International Journal of Molecular Sciences

35 pages, 1739 KB

Open AccessReview

Mesenchymal Stromal/Stem Cell-Based Therapies for Liver Regeneration: Current Status and Future Directions

by Seohyun Choi and Jaemin Jeong

Int. J. Mol. Sci. 2026, 27(2), 619; https://doi.org/10.3390/ijms27020619 (registering DOI) - 7 Jan 2026

The global burden of acute and chronic liver diseases warrants safe and effective regenerative therapies that can complement or defer liver transplantation. Mesenchymal stromal/stem cells (MSCs) have been recognized as versatile biologics that modulate inflammation, reverse fibrosis, and promote hepatic repair predominantly through [...] Read more.

The global burden of acute and chronic liver diseases warrants safe and effective regenerative therapies that can complement or defer liver transplantation. Mesenchymal stromal/stem cells (MSCs) have been recognized as versatile biologics that modulate inflammation, reverse fibrosis, and promote hepatic repair predominantly through paracrine signaling. In hepatic milieu, MSCs act on hepatocytes, hepatic stellate cells, endothelial cells, and immune cell subsets through trophic factors and extracellular vesicles (EVs). Despite demonstrating hepatocyte-like differentiation of MSCs, their in vivo efficacy is primarily attributed to micro-environmental reprogramming rather than durable engraftment. This review covers MSC biology, liver regeneration, and cell-based versus EV therapies, including administration, dosing, quality, and safety. Future directions focus on biomarkers, multi-center trials, and engineered MSC/EV platforms for scalable personalized liver regeneration. Full article

(This article belongs to the Special Issue Multifaceted Roles of Extracellular Vesicles in Cancer and Other Diseases)

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17 pages, 2346 KB

Open AccessArticle

Gasdermin D Cleavage and Cytokine Release, Indicative of Pyroptotic Cell Death, Induced by Ophiobolin A in Breast Cancer Cell Lines

by Santhalakshmi Ranganathan, Tolulope Ojo, Alagu Subramanian, Jenna Tobin, Alexander Kornienko, Angela Boari, Antonio Evidente, Mary Lauren Benton, Daniel Romo and Joseph H. Taube

Int. J. Mol. Sci. 2026, 27(2), 618; https://doi.org/10.3390/ijms27020618 - 7 Jan 2026

Abstract

An unmet challenge in managing breast cancer is treatment failure due to resistance to apoptosis-inducing chemotherapies. Thus, it is important to identify novel non-apoptotic therapeutic agents. Several non-apoptotic programmed cell death pathways utilize specific cellular signaling events to trigger lytic and pro-inflammatory cell [...] Read more.

An unmet challenge in managing breast cancer is treatment failure due to resistance to apoptosis-inducing chemotherapies. Thus, it is important to identify novel non-apoptotic therapeutic agents. Several non-apoptotic programmed cell death pathways utilize specific cellular signaling events to trigger lytic and pro-inflammatory cell death, examples of which are pyroptosis and necroptosis. Our study illustrates that ophiobolin A (OpA) is an anti-cancer agent that triggers lytic cell death in breast cancer cells, including triple-negative breast cancer (TNBC). This study reveals that OpA induces typical pyroptosis-like characteristics, including cellular swelling, plasma membrane rupture, GSDMD cleavage, and release of cytokines in breast cancer cells. However, the additional involvement of RIPK1 and induction of RIPK3 clustering in select cell lines suggest that multiple pathways may be triggered upon OpA treatment. The induction of pro-inflammatory cell death suggests potential applications for OpA in cancer treatment. Full article

(This article belongs to the Special Issue The Role of Natural Compounds in Cancer and Inflammation, 2nd Edition)

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13 pages, 9915 KB

Open AccessArticle

Acute Dehydration Drives Organ-Specific Modulation of Phosphorylated AQP4ex in Brain and Kidney

by Claudia Palazzo, Roberta Pati, Raffaella Pia Gatta, Onofrio Valente, Pasqua Abbrescia, Grazia Paola Nicchia and Antonio Frigeri

Int. J. Mol. Sci. 2026, 27(2), 617; https://doi.org/10.3390/ijms27020617 - 7 Jan 2026

Abstract

Water deprivation triggers coordinated physiological responses to preserve body fluid balance, yet the molecular mechanisms that regulate aquaporin-mediated water transport under dehydration remain incompletely understood. Aquaporin-4 (AQP4), the main water channel in the brain and a basolateral water pathway in the kidney collecting [...] Read more.

Water deprivation triggers coordinated physiological responses to preserve body fluid balance, yet the molecular mechanisms that regulate aquaporin-mediated water transport under dehydration remain incompletely understood. Aquaporin-4 (AQP4), the main water channel in the brain and a basolateral water pathway in the kidney collecting duct, exists in multiple isoforms, including the translational readthrough variant AQP4ex, whose regulatory role is only beginning to be defined. Here, we investigated the effects of acute water deprivation (6–12 h) on AQP4 isoform expression and phosphorylation in a mouse kidney and brain. While total AQP4 and AQP4ex protein levels remained largely unchanged in both tissues, dehydration induced a marked and divergent regulation of the phosphorylated form of AQP4ex. Levels increased in the kidney medulla, consistent with enhanced antidiuretic water transport, but decreased in the cerebral cortex, suggesting a protective reduction in perivascular water permeability. No changes were detected in the cerebellum. These findings identify phosphorylation of AQP4ex as a rapid, tissue-specific regulatory mechanism that adjusts water flux according to the physiological needs of each organ, revealing an additional layer of control in systemic water homeostasis and highlighting AQP4ex as a potential target in dehydration-related and osmotic disorders. Future studies could explore the signaling pathways regulating AQP4ex phosphorylation and investigate its potential involvement in pathological conditions, such as diabetes insipidus or cerebral edema. Full article

(This article belongs to the Special Issue New Insights into Aquaporins: 2nd Edition)

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21 pages, 3027 KB

Open AccessArticle

Camphor-10-Sulfonamide Amino Acid Esters: Synthesis, Antiviral Evaluation, and Molecular Docking Insights

by Krasimira Dikova, Neli Vilhelmova-Ilieva, Emilio Mateev and Zhanina Petkova

Int. J. Mol. Sci. 2026, 27(2), 616; https://doi.org/10.3390/ijms27020616 - 7 Jan 2026

Abstract

The ongoing emergence of antiviral drug resistance underscores the critical need for new broad-spectrum antiviral agents. Sulfonamides and their derivatives have emerged as promising candidates for the development of new antiviral therapeutics. In this study, a series of camphor-10-sulfonamide derivatives was synthesized through [...] Read more.

The ongoing emergence of antiviral drug resistance underscores the critical need for new broad-spectrum antiviral agents. Sulfonamides and their derivatives have emerged as promising candidates for the development of new antiviral therapeutics. In this study, a series of camphor-10-sulfonamide derivatives was synthesized through a feasible and sustainable synthetic approach starting from naturally available precursors and evaluated for antiviral properties. Their activity was examined against three structurally distinct viruses—herpes simplex virus type 1 (HSV-1), human coronavirus (HCoV-OC43), and feline calicivirus (FCV)—representing both DNA and RNA, enveloped and non-enveloped types. The compounds were examined for their effects on viral replication, the stage of viral adsorption to the cell, and extracellular virions. The weakest cytotoxicity and the most pronounced activity of all the tested substances was demonstrated by the tryptophan derivative 7a. A time-dependent inhibition of the stage of adsorption of HCoV-OC43 (Δlg = 2.0 at 120 min) and FCV (Δlg = 1.75 at 60 min) to susceptible cells was established, as well as virucidal activity on the three types of virions tested, with the most pronounced effect at 120 min—for HSV-1 (Δlg = 2.75) and Δlg = 2.0 for HCoV-OC43 and FCV. Molecular docking studies performed using Glide (Schrödinger) provided insights into the active conformations of the most effective ligands and predicted possible interactions with relevant viral targets, supporting their potential as lead structures for further therapeutic development. Full article

(This article belongs to the Special Issue New Pharmacological Insights on Natural Macromolecules and Natural Small Molecules: 2nd Edition)

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22 pages, 2325 KB

Open AccessArticle

Modulation of the miR-485-3p/PGC-1α Pathway by ASO-Loaded Nanoparticles Attenuates ALS Pathogenesis

by In Soo Ryu, Dae-In Ha, Yeon-Joo Jung, Hyo Jin Lee, Insun Kim, Yu Na Lim, Hyun Su Min, Seung Hyun Kim, Ilsang Yoon, Hyun-Jeong Cho and Jin-Hyeob Ryu

Int. J. Mol. Sci. 2026, 27(2), 615; https://doi.org/10.3390/ijms27020615 - 7 Jan 2026

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration with limited treatment options. In this study, we investigated the pathological role of microRNA-485-3p (miR-485-3p) in ALS, particularly its regulation of PGC-1α, a transcriptional coactivator essential for mitochondrial [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration with limited treatment options. In this study, we investigated the pathological role of microRNA-485-3p (miR-485-3p) in ALS, particularly its regulation of PGC-1α, a transcriptional coactivator essential for mitochondrial function and neuroprotection. We also evaluated the therapeutic potential of BMD-001S, a nanoparticle-based formulation encapsulating an antisense oligonucleotide targeting miR-485-3p. Our results demonstrated that miR-485-3p expression was significantly elevated in both SOD1^G93A-expressing HMC3 microglial cells and in the spinal cords of SOD1^G93A transgenic mice at late disease stages, implicating its contribution to ALS pathogenesis. Intravenous administration of BMD-001S effectively reduced miR-485-3p levels and restored PGC-1α mRNA and PGC-1α protein expression in the spinal cord. These molecular changes were associated with notable therapeutic outcomes, including reduced SOD1 protein aggregation, decreased neuroinflammation, and lower neurofilament light chain concentrations in cerebrospinal fluid. Moreover, BMD-001S treatment was associated with improvements in electrophysiological parameters and preservation of neuromuscular junction integrity during the observation period in SOD1^G93A transgenic mice. Taken together, these findings suggest that miR-485-3p/PGC-1α pathway is a promising therapeutic target in ALS and support the potential of BMD-001S as a novel treatment strategy for the disease. Full article

(This article belongs to the Special Issue Understanding and Treating Amyotrophic Lateral Sclerosis and Related Motor Neuron Diseases)

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16 pages, 2693 KB

Open AccessArticle

Vitamin E Modulates Hepatic Extracellular Adenosine Signaling to Attenuate Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

by Mengting Shan, Magdeline E. Carrasco Apolinario, Tomoko Tokumaru, Kenshiro Shikano, Phurpa Phurpa, Ami Kato, Hitoshi Teranishi, Shinichiro Kume, Nobuyuki Shimizu, Tatsuki Kurokawa, Takatoshi Hikida, Toshikatsu Hanada, Yulong Li and Reiko Hanada

Int. J. Mol. Sci. 2026, 27(2), 614; https://doi.org/10.3390/ijms27020614 (registering DOI) - 7 Jan 2026

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves early disturbances such as excessive lipid accumulation, sterile inflammation, and hepatocellular stress. The results of recent studies have highlighted extracellular ATP and its metabolite adenosine (Ado) as damage-associated molecular patterns (DAMPs) that drive inflammation, endoplasmic reticulum [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves early disturbances such as excessive lipid accumulation, sterile inflammation, and hepatocellular stress. The results of recent studies have highlighted extracellular ATP and its metabolite adenosine (Ado) as damage-associated molecular patterns (DAMPs) that drive inflammation, endoplasmic reticulum (ER) stress, and steatosis, contributing to MASLD progression. Although vitamin E is clinically used for its antioxidant and anti-inflammatory properties, it remains unclear whether its therapeutic effects involve modulation of DAMP-associated signaling. To address this gap, we used transgenic zebrafish expressing a liver-specific G-protein-coupled receptor activation-based adenosine sensor (GRAB_Ado). We found that a high-cholesterol diet markedly increased hepatic extracellular Ado levels, combined with inflammatory and ER stress-associated gene expression. Vitamin E significantly reduced extracellular Ado levels and hepatic lipid accumulation. Based on RNA sequencing results, vitamin E restored the expression of genes encoding calcium-handling proteins, including atp2a1 and atp1b1b. These genes encode components of the sarco/ER Ca²⁺-ATPase (SERCA) machinery, which is essential for maintaining ER Ca²⁺ homeostasis and preventing stress-induced hepatic injury. CDN1163-mediated SERCA activation phenocopied the protective effect of vitamin E, supporting a Ca²⁺-dependent mechanism. Together, these findings highlight extracellular Ado signaling and impaired SERCA-mediated Ca²⁺ regulation as early drivers of MASLD and demonstrate that vitamin E ameliorates steatosis by targeting both pathways. Full article

(This article belongs to the Special Issue Molecular Mechanisms Driving Liver Disease: From Cellular Stress to Therapeutic Targets)

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21 pages, 3577 KB

Open AccessArticle

Differential Circulating miRNA Responses to PM Exposure in Healthy and Diabetes Mellitus Patients: Implications for Lung Cancer Susceptibility

by Moe Thi Thi Han, Nichakorn Satitpornbunpot, Naoomi Tominaga, Saranta Freeouf, Khanittha Punturee, Chidchamai Kewchareonwong, Busayamas Chewaskulyong, Ganjana Lertmemongkolchai and Ratchada Cressey

Int. J. Mol. Sci. 2026, 27(2), 613; https://doi.org/10.3390/ijms27020613 - 7 Jan 2026

Abstract

Seasonal biomass-burning haze in Northern Thailand produces sharp fluctuations in ambient fine particulate matter (PM), posing heightened health risks, particularly for individuals with diabetes mellitus (DM). To identify PM-responsive biomarkers and assess whether metabolic status modifies these responses, we first performed small RNA [...] Read more.

Seasonal biomass-burning haze in Northern Thailand produces sharp fluctuations in ambient fine particulate matter (PM), posing heightened health risks, particularly for individuals with diabetes mellitus (DM). To identify PM-responsive biomarkers and assess whether metabolic status modifies these responses, we first performed small RNA sequencing in a discovery cohort using plasma samples collected during low- and high-PM periods. Thirteen circulating microRNAs (miRNAs) were differentially expressed, including reduced miR-542-3p and elevated miR-29a-3p, novelmiR-203, and novelmiR-754, with predicted targets enriched in immune and endoplasmic-reticulum stress pathways. These four miRNAs were quantified by RT-qPCR in a longitudinal cohort of adults with (n = 28) and without DM (n = 29) sampled at three PM-defined timepoints across one full haze cycle. In non-DM individuals, miR-542-3p decreased at peak exposure while miR-29a-3p and novelmiR-203 increased, with values returning toward baseline at re-exposure. DM participants showed altered baseline levels and attenuated or reversed seasonal changes. Plasma IL-8 rose markedly at peak PM in both groups, mirroring exosome concentration increases measured by NTA, indicating a transient systemic inflammatory response. In an independent clinical cohort, only miR-542-3p differed significantly between lung-cancer patients and healthy controls. These findings indicate that PM exposure reconfigures circulating miRNA, exosomal, and cytokine profiles, and that DM modifies these responses, highlighting miR-542-3p and miR-29a-3p as environmentally responsive and disease-relevant biomarker candidates. Full article

(This article belongs to the Section Molecular Toxicology)

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28 pages, 866 KB

Open AccessReview

The Adipokine Axis in Heart Failure: Linking Obesity, Sarcopenia and Cardiac Dysfunction in HFpEF

by Luka Komić, Jelena Komić, Nikola Pavlović, Marko Kumrić, Josipa Bukić, Iris Jerončić Tomić and Joško Božić

Int. J. Mol. Sci. 2026, 27(2), 612; https://doi.org/10.3390/ijms27020612 - 7 Jan 2026

Abstract

Obesity, sarcopenia, and heart failure with preserved ejection fraction (HFpEF) constitute an interconnected clinical triad driven by multisystem mechanisms centered on the adipokine axis. Adipose tissue, now recognized as a dynamic endocrine organ, undergoes pathological remodeling in obesity, characterized by hypoxia, chronic low-grade [...] Read more.

Obesity, sarcopenia, and heart failure with preserved ejection fraction (HFpEF) constitute an interconnected clinical triad driven by multisystem mechanisms centered on the adipokine axis. Adipose tissue, now recognized as a dynamic endocrine organ, undergoes pathological remodeling in obesity, characterized by hypoxia, chronic low-grade inflammation, and dysregulated adipokine secretion. These changes impair endothelial function, promote myocardial fibrosis, and disrupt skeletal muscle metabolism, thereby linking cardiometabolic and musculoskeletal dysfunction. This review integrates current evidence on homeostatic adipokines, such as adiponectin, apelin, and omentin, that preserve vascular and muscular resilience, as well as stress-inducible adipokines, such as leptin, resistin, and GDF15, that reflect or amplify metabolic and inflammatory injury. A maladaptive adipokine milieu associates with a self-reinforcing cycle of endothelial dysfunction, myocardial stiffening, and muscle atrophy that characterizes s HFpEF in the context of obesity and sarcopenia. We further discuss emerging translational applications, including diagnostic and prognostic adipokine signatures, targeted modulation of adipokine pathways, and the therapeutic impact of GLP-1 receptor agonists on adipose–cardiovascular–muscle crosstalk. Remaining challenges, including the adiponectin paradox and pleiotropic adipokine effects, highlight the need for precision-medicine approaches integrating multimodal biomarker profiling with cardiometabolic and musculoskeletal phenotyping. Full article

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

4 pages, 190 KB

Open AccessEditorial

Special Issue “Modern Analytical Strategies for Foodomics: From Nutritional Value to Food Security”

by Cosima Damiana Calvano and Mariachiara Bianco

Int. J. Mol. Sci. 2026, 27(2), 611; https://doi.org/10.3390/ijms27020611 - 7 Jan 2026

Abstract

Considering current research trends shaped by critical challenges in food science and the food industry, foodomics can be defined as a scientific discipline that investigates changes in the molecular composition and quality of foods arising from raw materials, processing, and cooking, as well [...] Read more.

Considering current research trends shaped by critical challenges in food science and the food industry, foodomics can be defined as a scientific discipline that investigates changes in the molecular composition and quality of foods arising from raw materials, processing, and cooking, as well as the effects of food consumption on human health and metabolism [...] Full article

(This article belongs to the Special Issue Modern Analytical Strategies for Foodomics: From Nutritional Value to Food Security)

23 pages, 2399 KB

Open AccessArticle

Advancements in Functional Dressings and a Case for Cotton Fiber Technology: Protease Modulation, Hydrogen Peroxide Generation, and ESKAPE Pathogen Antibacterial Activity

by J. Vincent Edwards, Nicolette T. Prevost, Doug J. Hinchliffe, Sunghyun Nam and Crista A. Madison

Int. J. Mol. Sci. 2026, 27(2), 610; https://doi.org/10.3390/ijms27020610 - 7 Jan 2026

Abstract

The development of functionality in wound dressings has progressed since the discovery by Winter that moist wounds heal more rapidly. Approaches to incorporate functionality on several fronts of wound healing have been targeted. Here, we consider three functional features that have received increased [...] Read more.

The development of functionality in wound dressings has progressed since the discovery by Winter that moist wounds heal more rapidly. Approaches to incorporate functionality on several fronts of wound healing have been targeted. Here, we consider three functional features that have received increased attention for their role in promoting healing in hard-to-heal wounds: control of protease levels, hydrogen peroxide generation, and antibacterial efficacy against multidrug resistance bacteria, the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. We review some clinically employed dressings used to treat chronic and burn wounds that have been characterized by their functional protease-modulating activity and contrast one well-studied analog with a cotton-based technology. Similarly, hydrogen peroxide generation profiles were obtained for dressings in different moist wound healing categories and contrasted with a modified form of a known hemostatic cotton-based technology. We examined ascorbic acid-modified forms of a cotton-based technology used for bleeding control in an ESKAPE antibacterial assessment using the AATCC 100 TM. The results for the cotton-based technology were significant protease uptake, hydrogen peroxide generation capacities at proliferative and antimicrobial levels, and >99.99% efficacy against ESKAPE pathogens. These results reflect the importance of considering new forms of cotton fiber technology for incorporation in advanced wound dressing approaches. Full article

(This article belongs to the Special Issue Molecular Research Progress of Skin and Skin Diseases)

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18 pages, 2664 KB

Open AccessArticle

The Protective Role of Curcumin in Osteoarthritis: Establishing Mitochondrial Homeostasis Through Autophagy Induction and Apoptosis Inhibition

by Kavitha Raja, Rajashree Patnaik, Dineshwary Suresh, Riah Varghese, Adam Eid, Thomas Nau, Yajnavalka Banerjee and Nerissa Naidoo

Int. J. Mol. Sci. 2026, 27(2), 609; https://doi.org/10.3390/ijms27020609 - 7 Jan 2026

Abstract

Osteoarthritis (OA) is a progressive joint disorder affecting over 250 million people globally and is characterized by chronic pain and disability. Among its key pathogenic mechanisms are mitochondrial dysfunction and elevated reactive oxygen species (ROS), often triggered by inflammatory mediators such as lipopolysaccharide [...] Read more.

Osteoarthritis (OA) is a progressive joint disorder affecting over 250 million people globally and is characterized by chronic pain and disability. Among its key pathogenic mechanisms are mitochondrial dysfunction and elevated reactive oxygen species (ROS), often triggered by inflammatory mediators such as lipopolysaccharide (LPS). This study evaluates the protective effects of curcumin on mitochondrial function, autophagy, and apoptosis in an in vitro model of OA. Human bone marrow-derived mesenchymal stem cells (BMSCs) were differentiated into chondrocytes using MesenCult™-ACF medium. Differentiation was confirmed by histological staining for Type II Collagen, Alcian Blue, and Toluidine Blue. LPS was used to induce an OA-like inflammatory response. Mitochondrial membrane potential (ΔΨm) was assessed using Rhodamine 123 staining. Autophagy and apoptosis were evaluated using Acridine orange and propidium iodide staining, respectively. Western blotting was performed to analyze the expression of pro-caspase-3, Bcl-2, Beclin-1, LC3-I/II, and GAPDH. LPS significantly impaired mitochondrial function, limited autophagy, and enhanced apoptotic signaling (reduced pro-caspase-3). Curcumin (25 µM and 100 µM) restored ΔΨm, increased Beclin-1 and LC3-II, and maintained pro-caspase-3 expression, with Bcl-2 showing a non-monotonic response (higher at 25 µM than at 100 µM). Curcumin exerted cytoprotective effects in inflamed chondrocytes by stabilizing ΔΨm, promoting autophagy, and attenuating apoptotic activation, supporting its multi-target therapeutic potential in OA. Full article

(This article belongs to the Special Issue Advanced Therapy Using Human Mesenchymal Stem Cells (MSCs) and MSC Extracellular Vesicles)

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30 pages, 1409 KB

Open AccessArticle

Agent- and Dose-Specific Intestinal Obstruction Safety of GLP-1 Receptor Agonists and SGLT2 Inhibitors: A Network Meta-Analysis of Randomized Trials

by Jiann-Jy Chen, Chih-Wei Hsu, Chao-Ming Hung, Mein-Woei Suen, Hung-Yu Wang, Wei-Chieh Yang, Brendon Stubbs, Yen-Wen Chen, Tien-Yu Chen, Wei-Te Lei, Andre F. Carvalho, Shih-Pin Hsu, Yow-Ling Shiue, Bing-Yan Zeng, Cheng-Ta Li, Kuan-Pin Su, Chih-Sung Liang, Bing-Syuan Zeng and Ping-Tao Tseng

Int. J. Mol. Sci. 2026, 27(2), 608; https://doi.org/10.3390/ijms27020608 - 7 Jan 2026

Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose cotransporter-2 (SGLT2) inhibitors have reshaped pharmacological management of type 2 diabetes, but emerging safety signals suggest a possible association with intestinal obstruction. Because many candidates for these agents already harbor risk factors for ileus and bowel [...] Read more.

Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose cotransporter-2 (SGLT2) inhibitors have reshaped pharmacological management of type 2 diabetes, but emerging safety signals suggest a possible association with intestinal obstruction. Because many candidates for these agents already harbor risk factors for ileus and bowel obstruction, clarifying agent- and dose-specific gastrointestinal safety is clinically important. We aimed to re-evaluate the risk of intestinal obstruction across individual GLP-1 receptor agonists and SGLT2 inhibitors, with particular attention to dose stratification. We systematically searched eight databases through 21 January 2025 to identify randomized controlled trials (RCTs) comparing GLP-1 receptor agonists or SGLT2 inhibitors with placebo or active comparators in adults. The primary outcome was incident intestinal obstruction (small or large bowel). A frequentist random-effects network meta-analysis estimated odds ratios (ORs) with 95% confidence intervals (CIs) across drugs and dose tiers; Bayesian models and surface under the cumulative ranking (SUCRA) metrics were used for sensitivity analyses and treatment ranking. Risk of bias and certainty of evidence were assessed with standard Cochrane and GRADE-adapted tools. Fifty RCTs (47 publications; 192,359 participants) met inclusion criteria. Overall, canagliflozin use was associated with a higher incidence of intestinal obstruction than control therapies (OR 2.56, 95% CI 1.01–6.49), corresponding to an absolute risk difference of 0.15% and a number needed to harm of 658. High-dose canagliflozin (300 mg/day) showed the clearest signal (OR 3.42, 95% CI 1.08–10.76). In contrast, liraglutide was associated with a lower risk of intestinal obstruction (OR 0.44, 95% CI 0.24–0.81), with an absolute risk reduction of 0.34% and a number needed to treat of 295. No other GLP-1 receptor agonist or SGLT2 inhibitor demonstrated a statistically significant increase in obstruction risk. Frequentist and Bayesian analyses yielded concordant estimates and rankings. From a randomized-trial perspective, intestinal obstruction risk is not elevated for most GLP-1 receptor agonists and SGLT2 inhibitors. A dose-dependent safety signal was observed only for high-dose canagliflozin, whereas liraglutide may confer a protective effect. These findings refine gastrointestinal safety profiles for modern antidiabetic agents and may inform perioperative bowel management, drug selection, and dose optimization in patients at risk for ileus or adhesive obstruction. Full article

(This article belongs to the Special Issue Targeted Peptide Drugs for Metabolic Diseases)

27 pages, 7523 KB

Open AccessArticle

Upregulation of the TCA Cycle and Oxidative Phosphorylation Enhances the Fitness of CD99 CAR-T Cells Under Dynamic Cultivation

by Jiaxuan Zhao, Youyong Wang, Yixuan Wang, Ge Dong, Han Wu, Yeting Cui, Lixing Gu, Fenfang Zhao, Guanlin Zhao, Jinyu Kang, Qian Zhang, Nan Liu, Ning Wang, Xiao Sun, Yao Xu, Tongcun Zhang and Jiangzhou Shi

Int. J. Mol. Sci. 2026, 27(2), 607; https://doi.org/10.3390/ijms27020607 - 7 Jan 2026

Abstract

The manufacturing process contributes significantly to the proliferation, metabolic state, and functional persistence of chimeric antigen receptor (CAR)-T cells. However, how different culture systems regulate CAR-T cell metabolism and thereby influence their long-term antitumor activity remains poorly understood. In this study, we compared [...] Read more.

The manufacturing process contributes significantly to the proliferation, metabolic state, and functional persistence of chimeric antigen receptor (CAR)-T cells. However, how different culture systems regulate CAR-T cell metabolism and thereby influence their long-term antitumor activity remains poorly understood. In this study, we compared dynamic cultivation using a wave bioreactor with static expansion systems (gas-permeable and conventional T-flasks) for the production of CD99-specific CAR-T cells. CAR-T cells expanded by the wave bioreactor exhibited faster proliferation and stronger cytotoxicity during culture. Upon repeated antigen stimulation, they retained these enhanced functional properties and showed the reduced expression of immune checkpoint molecules, preferentially preserved memory-like subsets, and displayed transcriptional features consistent with memory maintenance and exhaustion resistance. Targeted metabolomic profiling revealed enhanced Tricarboxylic Acid (TCA) cycle activity and features consistent with sustained oxidative phosphorylation, supporting mitochondrial-centered metabolic reprogramming. In a Ewing sarcoma xenograft model, wave bioreactor-cultured CAR-T cells showed a greater percentage of memory-like tumor-infiltrating lymphocytes. Collectively, these results indicate that wave bioreactor-based dynamic cultivation promotes mitochondrial metabolic reprogramming, which is characterized by an enhanced TCA cycle and sustained oxidative phosphorylation, thereby sustaining CAR-T cell functionality and providing a robust platform for the manufacturing of potent and durable cellular therapeutics. Full article

(This article belongs to the Special Issue Chimeric Antigen Receptors Against Cancers and Autoimmune Diseases)

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17 pages, 3719 KB

Open AccessArticle

Influence of Aza-Substitution on Molecular Structure, Spectral and Electronic Properties of t-Butylphenyl Substituted Vanadyl Complexes

by Daniil N. Finogenov, Alexander E. Pogonin, Yuriy A. Zhabanov, Ksenia V. Ksenofontova, Dominika Yu. Parfyonova, Alexey V. Eroshin and Pavel A. Stuzhin

Int. J. Mol. Sci. 2026, 27(2), 606; https://doi.org/10.3390/ijms27020606 - 7 Jan 2026

Abstract

Vanadyl octa-(4-tert-butylphenyl)phthalocyanine (VOPc(t-BuPh)₈) and vanadyl octa-(4-tert-butylphenyl)tetrapyrazinoporphyrazine (VOTPyzPz(t-BuPh)₈) complexes were synthesized for the first time and confirmed by IR and UV-Vis spectroscopy and MALDI-TOF spectrometry. The method of synthesis of [...] Read more.

Vanadyl octa-(4-tert-butylphenyl)phthalocyanine (VOPc(t-BuPh)₈) and vanadyl octa-(4-tert-butylphenyl)tetrapyrazinoporphyrazine (VOTPyzPz(t-BuPh)₈) complexes were synthesized for the first time and confirmed by IR and UV-Vis spectroscopy and MALDI-TOF spectrometry. The method of synthesis of their precursors, 4,5-bis(4-tert-butylphenyl)phthalonitrile ((t-BuPh)₂PN) and 5,6-bis(4-tert-butylphenyl)pyrazine-2,3-dicarbonitrile ((t-BuPh)₂PDC), was modified, resulting in higher yields. For the vanadyl complexes, the basic properties were studied, and it was found that the red shift in the Q band in the first protonation step is approximately two times greater than that of previously known complexes. An electrochemical study showed the influence of aza-substitution on the redox properties and on the energies of the frontier orbitals of all the compounds presented. For all four considered compounds, quantum chemical calculations of the molecular structure, IR spectra, and electronic absorption spectra were carried out using density functional theory (DFT) and time-dependent density functional theory (TDDFT and simplified sTDDFT) approaches. According to the DFT calculations, vanadyl macrocyclic complexes have dome-shaped distorted structures. Experimental and theoretical IR and electronic absorption spectra were compared and interpreted. Full article

(This article belongs to the Section Molecular Biophysics)

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18 pages, 6138 KB

Open AccessArticle

Dissolving Silver Nanoparticles Modulate the Endothelial Monocyte-Activating Polypeptide II (EMAP II) by Partially Unfolding the Protein Leading to tRNA Binding Enhancement

by Lesia Kolomiiets, Paulina Szczerba, Wojciech Bal and Igor Zhukov

Int. J. Mol. Sci. 2026, 27(2), 605; https://doi.org/10.3390/ijms27020605 - 7 Jan 2026

Abstract

Metal nanoparticles (NP) are increasingly used in biomedical applications. Among them, silver NPs (AgNPs) are used as active components in antibacterial coatings for wound dressings, medical devices, implants, cosmetics, textiles, and food packaging. On the other hand, AgNPs can be toxic to humans, [...] Read more.

Metal nanoparticles (NP) are increasingly used in biomedical applications. Among them, silver NPs (AgNPs) are used as active components in antibacterial coatings for wound dressings, medical devices, implants, cosmetics, textiles, and food packaging. On the other hand, AgNPs can be toxic to humans, depending on the dose and route of exposure, as agents delivering silver to cells. The cysteine residues are the primary molecular targets in such exposures, due to the high affinity of Ag

^{+}

ions to thiol groups. The Endothelial monocyte-activating polypeptide II (EMAP II), a cleaved C-terminal peptide of the intracellular aminoacyl-tRNA synthetase multifunctional protein AIMP1, contains five cysteines exposed at its surface. This prompted the question of whether they can be targeted by Ag

^{+}

ions present at the AgNPs surface or released from AgNPs in the course of oxidative metabolism of the cell. We explored the interactions between recombinant EMAP II, tRNA, and AgNPs using UV-Vis and fluorescence spectroscopy, providing insight into the effects of AgNPs dissolution kinetics on interaction EMAP II with tRNA. In addition, the EMAP II fragments binding to intact AgNPs were established by heteronuclear

^{1}

H-

^{15}

N HSQC spectra utilizing a paramagnetic probe. Structural analysis of the EMAP II reveal that the 3D structure of protein was destabilized (partially denatured) by the binding of Ag

^{+}

ions released from AgNPs at the most exposed cysteines. Surprisingly, this effect enhanced tRNA affinity to EMAP II, lowering its

K_{d}

. The course of the EMAP II/tRNA/AgNP reaction was also modulated by other factors, such as the presence of Mg

^{2 +}

ions and TCEP, a thiol-group protector used to mimic the reducing conditions of the cell. Full article

(This article belongs to the Section Molecular Nanoscience)

27 pages, 778 KB

Open AccessReview

Targeting the Gut Microbiota: Mechanistic Investigation of Polyphenol Modulation of the Gut–Brain Axis in Alzheimer’s Disease

by Zhenning Wang, Shanshan Ba, Man Li, Yuanyuan Wei, Yuenan Wang, Jianqin Mao, Yang Xiang, Dongdong Qin and Chuhua Zeng

Int. J. Mol. Sci. 2026, 27(2), 604; https://doi.org/10.3390/ijms27020604 - 7 Jan 2026

Abstract

Alzheimer’s disease (AD) represents an increasingly severe global health challenge. Recently, the role of the gut–brain axis in AD pathogenesis has garnered significant attention. Dysbiosis of the gut microbiota can exacerbate core pathologies such as neuroinflammation, amyloid beta (Aβ) deposition, and tau hyperphosphorylation [...] Read more.

Alzheimer’s disease (AD) represents an increasingly severe global health challenge. Recently, the role of the gut–brain axis in AD pathogenesis has garnered significant attention. Dysbiosis of the gut microbiota can exacerbate core pathologies such as neuroinflammation, amyloid beta (Aβ) deposition, and tau hyperphosphorylation through neural, endocrine, and immune pathways. Polyphenolic compounds have emerged as a focal point in neuroprotective research owing to their pronounced anti-inflammatory and antioxidant properties. Notably, polyphenols exert effects not only by directly influencing the central nervous system (CNS) but also through indirectly modulating the composition and function of the gut microbiota, thereby impacting bidirectional gut–brain communication. This dual mechanism offers a potential avenue for their application in the prevention and treatment of AD. This review aims to compile recent research on the relationship between polyphenols and the gut microbiota. We assessed the literature from PubMed, Google Scholar, and Web of Science databases, published from the establishment of the database to 24 November 2025. The keywords used include “Polyphenols”, “Gut–brain axis”, “Gut microbiota”, “Alzheimer’s disease”, “Epigallocatechin gallate”, “Quercetin”, “Curcumin”, “Ferulic acid”, “Resveratrol”, “Anthocyanin”, “Myricetin”, “Chlorogenic acid”, etc. This review discusses the various mechanisms by which polyphenols influence AD through modulating the gut microbiota. Polyphenols and gut microbiota exhibit critical bidirectional interactions. On one hand, the bioavailability and activity of polyphenols are highly dependent on metabolic conversion by gut microbiota. On the other hand, polyphenols selectively promote the proliferation of beneficial bacteria such as bifidobacteria and lactobacilli like prebiotics, while inhibiting the growth of pathogenic bacteria. This reshapes the intestinal microecology, enhances barrier function, and regulates beneficial metabolites. Utilizing a nanotechnology-based drug delivery system, the pharmacokinetic stability and brain targeting efficacy of polyphenols can be significantly enhanced, providing innovative opportunities for the targeted prevention and management of AD. Full article

(This article belongs to the Special Issue Nutrition in Neurodegenerative Diseases: Molecular Perspectives)

14 pages, 1662 KB

Open AccessArticle

Approach to Design of Potent RNA Interference-Based Preparations Against Hepatocellular Carcinoma-Related Genes

by Petr V. Chernov, Vladimir N. Ivanov, Nikolai A. Dmitriev, Artem E. Gusev, Valeriia I. Kovchina, Ivan S. Gongadze, Alexander V. Kholstov, Maiia V. Popova, Dmitry A. Kudlay, Daria S. Kryuchko, Ilya A. Kofiadi and Musa R. Khaitov

Int. J. Mol. Sci. 2026, 27(2), 603; https://doi.org/10.3390/ijms27020603 - 7 Jan 2026

Abstract

Every year, the scientific community continues to drive advances in healthcare, opening up new perspectives in the treatment and management of various diseases. Despite vast strides being made in the quality of life and longevity, we still face an equally significant growth in [...] Read more.

Every year, the scientific community continues to drive advances in healthcare, opening up new perspectives in the treatment and management of various diseases. Despite vast strides being made in the quality of life and longevity, we still face an equally significant growth in the burden of oncological pathologies. Although current trends lean towards preventive and personalized medicine, numerous hurdles remain to be cleared to develop robust strategies in the field of oncology. Among all types of tumors, one of the prominent positions is occupied by hepatocellular carcinoma (HCC), which is one of the most widespread primary cancers with a high mortality rate. Conventional approaches to HCC therapy, such as surgery or chemotherapy, rarely provide steady performance due to the highly polymorphous nature of the cancerous process. In this study, we suggest an alternative methodological framework for designing potent siRNAs targeting genes implicated in hepatocellular carcinoma, implementing RNA interference mediated by synthetic small interfering RNAs (siRNAs) against mRNAs of ITGB1 and CD47 genes. Products of these genes are renowned drivers of tumor progression. We have developed a software algorithm for the design of unmodified and modified siRNAs, carried out solid-phase synthesis of the most promising molecules, and proved their capability to perform a more than 50-fold suppression of expression of the target genes in vitro. Full article

(This article belongs to the Special Issue Non-Coding RNAs’ Functionality—Diagnosis and Therapy in Cancer and Other Indications (2nd Edition))

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18 pages, 14362 KB

Open AccessArticle

Asiatic Acid Attenuates Salmonella typhimurium-Induced Neuroinflammation and Neuronal Damage by Inhibiting the TLR2/Notch and NF-κB Pathway in Microglia

by Wenshu Zou and Jianxi Li

Int. J. Mol. Sci. 2026, 27(2), 602; https://doi.org/10.3390/ijms27020602 - 7 Jan 2026

Abstract

Salmonella typhimurium (S.T) infection of the central nervous system (CNS) induces severe inflammation, leading to elevated expression of inducible nitric oxide synthase (iNOS) in microglia. This process catalyzes excessive production of nitric oxide (NO), resulting in irreversible damage to neuronal mitochondria. [...] Read more.

Salmonella typhimurium (S.T) infection of the central nervous system (CNS) induces severe inflammation, leading to elevated expression of inducible nitric oxide synthase (iNOS) in microglia. This process catalyzes excessive production of nitric oxide (NO), resulting in irreversible damage to neuronal mitochondria. Asiatic acid (AA) is a small molecule with neuroprotective potential; however, its ability to counteract nerve injury induced by S.T and the underlying mechanisms remain unclear. In this study, we established an S.T-infected mouse model (in vivo) and an S.T-stimulated microglial model using BV-2 cells (in vitro) and employed techniques including immunofluorescence (IF), Western blot, co-immunoprecipitation (Co-IP), and RNA extraction and quantitative reverse transcription PCR (RT-qPCR) to systematically evaluate the protective effects and mechanisms of AA. The results showed that pre-treatment with AA significantly reduced the expression of iNOS and the production of NO caused by S.T infection in mouse hippocampal tissue and BV-2 cells. Mechanistically, AA exerts its effects by inhibiting the upstream Toll-like receptor 2 (TLR2)/Notch and nuclear factor-κB (NF-κB) signaling axis. It interferes with the nuclear translocation of Notch and p65 proteins and their complex formation under S.T stimulation, thereby blocking downstream expression of iNOS and production of NO. This study reveals a novel mechanism by which AA alleviates infection-related neuroinflammation through targeting Notch-p65 interactions, providing a new theoretical basis for its clinical application. Full article

(This article belongs to the Special Issue Molecular Pharmacology of Medicinal Plants)

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27 pages, 915 KB

Open AccessReview

Insights into Cardiomyocyte Regeneration from Screening and Transcriptomics Approaches

by Daniela T. Fuller, Aaron H. Wasserman and Ruya Liu

Int. J. Mol. Sci. 2026, 27(2), 601; https://doi.org/10.3390/ijms27020601 - 7 Jan 2026

Abstract

Human adult cardiomyocytes (CMs) have limited regenerative capacity, posing a significant challenge in restoring cardiac function following substantial CM loss due to an acute ischemic event or chronic hemodynamic overload. Nearly half of patients show no improvement in left ventricular ejection fraction during [...] Read more.

Human adult cardiomyocytes (CMs) have limited regenerative capacity, posing a significant challenge in restoring cardiac function following substantial CM loss due to an acute ischemic event or chronic hemodynamic overload. Nearly half of patients show no improvement in left ventricular ejection fraction during recovery from acute myocardial infarction. At baseline, both humans and mice exhibit low but continuous cell turnover originating from the existing CMs. Moreover, myocardial infarction can induce endogenous CM cell cycling. Consequently, research has focused on identifying drivers of CM rejuvenation and proliferation from pre-existing CMs. High-throughput screening has facilitated the discovery of novel pro-proliferative targets through small molecules, microRNAs, and pathway-specific interventions. More recently, omics-based approaches such as single-nucleus RNA sequencing and spatial transcriptomics have expanded our understanding of cardiac cellular heterogeneity. The big-data strategies provide critical insights into why only a subset of CMs re-enter the cell cycle while most remain quiescent. In this review, we compare several high-throughput screening strategies used to identify novel targets for CM proliferation. We also summarize the benefits and limitations of various screening models—including zebrafish embryos, rodent CMs, human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), and cardiac organoids—underscoring the importance of integrating multiple systems to uncover new regenerative mechanisms. Further work is needed to identify translatable and safe targets capable of inducing functional CM expansion in clinical settings. By integrating high-throughput screening findings with insights into CM heterogeneity, this review provides a comprehensive framework for advancing cardiac regeneration research and guiding future therapeutic development. Full article

(This article belongs to the Special Issue Cardiac Repair and Regeneration: From Pathogenesis to Therapeutic Perspectives)

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24 pages, 1826 KB

Open AccessReview

The Role of Glucose-Dependent Insulinotropic Polypeptide (GIP) in Bone Metabolism

by Angyi Lin, Hideki Kitaura, Fumitoshi Ohori, Aseel Marahleh, Jinghan Ma, Ziqiu Fan, Kohei Narita, Kou Murakami and Hiroyasu Kanetaka

Int. J. Mol. Sci. 2026, 27(2), 600; https://doi.org/10.3390/ijms27020600 - 7 Jan 2026

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin hormone identified, best known for promoting glucose-stimulated insulin secretion. Increasing evidence has expanded its physiological relevance beyond glucose metabolism, revealing a significant role for GIP in the gut–bone axis. In vitro studies demonstrate that GIP [...] Read more.

Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin hormone identified, best known for promoting glucose-stimulated insulin secretion. Increasing evidence has expanded its physiological relevance beyond glucose metabolism, revealing a significant role for GIP in the gut–bone axis. In vitro studies demonstrate that GIP inhibits osteoclast differentiation and activity while promoting osteoblastic bone formation. Findings from genetic animal models and human variant analyses further support the essential role of endogenous GIP signaling in maintaining bone mass and quality. Exogenous administration of GIP suppresses the bone-resorption marker C-terminal telopeptide of type I collagen (CTX) and increases the bone-formation marker procollagen type I N-terminal propeptide (P1NP) in healthy individuals, reflecting an acute shift toward reduced bone resorption and enhanced bone formation. Moreover, GIP confers protection against bone deterioration in multiple pathological conditions, including postmenopausal osteoporosis, inflammatory bone loss, obesity, and diabetes, etc., suggesting therapeutic potential beyond physiological contexts. Recent evidence also shows that GIP attenuates orthodontic tooth movement by limiting mechanically induced osteoclast activity, highlighting its broader skeletal actions. In this review, we summarize recent advances regarding the role of GIP in bone metabolism, integrating evidence from cellular studies, animal models and human investigations, and discuss future directions for GIP-based interventions. Full article

(This article belongs to the Special Issue Diabetic Bone Disease: New Insights into Molecular Mechanisms and Therapeutic Approaches)

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14 pages, 371 KB

Open AccessArticle

Variants in IRF5 Increase the Risk of Primary Sjögren’s Syndrome in the Mexican Population

by Julian Ramírez-Bello, Isaac Alberto López-Briceño, Guillermo Valencia-Pacheco, Rosa Elda Barbosa-Cobos, Gabriela Hernández-Molina, Silvia Jiménez-Morales, Iván Sammir Aranda-Uribe, Isela Montúfar-Robles and Swapan K. Nath

Int. J. Mol. Sci. 2026, 27(2), 599; https://doi.org/10.3390/ijms27020599 - 7 Jan 2026

Abstract

Primary Sjögren’s syndrome (pSS) is an autoimmune disease characterized by inflammation and damage to salivary and lacrimal glands. Its etiology involves both genetic and environmental factors. Among susceptibility genes, IRF5 has been highlighted in European populations, but evidence in non-European groups remains limited. [...] Read more.

Primary Sjögren’s syndrome (pSS) is an autoimmune disease characterized by inflammation and damage to salivary and lacrimal glands. Its etiology involves both genetic and environmental factors. Among susceptibility genes, IRF5 has been highlighted in European populations, but evidence in non-European groups remains limited. This study evaluated whether IRF5 variants rs2004640G/T, rs2070197T/C, rs10954213G/A, and rs59110799G/T are associated with pSS susceptibility, clinical manifestations, or the presence of autoantibodies in a Mexican population. The diagnosis was confirmed by rheumatologists using the 2016 ACR–EULAR classification criteria for pSS. Genotyping was performed using TaqMan probes in 231 controls and 132 pSS patients from central Mexico. Associations were analyzed through binary logistic regression under different genetic models, adjusting for age and geographic origin. Clinical correlations were examined with SNPStats, and haplotypes were constructed using Haploview. Results showed that all four IRF5 variants were significantly associated with pSS susceptibility. Moreover, rs2004640, rs2070197, and rs10954213 variants were associated with arthritis, a frequent clinical manifestation in pSS patients. This represents the first evidence in a Latin American population demonstrating that IRF5 variants contribute to increased risk of developing pSS. These findings suggest ethnicity-specific genetic influences and highlight the importance of expanding research beyond European cohorts. Replication in larger samples and functional analyses are needed to confirm these associations and clarify their biological relevance. Full article

(This article belongs to the Special Issue Genetics and Omics in Autoimmune Diseases)

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17 pages, 2987 KB

Open AccessArticle

Citrus limon Peel Extract Modulates Redox Enzymes and Induces Cytotoxicity in Human Gastric Cancer Cells

by Rosarita Nasso, Rosario Rullo, Antonio D’Errico, Pierluigi Reveglia, Lucia Lecce, Annarita Poli, Paola Di Donato, Gaetano Corso, Emmanuele De Vendittis, Rosaria Arcone and Mariorosario Masullo

Int. J. Mol. Sci. 2026, 27(2), 598; https://doi.org/10.3390/ijms27020598 - 7 Jan 2026

Abstract

Gastric cancer remains a leading cause of cancer-related mortality worldwide. Citrus fruits are rich in polyphenols, exerting antioxidant and chemo-preventive activities, and lemon peel represents a valuable source of such bioactive compounds. Previous studies showed that Citrus limon peel extracts (LPE) inhibited the [...] Read more.

Gastric cancer remains a leading cause of cancer-related mortality worldwide. Citrus fruits are rich in polyphenols, exerting antioxidant and chemo-preventive activities, and lemon peel represents a valuable source of such bioactive compounds. Previous studies showed that Citrus limon peel extracts (LPE) inhibited the activity of some enzymes of the antioxidant system and reduced the interleukin-6-dependent invasiveness of gastric and colon cancer cells. In the present study, we have investigated the effects of LPE on the human gastric adenocarcinoma AGS and MKN-28 cells and on the activity of a crucial redox enzyme, catalase (CAT). Indeed, LPE significantly reduced the cell viability and clonogenic potential of the gastric cancer cells and induced morphological changes indicative of cytotoxicity. Moreover, LPE modulated the intracellular redox homeostasis by decreasing levels of the hydrogen peroxide-related reactive oxygen species (ROS) while increasing those of superoxide anions and decreasing levels of superoxide dismutases (SODs). Western blotting analysis revealed that LPE downregulated CAT, SOD-1, SOD-2, and monoamine oxidase A (MAO-A) protein expression level in both cell lines. Finally, the extract inhibited CAT activity in a dose-dependent manner (IC₅₀ = 0.008 ± 0.003 mg/mL; K_i = 0.012 ± 0.002 mg/mL). These findings indicate that LPE exerts cytotoxic and redox-modulating effects through the inhibition of antioxidant enzymes and the alteration of ROS balance. Therefore, the agro-industrial by-product LPE could be considered as a promising natural source of polyphenolic compounds with potential applications in the prevention and therapy of gastric cancer. Full article

(This article belongs to the Special Issue Natural Products in Lifestyle-Related Diseases: Molecular Mechanisms, Prevention and Treatments)

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11 pages, 2189 KB

Open AccessArticle

Assessment of Anxiety- and Depression-like Behaviors and Local Field Potential Changes in a Cryogenic Lesion Model of Traumatic Brain Injury

by Yeon Hee Yu, Yu Ran Lee, Dae-Kyoon Park, Beomjong Song and Duk-Soo Kim

Int. J. Mol. Sci. 2026, 27(2), 597; https://doi.org/10.3390/ijms27020597 - 7 Jan 2026

Abstract

Patients with traumatic brain injury (TBI) have an elevated risk of developing chronic psychiatric and behavioral disorders, including impairments in motor function, memory deficits, anxiety, and depression. Although a substantial body of work has addressed the treatment and rehabilitation of sensory, motor, and [...] Read more.

Patients with traumatic brain injury (TBI) have an elevated risk of developing chronic psychiatric and behavioral disorders, including impairments in motor function, memory deficits, anxiety, and depression. Although a substantial body of work has addressed the treatment and rehabilitation of sensory, motor, and cognitive symptoms after TBI, there is a relative scarcity of comprehensive behavioral assessments targeting neuropsychiatric manifestations in preclinical models. This study aims to investigate the connections between emotional sequelae after TBI and modifications in local field potentials (LFPs). Following cryogenic lesion-induced TBI, animals exhibited anxiety-like behaviors as assessed by the open field test (p < 0.001), light/dark box test (p < 0.001), and elevated plus maze test (p < 0.01). Depression-like behavior was observed using the forced swim test (p < 0.001). LFP analysis demonstrated a marked elevation in neural oscillatory activity associated with anxiety and depression in the contralateral hemisphere relative to the ipsilateral side (p < 0.001). These results indicate that the emotional consequences triggered by TBI may be linked to dysregulated synchronous neural activity between the ipsilateral and contralateral hemispheres. Full article

(This article belongs to the Special Issue New Molecular Insights into Ischemia/Reperfusion: 2nd Edition)

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48 pages, 1505 KB

Open AccessReview

The Role of Natural Compounds in Bladder Urothelial Carcinoma Treatment

by Hangfei Jiang, Yueyin Chen, Xi Zeng, Rui Yang, Feng Zhang, Huanling Zhang, Erxiang Zhang, Xuzhang Wu, Deye Yan and Chunping Yu

Int. J. Mol. Sci. 2026, 27(2), 596; https://doi.org/10.3390/ijms27020596 - 7 Jan 2026

Abstract

Bladder urothelial carcinoma (BUC) ranks among the most common malignant tumors of the urinary system, with alarmingly high incidence and mortality rates. Current clinical treatments face challenges such as strong chemotherapy resistance and limited response rates to immunotherapy, creating an urgent need for [...] Read more.

Bladder urothelial carcinoma (BUC) ranks among the most common malignant tumors of the urinary system, with alarmingly high incidence and mortality rates. Current clinical treatments face challenges such as strong chemotherapy resistance and limited response rates to immunotherapy, creating an urgent need for novel alternative therapies. Natural products, characterized by multi-targeted antitumor activity, low toxicity, and broad availability, have emerged as highly promising adjunctive or alternative strategies in cancer treatment. Extensive research has elucidated the antitumor activities of natural products, including inhibition of cancer cell proliferation, induction of apoptosis, and modulation of the immune microenvironment. What’s more, their bioactive components, such as terpenoids and polyphenols, can synergistically enhance therapeutic efficacy while reducing toxicity risks associated with traditional therapies. This review will examine the roles of terpenoids, phenolics, alkaloids, and other natural products in BUC treatment, to provide directions for future research. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

15 pages, 1873 KB

Open AccessArticle

Phosphatidylinositol 4-Kinase IIIβ: A Therapeutic Target for Contractile Dysfunction in Hypertrophic Cardiomyocytes

by Myrthe M. A. Willemars, Aomin Sun, Shujin Wang, Ozlenen Simsek Papur, Agnieszka Brouns-Strzelecka, Rick van Leeuwen, Sabina J. V. Vanherle, Dimitrios Kapsokalyvas, Jan F. C. Glatz, Dietbert Neumann, Miranda Nabben and Joost J. F. P. Luiken

Int. J. Mol. Sci. 2026, 27(2), 595; https://doi.org/10.3390/ijms27020595 - 7 Jan 2026

Abstract

Cardiac hypertrophy is an important risk factor for heart failure and is often accompanied by contractile dysfunction. While hypertrophic growth contributes to disease progression, the underlying molecular mechanisms remain incompletely understood. A proposed contributor is a metabolic shift toward glucose uptake, suggesting that [...] Read more.

Cardiac hypertrophy is an important risk factor for heart failure and is often accompanied by contractile dysfunction. While hypertrophic growth contributes to disease progression, the underlying molecular mechanisms remain incompletely understood. A proposed contributor is a metabolic shift toward glucose uptake, suggesting that kinases regulating this process, such as protein kinase D1 (PKD1) and downstream target phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), might be effective targets to mitigate cardiac hypertrophy-induced contractile dysfunction. We investigated whether PI4KIIIβ inhibition downregulates enhanced glucose uptake in hypertrophic cardiomyocytes and thereby treats cardiac hypertrophy-induced contractile dysfunction. Hypertrophy was induced in cultured adult rat cardiomyocytes and human stem cell-derived cardiomyocytes using either phenylephrine (PE) or adenoviral PKD1 overexpression. PE-induced hypertrophy was associated with increased mRNA expression of BNP, activation of hypertrophic signaling, morphological alterations, enhanced protein synthesis and glucose uptake, and impaired contractile function. Treatment with the PI4KIIIβ inhibitor MI14 prevented and reversed PE-stimulated glucose uptake and contractile dysfunction, while hypertrophic signaling, cell size, and protein synthesis remained unaffected. Similar effects on glucose uptake were observed in the PKD1 overexpression model. These findings suggest that targeting myocardial substrate metabolism via the PI4KIIIβ pathway, rather than hypertrophic growth itself, could be a promising strategy to treat hypertrophy-induced contractile dysfunction. Full article

(This article belongs to the Special Issue Metabolic Crossroads in Cardiac Pathophysiology)

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17 pages, 5375 KB

Open AccessArticle

Anti-Fibrotic and Anti-Inflammatory Effects of Hesperidin in an Ex Vivo Mouse Model of Early-Onset Liver Fibrosis

by Ilenia Saponara, Miriam Cofano, Valentina De Nunzio, Giusy Bianco, Raffaele Armentano, Giuliano Pinto, Emanuela Aloisio Caruso, Matteo Centonze and Maria Notarnicola

Int. J. Mol. Sci. 2026, 27(2), 594; https://doi.org/10.3390/ijms27020594 - 7 Jan 2026

Abstract

Liver fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) proteins as a wound-healing response to chronic liver injury, leading to tissue scarring and organ dysfunction. Natural compounds, including phytonutrients and polyphenols, have been shown to exert protective effects by reducing [...] Read more.

Liver fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) proteins as a wound-healing response to chronic liver injury, leading to tissue scarring and organ dysfunction. Natural compounds, including phytonutrients and polyphenols, have been shown to exert protective effects by reducing profibrotic biomarkers in vitro and in vivo models. Here, we provide the first evidence that the polyphenol hesperidin (HE) can counteract the onset of fibrotic responses in an ex vivo mouse liver fibrosis model induced by Transforming Growth Factor-β1 (TGF-β1) (5 ng/mL). Notably, HE drives early ECM remodeling in the fibrotic mouse liver tissue. Fibrosis-related parameters were assessed at both the transcriptional and translational levels after treatment with HE at increasing concentrations of 50, 75, and 100 µg/mL. Interestingly, HE at 75 µg/mL exerted the strongest beneficial effect, significantly decreasing the gene expression of α-SMA, SERPINH-1, FN-1, VIM and COL1A1 and counteracting the TGF-β1-induced upregulation of key fibrotic markers, including α-SMA, COL1A2, and VIM, reflecting its capacity to attenuate myofibroblast activation and ECM production and modulating membrane lipid peroxidation. Furthermore, HE inhibited SMAD2 phosphorylation, suggesting that its antifibrotic activity may involve the modulation of the TGF-β/SMAD signaling pathway. Moreover, it promoted an anti-inflammatory response, due to a decrease in IL-1β and IL-6 expression. Our study highlights the potential of the ex vivo model as a platform for evaluating the antifibrotic efficacy of natural molecules, and it suggests significant translational implications and new opportunities for developing innovative therapeutic strategies. Full article

(This article belongs to the Section Molecular Biology)

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19 pages, 4649 KB

Open AccessArticle

Physiological and Molecular Response Mechanisms of Betaphycus gelatinus to Low- and High-Temperature Stress

by Yongqiu Deng, Siqi Xu, Kangtai Liao and Linwen He

Int. J. Mol. Sci. 2026, 27(2), 593; https://doi.org/10.3390/ijms27020593 - 7 Jan 2026

Abstract

Betaphycus gelatinus, a member of the Eucheumatoideae, serves as the primary source for carrageenan extraction and has significant economic value. The growth and reproduction of B. gelatinus are significantly impacted by seasonal fluctuations in seawater temperature. To explore its adaptive mechanisms under [...] Read more.

Betaphycus gelatinus, a member of the Eucheumatoideae, serves as the primary source for carrageenan extraction and has significant economic value. The growth and reproduction of B. gelatinus are significantly impacted by seasonal fluctuations in seawater temperature. To explore its adaptive mechanisms under temperature stress, we cultured the algae at 15 °C (Low temperature, LT), 27 °C (Medium temperature, MT), and 36 °C (High temperature, HT) for 2 h and conducted subsequent physiological, transcriptomics, and metabolomics analyses. The photosynthetic performance of B. gelatinus significantly declined under both LT and HT stress conditions. Carotenoid content increased significantly under LT conditions, while chlorophyll a showed no significant change. Phycocyanin and phycoerythrin decreased significantly under LT conditions, but there was no significant difference under HT conditions. Under LT stress, glutathione (GSH) levels, ascorbate peroxidase (APX) activity, and catalase (CAT) activity all increased significantly. Under HT stress, APX and CAT activities increased significantly, while superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels remained unchanged. Transcriptomics and metabolomics analyses suggested that photosynthesis, carbohydrate metabolism, amino acid biosynthesis, porphyrin metabolism, and vitamin B6 metabolism are involved in the acute temperature stress response of B. gelatinus. Under both HT and LT, most genes in the targeted metabolic pathways were significantly downregulated (p < 0.05), while only a few were upregulated. Specifically, in carbohydrate metabolism, only nine genes were upregulated, while all others were downregulated. Moreover, all the genes involved in photosynthesis, photosynthetic carbon fixation, arginine biosynthesis, and porphyrin metabolism were downregulated. In contrast, only four genes involved in GSH metabolism, alanine, aspartate, and glutamate metabolism, and glycine, serine, and threonine metabolism were upregulated. These results suggest that temperature stress markedly suppresses the transcription of key genes in these pathways and that the few upregulated genes in these pathways may contribute to compensatory mechanisms or regulatory network reprogramming during stress responses. These findings help clarify how B. gelatinus adapts to different temperature stresses and provide a basis for developing improved germplasm to support stable production under climate variability. Full article

(This article belongs to the Section Molecular Biology)

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33 pages, 3255 KB

Open AccessArticle

Integrated Blood Biomarker and Neurobehavioural Signatures of Latent Neuroinjury in Experienced Military Breachers Exposed to Repetitive Low-Intensity Blast

by Alex P. Di Battista, Maria Y. Shiu, Oshin Vartanian, Catherine Tenn, Ann Nakashima, Janani Vallikanthan, Timothy Lam and Shawn G. Rhind

Int. J. Mol. Sci. 2026, 27(2), 592; https://doi.org/10.3390/ijms27020592 - 6 Jan 2026

Abstract

Repeated exposure to low-level blast overpressure (BOP) during controlled detonations is an emerging occupational health concern for military breachers and Special Operations Forces personnel, given accumulating evidence that chronic exposure may produce subtle, subclinical neurotrauma. This study derived a latent neuroinjury construct integrating [...] Read more.

Repeated exposure to low-level blast overpressure (BOP) during controlled detonations is an emerging occupational health concern for military breachers and Special Operations Forces personnel, given accumulating evidence that chronic exposure may produce subtle, subclinical neurotrauma. This study derived a latent neuroinjury construct integrating three complementary domains of brain health—post-concussive symptoms, working-memory performance, and circulating biomarkers—to determine whether breachers exhibit coherent patterns of neurobiological alteration. Symptom severity was assessed using the Rivermead Post-Concussion Questionnaire (RPQ), and working memory was assessed with the N-Back task and a panel of thirteen neuroproteomic biomarkers was measured reflecting astroglial activation, neuronal and axonal injury, oxidative stress, inflammatory signaling, and neurotrophic regulation. Experienced Canadian Armed Forces breachers with extensive occupational BOP exposure were compared with unexposed controls. Bayesian latent-variable modeling provided probabilistic evidence for a chronic, subclinical neurobiological signal, with the strongest contributions arising from self-reported symptoms and smaller but consistent contributions from the biomarker domain. Working-memory performance did not load substantively on the latent factor. Several RPQ items and circulating biomarkers showed robust loadings, and the latent neuroinjury factor was elevated in breachers relative to controls (97% posterior probability). The pattern is broadly consistent with subclinical neurobiological stress in the absence of measurable cognitive impairment, suggesting early or compensated physiological alterations rather than overt dysfunction. This multidomain, biomarker-informed framework provides a mechanistically grounded and scalable approach for identifying subtle neurobiological strain in military personnel routinely exposed to repetitive low-level blast. It may offer value for risk stratification, operational health surveillance, and the longitudinal monitoring of neurobiological change in high-risk occupations. Full article

(This article belongs to the Section Molecular Neurobiology)

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20 pages, 1618 KB

Open AccessReview

Cholesterol Metabolism: An Ally in the Development and Progression of Cervical Cancer

by Imelda Martínez-Ramírez, J. Omar Muñoz-Bello, Adriana Contreras-Paredes, Elías Parra-Hernández, Adela Carrillo-García and Marcela Lizano

Int. J. Mol. Sci. 2026, 27(2), 591; https://doi.org/10.3390/ijms27020591 - 6 Jan 2026

Abstract

Despite screening programs and vaccination campaigns, cervical cancer (CC) remains a health problem worldwide. The involvement of the E6 and E7 oncoproteins of Human Papillomavirus (HPV) is crucial for the development and progression of this type of cancer. Metabolic reprogramming by cancer cells [...] Read more.

Despite screening programs and vaccination campaigns, cervical cancer (CC) remains a health problem worldwide. The involvement of the E6 and E7 oncoproteins of Human Papillomavirus (HPV) is crucial for the development and progression of this type of cancer. Metabolic reprogramming by cancer cells has gained relevance in the last decade due to its ability to promote cell growth, survival, invasion, metastasis, and resistance to therapy. In this review, we focus on alterations in cholesterol metabolism that significantly influence the development and progression of CC, as well as the clinical outcome of patients. Furthermore, evidence from comprehensive omics studies suggesting that E6 and E7 are involved in the exacerbation of elements related to cholesterol metabolism is analyzed. Preclinical and clinical studies are also discussed that demonstrate that cholesterol metabolism is a potential therapeutic target, highlighting its impact on reducing tumor growth, altering the tumor microenvironment, and improving antitumor immunity. Full article

(This article belongs to the Special Issue Molecular Insights and Treatments for Gynecological Cancers)

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26 pages, 377 KB

Open AccessReview

Airborne Radioiodine: A Comparative View of Chemical Forms in Medicine, Nuclear Industry, and Fallout Scenarios

by Klaus Schomäcker, Ferdinand Sudbrock, Thomas Fischer, Felix Dietlein, Markus Dietlein, Philipp Krapf and Alexander Drzezga

Int. J. Mol. Sci. 2026, 27(2), 590; https://doi.org/10.3390/ijms27020590 - 6 Jan 2026

Abstract

Airborne iodine-131 plays a pivotal role in both nuclear medicine and nuclear safety due to its radiotoxicity, volatility, and affinity for the thyroid gland. Although the total exhaled activity after medical I-131 therapy is minimal, over 95% of this activity appears in volatile [...] Read more.

Airborne iodine-131 plays a pivotal role in both nuclear medicine and nuclear safety due to its radiotoxicity, volatility, and affinity for the thyroid gland. Although the total exhaled activity after medical I-131 therapy is minimal, over 95% of this activity appears in volatile organic forms, which evade standard filtration and reflect metabolic pathways of iodine turnover. Our experimental work in patients and mice confirms the metabolic origin of these species, modulated by thyroidal function. In nuclear reactor environments, both under routine operation and during accidents, organic iodides such as [¹³¹I]CH₃I have also been identified as major airborne components, often termed “penetrating iodine” due to their low adsorption to conventional filters. This review compares the molecular speciation, environmental persistence, and dosimetric impact of airborne I-131 across clinical, technical, and accidental release scenarios. While routine reactor emissions yield negligible doses (<0.1 µSv/year), severe nuclear incidents like Chernobyl and Fukushima have resulted in significant thyroid exposures. Doses from these events ranged from tens of millisieverts to several Sieverts, particularly in children. We argue that a deeper understanding of chemical forms is essential for effective risk assessment, filtration technology, and emergency preparedness. Iodine-131 exemplifies the dual nature of radioactive substances: in nuclear medicine its radiotoxicity is therapeutically harnessed, whereas in industrial or reactor contexts it represents an unwanted hazard. The same physicochemical properties that enable therapeutic efficacy also determine, in the event of uncontrolled release, the range, persistence, and the potential for unwanted radiotoxic exposure in the general population. In nuclear medicine, exhaled activity after radioiodine therapy is minute but largely organically bound, reflecting enzymatic and metabolic methylation processes. During normal reactor operation, airborne iodine levels are negligible and dominated by inorganic vapors efficiently captured by filtration systems. In contrast, major accidents released large fractions of volatile iodine, primarily as elemental [¹³¹I]I₂ and organically bound iodine species like [¹³¹I]CH₃I. The chemical nature of these compounds defined their atmospheric lifetime, transport distance, and deposition pattern, thereby governing the thyroid dose to exposed populations. Chemical speciation is the key determinant across all scenarios. Exhaled iodine in medicine is predominantly organic; routine reactor releases are negligible; severe accidents predominantly release elemental and organic iodine that drive environmental transport and exposure. Integrating these domains shows how chemical speciation governs volatility, mobility, and bioavailability. The novelty of this review lies not in introducing new iodine chemistry, but in the systematic comparative synthesis of airborne radioiodine speciation across medical therapy, routine nuclear operation, and severe accident scenarios, identifying chemical form as the unifying determinant of volatility, environmental transport, and dose. Full article

(This article belongs to the Topic Environmental Toxicology and Human Health—2nd Edition)

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Int. J. Mol. Sci., Volume 27, Issue 2 (January-2 2026) – 64 articles

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