol are powerful phenolic antioxidants occurring in olive oil and in by-products from olive processing. Due to their high polarity, esterification or other lipophilization is necessary to make them compatible with lipid matrices. Hydroxytyrosol methyl carbonate is a more effective antioxidant than dibutylhydroxytoluene or α-tocopherol and together with tyrosol methyl carbonate exerts interesting pharmacological properties. The purpose of this work was the enzymatic preparation of alkyl carbonates of tyrosol and hydroxytyrosol. A set of 17 hydrolases was tested in the catalysis of tyrosol methoxycarbonylation in neat dimethyl carbonate to find an economically feasible alternative to the recently reported synthesis of methyl carbonates catalyzed by Novozym 435. Novozym 435 was, however, found to be the best performing catalyst, while Novozym 735, pig pancreatic lipase, lipase F-AK and Lipex 100T exhibited limited reactivity. No enzyme accepted 1,2-propylene carbonate as the acylation donor. Under optimized reaction conditions, Novozym 435 was used in the batch preparation of tyrosol methyl carbonate and hydroxytyrosol methyl carbonate in quantitative yields. The enzymatic methoxycarbonylation of tyrosol and hydroxytyrosol can also be used as a method for their selective protection in enzymatic syntheses of phenylethanoid glycosides catalyzed with enzymes comprising high levels of acetyl esterase side activity. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 1717 KiB

Open AccessArticle

Candidate Genes Associated with Survival Following Highly Pathogenic Avian Influenza Infection in Chickens

by Wioleta Drobik-Czwarno, Anna Wolc, Callie R. Petal, Katarzyna Miedzinska, Jack Dekkers, Janet E. Fulton and Jacqueline Smith

Int. J. Mol. Sci. 2024, 25(18), 10056; https://doi.org/10.3390/ijms251810056 (registering DOI) - 19 Sep 2024

Highly pathogenic strains of avian influenza (HPAI) devastate poultry flocks and result in significant economic losses for farmers due to high mortality, reduced egg production, and mandated euthanization of infected flocks. Within recent years, HPAI outbreaks have affected egg production flocks across the [...] Read more.

Highly pathogenic strains of avian influenza (HPAI) devastate poultry flocks and result in significant economic losses for farmers due to high mortality, reduced egg production, and mandated euthanization of infected flocks. Within recent years, HPAI outbreaks have affected egg production flocks across the world. The H5N2 outbreak in the US in 2015 resulted in over 99% mortality. Here, we analyze sequence data from chickens that survived (42 cases) along with uninfected controls (28 samples) to find genomic regions that differ between these two groups and that, therefore, may encompass prime candidates that are resistant to HPAI. Blood samples were obtained from survivors of the 2015 HPAI outbreak plus age and genetics-matched non-affected controls. A whole-genome sequence was obtained, and genetic variants were characterized and used in a genome-wide association study to identify regions showing significant association with survival. Regions associated with HPAI resistance were observed on chromosomes 1, 2, 5, 8, 10, 11, 15, 20, and 28, with a number of candidate genes identified. We did not detect a specific locus which could fully explain the difference between survivors and controls. Influenza virus replication depends on multiple components of the host cellular machinery, with many genes involved in the host response. Full article

(This article belongs to the Special Issue Molecular Research in Avian Genetics)

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16 pages, 9827 KiB

Open AccessArticle

The Transcriptome Characterization of the Hypothalamus and the Identification of Key Genes during Sexual Maturation in Goats

by Qing Li, Tianle Chao, Yanyan Wang, Rong Xuan, Yanfei Guo, Peipei He, Lu Zhang and Jianmin Wang

Int. J. Mol. Sci. 2024, 25(18), 10055; https://doi.org/10.3390/ijms251810055 (registering DOI) - 19 Sep 2024

Sexual maturation in goats is a dynamic process regulated precisely by the hypothalamic–pituitary–gonadal axis and is essential for reproduction. The hypothalamus plays a crucial role in this process and is the control center of the reproductive activity. It is significant to study the [...] Read more.

Sexual maturation in goats is a dynamic process regulated precisely by the hypothalamic–pituitary–gonadal axis and is essential for reproduction. The hypothalamus plays a crucial role in this process and is the control center of the reproductive activity. It is significant to study the molecular mechanisms in the hypothalamus regulating sexual maturation in goats. We analyzed the serum hormone profiles and hypothalamic mRNA expression profiles of female goats during sexual development (1 day old (neonatal, D1, n = 5), 2 months old (prepuberty, M2, n = 5), 4 months old (sexual maturity, M4, n = 5), and 6 months old (breeding period, M6, n = 5)). The results indicated that from D1 to M6, serum hormone levels, including FSH, LH, progesterone, estradiol, IGF1, and leptin, exhibited an initial increase followed by a decline, peaking at M4. Furthermore, we identified a total of 508 differentially expressed genes in the hypothalamus, with a total of four distinct expression patterns. Nuclear receptor subfamily 1, group D, member 1 (NR1D1), glucagon-like peptide 1 receptor (GLP1R), and gonadotropin-releasing hormone 1 (GnRH-1) may contribute to hormone secretion, energy metabolism, and signal transduction during goat sexual maturation via circadian rhythm regulation, ECM receptor interactions, neuroactive ligand–receptor interactions, and Wnt signaling pathways. This investigation offers novel insights into the molecular mechanisms governing the hypothalamic regulation of goat sexual maturation. Full article

(This article belongs to the Special Issue Central and Local Modulators of Reproduction and Fertility: An Update (4th Edition))

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23 pages, 12194 KiB

Open AccessArticle

Characterization of Neutrophil Functional Responses to SARS-CoV-2 Infection in a Translational Feline Model for COVID-19

by Sachithra Gunasekara, Miruthula Tamil Selvan, Chelsea L. Murphy, Shoroq Shatnawi, Shannon Cowan, Sunil More, Jerry Ritchey, Craig A. Miller and Jennifer M. Rudd

Int. J. Mol. Sci. 2024, 25(18), 10054; https://doi.org/10.3390/ijms251810054 (registering DOI) - 19 Sep 2024

There is a complex interplay between viral infection and host innate immune response regarding disease severity and outcomes. Neutrophil hyperactivation, including excessive release of neutrophil extracellular traps (NETs), is linked to exacerbated disease in acute COVID-19, notably in hospitalized patients. Delineating protective versus [...] Read more.

There is a complex interplay between viral infection and host innate immune response regarding disease severity and outcomes. Neutrophil hyperactivation, including excessive release of neutrophil extracellular traps (NETs), is linked to exacerbated disease in acute COVID-19, notably in hospitalized patients. Delineating protective versus detrimental neutrophil responses is essential to developing targeted COVID-19 therapies and relies on high-quality translational animal models. In this study, we utilize a previously established feline model for COVID-19 to investigate neutrophil dysfunction in which experimentally infected cats develop clinical disease that mimics acute COVID-19. Specific pathogen-free cats were inoculated with SARS-CoV-2 (B.1.617.2; Delta variant) (n = 24) or vehicle (n = 6). Plasma, bronchoalveolar lavage fluid, and lung tissues were collected at various time points over 12 days post-inoculation. Systematic and temporal evaluation of the kinetics of neutrophil activation was conducted by measuring markers of activation including myeloperoxidase (MPO), neutrophil elastase (NE), and citrullinated histone H3 (citH3) in SARS-CoV-2-infected cats at 4 and 12 days post-inoculation (dpi) and compared to vehicle-inoculated controls. Cytokine profiling supported elevated innate inflammatory responses with specific upregulation of neutrophil activation and NET formation-related markers, namely IL-8, IL-18, CXCL1, and SDF-1, in infected cats. An increase in MPO-DNA complexes and cell-free dsDNA in infected cats compared to vehicle-inoculated was noted and supported by histopathologic severity in respiratory tissues. Immunofluorescence analyses further supported correlation of NET markers with tissue damage, especially 4 dpi. Differential gene expression analyses indicated an upregulation of genes associated with innate immune and neutrophil activation pathways. Transcripts involved in activation and NETosis pathways were upregulated by 4 dpi and downregulated by 12 dpi, suggesting peak activation of neutrophils and NET-associated markers in the early acute stages of infection. Correlation analyses conducted between NET-specific markers and clinical scores as well as histopathologic scores support association between neutrophil activation and disease severity during SARS-CoV-2 infection in this model. Overall, this study emphasizes the effect of neutrophil activation and NET release in SARS-CoV-2 infection in a feline model, prompting further investigation into therapeutic strategies aimed at mitigating excessive innate inflammatory responses in COVID-19. Full article

(This article belongs to the Special Issue Exploring the Pathogenetic Mechanisms in Respiratory Virus Infections: Recent Advances and Future Directions)

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25 pages, 3622 KiB

Open AccessReview

Challenging the Norm: The Unrecognized Impact of Soluble Guanylyl Cyclase Subunits in Cancer

by María Teresa L. Pino, María Victoria Rocca, Lucas H. Acosta and Jimena P. Cabilla

Int. J. Mol. Sci. 2024, 25(18), 10053; https://doi.org/10.3390/ijms251810053 (registering DOI) - 19 Sep 2024

Since the discovery of nitric oxide (NO), a long journey has led us to the present, during which much knowledge has been gained about its pathway members and their roles in physiological and various pathophysiological conditions. Soluble guanylyl cyclase (sGC), the main NO [...] Read more.

Since the discovery of nitric oxide (NO), a long journey has led us to the present, during which much knowledge has been gained about its pathway members and their roles in physiological and various pathophysiological conditions. Soluble guanylyl cyclase (sGC), the main NO receptor composed of the sGCα1 and sGCβ1 subunits, has been one of the central figures in this narrative. However, the sGCα1 and sGCβ1 subunits remained obscured by the focus on sGC’s enzymatic activity for many years. In this review, we restore the significance of the sGCα1 and sGCβ1 subunits by compiling and analyzing available but previously overlooked information regarding their roles beyond enzymatic activity. We delve into the basics of sGC expression regulation, from its transcriptional regulation to its interaction with proteins, placing particular emphasis on evidence thus far demonstrating the actions of each sGC subunit in different tumor models. Exploring the roles of sGC subunits in cancer offers a valuable opportunity to enhance our understanding of tumor biology and discover new therapeutic avenues. Full article

(This article belongs to the Special Issue cGMP Signaling: From Bench to Bedside)

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16 pages, 7118 KiB

Open AccessArticle

Comparative Genomics Analysis of the Populus Epidermal Pattern Factor (EPF) Family Revealed Their Regulatory Effects in Populus euphratica Stomatal Development

by Mingyu Jia, Ying Wang, Hongyan Jin, Jing Li, Tongrui Song, Yongqiang Chen, Yang Yuan, Honghong Hu, Ruting Li, Zhihua Wu and Peipei Jiao

Int. J. Mol. Sci. 2024, 25(18), 10052; https://doi.org/10.3390/ijms251810052 (registering DOI) - 19 Sep 2024

Drought stress seriously threatens plant growth. The improvement of plant water use efficiency (WUE) and drought tolerance through stomatal regulation is an effective strategy for coping with water shortages. Epidermal patterning factor (EPF)/EPF-like (EPFL) family proteins regulate stomatal formation and development in plants [...] Read more.

Drought stress seriously threatens plant growth. The improvement of plant water use efficiency (WUE) and drought tolerance through stomatal regulation is an effective strategy for coping with water shortages. Epidermal patterning factor (EPF)/EPF-like (EPFL) family proteins regulate stomatal formation and development in plants and thus contribute to plant stress adaptation. Here, our analysis revealed the presence of 14 PeEPF members in the Populus euphratica genome, which exhibited a relatively conserved gene structure with 1–3 introns. Subcellular localisation prediction revealed that 9 PeEPF members were distributed in the chloroplasts of P. euphratica, and 5 were located extracellularly. Phylogenetic analysis indicated that PeEPFs can be divided into three clades, with genes within the same clade revealing a relatively conserved structure. Furthermore, we observed the evolutionary conservation of PeEPFs and AtEPF/EPFLs in certain domains, which suggests their conserved function. The analysis of cis-acting elements suggested the possible involvement of PeEPFs in plant response to multiple hormones. Transcriptomic analysis revealed considerable changes in the expression level of PeEPFs during treatment with polyethylene glycol and abscisic acid. The overexpression of PeEPF2 resulted in low stomatal density in transgenetic lines. These findings provide a basis for gaining insights into the function of PeEPFs in response to abiotic stress. Full article

(This article belongs to the Special Issue Advances in Plant Genomics and Genetics)

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19 pages, 755 KiB

Open AccessReview

Molecular Therapeutics for Diabetic Kidney Disease: An Update

by Man Guo, Fangfang He and Chun Zhang

Int. J. Mol. Sci. 2024, 25(18), 10051; https://doi.org/10.3390/ijms251810051 (registering DOI) - 19 Sep 2024

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes mellitus (DM). With the increasing prevalence of DM worldwide, the incidence of DKD remains high. If DKD is not well controlled, it can develop into chronic kidney disease or end-stage renal disease [...] Read more.

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes mellitus (DM). With the increasing prevalence of DM worldwide, the incidence of DKD remains high. If DKD is not well controlled, it can develop into chronic kidney disease or end-stage renal disease (ESRD), which places considerable economic pressure on society. Traditional therapies, including glycemic control, blood pressure control, blood lipid control, the use of renin–angiotensin system blockers and novel drugs, such as sodium–glucose cotransporter 2 inhibitors, mineralocorticoid receptor inhibitors and glucagon-like peptide-1 receptor agonists, have been used in DKD patients. Although the above treatment strategies can delay the progression of DKD, most DKD patients still ultimately progress to ESRD. Therefore, new and multimodal treatment methods need to be explored. In recent years, researchers have continuously developed new treatment methods and targets to delay the progression of DKD, including miRNA therapy, stem cell therapy, gene therapy, gut microbiota-targeted therapy and lifestyle intervention. These new molecular therapy methods constitute opportunities to better understand and treat DKD. In this review, we summarize the progress of molecular therapeutics for DKD, leading to new treatment strategies. Full article

(This article belongs to the Special Issue Molecular Therapeutics for Diabetes and Related Complications)

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14 pages, 1544 KiB

Open AccessArticle

Staphylococcus aureus Co-Infection in COVID-19 Patients: Virulence Genes and Their Influence on Respiratory Epithelial Cells in Light of Risk of Severe Secondary Infection

by Lidia Piechowicz, Katarzyna Kosznik-Kwaśnicka, Tomasz Jarzembowski, Agnieszka Daca, Agnieszka Necel, Ada Bonawenturczak, Olesia Werbowy, Małgorzata Stasiłojć and Anna Pałubicka

Int. J. Mol. Sci. 2024, 25(18), 10050; https://doi.org/10.3390/ijms251810050 (registering DOI) - 18 Sep 2024

Pandemics from viral respiratory tract infections in the 20th and early 21st centuries were associated with high mortality, which was not always caused by a primary viral infection. It has been observed that severe course of infection, complications and mortality were often the [...] Read more.

Pandemics from viral respiratory tract infections in the 20th and early 21st centuries were associated with high mortality, which was not always caused by a primary viral infection. It has been observed that severe course of infection, complications and mortality were often the result of co-infection with other pathogens, especially Staphylococcus aureus. During the COVID-19 pandemic, it was also noticed that patients infected with S. aureus had a significantly higher mortality rate (61.7%) compared to patients infected with SARS-CoV-2 alone. Our previous studies have shown that S. aureus strains isolated from patients with COVID-19 had a different protein profile than the strains in non-COVID-19 patients. Therefore, this study aims to analyze S. aureus strains isolated from COVID-19 patients in terms of their pathogenicity by analyzing their virulence genes, adhesion, cytotoxicity and penetration to the human pulmonary epithelial cell line A549. We have observed that half of the tested S. aureus strains isolated from patients with COVID-19 had a necrotizing effect on the A549 cells. The strains also showed greater variability in terms of their adhesion to the human cells than their non-COVID-19 counterparts. Full article

(This article belongs to the Section Molecular Microbiology)

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31 pages, 1061 KiB

Open AccessReview

WISP1 and Macrophage Migration Inhibitory Factor in Respiratory Inflammation: Novel Insights and Therapeutic Potentials for Asthma and COPD

by Maria-Elpida Christopoulou, Alexios J. Aletras, Eleni Papakonstantinou, Daiana Stolz and Spyros S. Skandalis

Int. J. Mol. Sci. 2024, 25(18), 10049; https://doi.org/10.3390/ijms251810049 - 18 Sep 2024

Recent advancements highlight the intricate interplay between the extracellular matrix (ECM) and immune responses, notably in respiratory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). The ECM, a dynamic structural framework within tissues, orches-trates a plethora of cellular processes, including immune [...] Read more.

Recent advancements highlight the intricate interplay between the extracellular matrix (ECM) and immune responses, notably in respiratory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). The ECM, a dynamic structural framework within tissues, orches-trates a plethora of cellular processes, including immune cell behavior and tissue repair mecha-nisms. WNT1-inducible-signaling pathway protein 1 (WISP1), a key ECM regulator, controls immune cell behavior, cytokine production, and tissue repair by modulating integrins, PI3K, Akt, β-catenin, and mTOR signaling pathways. WISP1 also induces macrophage migration inhibitory factor (MIF) expression via Src kinases and epidermal growth factor receptor (EGFR) activation. MIF, through its wide range of activities, enhances inflammation and tissue restructuring. Rec-ognized for its versatile roles in regulating the immune system, MIF interacts with multiple immune components, such as the NLRP3 inflammasome, thereby sustaining inflammatory pro-cesses. The WISP1–MIF axis potentially unveils complex molecular mechanisms governing im-mune responses and inflammation. Understanding the intricate roles of WISP1 and MIF in the pathogenesis of chronic respiratory diseases such as asthma and COPD could lead to the identi-fication of novel targets for therapeutic intervention to alleviate disease severity and enhance patient outcomes. Full article

(This article belongs to the Section Molecular Immunology)

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28 pages, 8526 KiB

Open AccessArticle

Genome-Wide Identification and Expression Analysis of MYB Transcription Factor Family in Response to Various Abiotic Stresses in Coconut (Cocos nucifera L.)

by Cheng-Cheng Si, Yu-Bin Li, Xue Hai, Ci-Ci Bao, Jin-Yang Zhao, Rafiq Ahmad, Jing Li, Shou-Chuang Wang, Yan Li and Yao-Dong Yang

Int. J. Mol. Sci. 2024, 25(18), 10048; https://doi.org/10.3390/ijms251810048 - 18 Sep 2024

Abiotic stresses such as nitrogen deficiency, drought, and salinity significantly impact coconut production, yet the molecular mechanisms underlying coconut’s response to these stresses are poorly understood. MYB proteins, a large and diverse family of transcription factors (TF), play crucial roles in plant responses [...] Read more.

Abiotic stresses such as nitrogen deficiency, drought, and salinity significantly impact coconut production, yet the molecular mechanisms underlying coconut’s response to these stresses are poorly understood. MYB proteins, a large and diverse family of transcription factors (TF), play crucial roles in plant responses to various abiotic stresses, but their genome-wide characterization and functional roles in coconut have not been comprehensively explored. This study identified 214 CnMYB genes (39 1R–MYB, 171 R2R3–MYB, 2 3R–MYB, and 2 4R–MYB) in the coconut genome. Phylogenetic analysis revealed that these genes are unevenly distributed across the 16 chromosomes, with conserved consensus sequences, motifs, and gene structures within the same subgroups. Synteny analysis indicated that segmental duplication primarily drove CnMYB evolution in coconut, with low nonsynonymous/synonymous ratios suggesting strong purifying selection. The gene ontology (GO) annotation of protein sequences provided insights into the biological functions of the CnMYB gene family. CnMYB47/70/83/119/186 and CnMYB2/45/85/158/195 were identified as homologous genes linked to nitrogen deficiency, drought, and salinity stress through BLAST, highlighting the key role of CnMYB genes in abiotic stress tolerance. Quantitative analysis of PCR showed 10 CnMYB genes in leaves and petioles and found that the expression of CnMYB45/47/70/83/85/119/186 was higher in 3-month-old than one-year-old coconut, whereas CnMYB2/158/195 was higher in one-year-old coconut. Moreover, the expression of CnMYB70, CnMYB2, and CnMYB2/158 was high under nitrogen deficiency, drought, and salinity stress, respectively. The predicted secondary and tertiary structures of three key CnMYB proteins involved in abiotic stress revealed distinct inter-proteomic features. The predicted interaction between CnMYB2/158 and Hsp70 supports its role in coconut’s drought and salinity stress responses. These results expand our understanding of the relationships between the evolution and function of MYB genes, and provide valuable insights into the MYB gene family’s role in abiotic stress in coconut. Full article

(This article belongs to the Special Issue Changes and Adaptations of the Plant Metabolism under Elemental Nutrient Deficiencies)

12 pages, 780 KiB

Open AccessArticle

Gallium Uncouples Iron Metabolism to Enhance Glioblastoma Radiosensitivity

by Stephenson B. Owusu, Amira Zaher, Stephen Ahenkorah, Darpah N. Pandya, Thaddeus J. Wadas and Michael S. Petronek

Int. J. Mol. Sci. 2024, 25(18), 10047; https://doi.org/10.3390/ijms251810047 - 18 Sep 2024

Gallium-based therapy has been considered a potentially effective cancer therapy for decades and has recently re-emerged as a novel therapeutic strategy for the management of glioblastoma tumors. Gallium targets the iron-dependent phenotype associated with aggressive tumors by mimicking iron in circulation and gaining [...] Read more.

Gallium-based therapy has been considered a potentially effective cancer therapy for decades and has recently re-emerged as a novel therapeutic strategy for the management of glioblastoma tumors. Gallium targets the iron-dependent phenotype associated with aggressive tumors by mimicking iron in circulation and gaining intracellular access through transferrin-receptor-mediated endocytosis. Mechanistically, it is believed that gallium inhibits critical iron-dependent enzymes like ribonucleotide reductase and NADH dehydrogenase (electron transport chain complex I) by replacing iron and removing the ability to transfer electrons through the protein secondary structure. However, information regarding the effects of gallium on cellular iron metabolism is limited. As mitochondrial iron metabolism serves as a central hub of the iron metabolic network, the goal of this study was to investigate the effects of gallium on mitochondrial iron metabolism in glioblastoma cells. Here, it has been discovered that gallium nitrate can induce mitochondrial iron depletion, which is associated with the induction of DNA damage. Moreover, the generation of gallium-resistant cell lines reveals a highly unstable phenotype characterized by impaired colony formation associated with a significant decrease in mitochondrial iron content and loss of the mitochondrial iron uptake transporter, mitoferrin-1. Moreover, gallium-resistant cell lines are significantly more sensitive to radiation and have an impaired ability to repair any sublethal damage and to survive potentially lethal radiation damage when left for 24 h following radiation. These results support the hypothesis that gallium can disrupt mitochondrial iron metabolism and serve as a potential radiosensitizer. Full article

(This article belongs to the Special Issue Insights into Mitochondrial Iron Metabolism: Connections to Cancer and Other Pathologies)

23 pages, 578 KiB

Open AccessReview

Emerging Targets in Non-Small Cell Lung Cancer

by Louisa Liu, Joshua Soler, Karen L. Reckamp and Kamya Sankar

Int. J. Mol. Sci. 2024, 25(18), 10046; https://doi.org/10.3390/ijms251810046 - 18 Sep 2024

Lung cancer is responsible for a high burden of disease globally. Over the last two decades, the discovery of targetable oncogenic genomic alterations has revolutionized the treatment landscape for early-stage and advanced non-small cell lung cancer (NSCLC). New molecular drivers continue to emerge [...] Read more.

Lung cancer is responsible for a high burden of disease globally. Over the last two decades, the discovery of targetable oncogenic genomic alterations has revolutionized the treatment landscape for early-stage and advanced non-small cell lung cancer (NSCLC). New molecular drivers continue to emerge as promising therapeutic targets, including KRAS non-G12C, RAF/MEK, HER3, Nectin-4, folate receptor alpha, ITGB6, and PRMT5. In this review, we summarize the emerging molecular targets with a potential clinical impact in advanced NSCLC, elaborating on their clinical characteristics and specific mechanisms and molecular pathways for which targeted treatments are currently available. Additionally, we present an aggregate of ongoing clinical trials investigating the available treatment options targeting such alterations, in addition to their current recruitment status and preliminary efficacy data. These advancements may guide further research endeavors and inform future treatment strategies to improve the management of and transform outcomes for patients with advanced NSCLC. Full article

(This article belongs to the Special Issue Personalized Cancer Treatment: Harnessing the Power of Molecular Research)

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19 pages, 3524 KiB

Open AccessArticle

OXGR1-Dependent (Pro)Renin Receptor Upregulation in Collecting Ducts of the Clipped Kidney Contributes to Na⁺ Balance in Goldblatt Hypertensive Mice

by Pilar Cárdenas, Camila Nuñez-Allimant, Katherin Silva, Catalina Cid-Salinas, Allison C. León, Zoe Vallotton, Ramón A. Lorca, Lilian Caroline Gonçalves de Oliveira, Dulce E Casarini, Carlos Céspedes, Minolfa C. Prieto and Alexis A. Gonzalez

Int. J. Mol. Sci. 2024, 25(18), 10045; https://doi.org/10.3390/ijms251810045 (registering DOI) - 18 Sep 2024

The two-kidney, one-clip (2K1C) Goldblatt rodent model elicits a reduction in renal blood flow (RBF) in the clipped kidney (CK). The reduced RBF and oxygen bio-ability causes the accumulation of the tricarboxylic cycle intermediary, α-ketoglutarate, which activates the oxoglutarate receptor-1 (OXGR1). In the [...] Read more.

The two-kidney, one-clip (2K1C) Goldblatt rodent model elicits a reduction in renal blood flow (RBF) in the clipped kidney (CK). The reduced RBF and oxygen bio-ability causes the accumulation of the tricarboxylic cycle intermediary, α-ketoglutarate, which activates the oxoglutarate receptor-1 (OXGR1). In the kidney, OXGR1 is abundantly expressed in intercalated cells (ICs) of the collecting duct (CD), thus contributing to sodium transport and electrolyte balance. The (pro)renin receptor (PRR), a member of the renin–angiotensin system (RAS), is a key regulator of sodium reabsorption and blood pressure (BP) that is expressed in ICs. The PRR is upregulated in 2K1C rats. Here, we tested the hypothesis that chronic reduction in RBF in the CK leads to OXGR1-dependent PRR upregulation in the CD and alters sodium balance and BP in 2K1C mice. To determine the role of OXGR1 in regulating the PRR in the CDs during renovascular hypertension, we performed 2K1C Goldblatt surgery (clip = 0.13 mm internal gap, 14 days) in two groups of male mice: (1) mice treated with Montelukast (OXGR1 antagonist; 5 mg/Kg/day); (2) OXGR1^−/− knockout mice. Wild-type and sham-operated mice were used as controls. After 14 days, 2K1C mice showed increased systolic BP (SBP) (108 ± 11 vs. control 82 ± 5 mmHg, p < 0.01) and a lower natriuretic response after the saline challenge test. The CK group showed upregulation of erythropoietin, augmented α-ketoglutarate, and increased PRR expression in the renal medulla. The CK of OXGR1 knockout mice and mice subjected to the OXGR1 antagonist elicited impaired PRR upregulation, attenuated SBP, and better natriuretic responses. In 2K1C mice, the effect of reduced RBF on the OXGR1-dependent PRR upregulation in the CK may contribute to the anti-natriuretic and increased SBP responses. Full article

(This article belongs to the Special Issue Advances and Challenges of Molecular Research on Disease in Animal Models in Biomedicine)

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11 pages, 515 KiB

Open AccessArticle

Novel Metabolites Associated with Decreased GFR in Finnish Men: A 12-Year Follow-Up of the METSIM Cohort

by Lilian Fernandes Silva, Jagadish Vangipurapu, Anniina Oravilahti and Markku Laakso

Int. J. Mol. Sci. 2024, 25(18), 10044; https://doi.org/10.3390/ijms251810044 - 18 Sep 2024

Identification of the individuals having impaired kidney function is essential in preventing the complications of this disease. We measured 1009 metabolites at the baseline study in 10,159 Finnish men of the METSIM cohort and associated the metabolites with an estimated glomerular filtration rate [...] Read more.

Identification of the individuals having impaired kidney function is essential in preventing the complications of this disease. We measured 1009 metabolites at the baseline study in 10,159 Finnish men of the METSIM cohort and associated the metabolites with an estimated glomerular filtration rate (eGFR). A total of 7090 men participated in the 12-year follow-up study. Non-targeted metabolomics profiling was performed at Metabolon, Inc. (Morrisville, NC, USA) on EDTA plasma samples obtained after overnight fasting. We applied liquid chromatography mass spectrometry (LC-MS/MS) to identify the metabolites (the Metabolon DiscoveryHD4 platform). We performed association analyses between the eGFR and metabolites using linear regression adjusted for confounding factors. We found 108 metabolites significantly associated with a decrease in eGFR, and 28 of them were novel, including 12 amino acids, 8 xenobiotics, 5 lipids, 1 nucleotide, 1 peptide, and 1 partially characterized molecule. The most significant associations were with five amino acids, N-acetylmethionine, N-acetylvaline, gamma-carboxyglutamate, 3-methylglutaryl-carnitine, and pro-line. We identified 28 novel metabolites associated with decreased eGFR in the 12-year follow-up study of the METSIM cohort. These findings provide novel insights into the role of metabolites and metabolic pathways involved in the decline of kidney function. Full article

(This article belongs to the Special Issue Molecular Therapeutics for Diabetes and Related Complications)

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12 pages, 512 KiB

Open AccessReview

Ciliary Function, Antigen Stasis and Asthma

by Nadzeya Marozkina

Int. J. Mol. Sci. 2024, 25(18), 10043; https://doi.org/10.3390/ijms251810043 - 18 Sep 2024

The prevalence of asthma exceeds 3% of the population. Asthma is observed to be more common in children following severe viral lower respiratory illnesses that affect ciliary function, but mechanisms linking ciliary function to asthma pathogenesis have been obscure. Recent data regarding primary [...] Read more.

The prevalence of asthma exceeds 3% of the population. Asthma is observed to be more common in children following severe viral lower respiratory illnesses that affect ciliary function, but mechanisms linking ciliary function to asthma pathogenesis have been obscure. Recent data regarding primary ciliary dyskinesia (PCD) may help us to understand the association. Here, I will review what is known about the relationship between ciliary function and asthma. PCD is caused by pathologic variants in over 50 different genes that affect the structure and function of motile cilia. At the cellular level, a characteristic feature shared by most PCD patients is that antigens and other particles are not cleared from the epithelial surface. Poor antigen clearance results in pro-oxidant pathway activation and airway epithelial damage and may predispose PCD patients to DUOX1- and IL33-mediated asthma. Secondary ciliary dysfunction, such as that caused by viruses or by smoking, can also contribute to asthma development. Moreover, variants in genes that affect the function of cilia can be associated with poor lung function, even in the absence of PCD, and with increased asthma severity. The role of antigen stasis on the surface of dysfunctional airway cilia in the pathophysiology of asthma is a novel area for research, because specific airway clearance techniques and other therapeutic interventions, such as antioxidants, could be of value in preventing the development of asthma. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

17 pages, 2873 KiB

Open AccessArticle

Assembly of mTORC3 Involves Binding of ETV7 to Two Separate Sequences in the mTOR Kinase Domain

by Jun Zhan, Frank Harwood, Sara Ten Have, Angus Lamond, Aaron H. Phillips, Richard W. Kriwacki, Priyanka Halder, Monica Cardone and Gerard C. Grosveld

Int. J. Mol. Sci. 2024, 25(18), 10042; https://doi.org/10.3390/ijms251810042 - 18 Sep 2024

mTOR plays a crucial role in cell growth by controlling ribosome biogenesis, metabolism, autophagy, mRNA translation, and cytoskeleton organization. It is a serine/threonine kinase that is part of two distinct extensively described protein complexes, mTORC1 and mTORC2. We have identified a rapamycin-resistant mTOR [...] Read more.

mTOR plays a crucial role in cell growth by controlling ribosome biogenesis, metabolism, autophagy, mRNA translation, and cytoskeleton organization. It is a serine/threonine kinase that is part of two distinct extensively described protein complexes, mTORC1 and mTORC2. We have identified a rapamycin-resistant mTOR complex, called mTORC3, which is different from the canonical mTORC1 and mTORC2 complexes in that it does not contain the Raptor, Rictor, or mLST8 mTORC1/2 components. mTORC3 phosphorylates mTORC1 and mTORC2 targets and contains the ETS transcription factor ETV7, which binds to mTOR and is essential for mTORC3 assembly in the cytoplasm. Tumor cells that assemble mTORC3 have a proliferative advantage and become resistant to rapamycin, indicating that inhibiting mTORC3 may have a therapeutic impact on cancer. Here, we investigate which domains or amino acid residues of ETV7 and mTOR are involved in their mutual binding. We found that the mTOR FRB and LBE sequences in the kinase domain interact with the pointed (PNT) and ETS domains of ETV7, respectively. We also found that forced expression of the mTOR FRB domain in the mTORC3-expressing, rapamycin-resistant cell line Karpas-299 out-competes mTOR for ETV7 binding and renders these cells rapamycin-sensitive in vivo. Our data provide useful information for the development of molecules that prevent the assembly of mTORC3, which may have therapeutic value in the treatment of mTORC3-positive cancer. Full article

(This article belongs to the Special Issue mTOR Signaling in Anti-cancer Therapy Research)

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