International Journal of Molecular Sciences

24 pages, 8659 KB

Open AccessArticle

Liraglutide Attenuates Multiorgan Oxidative, Astroglial, and Mitochondrial Stress Responses in Thioacetamide-Induced Hepatic Encephalopathy

by Yasin Bilgin, Fatih Mehmet Sari, Betul Cicek, Engin Kurt, Mustafa Ozkaraca, Ali Gungor, Nezahat Kurt and Asli Ozbek Bilgin

Int. J. Mol. Sci. 2026, 27(17), 7538; https://doi.org/10.3390/ijms27177538 (registering DOI) - 23 Aug 2026

Abstract

Hepatic encephalopathy (HE) is a complex complication of liver failure involving oxidative stress, astroglial activation, mitochondrial dysfunction, and multiorgan disturbances along the gut–liver–brain axis. This study investigated the therapeutic effects of liraglutide (LIRA) in a thioacetamide (TAA)-induced rat model of HE. Thirty male [...] Read more.

Hepatic encephalopathy (HE) is a complex complication of liver failure involving oxidative stress, astroglial activation, mitochondrial dysfunction, and multiorgan disturbances along the gut–liver–brain axis. This study investigated the therapeutic effects of liraglutide (LIRA) in a thioacetamide (TAA)-induced rat model of HE. Thirty male Sprague–Dawley rats were assigned to control, TAA, and TAA+LIRA 100, 200, or 400 µg/kg groups. HE was induced with TAA (200 mg/kg, intraperitoneally) for three consecutive days, followed by subcutaneous LIRA treatment for 14 days. Serum biochemical parameters, tissue oxidative and inflammatory markers, histopathology, and Nrf2, MFN2, AKT1, mTOR, GFAP, and VEGFA immunoreactivity were evaluated. TAA caused marked hepatic and cerebral structural injury, increased serum and brain glutamine concentrations, disrupted redox homeostasis, elevated MPO activity, and increased cerebral GFAP and multiorgan VEGFA immunoreactivity. LIRA partially improved hepatic and cerebral histopathology, reduced glutamine disturbances, attenuated selected oxidative, nitrosative, and inflammatory alterations, and modulated Nrf2, MFN2, AKT1, mTOR, GFAP, and VEGFA immunoreactivity in a tissue- and dose-specific manner. The 200 µg/kg dose produced the most consistent overall improvement, whereas the 400 µg/kg dose was less favorable for several endpoints. LIRA may therefore alleviate multiorgan stress associated with experimental HE, although further studies are required to confirm functional and mechanistic relevance. Full article

(This article belongs to the Section Molecular Biology)

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26 pages, 8260 KB

Open AccessReview

The Crosstalk Between YAP/TAZ and Cancer Metabolism: From Mechanistic Insights to Drug Discovery

by Yinhuang Gao, Minghong Chen, Songxia Lin, Min Huang and Jing Jin

Int. J. Mol. Sci. 2026, 27(17), 7537; https://doi.org/10.3390/ijms27177537 (registering DOI) - 23 Aug 2026

Abstract

As the core transcriptional co-activators of the Hippo signaling pathway, YAP and TAZ play essential roles in maintaining tissue homeostasis and in tumorigenesis. Their aberrant activation is frequently observed in human malignancies, and accumulating evidence has identified them as crucial drivers of tumor [...] Read more.

As the core transcriptional co-activators of the Hippo signaling pathway, YAP and TAZ play essential roles in maintaining tissue homeostasis and in tumorigenesis. Their aberrant activation is frequently observed in human malignancies, and accumulating evidence has identified them as crucial drivers of tumor initiation and progression. YAP/TAZ have been recently recognized as key regulators of cellular metabolic reprogramming, a hallmark of cancer that fuels tumor cell proliferation by rewiring glucose, lipid, amino acid, and nucleotide metabolism. Conversely, the activity of YAP/TAZ is modulated by metabolites such as glucose and lipids, establishing a complex bidirectional regulatory circuit. Therefore, deciphering this intricate crosstalk is of great importance for cancer therapy and drug discovery. In this review, we systematically clarify the interplay between YAP/TAZ and metabolic reprogramming in cancer, delineate the core molecular networks through which YAP/TAZ govern each metabolic pathway, and summarize the current pharmacological inhibitors targeting YAP/TAZ-regulated metabolic networks. Collectively, these findings pave the way for therapeutic approaches targeting YAP/TAZ-driven metabolic vulnerabilities in cancer. Full article

(This article belongs to the Section Molecular Pharmacology)

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16 pages, 2749 KB

Open AccessArticle

LEAP2 Regulates Insulin Secretion from INS-1E Beta Cells and Rat Pancreatic Islets: An In Vitro Study

by Oskar Sosiński, Ewa Pruszyńska-Oszmałek, Maciej Sassek, Natalia Leciejewska, Piotr Pawlak and Paweł Antoni Kołodziejski

Int. J. Mol. Sci. 2026, 27(17), 7536; https://doi.org/10.3390/ijms27177536 (registering DOI) - 23 Aug 2026

Abstract

LEAP2 is an endogenous antagonist and inverse agonist of GHSR-1a, the receptor for acyl-ghrelin. Although LEAP2 is increasingly recognized as a regulator of appetite and glucose homeostasis, its direct effects on pancreatic endocrine cells remain incompletely understood. The present in vitro study evaluated [...] Read more.

LEAP2 is an endogenous antagonist and inverse agonist of GHSR-1a, the receptor for acyl-ghrelin. Although LEAP2 is increasingly recognized as a regulator of appetite and glucose homeostasis, its direct effects on pancreatic endocrine cells remain incompletely understood. The present in vitro study evaluated whether LEAP2 modulates insulin secretion and the expression of insulin-related genes in INS-1E beta cells and isolated rat pancreatic islets. LEAP2 treatment altered selected components of the insulin-related expression profile in a model- and time-dependent manner. In INS-1E cells, LEAP2 increased insulin protein expression after 6 h and IRSII protein expression after 24 h, whereas effects on mRNA expression were variable. In isolated rat islets, LEAP2 increased INS2 mRNA expression and decreased GHSR-1a and preproghrelin mRNA expression under the tested conditions. Acute exposure to 100 nM LEAP2 increased basal insulin release from both INS-1E cells and isolated islets. Immunofluorescence and Western blot analyses detected LEAP2- and GHSR-1a-related immunoreactivity in pancreatic models. LEAP2 did not adversely affect INS-1E cell metabolic activity, proliferation, or apoptosis. Overall, these data suggest that LEAP2 can modulate pancreatic endocrine cell function under in vitro conditions, but further studies using standard glucose-stimulated insulin secretion protocols and in vivo models are required to define its physiological relevance. Full article

(This article belongs to the Section Molecular Biology)

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21 pages, 17187 KB

Open AccessArticle

Integrated Transcriptomic Analyses Identify Four Prognosis-Associated Genes in Hepatocellular Carcinoma

by Yuxian Liu, Xingjie Chen, Junyuan Zhang, Xueyan Zhou, Xiaohui Li, Kangcheng Xu, Hao Lin and Yanni Cao

Int. J. Mol. Sci. 2026, 27(17), 7535; https://doi.org/10.3390/ijms27177535 (registering DOI) - 23 Aug 2026

Abstract

Hepatocellular carcinoma (HCC) is one of the malignant tumors with high incidence and mortality rates worldwide. Given the poor prognosis of patients with HCC, it is crucial to explore the molecular mechanisms underlying HCC development and to evaluate prognostic markers. Differential expression analysis [...] Read more.

Hepatocellular carcinoma (HCC) is one of the malignant tumors with high incidence and mortality rates worldwide. Given the poor prognosis of patients with HCC, it is crucial to explore the molecular mechanisms underlying HCC development and to evaluate prognostic markers. Differential expression analysis followed by univariate Cox, LASSO, and multivariate Cox regression identified four genes (EPO, SOCS2, IL18RAP, and KPNA2), and a Cox-based risk score was evaluated in the TCGA-LIHC cohort and externally in GSE14520 using Kaplan–Meier and time-dependent ROC analyses. Bulk, single-cell, and protein resources provided convergent expression context. Survival machine-learning analysis using observed overall-survival time and censoring status identified Cox–Ridge as the best-performing model in TCGA-LIHC, with more modest performance in GSE14520, and immune profiling revealed risk-group-associated differences in estimated immune and stromal components, immune-cell composition, and immune-checkpoint expression. The oncoPredict/GDSC2 screen highlighted five potential drug candidates for experimental prioritization. Because the drug screen is based on computationally predicted sensitivities, these findings should be regarded as hypothesis-generating and require validation in prospective cohorts and experimental systems before clinical translation. Full article

(This article belongs to the Section Molecular Informatics)

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19 pages, 9364 KB

Open AccessArticle

Diabetes-Associated Neuroplastic Changes in Neuropeptide Y-Immunoreactive Enteric Neurons Along the Porcine Gastrointestinal Tract

by Michał Bulc, Barbara Jana and Katarzyna Palus

Int. J. Mol. Sci. 2026, 27(17), 7534; https://doi.org/10.3390/ijms27177534 (registering DOI) - 23 Aug 2026

Abstract

Diabetes mellitus is frequently associated with gastrointestinal dysfunction, in which alterations in the enteric nervous system (ENS) are considered important contributing factors. Neuropeptide Y (NPY) is a key enteric neuromodulator involved in the regulation of gastrointestinal motility, secretion, and blood flow; however, its [...] Read more.

Diabetes mellitus is frequently associated with gastrointestinal dysfunction, in which alterations in the enteric nervous system (ENS) are considered important contributing factors. Neuropeptide Y (NPY) is a key enteric neuromodulator involved in the regulation of gastrointestinal motility, secretion, and blood flow; however, its response to diabetes remains insufficiently characterized, particularly in large animal models. This study investigated the effect of experimental diabetes on the distribution of NPY-immunoreactive enteric neurons in the porcine gastrointestinal tract. Diabetes was induced in juvenile female pigs by streptozotocin administration. Six weeks later, the stomach, duodenum, jejunum, ileum, and descending colon were collected, and the population of NPY-immunoreactive neurons in the myenteric and submucosal plexuses was evaluated by double-label immunofluorescence. Experimental diabetes significantly increased the population of NPY-immunoreactive neurons in the myenteric plexus of the stomach, jejunum, ileum, and descending colon, whereas no statistically significant changes were detected in the duodenum after correction for multiple comparisons. In the submucosal plexuses, significant increases were restricted to the inner and outer submucosal plexuses of the descending colon. These findings demonstrate that diabetes induces region- and plexus-specific neurochemical plasticity of NPY-immunoreactive enteric neurons in pigs. Given the predominantly inhibitory effects of NPY on gastrointestinal motility and secretion, together with its vasoconstrictive actions, the observed changes may contribute to altered neural regulation of gastrointestinal function during diabetes and may represent one of the mechanisms involved in diabetic gastroenteropathy. Full article

(This article belongs to the Special Issue Advances in Research on Neurotransmitters (Second Edition))

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19 pages, 332 KB

Open AccessArticle

Hormetic Antioxidant Effects of Uncaria gambir on Male Reproductive Function: A Comprehensive Experimental and Computational Analysis

by Hendri Devita, Idris Adewale Ahmed, Yudha Endra Pratama and Maryam Abimbola Mikail

Int. J. Mol. Sci. 2026, 27(17), 7533; https://doi.org/10.3390/ijms27177533 (registering DOI) - 22 Aug 2026

Abstract

Oxidative stress is a key mechanism underlying nicotine-induced male reproductive dysfunction, yet evidence-based phytopharmacological interventions remain limited. Uncaria gambir Roxb., a catechin-rich medicinal plant from West Sumatra, Indonesia, exhibits strong antioxidant potential; however, a comprehensive multi-regional evaluation combined with in vivo androgenic assessment [...] Read more.

Oxidative stress is a key mechanism underlying nicotine-induced male reproductive dysfunction, yet evidence-based phytopharmacological interventions remain limited. Uncaria gambir Roxb., a catechin-rich medicinal plant from West Sumatra, Indonesia, exhibits strong antioxidant potential; however, a comprehensive multi-regional evaluation combined with in vivo androgenic assessment is lacking. This study aimed to characterize the antioxidant activity, phytochemical composition (HPLC-DAD), and antimicrobial properties of gambir extracts from three production regions (Halaban, Mungka, and Pesisir Selatan), to evaluate catechin pharmacokinetics in silico (PASS Online; SwissADME), and to assess dose-dependent effects in male Wistar rats exposed to nicotine (n = 36). The Halaban extract showed the highest antioxidant activity (IC₅₀ = 6.99 ± 0.28 µg mL⁻¹) and catechin content (7.91 ± 0.07 mg g⁻¹). All extracts demonstrated broad-spectrum antimicrobial activity. PASS analysis predicted strong membrane integrity agonism (Pa = 0.950) and HMOX1 induction (Pa = 0.778), while SwissADME indicated favorable pharmacokinetic properties, including full Lipinski compliance and high gastrointestinal absorption. In the in vivo study, gambir Halaban extract at 300 mg kg⁻¹ day⁻¹ significantly increased follicle-stimulating hormone, luteinizing hormone, and testosterone levels compared to controls (p < 0.05), exceeding baseline values and indicating HPG axis stimulation. A non-linear (hormetic) response was observed, with reduced efficacy at higher doses. These findings highlight bioactive-rich gambir as a promising multi-target natural antioxidant for mitigating oxidative-stress-related reproductive dysfunction, warranting further mechanistic and translational studies. Full article

(This article belongs to the Special Issue Next-Generation Natural Products in Drug Discovery: From Ethnopharmacology to Precision Medicine)

24 pages, 9600 KB

Open AccessArticle

Potential Shared Immunometabolic Signatures Between Familial Hypercholesterolemia and Major Depressive Disorder: Integrative Transcriptomic Analysis, Mendelian Randomization, and Clinical Validation

by Chenxi Liu, Yuting Li, Xiang Cao, Zixuan Ye, Quanzhou Shi, Feng Chen, Zihao Li, Jiamei Guo and Tian Qiu

Int. J. Mol. Sci. 2026, 27(17), 7532; https://doi.org/10.3390/ijms27177532 (registering DOI) - 22 Aug 2026

Abstract

Familial hypercholesterolemia (FH) has been associated with an increased risk of major depressive disorder (MDD), but their shared molecular signatures remain unclear. This study aimed to identify candidate genes associated with FH-MDD co-occurrence through integrative transcriptomic analysis, machine learning, summary-data-based Mendelian randomization (SMR), [...] Read more.

Familial hypercholesterolemia (FH) has been associated with an increased risk of major depressive disorder (MDD), but their shared molecular signatures remain unclear. This study aimed to identify candidate genes associated with FH-MDD co-occurrence through integrative transcriptomic analysis, machine learning, summary-data-based Mendelian randomization (SMR), and clinical validation. Transcriptomic datasets from the Gene Expression Omnibus were analyzed, including GSE6054 and GSE13985 for FH and GSE98793 for MDD. Differential expression analysis and weighted gene co-expression network analysis were used to identify shared candidate genes. Candidate biomarkers were screened using least absolute shrinkage and selection operator regression and Random Forest algorithms, followed by the construction of an exploratory nomogram. SMR analysis was performed to assess genetically supported associations between candidate-gene expression and MDD risk. Selected genes were validated by PBMC RT-qPCR in an independent four-group clinical cohort comprising healthy controls and participants with FH, MDD, or co-occurring FH and MDD. Flow cytometry was subsequently used to characterize the peripheral CD4+ T-cell profile. A total of 54 shared candidate genes were identified. CD4, MRPS21, and CRTC2 were selected by machine learning and incorporated into the nomogram, which showed good discrimination in the training set and moderate performance in external validation. Immune infiltration and enrichment analyses highlighted monocyte alterations, reduced T-cell-related signals, and enrichment of T-cell receptor and TNF-mediated pathways. SMR analysis indicated that genetically predicted higher CD4 expression was inversely associated with MDD risk, whereas RT-qPCR showed higher CD4 expression in patients with FH-MDD. Flow-cytometric analysis showed that FH-MDD participants had a higher circulating CD3+CD4+ T-cell proportion, an increased effector-memory CD4+ T-cell proportion, and a higher proportion of HLA-DR+ CD4+ T cells than participants in the comparison groups. These findings suggest that CD4 may represent a promising immune-related candidate signature associated with the co-occurrence of FH and MDD, warranting further functional validation. Full article

(This article belongs to the Section Molecular Neurobiology)

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30 pages, 4957 KB

Open AccessArticle

Preliminary Formulation-Dependent Angiogenesis-Related and Early Osteogenic Responses to Three-Dimensional Bioprinted Hydroxyapatite–Acrylated Palm Olein Scaffolds: An In Vitro Study

by Xi Chen, Nik Madihah Nik Azis, Syafira Masri and Masfueh Razali

Int. J. Mol. Sci. 2026, 27(17), 7531; https://doi.org/10.3390/ijms27177531 (registering DOI) - 22 Aug 2026

Abstract

Periodontal and alveolar bone regeneration requires coordinated angiogenic and osteogenic responses supported by biomimetic scaffolds. This study compared three-dimensional bioprinted hydroxyapatite–acrylated palm olein (3D-HA–APO) scaffold formulations containing 5%, 7% and 10% (w/v) hydroxyapatite (HA), designated F1, F2 and F3, [...] Read more.

Periodontal and alveolar bone regeneration requires coordinated angiogenic and osteogenic responses supported by biomimetic scaffolds. This study compared three-dimensional bioprinted hydroxyapatite–acrylated palm olein (3D-HA–APO) scaffold formulations containing 5%, 7% and 10% (w/v) hydroxyapatite (HA), designated F1, F2 and F3, respectively. Human umbilical vein endothelial cells were cultured on the scaffolds, and background-corrected soluble vascular endothelial growth factor (VEGF) concentrations in culture supernatants were quantified by enzyme-linked immunosorbent assay (ELISA). Angiogenic-related responses of human periodontal ligament stem cells were assessed by VEGF and cluster of differentiation 31 (CD31) immunofluorescence after endothelial induction, while alkaline phosphatase (ALP) activity in construct lysates was used as an indicator of early osteogenic activity. Soluble VEGF concentrations increased from F1 to F3, with significant differences between all formulations. VEGF-associated signal proportions differed among formulations, with F3 significantly higher than F1. CD31-associated signal proportions increased progressively from F1 to F3, with significant differences between all formulation pairs. ALP activity increased over time in all scaffold groups, and F3 generally showed the highest activity from Day 4 onwards. Overall, F3 showed the most favourable formulation-level profile across the selected angiogenic-related and early osteogenic outcomes. Full article

(This article belongs to the Special Issue Biological Materials: Molecular Mechanisms, Tissue Responses, and Translational Perspectives)

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18 pages, 11554 KB

Open AccessArticle

Plasma-Derived Extracellular Vesicle microRNAs in Multiple Sclerosis: An Exploratory Case-Control Study on Phenotypic Discrimination

by Oana Vrînceanu, Doina Manu, Smaranda Maier, Claudia Bănescu, Ana-Claudia Carstea and Rodica Bălașa

Int. J. Mol. Sci. 2026, 27(17), 7530; https://doi.org/10.3390/ijms27177530 (registering DOI) - 22 Aug 2026

Abstract

Distinguishing relapsing–remitting multiple sclerosis (RRMS) from secondary-progressive disease (SPMS) remains a clinical challenge, as no single laboratory test reliably identifies the transition. We explored whether plasma extracellular-vesicle (EV) microRNAs could separate the two phenotypes. Four candidate EV-miRNAs: miR-30a-5p, miR-223-5p, miR-155-5p, and miR-146a-5p, were [...] Read more.

Distinguishing relapsing–remitting multiple sclerosis (RRMS) from secondary-progressive disease (SPMS) remains a clinical challenge, as no single laboratory test reliably identifies the transition. We explored whether plasma extracellular-vesicle (EV) microRNAs could separate the two phenotypes. Four candidate EV-miRNAs: miR-30a-5p, miR-223-5p, miR-155-5p, and miR-146a-5p, were quantified by qRT-PCR in plasma-derived EVs from 13 healthy controls (HC), 7 RRMS, and 16 SPMS patients, normalized to miR-16-5p. EVs were characterized by electron microscopy, dynamic light scattering, and zeta potential, confirming vesicles of expected morphology, size, and negative surface charge. Two miRNAs were informative. miR-155-5p was significantly downregulated in both RRMS and SPMS versus controls but did not differentiate the phenotypes (AUC 0.52), behaving as a disease-general marker. In contrast, miR-223-5p was selectively reduced in SPMS, to approximately one-quarter of control abundance, and provided the only signal distinguishing progressive from relapsing disease (AUC 0.73; rank-biserial −0.46). miR-30a-5p and miR-146a-5p were uninformative. These findings, consistent with the circulating/EV literature, suggest EV-miR-223-5p as a candidate marker of the progressive phenotype and EV-miR-155-5p as a disease indicator. Given the small cohort and near-detection-limit measurements, the study is hypothesis-generating and requires validation in larger, longitudinal cohorts. Full article

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27 pages, 11965 KB

Open AccessArticle

Estradiol Ameliorates Postmenopausal Bladder Dysfunction by Restoring Mitophagy via the miRNA-200/KLF4/mTOR Signaling Pathway

by Kuang-Shun Chueh, Jian-He Lu, Jing-Wen Mao, Bin-Nan Wu, Cheng-Yu Long, Zhi-Feng Miao, Tai-Jui Juan, Rong-Jyh Lin, Shu-Mien Chuang, Mei-Chen Shen, Ting-Wei Sun, Mei-Chin Lu and Yung-Shun Juan

Int. J. Mol. Sci. 2026, 27(17), 7529; https://doi.org/10.3390/ijms27177529 (registering DOI) - 22 Aug 2026

Abstract

Postmenopausal ovarian hormone deficiency (OHD) contributes to overactive bladder (OAB) through oxidative stress, mitochondrial dysfunction, and dysregulated estrogen receptor (ER) signaling. This study investigated whether estradiol (E2) alleviates dysfunction by modulating the ER/Smad/miRNA-200/KLF4/mTOR signaling pathway to restore mitochondrial quality control. Thirty female Sprague-Dawley [...] Read more.

Postmenopausal ovarian hormone deficiency (OHD) contributes to overactive bladder (OAB) through oxidative stress, mitochondrial dysfunction, and dysregulated estrogen receptor (ER) signaling. This study investigated whether estradiol (E2) alleviates dysfunction by modulating the ER/Smad/miRNA-200/KLF4/mTOR signaling pathway to restore mitochondrial quality control. Thirty female Sprague-Dawley rats were initially allocated to Sham, Ovariectomy (OVX) and OVX + E2 group; after attrition during the 12-month protocol, six surviving animals per group were included in the principal analyses. The OVX + E2 group received daily intramuscular E2 (IM, 30 μg/kg/day) for one month. Bladder function was assessed via micturition volume and frequency by metabolic cages, cystometrograms, and contractility assays. Mechanisms were analyzed using immunofluorescence, Western blotting, transmission electron microscopy (TEM), and miRNA sequencing. OVX rats exhibited significant overactivity and compromised contractility, accompanied by upregulated ERα and downregulated ERβ/GPER. Molecularly, OHD was associated with the upregulation of the miRNA-200 family (miRNA-200a-3p, miRNA-200b-3p and miRNA-200b-5p), which was accompanied by reduced levels of KLF4 and autophagy proteins (ATG7, ATG12 and Beclin-1), as well as elevated p-mTOR expression. TEM revealed the accumulation of damaged mitochondria with ultrastructural features associated with impaired mitophagy. However, E2 treatment ameliorated these abnormalities. These improvements were associated with the restoration of TGF-β/Smad signaling, downregulation of selected miRNA-200 family members, recovery of KLF4 level, and increased expression of autophagy-related markers, accompanied by improved mitochondrial ultrastructural integrity. This cellular restoration might be correlated with improved urodynamic parameters. E2 might exert therapeutic effects by improving mitochondrial quality, potentially via the ER/Smad/miRNA-200/KLF4 signaling pathway. These findings provided mechanistic insights into estrogen-mediated protection and highlight this proposed signaling pathway as a therapeutic target for postmenopausal OAB. Full article

(This article belongs to the Special Issue Autophagy and Apoptosis in Mammal Cells)

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23 pages, 15391 KB

Open AccessArticle

Antibiofilm and Anti-Hyphal Activities of Halogenated Benzophenones Against Azole-Resistant Candida albicans

by Juyeon Jo, Ziyad Abdelaal, Yong-Guy Kim, Jin-Hyung Lee and Jintae Lee

Int. J. Mol. Sci. 2026, 27(17), 7528; https://doi.org/10.3390/ijms27177528 (registering DOI) - 22 Aug 2026

Abstract

Candida albicans biofilms are a major cause of persistent infections and contribute to antifungal resistance as well as limitations in drug delivery. Targeting virulence traits such as biofilm formation and hyphal transition represents an effective strategy for controlling fungal pathogenicity without exerting strong [...] Read more.

Candida albicans biofilms are a major cause of persistent infections and contribute to antifungal resistance as well as limitations in drug delivery. Targeting virulence traits such as biofilm formation and hyphal transition represents an effective strategy for controlling fungal pathogenicity without exerting strong selective pressure on planktonic growth. In this study, a library of structurally diverse benzophenone derivatives was screened to identify compounds with antibiofilm and anti-hyphal activities against azole-resistant C. albicans. Most benzophenone derivatives exhibited weak antifungal activity (MIC ≥ 200 µg/mL). However, several halogenated benzophenones markedly suppressed biofilm formation. Among them, decafluorobenzophenone at 10 µg/mL displayed the strongest inhibition, reducing biofilm formation to approximately 1–2% of control levels while maintaining substantial planktonic cell viability. Microscopy confirmed hyphal suppression, while qRT-PCR showed a 36-fold reduction in ALS3 expression. These findings indicate that multi-halogenated benzophenones act primarily as anti-virulence agents targeting biofilm formation and hyphal development. Molecular docking suggested a possible interaction of decafluorobenzophenone with the Als3 binding pocket. Decafluorobenzophenone showed low toxicity, with unaffected Caenorhabditis elegans viability at 10 µg/mL, plant germination at 100 µg/mL, and only slight hemolysis at 100 µg/mL. The results highlight halogen substitution as a key structural determinant and identify benzophenone scaffolds as promising leads for developing novel antibiofilm strategies against azole-resistant Candida infections. Full article

(This article belongs to the Special Issue Advances in Molecular Research on Candida Resistance)

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33 pages, 9825 KB

Open AccessReview

Exercise-Induced Skeletal Muscle Secretory Factors and Macrophage Functional Remodeling: Mechanistic Advances

by Ziyan Li, Chenyu Lin, Linjia Tang, Yiyao Xu, Jieming Liang, Dehui Pan, Ziran Huang, Xianyan Xie, Yu Wang, Shuqi Qin, Gaoyuan Yang, Xiaoguang Liu and Huiguo Wang

Int. J. Mol. Sci. 2026, 27(17), 7527; https://doi.org/10.3390/ijms27177527 (registering DOI) - 22 Aug 2026

Abstract

Regular exercise mediates inter-tissue communication between skeletal muscle and the immune system through skeletal muscle-derived secretory factors, providing an important molecular basis for the beneficial effects of exercise on chronic inflammation, metabolic dysregulation, and impaired tissue repair. As key effector cells of the [...] Read more.

Regular exercise mediates inter-tissue communication between skeletal muscle and the immune system through skeletal muscle-derived secretory factors, providing an important molecular basis for the beneficial effects of exercise on chronic inflammation, metabolic dysregulation, and impaired tissue repair. As key effector cells of the innate immune system, macrophages do not simply conform to a dichotomous classification of classically activated M1 macrophages and alternatively activated M2 macrophages; rather, their functional states constitute a dynamic spectrum shaped by exercise load, recovery time window, tissue microenvironment, and disease context. This review focuses on recent advances in exercise-induced skeletal muscle secretory factors involved in macrophage functional remodeling. Representative signals, including interleukin-6 (IL-6), irisin, meteorin-like protein (METRNL), fibroblast growth factor 21 (FGF21), oncostatin M (OSM), decorin, myostatin, chemokines, and extracellular vesicles, are systematically summarized in terms of their exercise responsiveness, evidence for skeletal muscle origin, and evidence supporting macrophage regulation. Based on these dimensions, an evidence-strength grading framework is further proposed. Moreover, this review integrates key signaling axes, including glycoprotein 130 (gp130)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT), signal transducer and activator of transcription 6 (STAT6)/peroxisome proliferator-activated receptor gamma (PPARγ), AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2)/nuclear factor kappa B (NF-κB), transforming growth factor beta (TGF-β)/Smad, and chemokine receptor pathways, to explain how exercise-induced secretory networks participate in the dynamic regulation of the macrophage functional spectrum through immune cell recruitment, inflammatory clearance, immunometabolic reprogramming, matrix remodeling, and repair-niche formation. Current evidence indicates the translational potential of exercise-induced skeletal muscle secretory factors in skeletal muscle repair, metabolic inflammation, aging-related functional decline, and cancer rehabilitation. However, this field still faces several major challenges, including insufficient tracing of skeletal muscle-derived signals, limited direct causal validation, a lack of human tissue-level evidence, and unclear exercise dose–response relationships. Future studies should combine tissue-specific genetic interventions, receptor blockade, single-cell and spatial omics, metabolic flux analysis, and standardized human exercise interventions to further clarify the mechanistic basis and application boundaries of exercise-induced skeletal muscle–macrophage communication, thereby providing a theoretical foundation for precision exercise prescription and chronic inflammation intervention. Full article

(This article belongs to the Section Molecular Endocrinology and Metabolism)

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72 pages, 9476 KB

Open AccessReview

Protease-Activated Receptor-2 as a Proteolytic Rheostat in Colorectal and Pancreatic Cancer: From Mechanism to Biomarker-Guided Therapy

by Hodasadat Tabatabaei Yeganeh, Malak Sellat, Zayd Anis, Reine Chiri, Rajashree Patnaik, Shloka Gambhir and Yajnavalka Banerjee

Int. J. Mol. Sci. 2026, 27(17), 7526; https://doi.org/10.3390/ijms27177526 (registering DOI) - 22 Aug 2026

Abstract

Protease-activated receptor-2 (PAR-2; encoded by F2RL1) is emerging as a context-dependent driver of gastrointestinal cancer. Activated by irreversible N-terminal cleavage, its signalling output is not fixed but is calibrated by the identity and source of the activating protease, the receptor cleavage state, [...] Read more.

Protease-activated receptor-2 (PAR-2; encoded by F2RL1) is emerging as a context-dependent driver of gastrointestinal cancer. Activated by irreversible N-terminal cleavage, its signalling output is not fixed but is calibrated by the identity and source of the activating protease, the receptor cleavage state, cellular context and biased coupling to G-protein αq (Gαq), G-protein α12/13 (Gα12/13) and β-arrestin. PAR-2 is best understood not as a simple inflammatory receptor but as a proteolytic rheostat that converts diverse coagulation, inflammatory, microbial and stromal protease inputs into distinct oncogenic programmes. Colorectal cancer and pancreatic ductal adenocarcinoma provide complementary models: in colorectal cancer, PAR-2 links mucosal inflammation and coagulation to proliferation, metastatic competence and resistance to epidermal growth factor receptor (EGFR)-targeted therapy, whereas in pancreatic cancer, it is embedded in a tissue-factor-rich desmoplastic microenvironment that promotes invasion, immune exclusion and chemoresistance. Therapeutic strategies suggested by this framework include direct and biased PAR-2 modulators, upstream protease and factor Xa (FXa) inhibition, statin repurposing and activated-fragment biomarkers such as the PAR-2 activation neoepitope (PRO-PAR2). These strategies must be applied under biomarker guidance, since PAR-2 blockade may benefit inflammation-dominant tumours yet prove counterproductive where PAR-2 sustains antitumour immunity. Full article

(This article belongs to the Special Issue Signaling Pathways Dysregulation in Cancer: Advances and New Therapeutics Hopes: 2nd Edition)

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23 pages, 3181 KB

Open AccessArticle

Silencing of Kinesin Light Chain 1 Suppresses Aggressive Phenotypes in Cholangiocarcinoma Cells Through Transcriptomic Alterations

by Thanakrit Rattanaarchanai, Phonprapavee Tantimetta, Phanthipha Runsaeng, Sompop Saeheng and Sumalee Obchoei

Int. J. Mol. Sci. 2026, 27(17), 7525; https://doi.org/10.3390/ijms27177525 (registering DOI) - 22 Aug 2026

Abstract

Cholangiocarcinoma (CCA) is an aggressive malignancy with limited treatment options and poor clinical outcomes. Kinesin light chain 1 (KLC1), a component of the kinesin-1 motor complex involved in intracellular transport, has been implicated in cancer biology; however, its role in CCA remains unclear. [...] Read more.

Cholangiocarcinoma (CCA) is an aggressive malignancy with limited treatment options and poor clinical outcomes. Kinesin light chain 1 (KLC1), a component of the kinesin-1 motor complex involved in intracellular transport, has been implicated in cancer biology; however, its role in CCA remains unclear. This study investigated the functional role and molecular alterations associated with KLC1 silencing in CCA. Analysis of publicly available datasets showed that KLC1 mRNA expression was significantly elevated in CCA tissues, and immunohistochemical images from the Human Protein Atlas demonstrated stronger KLC1 protein expression in tumor tissues. siRNA-mediated KLC1 knockdown markedly suppressed cell proliferation, migration, and invasion in KKU-213A and KKU-055 cells and altered the expression of epithelial–mesenchymal transition-associated proteins. Transcriptomic profiling identified 2074 differentially expressed genes following KLC1 knockdown. Functional enrichment analyses revealed significant alterations in cytoskeleton-associated processes and mitogen-activated protein kinase (MAPK) signaling. Protein–protein interaction network analysis identified interconnected gene networks associated with these pathways. Selected differentially expressed genes were validated by RT–qPCR, supporting the transcriptomic findings. Collectively, these results suggest that KLC1 contributes to aggressive phenotypes in CCA cells and is associated with transcriptomic alterations involving cytoskeletal regulation and MAPK signaling, highlighting KLC1 as a potential contributor to CCA progression and warranting further investigation. Full article

(This article belongs to the Section Molecular Oncology)

19 pages, 1943 KB

Open AccessArticle

Whole-Exome Sequencing Identifies Candidate Genomic Features Associated with Response to Platinum-Based Chemotherapy and Ixabepilone-Based Treatment in Ovarian Cancer

by Tobias M. P. Hartwich, Stefania Bellone, Orazio De Tommasi, Sarah Ottum, Victoria Ettorre, Michelle Greenman, Namrata Sethi, Cem Demirkiran, Kevin Y. Yang, Ammal Abbasi, Ludmil B. Alexandrov and Alessandro D. Santin

Int. J. Mol. Sci. 2026, 27(17), 7524; https://doi.org/10.3390/ijms27177524 (registering DOI) - 22 Aug 2026

Abstract

Carboplatin/paclitaxel (CP) chemotherapy is the cornerstone of therapy for advanced stage ovarian cancer (OC). However, despite initial sensitivity, this regimen cannot avoid the emergence of resistance. Ixabepilone ± bevacizumab (IB) is a combination recently added to NCCN guidelines for the treatment of platinum-resistant [...] Read more.

Carboplatin/paclitaxel (CP) chemotherapy is the cornerstone of therapy for advanced stage ovarian cancer (OC). However, despite initial sensitivity, this regimen cannot avoid the emergence of resistance. Ixabepilone ± bevacizumab (IB) is a combination recently added to NCCN guidelines for the treatment of platinum-resistant OC. It would be desirable to identify biomarkers able to differentiate patients who are resistant to CP and IB, and biomarkers that identify which patients may benefit from IB treatment. We analyzed whole-exome-sequencing (WES) data from 49 OC patients exposed to CP, including 28 platinum-sensitive vs. 21 platinum-resistant, and 31 additional platinum-resistant patients, including 16 responders (i.e., CR/PR) vs. 15 non-responders (SD/PD) to ixabepilone ± bevacizumab. Comprehensive genetic analyses were performed to identify alterations correlated with resistance to CP and IB. WES analysis of CP responders vs. non-responders revealed differences in HRD-signatures (p < 0.05), OS (p < 0.005) and gain/loss-of-function in multiple genes associated with tumor growth/progression including but not limited to ACVR2A, INHBA, MAP3K7, ATG5, SGK1, FYN, RSPO3, NOD1 and LRRK2. WES analysis of platinum-resistant IB-treated patients revealed additional nominally significant genes and deranged pathways including gains in the DROSHA and SDHA genes in responders vs. non-responders (p < 0.05). Patients harboring HRD-signatures showed significantly higher sensitivity to CP and prolonged survival compared to HRD-negative patients. Alterations in genes associated with tumor growth/progression correlated with resistance to CP regimen and may represent novel “druggable” candidate biomarkers for the targeted treatment of CP/IB-resistant patients. Further validation in independent cohorts and preclinical experiments in CP/IB-resistant models are warranted to establish the clinical utility of these findings. Full article

(This article belongs to the Special Issue Current Research for Ovarian Cancer Biology and Therapeutics (Second Edition))

18 pages, 1896 KB

Open AccessReview

The Gut–Ear Axis: From Dysbiosis to Auditory and Vestibular Disorders

by Yutian Li, Xinyu Shi, Xiaozhou Liu and Yu Sun

Int. J. Mol. Sci. 2026, 27(17), 7523; https://doi.org/10.3390/ijms27177523 (registering DOI) - 22 Aug 2026

Abstract

With further research on the relationship between gut microbiota and human health, discussions on various gut-X axis have been increasingly prevalent. Evidence indicates that microbiota dysbiosis is closely linked to the onset and progression of audiovestibular disorders and the gut-ear axis has gradually [...] Read more.

With further research on the relationship between gut microbiota and human health, discussions on various gut-X axis have been increasingly prevalent. Evidence indicates that microbiota dysbiosis is closely linked to the onset and progression of audiovestibular disorders and the gut-ear axis has gradually been recognized as a vital systemic regulatory pathway. This article systematically reviewed the interaction mechanisms between microbiota dysbiosis and audiovestibular diseases, intervention strategies, research limitations and future perspectives. This axis functions mainly through immune-mediated barrier damage, metabolic disorder and neurotransmitter crosstalk. Modulation of the gut microbiota can alleviate symptoms of certain audiovestibular disorders. This review aims to provide novel insights for the pathogenesis, intervention and clinical management of audiovestibular disorders. Full article

(This article belongs to the Special Issue Research in Nutritional Physiology and Gut Microbiome)

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19 pages, 15025 KB

Open AccessArticle

Dose-Dependent Alterations in Lung Immune Subpopulations in Influenza a Virus Infection

by Tatiana Betáková, Miriam Mladá, Karin Donátová and Jana Jakubíková

Int. J. Mol. Sci. 2026, 27(17), 7522; https://doi.org/10.3390/ijms27177522 (registering DOI) - 22 Aug 2026

Abstract

This study aimed to characterize the modulation in immune cell subpopulations in murine lungs following influenza A virus (IAV) infection, assessing the effects of infectious dose, viral adaptation, and NS1 expression. Immune cell subsets were profiled by surface receptor expression using multiparametric flow [...] Read more.

This study aimed to characterize the modulation in immune cell subpopulations in murine lungs following influenza A virus (IAV) infection, assessing the effects of infectious dose, viral adaptation, and NS1 expression. Immune cell subsets were profiled by surface receptor expression using multiparametric flow cytometry with a 10-antibody immunophenotyping panel. Neutrophils expressing Ly-6G were significantly increased in the lungs following lethal-dose infection with IAV, independently of NS1 expression; in contrast, lethal-dose infection with all viruses reduced CD163⁺ and F4/80⁺ neutrophil subpopulations. Lethal-dose infection increased pulmonary CD68⁺ macrophages while decreasing CD163⁺, CD193⁺, and F4/80⁺ macrophage subsets, as well as F4/80⁺ myeloid cells, by day 3 post-infection; these reductions were independent of NS1 expression and infectious dose. Following lethal-dose IAV infection, NK cells exhibited upregulation of IL-23R⁺ and IL-12Rβ2⁺ subsets, while the CD193⁺ NK subpopulation was decreased on day 3 post-infection. Profiling of NKT cells revealed an expansion of the IL-12Rβ2⁺ NKT subset on day 3 post-infection. Adaptive immune profiling of lung CD4⁺ T cells revealed a selective increase in Th1-like cells (IL-12Rβ2⁺ CD4⁺) after WSN infection, a marked reduction in Th2-like cells (CD193⁺ CD4⁺) following infection with IAV regardless of NS1 status or dose, and an expansion of CD4⁺NK1.1⁺ cells only after lethal-dose infection. Immune cell subset frequencies were comparable between infections with NS1-expressing and wild-type viruses; NS1 expression did not alter subset composition, whereas the infection dose modulated their abundance. These findings expand our understanding of the subpopulation of immune cells and their possible role in influenza virus pathogenesis. Full article

(This article belongs to the Special Issue Immune Response in Animals)

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43 pages, 1845 KB

Open AccessReview

Geroprotective Effects of Drugs Modulating Metabolic Pathways: Perspectives of Pharmacology in Anti-Aging Therapy

by Marta Grycan, Rafał Zyśk, Gabriela Grycan, Grzegorz Jakiel, Alicja Dudek and Grażyna Gromadzka

Int. J. Mol. Sci. 2026, 27(17), 7521; https://doi.org/10.3390/ijms27177521 (registering DOI) - 22 Aug 2026

Abstract

Aging is the strongest risk factor for chronic diseases such as cardiovascular diseases, cancer, diabetes, and neurodegenerative disorders. Advances in geroscience indicate that pharmacological modulation of conserved molecular pathways may extend healthspan and delay multimorbidity. A structured narrative review of the PubMed, Scopus, [...] Read more.

Aging is the strongest risk factor for chronic diseases such as cardiovascular diseases, cancer, diabetes, and neurodegenerative disorders. Advances in geroscience indicate that pharmacological modulation of conserved molecular pathways may extend healthspan and delay multimorbidity. A structured narrative review of the PubMed, Scopus, and Web of Science literature published between January 2010 and May 2026 was conducted, with seminal earlier studies retained where relevant. The review focused on molecular pathways implicated in aging, pharmacological interventions targeting these pathways, and their preclinical and clinical evaluation. Particular emphasis was placed on translational evidence, including human biomarker studies and randomized clinical trials, and on the distinction between biomarker modulation and clinically meaningful outcomes. Repurposed drugs such as metformin and rapamycin have among the most extensive preclinical and translational evidence, although clinical evidence for broadly applicable geroprotection remains limited. Statins, SGLT2 inhibitors, GLP-1 receptor agonists, and menopausal hormone therapy have established disease-specific or cardiometabolic benefits that may have indirect relevance to geroprotection, but direct effects on biological aging and healthspan remain unproven. Other candidates, including senolytics, NAD⁺ precursors, taurine, and epigenetic reprogramming approaches, are at different stages of translational development, with evidence ranging from promising preclinical findings to early human studies. Across interventions, a substantial gap remains between mechanistic plausibility and clinically validated geroprotection. Geroprotective pharmacology represents a promising but incompletely validated approach to extending healthspan. Major uncertainties include the absence of universally accepted biomarkers and clinical endpoints of biological aging, heterogeneity in treatment response, optimal timing and duration of interventions, and long-term safety. Future research should prioritize adequately powered randomized clinical trials integrating standardized measures of biological aging with clinically meaningful outcomes, alongside biomarker-guided patient selection, appropriate treatment timing, and careful assessment of long-term safety. The future of geroprotective medicine will depend not only on identifying additional pharmacological targets, but on demonstrating that their modulation produces durable and clinically meaningful benefits in humans. Full article

(This article belongs to the Section Molecular Pharmacology)

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24 pages, 6906 KB

Open AccessArticle

Infection with Tomato Mosaic Virus in Nicotiana tabacum cv. Samsun—Physiological and Molecular Approach During Early Stage of Infection

by Wojciech Makowski, Ingrida Mažeikienė, Łucja Kmita, Edvinas Misiukevičius, Damian Adamus, Barbara Tokarz, Marta Stafiniak, Barbara Nowak, Zbigniew Gajewski and Krzysztof M. Tokarz

Int. J. Mol. Sci. 2026, 27(17), 7520; https://doi.org/10.3390/ijms27177520 (registering DOI) - 22 Aug 2026

Abstract

Although tomato mosaic virus (ToMV) is an economically important tobamovirus, the physiological and molecular events occurring during the asymptomatic phase of infection remain poorly understood. In this study, we investigated the early responses of Nicotiana tabacum cv. Samsun to ToMV infection using an [...] Read more.

Although tomato mosaic virus (ToMV) is an economically important tobamovirus, the physiological and molecular events occurring during the asymptomatic phase of infection remain poorly understood. In this study, we investigated the early responses of Nicotiana tabacum cv. Samsun to ToMV infection using an integrated physiological, biochemical, photosynthetic, and molecular approach. Viral accumulation was quantified via RT-PCR. Oxidative stress markers, antioxidant systems, photosynthetic performance, and gene expression were analyzed at 7 days post inoculation (DPI), before visible symptoms developed. Although infected plants remained symptomless, ToMV was detected in 80% of inoculated plants. Early infection induced oxidative stress, evidenced by increased malondialdehyde content, reduced free amino acid levels, and enhanced activities of superoxide dismutase and peroxidase. Total glutathione, phenolic compounds, and phenylpropanoids remained unchanged, whereas flavonoid content decreased significantly. ToMV infection also impaired the photosynthetic apparatus, resulting in reduced chlorophyll and carotenoid contents, decreased electron transport efficiency, and increased energy dissipation within photosystem II. Gene expression analysis revealed significant upregulation of defense- and stress-related genes (WRKY1, HSP70, GR, and DHAR), as well as chloroplast-associated genes (psaA and rbcL). Correlation analyses demonstrated coordinated relationships among viral accumulation, oxidative stress, antioxidant responses, and photosynthetic performance. These findings provide new insights into the asymptomatic phase of ToMV infection and identify potential early markers of host responses to viral infection. Full article

(This article belongs to the Special Issue Developing Methods and Molecular Basis in Plant Biotechnology: 2nd Edition)

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