International Journal of Molecular Sciences

24 pages, 801 KB

Open AccessReview

Olfactory-Cleft Biopsy in Alzheimer’s Disease: An Emerging Neuroimmune Window into Preclinical Pathobiology

by James Chmiel and Aleksandra Kładna

Int. J. Mol. Sci. 2026, 27(18), 8043; https://doi.org/10.3390/ijms27188043 (registering DOI) - 10 Sep 2026

Olfactory dysfunction is an early non-cognitive feature of Alzheimer’s disease (AD), but smell impairment has traditionally been used mainly as a behavioral marker. This review examines the emerging use of the olfactory cleft as an accessible source of living neuronal, epithelial, progenitor, and [...] Read more.

Olfactory dysfunction is an early non-cognitive feature of Alzheimer’s disease (AD), but smell impairment has traditionally been used mainly as a behavioral marker. This review examines the emerging use of the olfactory cleft as an accessible source of living neuronal, epithelial, progenitor, and immune cells for studying AD pathobiology. Histopathological and patient-derived culture studies have reported amyloid-β, tau, oxidative-stress, mitochondrial, biometal, and transcriptional abnormalities in olfactory tissue. More recent endoscopically guided brush sampling with single-cell profiling has identified activated memory CD8 T-cell states, inflammatory myeloid programs, and neuronal metabolic changes, including in cognitively unimpaired individuals with abnormal cerebrospinal-fluid amyloid biomarkers. These findings support olfactory-cleft sampling as a research platform for investigating early neural–immune changes, but current evidence is based on small, largely cross-sectional cohorts and does not establish disease specificity, causality, or prognostic utility. Longitudinal multicenter studies integrating olfactory-tissue profiling with established fluid, imaging, genetic, cognitive, and olfactory biomarkers are required before clinical translation. Full article

(This article belongs to the Special Issue Advances in Olfactory Neurobiology, Adult Neurogenesis and Dopaminergic Neuron Research)

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16 pages, 14875 KB

Open AccessArticle

Spatio-Temporal Expression Patterns of Connexins 43 and 30 in Hippocampal Astrocytes During Postnatal Development

by Alejandro Uribe-Arias, Jérôme Ribot, Pascal Ezan, Philippe Mailly and Nathalie Rouach

Int. J. Mol. Sci. 2026, 27(18), 8042; https://doi.org/10.3390/ijms27188042 - 9 Sep 2026

Abstract

Astrocytes are extensively interconnected via gap junction channels formed primarily by connexin 43 (Cx43) and connexin 30 (Cx30), two proteins that play central roles in intercellular signaling and homeostatic regulation in the brain. Although the functional properties of these connexins have been widely [...] Read more.

Astrocytes are extensively interconnected via gap junction channels formed primarily by connexin 43 (Cx43) and connexin 30 (Cx30), two proteins that play central roles in intercellular signaling and homeostatic regulation in the brain. Although the functional properties of these connexins have been widely investigated, their spatial organization within astrocytes and its evolution during postnatal development remain poorly characterized. Here, we combined confocal and stimulated emission depletion (STED) super-resolution microscopy to examine the expression, distribution and colocalization of Cx43 and Cx30 immunoreactive puncta in hippocampal astrocytes from postnatal day 15 to adulthood. Quantitative analyses revealed a progressive increase in the number of both Cx43 and Cx30 puncta during development, whereas puncta size remained largely unchanged. Although connexin puncta appeared more distally distributed in mature astrocytes, this shift was fully accounted for by the growth of astrocytes during development. In addition, colocalization between Cx43 and Cx30 increased during maturation, reaching a stable level after postnatal day 30. Finally, STED super-resolution imaging revealed a diversity of connexin arrangements, including isolated puncta as well as complex assemblies composed of multiple neighboring connexin clusters. Together, these findings provide a quantitative characterization of the developmental remodeling of astroglial connexins and identify structural features that may contribute to the maturation of astrocytic networks. Full article

(This article belongs to the Special Issue Membrane Channels in Intercellular Communication)

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19 pages, 1674 KB

Open AccessArticle

Multivariate Genome-Wide Association Analysis Identifies Genetic Susceptibility Loci for Metabolic Syndrome in the Korean Genome and Epidemiology Study

by Dasom Kim, Junho Cha and Sungkyoung Choi

Int. J. Mol. Sci. 2026, 27(18), 8041; https://doi.org/10.3390/ijms27188041 - 9 Sep 2026

Abstract

Metabolic syndrome (MetS), characterized by a cluster of interrelated metabolic abnormalities including central obesity, elevated blood pressure, dysglycemia, hypertriglyceridemia, and reduced high-density lipoprotein cholesterol (HDL-C), substantially increases type 2 diabetes and cardiovascular disease risk. Conventional genome-wide association studies (GWASs) analyze individual traits or [...] Read more.

Metabolic syndrome (MetS), characterized by a cluster of interrelated metabolic abnormalities including central obesity, elevated blood pressure, dysglycemia, hypertriglyceridemia, and reduced high-density lipoprotein cholesterol (HDL-C), substantially increases type 2 diabetes and cardiovascular disease risk. Conventional genome-wide association studies (GWASs) analyze individual traits or a dichotomized MetS status, only partially capturing its heritability and potentially overlooking variants with shared (pleiotropic) effects across correlated traits. Here, we performed a multiple-trait GWAS using data from the Korean Genome and Epidemiology Study. Using the Korea Biobank Array (K-Chip), we analyzed a discovery cohort from the Ansan and Ansung studies (1490 cases and 3856 controls) and validated the findings in CAVAS (3620 cases and 4461 controls) and HEXA (15,257 cases and 41,807 controls) cohorts. We jointly modeled six MetS-related traits using the complementary multivariate frameworks Multiple Phenotype Association Tests and Genome-wide Efficient Mixed Model Association, alongside a baseline logistic regression. Whereas logistic regression detected 2 APOA5 variants (rs662799 and rs2075291), the multivariate analyses identified 79 significant single-nucleotide polymorphisms; all were replicated in the HEXA cohort. Functional annotation prioritized 27 high-risk variants mapping to 12 genes, whereas pathway analysis (DAVID) implicated eight Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways related to lipid metabolism. Our findings demonstrate that multivariate analysis substantially improves the identification of pleiotropic susceptibility loci for MetS in the Korean population and indicates candidate genes for early detection and management. Full article

(This article belongs to the Special Issue Genomics of Human Disease)

19 pages, 1313 KB

Open AccessArticle

Inflammasome Dynamics in the High-Risk Clone ST235 with Altered Pyoverdine Structures

by Zeynep Gülçe Tanyolaç

Int. J. Mol. Sci. 2026, 27(18), 8040; https://doi.org/10.3390/ijms27188040 - 9 Sep 2026

Abstract

Pseudomonas aeruginosa ST235 isolates drive a distinct macrophage inflammatory program characterized by IL-1β axis dominance and suppression of canonical NF-κB-associated cytokine responses. In THP-1-derived macrophages, ST235 isolates induce robust inflammasome activation, resulting in elevated IL-1β production and altered cell death responses, while eliciting [...] Read more.

Pseudomonas aeruginosa ST235 isolates drive a distinct macrophage inflammatory program characterized by IL-1β axis dominance and suppression of canonical NF-κB-associated cytokine responses. In THP-1-derived macrophages, ST235 isolates induce robust inflammasome activation, resulting in elevated IL-1β production and altered cell death responses, while eliciting markedly lower TNFα, IL-6, IL-8, and IL-10 responses than non-ST235 isolates. In contrast, nonST235 isolates preferentially stimulate NF-κB-dependent cytokine production with weaker inflammasome activation. Mechanistically, ST235 infection suppresses NF-κB signaling and reduces caspase-1 expression, whereas caspase-8 remains unchanged, indicating that increased IL-1β production can be due to alternative inflammasome pathways or posttranscriptional modifications. Rapid macrophage death further restricts overall cytokine production, reinforcing an IL-1β-dominant inflammatory profile. ST235 isolates also selectively reprogram M2-polarized macrophages toward an M1 phenotype, as demonstrated by increased CD86 expression, while both isolate groups promote M1 polarization in unpolarized macrophages. Importantly, pyoverdine purified from ST235 isolates reproduced aspects of these responses by inducing IL-1β production and cytotoxicity more effectively than pyoverdine from non-ST235 isolates, supporting a potential contribution of ST235-derived pyoverdine to the IL-1β-dominant inflammatory phenotype. Collectively, these findings suggest that ST235 isolates modulate macrophage immune responses through suppression of NF-κB-associated responses and promotion of IL-1β-dominant inflammation, providing insights into the virulence of this high-risk clone and highlighting potential therapeutic targets. Significant statement: ST235 isolates of P. aeruginosa uniquely modulate macrophage immune responses by robustly activating inflammasome signaling, inducing IL-1β expression while suppressing other cytokines, and driving macrophage polarization toward a pro-inflammatory M1 phenotype. These findings highlight distinct pathogenic strategies of ST235 isolates that may inform targeted therapeutic interventions. Full article

(This article belongs to the Special Issue Advances in Inflammasomes)

18 pages, 2544 KB

Open AccessArticle

Diet-Dependent Effects of Intracerebroventricular Maresin-1 on Hypothalamus of Rats

by Cihan Suleyman Erdogan, Irem Solmaz, Cansu Yakin, Fatma Ozge Tuncel, Tuba Keskin, Suat Tekin, Suleyman Sandal and Bayram Yilmaz

Int. J. Mol. Sci. 2026, 27(18), 8039; https://doi.org/10.3390/ijms27188039 - 9 Sep 2026

Abstract

Obesity is associated with hypothalamic dysfunction, including altered arcuate nucleus (ARC) signaling-related impairment of energy homeostasis. However, the central metabolic effects of the specialized pro-resolving mediator Maresin-1 (Mar1) remain unclear. This study investigated whether central Mar1 administration alters ARC agouti-related peptide (AgRP), proopiomelanocortin [...] Read more.

Obesity is associated with hypothalamic dysfunction, including altered arcuate nucleus (ARC) signaling-related impairment of energy homeostasis. However, the central metabolic effects of the specialized pro-resolving mediator Maresin-1 (Mar1) remain unclear. This study investigated whether central Mar1 administration alters ARC agouti-related peptide (AgRP), proopiomelanocortin (POMC), and metabolic hormone profiles in rats under standard diet (STD) and high-fat diet (HFD) conditions. Male Wistar albino rats were fed either an STD or an HFD for 12 weeks and assigned to untreated control, vehicle, 50 ng/kg/day Mar1, or 100 ng/kg/day Mar1 groups within each diet condition. Mar1 was administered by continuous intracerebroventricular infusion for 7 days. Body weight, food intake, serum insulin, leptin, ghrelin levels, and ARC AgRP and POMC expressions were evaluated. Central Mar1 infusion did not alter body weight or food intake. In STD-fed rats, 100 ng Mar1 significantly increased serum insulin compared to control (p = 0.025), both Mar1 doses significantly increased leptin versus control (p = 0.0003 and p = 0.0091, respectively), and 50 ng Mar1 significantly increased ghrelin compared with control and vehicle groups (p = 0.0016 and p = 0.0055, respectively). In HFD-fed rats, Mar1 did not significantly change serum hormone levels, and the difference in ghrelin between the 50 ng Mar1 and vehicle groups did not reach statistical significance (p = 0.051). Mar1 did not alter AgRP expression in the ARC under either diet condition. However, under HFD, 100 ng Mar1 increased POMC expression relative to control, vehicle, and 50 ng Mar1 groups (p = 0.0076, p = 0.0078 and p = 0.0204, respectively). Central Mar1 infusion therefore altered circulating metabolic hormones with no significant diet x treatment interaction, and increased ARC POMC expression under HFD, an effect supported by a significant diet x treatment interaction (p = 0.0091), without changing energy intake or body weight over the 7-day infusion. These findings indicate a diet-dependent modulation of hypothalamic melanocortin tone rather than a significant effect on energy balance. Full article

(This article belongs to the Section Molecular Neurobiology)

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13 pages, 655 KB

Open AccessBrief Report

Targeted 3.34-Million CpG Site Sequencing Reveals Preliminary Cord Blood Epigenetic Alterations of Autism Spectrum Disorder: A Pilot Study Highlighting the PCDHA1–PCDHA8 Cluster

by Marina Armas-González, Nieves Luisa González-González, Enrique González-Dávila, Olivia Orribo-Morales, José Ramón Castro-Conde, Candelaria González-Campos, Carlos Flores, José Miguel Lorenzo-Salazar, Rafaela González-Montelongo, Adrián Muñoz-Barrera, Erika Padrón-Pérez, Laura Tascón-Padrón and María Núñez Catalán

Int. J. Mol. Sci. 2026, 27(18), 8038; https://doi.org/10.3390/ijms27188038 - 9 Sep 2026

Abstract

Rising reported Autism Spectrum Disorder (ASD) prevalence underscores the need to explore early perinatal biological markers. To conduct an exploratory pilot investigation of cord blood DNA methylation patterns as potential early epigenetic candidate loci associated with ASD in infants born to mothers with [...] Read more.

Rising reported Autism Spectrum Disorder (ASD) prevalence underscores the need to explore early perinatal biological markers. To conduct an exploratory pilot investigation of cord blood DNA methylation patterns as potential early epigenetic candidate loci associated with ASD in infants born to mothers with obesity and gestational diabetes. This prospective pilot study analyzed 14 mother-infant pairs comprising infants born to mothers with obesity and gestational diabetes later diagnosed with ASD (n = 2); healthy infants born to mothers with obesity and diabetes (IODM, n = 6); and healthy controls (IHM, n = 6). Targeted methyl-capture sequencing (covering 3.34 million CpG sites) identified differentially methylated region (DMR)-associated genes. Neurodevelopment was evaluated at 24–26 months using Bayley-III scales. ASD infants showed lower Bayley-III scores across all domains. In this small cohort (n = 2 ASD cases), we identified 249 DMR-associated genes common to both ASD vs. IHM and ASD vs. IODM comparisons, representing preliminary candidate loci. Enrichment analysis identified homophilic cell–cell adhesion as the most significant pathway (fold enrichment = 8.28; FDR = 6.31 × 10⁻⁶), driven by the PCDH1–PCDHA8 cluster, alongside morphogenesis in neuron differentiation (fold enrichment = 3.45; FDR = 2.08 × 10⁻²). Although prospective validation in larger independent cohorts is required, these pilot results suggest that cord blood PCDHA1–PCDHA8 cluster methylation alterations represent preliminary candidate loci for hypothesis generation and future biomarker evaluation, regardless of maternal metabolic status. Full article

(This article belongs to the Special Issue Advances in Epigenetics of Mental Disorders)

29 pages, 27687 KB

Open AccessArticle

Docosahexaenoic Acid Enhances the Cytotoxic Effects of Enzalutamide and the PARP Inhibitor in Castration-Resistant Prostate Cancer Cell Lines

by Alana Della Torre da Silva, Laurielle do Prado Ferreira, Daniele Lisboa Ribeiro, Guilherme Henrique Tamarindo and Rejane Maira Góes

Int. J. Mol. Sci. 2026, 27(18), 8037; https://doi.org/10.3390/ijms27188037 - 9 Sep 2026

Abstract

Docosahexaenoic acid (DHA), an omega-3 fatty acid, has emerged as a promising adjuvant treatment for castration-resistant prostate cancer (CRPC), but its interactions with current therapies remain unclear. This study investigated the antitumor effects of DHA alone or in combination with enzalutamide (ENZ) or [...] Read more.

Docosahexaenoic acid (DHA), an omega-3 fatty acid, has emerged as a promising adjuvant treatment for castration-resistant prostate cancer (CRPC), but its interactions with current therapies remain unclear. This study investigated the antitumor effects of DHA alone or in combination with enzalutamide (ENZ) or the PARP inhibitor AZD2461 (iP) in CRPC cell lines 22Rv1 and PC3. DHA enhanced the cytotoxic effect of iP in both cell lines and of ENZ in 22Rv1 cells. In PC3 cells, DHA-mediated potentiation of iP cytotoxicity was associated with downregulation of the AKT pathway, reduced expression of ERα and the lipid sensors PPARγ and LXRβ, and a shift in programmed cell death toward necroptosis. In 22Rv1 cells, the additive effects of DHA with ENZ or iP were independent of PI3K/pAKT and AR-FL/AR-V7 modulation but were associated with regulation of LXRβ, PPARγ, and TNFR1, along with activation of apoptosis. Wound-healing assays showed that DHA blocked the anti-migratory effects of ENZ and iP in 22Rv1 cells and did not alter iP effects in PC3 cells, indicating epithelial–mesenchymal transition heterogeneity. Overall, DHA potentiates the cytotoxic effects of iP in both models and of ENZ in 22Rv1 cells via differential modulation of cell death in a molecular context-dependent manner. Full article

(This article belongs to the Special Issue Latest Molecular Advances in Prostate Cancer)

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30 pages, 1440 KB

Open AccessReview

GLP-1 Receptor Agonists in Epilepsy: Separating Evidence for Antiseizure Activity, Neuroprotection, and Disease Modification

by Yuliy A. Gorgul and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2026, 27(18), 8036; https://doi.org/10.3390/ijms27188036 - 9 Sep 2026

Abstract

GLP-1 receptor (GLP-1R) agonists are increasingly investigated in epilepsy, but antiseizure activity, neuroprotection, and disease modification are distinct therapeutic claims. This critical narrative review with structured evidence mapping separates these claims across 21 preclinical primary publications and eight human studies identified through 6 [...] Read more.

GLP-1 receptor (GLP-1R) agonists are increasingly investigated in epilepsy, but antiseizure activity, neuroprotection, and disease modification are distinct therapeutic claims. This critical narrative review with structured evidence mapping separates these claims across 21 preclinical primary publications and eight human studies identified through 6 August 2026. Selected GLP-1R-related interventions show antiseizure and anti-kindling signals, but effects vary across compounds, models, treatment timing, and seizure types; null and pro-seizure findings in absence epilepsy preclude a uniform class-wide antiseizure effect, and concurrent anti-kindling does not establish antiepileptogenesis. Neuroprotective evidence is broader, although direct neuronal or tissue preservation is demonstrated only in selected studies; many findings remain biomarker-based, and seizure reduction may itself lessen downstream injury. Evidence for durable disease modification remains suggestive rather than established. Causal support is strongest at the receptor level, whereas most downstream synaptic, inflammatory, glial, oxidative, and mitochondrial evidence remains associative. Semaglutide has high translational relevance but remains directly under-tested in epilepsy, and human evidence is predominantly observational or safety-oriented and does not establish therapeutic epilepsy efficacy. Progress requires chronic epilepsy studies with longitudinal EEG/video-EEG and baseline seizure burden, post-insult designs controlling initial-insult severity and assessing persistence after withdrawal, and linked pharmacokinetic, target-engagement, and causal mechanistic testing. Full article

(This article belongs to the Special Issue Targeting Epilepsy: Molecular Mechanisms, Neuroinflammation and Emerging Therapies)

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48 pages, 2136 KB

Open AccessReview

Antimicrobial Peptides for Diabetic Foot Ulcers and Infections: Current Evidence and Translational Perspectives

by Victoria Alexandrovna Khotina, Arthur Anatolievich Lee, Dmitry Alexandrovich Kashirskikh, Olesya Olegovna Klychkova, Vitalia Sergeevna Novikova, Margarita Pavlovna Markina, Olga Evgenevna Voronko and Vagif Ali oglu Gasanov

Int. J. Mol. Sci. 2026, 27(18), 8035; https://doi.org/10.3390/ijms27188035 - 9 Sep 2026

Abstract

Diabetic foot ulcers (DFU) are among the most severe complications of diabetes, resulting from a combination of metabolic dysregulation, vascular insufficiency, neuropathy, chronic inflammation, and impaired tissue repair, whereas diabetic foot infection (DFI) may develop within this compromised wound environment and frequently involves [...] Read more.

Diabetic foot ulcers (DFU) are among the most severe complications of diabetes, resulting from a combination of metabolic dysregulation, vascular insufficiency, neuropathy, chronic inflammation, and impaired tissue repair, whereas diabetic foot infection (DFI) may develop within this compromised wound environment and frequently involves polymicrobial communities and biofilms. This review evaluates the mechanistic and translational basis for the use of antimicrobial peptides (AMP) in DFU and DFI, with emphasis on the diabetic wound microenvironment, polymicrobial ecology, endogenous AMP dysregulation, mechanisms of action, therapeutic development, and barriers to clinical translation. Hyperglycemia, ischemia, oxidative and proteolytic stress, and impaired innate immunity sustain inflammation, delay tissue repair, and promote microbial persistence. These conditions may also complicate antibiotic treatment through impaired tissue exposure and biofilm-associated tolerance. Depending on the peptide and experimental context, AMP may provide direct antimicrobial or antibiofilm activity and may also exert immunomodulatory or pro-reparative effects involving inflammatory signaling, angiogenesis, keratinocyte and fibroblast migration, and re-epithelialization. Approaches under investigation include engineered peptides, combination regimens, and local biomaterial-based platforms, including hydrogels, dressings, scaffolds, and nanoparticle-conjugated systems. Clinical translation remains constrained by proteolytic instability, potential host-tissue toxicity, limited selectivity, limited predictive value of preclinical models, heterogeneous clinical populations, nonstandardized endpoints, and manufacturing and regulatory requirements. Preclinical evidence supports further evaluation of approaches for local delivery of AMP, whereas clinical evidence in DFU and DFI remains limited and heterogeneous, with no AMP-based intervention yet demonstrating sufficiently consistent clinical benefit to support routine use. Full article

(This article belongs to the Special Issue Antimicrobial and Antiviral Peptides: 2nd Edition)

22 pages, 1261 KB

Open AccessArticle

Hypoxic Exercise Alleviates Diabetic Skeletal Myopathy in Zebrafish in Association with Hif1a/Foxo3a Signaling and Mitochondrial Quality Control

by Haoming Li, Zhanglin Chen, Qinghua Deng, Yunyi Zou, Shuaiwang Huang, Bihan Wang, Yelin Zeng, Lan Zheng, Changfa Tang, Zuoqiong Zhou, Yishan Chen and Xiyang Peng

Int. J. Mol. Sci. 2026, 27(18), 8034; https://doi.org/10.3390/ijms27188034 - 9 Sep 2026

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by skeletal muscle insulin resistance, which contributes to systemic metabolic dysregulation and diabetic myopathy (DM), a complication involving the loss of muscle mass and contractile function. Although hypoxic exercise has demonstrated metabolic benefits in chronic diseases, [...] Read more.

Type 2 diabetes mellitus (T2DM) is characterized by skeletal muscle insulin resistance, which contributes to systemic metabolic dysregulation and diabetic myopathy (DM), a complication involving the loss of muscle mass and contractile function. Although hypoxic exercise has demonstrated metabolic benefits in chronic diseases, its efficacy against DM remains unclear. We hypothesized that hypoxic exercise would be more effective than normoxic exercise in ameliorating diabetic myopathy-associated skeletal muscle abnormalities. Accordingly, adult zebrafish underwent an 8-week high-glucose intervention combining high-glucose feeding and glucose immersion to establish a T2DM-associated diabetic myopathy model and were subsequently subjected to 5 weeks of normoxic or hypoxic exercise (28.8 cm/s, corresponding to 70% of critical swimming speed (Ucrit) determined under normoxic conditions, 2 h/day, 5 days/week) to compare their effects on skeletal muscle outcomes. Hypoxic exercise produced greater improvements in glucose tolerance and locomotor performance than normoxic exercise, while the effects on skeletal muscle morphological and atrophy-related indices varied across outcomes. Both normoxic exercise and intermittent hypoxic exposure altered the abundance of mitochondrial quality-control-related proteins in the skeletal muscle of zebrafish with diabetic myopathy, whereas hypoxic exercise produced more pronounced changes in several of these proteins. Moreover, hypoxic exercise more markedly increased the abundance of mitochondrial respiratory-chain proteins than aerobic exercise or intermittent hypoxic exposure alone. Marked reactive oxygen species (ROS) accumulation was observed in the skeletal muscle of zebrafish with diabetic myopathy. Both aerobic and hypoxic exercise effectively reduced excessive ROS production, with hypoxic exercise producing the greater effect. Analysis of Foxo3a and its phosphorylation showed that p-Foxo3a expression decreased most prominently in the T2DM hypoxia exercise (DHE) group, indicating that hypoxic exercise is associated with modulation of Hif1a/Foxo3a-related signaling. Hypoxic exercise was associated with greater Hif1a protein abundance and lower Foxo3a Ser253 phosphorylation than normoxic exercise, accompanied by improved mitochondrial quality control and reduced ROS accumulation. In conclusion, hypoxic exercise ameliorated diabetic skeletal myopathy and was accompanied by modulation of Hif1a/Foxo3a-related signaling, more favorable mitochondrial morphology, altered abundance of mitochondrial quality-control-related and respiratory-chain proteins, and reduced dihydroethidium-detectable oxidative signals. Full article

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

16 pages, 4023 KB

Open AccessArticle

Ribitoborate Synergism with Histone Deacetylase Inhibitor Romidepsin as a Potential Treatment for Breast Cancer

by Ravi Doddapaneni, Jason D. Tucker, Jian Zhang, Pei J. Lu and Qi L. Lu

Int. J. Mol. Sci. 2026, 27(18), 8033; https://doi.org/10.3390/ijms27188033 - 9 Sep 2026

Abstract

Triple-negative breast cancer (TNBC) is a subtype associated with poor prognosis and low survival rates, largely due to limited treatment options. In recent years, histone deacetylase (HDAC) inhibitors have emerged as promising anti-cancer candidates due to their attractive epigenetic properties and distinct mechanisms [...] Read more.

Triple-negative breast cancer (TNBC) is a subtype associated with poor prognosis and low survival rates, largely due to limited treatment options. In recent years, histone deacetylase (HDAC) inhibitors have emerged as promising anti-cancer candidates due to their attractive epigenetic properties and distinct mechanisms of action but have shown limited success in solid tumors. Here, we explore ribitoborate along with HDAC inhibitors for potential use as a treatment for TNBC. Experiments were performed on the TNBC cell line MDA-MB-231. The results of the study revealed that ribitoborate and romidepsin showed synergistic responses leading to significant arrest of cell proliferation (80%) (p < 0.01) as well as migration inhibition. These effects were associated with downregulation of c-Myc, survivin, Bcl-2, and cyclin D1, as well as upregulation of p53 and p21 proteins; notably the changes were significantly greater with the combined treatment than with either ribitoborate or romidepsin alone. Romidepsin and ribitoborate combined treatment time-dependently increased cell death of MDA-MB-231 cells with greater efficiency than romidepsin alone. Cell death by apoptosis was supported by the upregulation of H3k9 and H3k27 acetylation with decreasing proliferation. These results suggest the great potential of the drug combination for treatment of TNBC. The underlying molecular mechanisms for synergy could be further explored for potential development of new combined therapy for breast cancer. Full article

(This article belongs to the Special Issue Natural Products and Compounds in Anticancer Drug Discovery)

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14 pages, 15057 KB

Open AccessArticle

The Therapeutic Aryl Hydrocarbon Receptor-Modulating Agent Tapinarof Restores Skin Barrier Dysfunction in a Mite Antigen-Induced Murine Model of Atopic Dermatitis

by Gaku Tsuji, Masaki Takemura, Koji Kawamura, Ayako Yumine, Noriko Konishi and Takeshi Nakahara

Int. J. Mol. Sci. 2026, 27(18), 8032; https://doi.org/10.3390/ijms27188032 - 9 Sep 2026

Abstract

Atopic dermatitis (AD) is characterized by pruritus and epidermal barrier dysfunction. Tapinarof, a therapeutic aryl hydrocarbon receptor (AHR)-modulating agent, is clinically effective in AD, but its mechanisms in allergen-driven models remain unclear. We evaluated tapinarof in a Dermatophagoides farinae (Df)-induced murine model of [...] Read more.

Atopic dermatitis (AD) is characterized by pruritus and epidermal barrier dysfunction. Tapinarof, a therapeutic aryl hydrocarbon receptor (AHR)-modulating agent, is clinically effective in AD, but its mechanisms in allergen-driven models remain unclear. We evaluated tapinarof in a Dermatophagoides farinae (Df)-induced murine model of AD, focusing on AHR-mediated barrier restoration. AD-like dermatitis was induced in female NC/Nga mice, followed by daily topical tapinarof or betamethasone for four days. Disease severity, transepidermal water loss (TEWL), histopathology, and gene/protein expression were assessed. Tapinarof significantly reduced dermatitis scores and TEWL and, unlike betamethasone, preserved epidermal architecture without suppressing ear swelling. Tapinarof upregulated the AHR-responsive genes Cyp1a1 and Nqo1 and induced Ovol1, an epidermal differentiation-associated transcription factor, with increased CYP1A1, NRF2, NQO1, and OVOL1 protein expression. Tapinarof markedly increased filaggrin (FLG)- and loricrin (LOR)-positive areas in lesional skin compared with vehicle (FLG: 11.3% vs. 3.1%; LOR: 18.9% vs. 3.9%; both p < 0.05), restoring FLG to a level comparable to the no-treatment control, while LOR significantly exceeded it. These findings indicate that tapinarof may restore skin barrier function in allergen-induced AD via AHR-NRF2 and AHR-OVOL1 signaling, supporting its potential as a steroid-sparing topical therapy for long-term AD management. Full article

(This article belongs to the Section Molecular Pharmacology)

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20 pages, 4424 KB

Open AccessArticle

Predicted STAT1-BRAF and IRF7-MET Regulatory Links Are Associated with MAPK Pathway Reactivation and Targeted Therapy Resistance in Melanoma

by Hao Fu, Mengyao Wang, Haibo Zhu, Weihua Li, Xiaopei Shen, Haidan Yan and Jun He

Int. J. Mol. Sci. 2026, 27(18), 8031; https://doi.org/10.3390/ijms27188031 - 9 Sep 2026

Abstract

Resistance to BRAF inhibitors (BRAFi), alone or with MEK inhibitors (MEKi), limits durable responses in BRAF-mutant melanoma. To characterize resistance-associated cell-state evolution, we analyzed 674 melanoma cells from six mice bearing tumors from a single patient-derived BRAF V600E-mutant melanoma xenograft (PDX) lineage [...] Read more.

Resistance to BRAF inhibitors (BRAFi), alone or with MEK inhibitors (MEKi), limits durable responses in BRAF-mutant melanoma. To characterize resistance-associated cell-state evolution, we analyzed 674 melanoma cells from six mice bearing tumors from a single patient-derived BRAF V600E-mutant melanoma xenograft (PDX) lineage before treatment, during initial regression, at minimal residual disease, and at resistant regrowth. Unsupervised clustering based on a BRAF-centered network feature set comprising 2506 candidate genes identified six transcriptional states, which were characterized using transcriptomic analyses. Cluster 4 was detected exclusively at resistant regrowth, a phase marked by MAPK pathway reactivation, and exhibited enhanced JAK-STAT/interferon signaling and increased STAT1, STAT2, IRF7, IRF9, and RELB regulon activities. Network inference predicted STAT1-BRAF and IRF7-MET regulatory links, suggesting candidate routes to MAPK reactivation through BRAF overexpression and MET-mediated bypass signaling. External analyses partially recapitulated the resistance-associated transcriptional program in independent melanoma cell-line datasets and yielded limited, inconclusive evidence for the predicted STAT1-BRAF association in public perturbation datasets. Cluster 2 represented a pre-existing proliferative state whose signature was associated with shorter progression-free survival in pretreatment clinical cohorts. Together, these findings distinguish a therapy-associated acquired-resistance state from a pre-existing proliferative resistance-associated state and nominate the predicted STAT1-BRAF and IRF7-MET links for functional validation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Melanoma Resistance to Targeted Therapy)

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14 pages, 536 KB

Open AccessReview

Antibody-Based Therapeutics in Autoimmune Diseases: Mechanisms, Challenges, and Future Perspectives

by Naim Mahroum

Int. J. Mol. Sci. 2026, 27(18), 8030; https://doi.org/10.3390/ijms27188030 - 9 Sep 2026

Abstract

Autoimmune diseases encompass nearly 100 distinct conditions characterized by dysregulated immune responses against self-antigens, resulting in tissue damage, chronic inflammation, and substantial morbidity. Over recent decades, the global burden of autoimmune diseases has increased, while their therapeutic management has undergone a paradigm shift [...] Read more.

Autoimmune diseases encompass nearly 100 distinct conditions characterized by dysregulated immune responses against self-antigens, resulting in tissue damage, chronic inflammation, and substantial morbidity. Over recent decades, the global burden of autoimmune diseases has increased, while their therapeutic management has undergone a paradigm shift from broad, nonspecific immunosuppression toward targeted biologic therapies. Among these, antibody-based therapeutics, including monoclonal antibodies targeting cytokines, cell-surface molecules, and co-stimulatory pathways, have transformed the treatment of numerous systemic and organ-specific autoimmune disorders. Nevertheless, important challenges remain, including primary non-response, secondary loss of efficacy related to immunogenicity or disease adaptation, increased susceptibility to infections, and mechanistic redundancy among therapeutic targets. This review provides a comprehensive overview of the cellular and molecular mechanisms underlying antibody-based therapies, summarizes major therapeutic target classes across autoimmune diseases, and examines their clinical and mechanistic limitations. Emerging therapeutic platforms, including bispecific antibodies, antibody–drug conjugates (ADCs), novel Fc-engineering, and cellular approaches such as CD19-targeted chimeric antigen receptor (CAR)-T therapy, are also discussed. Finally, antigen-specific immunotherapies designed to restore antigen-specific immune tolerance while preserving systemic host defense are explored. These approaches may represent an important next frontier in the treatment of autoimmune diseases, moving beyond broad systemic immune modulation toward more selective and durable immune control. Full article

(This article belongs to the Special Issue Antibody-Based Therapeutics for Autoimmune Diseases)

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36 pages, 1182 KB

Open AccessReview

Gut, Oral, and Fungal Microbiota in Hypertension: A Multi-Compartment Systematic Review

by Francesco Carini, Alessandra Sorce, Maria Elena Ciuppa, Sabrina David, Marco Giammanco, Paola Di Carlo, Salvatore Evola, Giovanni Tomasello, Giuseppe Mulè and Caterina Carollo

Int. J. Mol. Sci. 2026, 27(18), 8029; https://doi.org/10.3390/ijms27188029 - 9 Sep 2026

Abstract

The gut microbiota is an established modulator of blood pressure, but the oral bacteriome and the fungal mycobiome have been examined largely in isolation from it and from each other. No previous synthesis has evaluated all three compartments within one analytical framework, or [...] Read more.

The gut microbiota is an established modulator of blood pressure, but the oral bacteriome and the fungal mycobiome have been examined largely in isolation from it and from each other. No previous synthesis has evaluated all three compartments within one analytical framework, or treated sex and ethnicity as primary analytical axes rather than adjustment covariates. Systematic review reported according to PRISMA 2020 and, for the synthesis, the SWiM guideline. PubMed/MEDLINE, Embase, Scopus, and Web of Science were searched from inception to 30 June 2026. Observational human studies in adults reporting gut, oral, or fungal microbiota data stratified by blood pressure status were eligible, together with Mendelian randomisation studies and studies with a nested experimental causal component. Two reviewers screened and extracted independently, with a third resolving disagreement. Risk of bias was assessed with the Newcastle–Ottawa Scale and certainty of evidence with GRADE adapted for exposure–outcome questions. Increased abundance of the Ruminococcus gnavus group was the most convergent taxon-level finding, replicated in three independent populations on two continents, including one prospective multi-ethnic cohort with full adjustment and correction for multiple comparisons (OR 1.07, 95% CI 1.01–1.14 for incident hypertension). In the oral compartment, depletion of the nitrate-reducing commensal Neisseria subflava converged across a United States prospective cohort and an Italian case–control study using unrelated methods, and salivary nitric oxide was approximately three-fold lower in hypertensive subjects. Depletion of the short-chain fatty acid producers Faecalibacterium and Roseburia and enrichment of Klebsiella were convergent but geographically restricted. Mycobiome evidence was contradictory: two studies reported fungal dysbiosis, one of them already at the pre-hypertensive stage, while a cross-cohort metagenome-wide study on two independent cohorts from Beijing and Dalian (N = 159 hypertensive patients, 101 healthy controls) identified 61 gut bacterial species with consistent altered abundance across both cohorts while finding no replicable mycobiome signal. Recurring across compartments and kingdoms was the collapse of microbial co-correlation networks in hypertension, alongside a dissociation between null alpha diversity and significant beta diversity. Associations differed by ethnicity within a single multi-ethnic cohort and were generally stronger in women. Certainty of evidence, assessed per individual convergent finding, was very low for every taxon-level finding and low for salivary nitric oxide; these ratings concern the attribution of hypertension to specific organisms, not the existence of a microbiota–hypertension association, which is supported at community level in every compartment examined and by experimental transfer models. That the microbiota differs in hypertension is well supported; which organisms are responsible is not. The most reproducible signal is structural rather than taxonomic, and conventional differential-abundance analysis is not designed to detect it. No individual microbial taxon is currently ready to serve as a marker of hypertension or to inform clinical practice. Full article

(This article belongs to the Section Molecular Microbiology)

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30 pages, 26261 KB

Open AccessArticle

Establishment of an In Vitro DSS-Induced Epithelial Injury Model to Investigate Dose-Dependent Effects of IL-6 and Butyrate on Barrier Function

by Srijal Kunwar and Saleh A. Naser

Int. J. Mol. Sci. 2026, 27(18), 8028; https://doi.org/10.3390/ijms27188028 - 9 Sep 2026

Abstract

Dextran sodium sulfate (DSS) is widely used in vivo to induce epithelial injury; however, the epithelial-specific responses to DSS and mechanisms associated with barrier restoration remain incompletely understood. Here, we establish an in vitro DSS-induced epithelial damage model using differentiated Caco-2 cell monolayers. [...] Read more.

Dextran sodium sulfate (DSS) is widely used in vivo to induce epithelial injury; however, the epithelial-specific responses to DSS and mechanisms associated with barrier restoration remain incompletely understood. Here, we establish an in vitro DSS-induced epithelial damage model using differentiated Caco-2 cell monolayers. Exposure to 2.5%(w/v) DSS for 24 h resulted in significant upregulation of the pore-forming protein Claudin-2(CLDN2) (2.677-fold) and elevated oxidative marker protein levels of NADPH oxidase 1 (NOX1), accompanied by increased reactive oxygen species (ROS) production confirmed via dihydroethidium (DHE) staining. Increased epithelial permeability was observed by transepithelial electrical resistance (TEER) analysis, without significant cytotoxicity. Surprisingly, ELISA analysis revealed significant downregulation of Interleukin-6 (IL-6) (0.364 ± 0.034 pg/mL) following DSS exposure. Treatment with 1 ng/mL recombinant IL-6 (rIL-6) improved epithelial barrier function during continued DSS exposure, whereas a higher dose of 5 ng/mL did not produce the same restorative response. Furthermore, treatment of DSS-damaged Caco-2 monolayer with 10 mM butyrate significantly improved epithelial barrier function. Collectively, this study establishes a reproducible DSS-induced Caco-2 epithelial injury model and demonstrates concentration-dependent effects of rIL-6 and barrier-restorative effects of butyrate, providing an epithelial-specific platform for investigating intestinal barrier dysfunction relevant to IBD. Full article

(This article belongs to the Section Molecular Biology)

21 pages, 2666 KB

Open AccessFeature PaperArticle

Effects of Dictyophora indusiata on Cognitive Impairment and Associated Neurobiological Changes in Chronic Mild Stress Mouse Model

by Jatuporn Prathumtet, Tantima Kumlung, Warisada Sila-On, Sureewan Duangjit, Rawiwun Kaewamatawong, Wiwat Pichayakorn, Yaowared Sumanont, Orawan Monthakantirat and Utsana Puapermpoonsiri

Int. J. Mol. Sci. 2026, 27(18), 8027; https://doi.org/10.3390/ijms27188027 - 9 Sep 2026

Abstract

Chronic stress is associated with changes in cognitive performance involving oxidative stress and inflammatory responses. This study investigated the bioactive compounds, antioxidant and acetylcholinesterase (AChE) inhibitory activities, and potential effects of Dictyophora indusiata (D. indusiata) on cognitive performance in an unpredictable [...] Read more.

Chronic stress is associated with changes in cognitive performance involving oxidative stress and inflammatory responses. This study investigated the bioactive compounds, antioxidant and acetylcholinesterase (AChE) inhibitory activities, and potential effects of Dictyophora indusiata (D. indusiata) on cognitive performance in an unpredictable chronic mild stress (UCMS) mouse model. D. indusiata extracts contained phenolics, flavonoids, polysaccharides, and ergosterol. These extracts exhibited in vitro antioxidant and acetylcholinesterase (AChE) inhibitory activities. Oral administration of D. indusiata powder improved performance on cognitive tasks in UCMS mice, as assessed using the Y-maze test, novel object recognition test, and Morris water maze test. These improvements were accompanied by upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression, downregulated Kelch-like ECH-associated protein 1 (Keap1) mRNA expression, increased superoxide dismutase (SOD) and catalase (CAT) activities, and reduced malondialdehyde (MDA) levels in the frontal cortex and hippocampus, suggesting potential involvement of the Keap1–Nrf2 signaling pathway. Furthermore, D. indusiata reduced mRNA expression of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Taken together, these findings suggest potential involvement of antioxidant defense and inflammatory responses in the effects of D. indusiata on cognitive performance under chronic stress, while the relevance of in vitro AChE inhibition warrants further investigation. Full article

(This article belongs to the Special Issue Natural Products for Neuroprotection and Neurodegeneration)

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26 pages, 9586 KB

Open AccessArticle

Discovery of Quercetin as a Potential Entry Inhibitor of Nipah Virus: A Path Toward Antiviral Therapy

by Mohammad Mamun Alam, Md. Mohibur Rahman, Khalid Hasan Raj, Abdul Hadi Nahid, Poulomi Saha, Abir Hossain, Moushimi Amaya, Eric D. Laing, Syed Moinuddin Satter, Christopher C. Broder, Mohammad Enayet Hossain and Mohammed Ziaur Rahman

Int. J. Mol. Sci. 2026, 27(18), 8026; https://doi.org/10.3390/ijms27188026 - 9 Sep 2026

Abstract

Nipah virus (NiV) is a zoonotic virus that causes severe encephalitis and respiratory disease with a mortality rate often exceeding 70%. Currently, there are no licensed vaccines or therapeutics for NiV disease. This study aimed to identify and experimentally evaluate small-molecule inhibitors targeting [...] Read more.

Nipah virus (NiV) is a zoonotic virus that causes severe encephalitis and respiratory disease with a mortality rate often exceeding 70%. Currently, there are no licensed vaccines or therapeutics for NiV disease. This study aimed to identify and experimentally evaluate small-molecule inhibitors targeting the NiV-G (attachment) glycoprotein using integrated in silico and in vitro approaches. A high-throughput virtual screening of >215,000 compounds was conducted against the NiV-G glycoprotein, using docking and molecular dynamics (MD) simulations. The next potential candidates were evaluated using an established, BSL-2-compatible recombinant Cedar virus (rCedV)-based green fluorescent protein (GFP) reporter virus expressing the NiV-F (fusion) and G glycoproteins (rCedV-NiV-B-GFP). During MD simulations, quercetin demonstrated the most stable binding, maintaining a consistent RMSD (3.25 ± 0.3 Å). In vitro testing showed dose-dependent inhibition of rCedV-NiV-B-GFP infection. Although quercetin alone was less potent (IC₅₀ = 24 µM; 95% CI: 7.6–93.6 µM) than a reference NiV-neutralizing monoclonal antibody mAb-7B7 (IC₅₀ = 0.027 μg/mL; approximately 0.00018 μM; 95% CI: 0.0108 to 0.0735), combination with ascorbic acid enhanced neutralization (IC₅₀ = 4.4 µM; 95% CI: 2.9–6.8 µM). Quercetin demonstrated a high Selectivity Index of >20.8. The study identifies quercetin as a promising small-molecule inhibitor of NiV cellular infection, potentially through a stable interaction with NiV-G at the ephrin-B2/B3 binding interface identified computationally. These findings highlight the importance of combining computational screening with BSL-2 cell-based bioassays to accelerate NiV countermeasure discovery. Full article

(This article belongs to the Special Issue Novel Antiviral Agents: Challenges and Opportunities from Molecular Targeting to Validation)

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25 pages, 7628 KB

Open AccessReview

Artificial Intelligence-Based Prediction of Molecular Alterations in Colorectal Cancer Using Routine H&E Whole-Slide Images

by Marius Florentin Popa, Paul Șiancu, Călin-Ilie Mohor, Lilioara-Alexandra Oprinca-Muja, George-Călin Oprinca, Cosmin-Ioan Mohor, Ciprian Tănăsescu, Denisa Tănăsescu, Alina Cristian, Vicențiu-Vasile Vereș and Alina Bereanu

Int. J. Mol. Sci. 2026, 27(18), 8025; https://doi.org/10.3390/ijms27188025 - 9 Sep 2026

Abstract

From a molecular perspective, colorectal cancer is a heterogeneous disease in which microsatellite instability (MSI) phenotypes, mismatch repair (MMR) status, chromosomal instability, or mutations in BRAF, KRAS, NRAS, and TP53 can influence prognosis, hereditary cancer risk assessment, and therapeutic approaches. [...] Read more.

From a molecular perspective, colorectal cancer is a heterogeneous disease in which microsatellite instability (MSI) phenotypes, mismatch repair (MMR) status, chromosomal instability, or mutations in BRAF, KRAS, NRAS, and TP53 can influence prognosis, hereditary cancer risk assessment, and therapeutic approaches. Conventional biomarker testing via immunohistochemistry, polymerase chain reaction, and next-generation sequencing remains the diagnostic standard, but it can be limited by cost, turnaround time, tissue consumption, and uneven access. This narrative review synthesizes 30 peer-reviewed studies, identified across major scientific databases, that evaluate artificial intelligence (AI) platforms designed to detect molecular alterations from routine hematoxylin and eosin-stained colorectal cancer tissue slides. The strongest and most reproducible evidence exists for MSI phenotypes and MMR status, for which weakly supervised, attention-based, transformer-based, foundation-model, and clinically oriented multiple-instance learning systems achieve high discriminatory performance and particularly high negative predictive values at screening thresholds. BRAF mutation status is moderately predictable, although often through morphology associated with microsatellite instability or the CpG island methylator phenotype (CIMP). In contrast, despite promising single-center results, the predictability of KRAS, NRAS, PIK3CA, and other point mutations remains less consistently generalizable. Interpretability analyses indicate that these algorithms rely on features such as tumor-infiltrating lymphocytes, plasma cells, mucinous and medullary differentiation, necrosis, stromal architecture, tumor heterogeneity, nuclear morphometry, and tumor purity. Current evidence supports the use of AI as a triage and enrichment tool rather than a replacement for validated molecular diagnostics. Ultimately, prospective validation, pre-analytical standardization, calibrated thresholds, regulatory oversight, and pathologist-centered workflow integration are essential for successful clinical translation. Full article

(This article belongs to the Special Issue Identification of Molecular Biomarkers Through Digital Pathology)

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