International Journal of Molecular Sciences

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18 pages, 2423 KB

Open AccessArticle

UK Biobank-Based Genetic and Proteomic Network Insights into Metabolic Dysfunction-Associated Steatotic Liver Disease Pathogenesis

by Sang Wook Kang, Su Kang Kim, Ju Yeon Ban and Min Su Park

Int. J. Mol. Sci. 2026, 27(9), 3920; https://doi.org/10.3390/ijms27093920 - 28 Apr 2026

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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic disorder shaped by genetic variants and network-level interactions beyond obesity and insulin resistance. This study aimed to define the genetic and proteomic architecture of MASLD by integrating GWAS and plasma proteomic [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic disorder shaped by genetic variants and network-level interactions beyond obesity and insulin resistance. This study aimed to define the genetic and proteomic architecture of MASLD by integrating GWAS and plasma proteomic profiling from the UK Biobank. Genome-wide association analyses were conducted under additive and dominant models, with functional annotations performed using SIFT, PolyPhen-2, PROVEAN, REVEL, CADD, MutationTaster, and conservation metrics (GERP++, phyloP, phastCons, and B-statistic). Differential protein expression was assessed using the Olink^® platform, and STRING was applied for protein–protein interaction analysis. MASLD patients showed male predominance and significant differences in hepatic (AST, ALT, GGT, PDFF), metabolic (glucose, triglycerides, TyG index), and inflammatory markers (CRP, neutrophils, NLR, CAR). GWAS confirmed PNPLA3 (rs738409, I148M) and TM6SF2 (rs58542926, E167K) as major risk variants, while SAMM50 and NCAN showed weaker but conserved associations. Proteomics revealed downregulation of IGFBP2, IGFBP1, PON3, CKB, and APOF and upregulation of CPM, IGSF9, GUSB, ACY1, AFM, LEP, and GSTA1/3. PPI analysis identified ADIPOQ, LEP, FGF21, and ADH1B as central hubs in metabolic and inflammatory regulation. MASLD should be regarded as a network disease involving lipid metabolism, insulin/IGF signaling, mitochondrial function, and ECM–inflammatory pathways. These findings highlight PNPLA3 and TM6SF2 as major genetic drivers, while SAMM50, NCAN, and peripheral proteins contribute regulatory roles, suggesting novel biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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18 pages, 4861 KB

Open AccessArticle

Emodin Promoted Intestinal Secretion of GLP-1 and Limited Cognitive Deficits in Young Bilateral Ovariectomized Rats

by Xin-Yuan Liu, Chao-Yuan Ye, Yuan-Cheng Liu, Meng-Ying Zhao, Ya-Nan Li, Li Lin, Yan-Jun Du, Ying-Yan Fang and Qing Tian

Int. J. Mol. Sci. 2026, 27(8), 3414; https://doi.org/10.3390/ijms27083414 - 10 Apr 2026

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Abstract

Estrogen deficiency is an established risk factor for menopausal brain dysfunctions in women. Urgent exploration of drugs is needed to improve estrogen deficiency-related brain dysfunctions without the side effects of estrogen supplements. Three-month-old rats had bilateral ovariectomy (OVX) performed and were treated with [...] Read more.

Estrogen deficiency is an established risk factor for menopausal brain dysfunctions in women. Urgent exploration of drugs is needed to improve estrogen deficiency-related brain dysfunctions without the side effects of estrogen supplements. Three-month-old rats had bilateral ovariectomy (OVX) performed and were treated with emodin (EMO, 80 mg/kg/day) and 17 β-estradiol (EST, 0.5 mg/kg/day). Brain functions were evaluated by cognition and emotion-related behavioral tests. Levels of glucagon-like peptide-1 (GLP-1) and estrogen in blood, mRNA levels of estrogen receptor (ER) α, ERβ, GLP-1 receptor (GLP-1R), proprotein convertase subtilisin/kexin type 1 (PCSK1) and proglucagon (proGCG) in intestinal segments, and brain ERα and GLP-1R levels were evaluated. Contractions of isolated intestinal segments were recorded. Additionally, an ERβ antagonist, PHTPP (200 μg/kg/day), was used to clarify the role of ERβ. EST and EMO significantly ameliorated cognition deficit and depressive behaviors in OVX rats, and reduced neuronal loss and synaptic abnormalities in the hippocampus and prefrontal cortex. The blood GLP-1 levels of sham operation rats (sham, 3.09 pg/mL), EMO-treated (2.57 pg/mL) and EST-treated OVX rats (2.64 pg/mL), were higher than that of OVX rats (1.03 pg/mL). EMO had no effect on the blood estrogen level. Furthermore, EMO up-regulated mRNA levels of ERβ in ileum, colon, and cerebral GLP-1R level, while EST increased mRNA levels of ERβ in colon and cerebral ERα level. In vitro intestinal segment spontaneous contraction tests revealed that EMO reduced contraction amplitudes in isolated intestinal segments from OVX rats, with the ileum and proximal colon showing greater sensitivity to EMO. The ileum and colon segments from OVX rats were less sensitive to EST as compared to those of normal rats. Upon PHTPP intervention, the up-regulated intestinal mRNA levels of ERβ, PCSK1, proGCG, blood GLP-1 level by EMO, and the beneficial effects of EMO in abnormal behaviors of OVX rats were significantly inhibited. Overall, it was found that EMO up-regulated blood GLP-1 level via intestinal Erβ-dependent mechanism and increased brain GLP-1R level, which may be involved in the neuroprotection of EMO in OVX animals. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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16 pages, 670 KB

Open AccessArticle

Expression of Hypoxia-Inducible Factor 1a (HIF-1a), Regulatory T Cells (Treg) and T Helper 17 Cells (Th17) in PCOS Phenotype D Patients from Polish Population

by J. Kuliczkowska-Płaksej, D. Szymczak, J. Halupczok-Żyła, M. Strzelec, A. Podsiadły, N. Słoka, M. Bolanowski, B. Stachowska, A. Zdrojowy-Wełna and A. Jawiarczyk-Przybyłowska

Int. J. Mol. Sci. 2026, 27(7), 3108; https://doi.org/10.3390/ijms27073108 - 29 Mar 2026

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Abstract

Polycystic ovary syndrome (PCOS) is associated with reproductive, metabolic, and inflammatory disturbances. Alterations in T-cell subpopulations—particularly increased T helper 17 cells (Th17) and decreased regulatory T cells (Treg)—have been reported in PCOS; however, data on normoandrogenic phenotype D remain limited. Hypoxia-inducible factor 1α [...] Read more.

Polycystic ovary syndrome (PCOS) is associated with reproductive, metabolic, and inflammatory disturbances. Alterations in T-cell subpopulations—particularly increased T helper 17 cells (Th17) and decreased regulatory T cells (Treg)—have been reported in PCOS; however, data on normoandrogenic phenotype D remain limited. Hypoxia-inducible factor 1α (HIF-1α), a key regulator of hypoxic response, also influences immune and metabolic processes and may affect the Treg/Th17 balance. To assess Treg and Th17 abundance, HIF-1α expression within these cells, and their ratios in women with phenotype D PCOS compared with healthy controls. The study included 49 women with phenotype D PCOS and 40 controls comparable in terms of age and BMI. Anthropometric, hormonal, metabolic, and inflammatory parameters were evaluated. Peripheral T-cell subsets and intracellular HIF-1α expression were analyzed by multiparameter flow cytometry. Absolute numbers of Treg and Th17 cells did not differ between groups. However, PCOS patients showed significantly higher Treg/Th17 and HIF-1α-positive Treg/HIF-1α-positive Th17 ratios. HIF-1α-positive Treg cells correlated positively with adiposity and insulin resistance markers; however, after False Discovery Rate (FDR) correction, correlations no longer remained statistically significant. Despite normoandrogenemia, PCOS patients exhibited higher hs-CRP levels. Phenotype D PCOS is characterized by altered immune cell ratios rather than absolute T-cell differences, suggesting distinct immunological features and persistent low-grade inflammation. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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28 pages, 1251 KB

Open AccessArticle

Analysis of Antimicrobial Peptide Expression Under Acute and Chronic Alcohol Exposure: A Cross-Sectional Study and a Systematic Review of the Literature

by Maura Rojas-Pirela, Cristian Herrera-Flores, Pilar Costa-Alba, Daniel Salete-Granado, María-Lourdes Aguilar, David Puertas-Miranda, Beatriz Cicuéndez, María-Ángeles Pérez-Nieto, Candy Pérez-Albornoz, Cintia Folgueira, Alfonso Mora, Guadalupe Sabio and Miguel Marcos

Int. J. Mol. Sci. 2026, 27(4), 2026; https://doi.org/10.3390/ijms27042026 - 20 Feb 2026

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Abstract

Alcohol exposure affects immune regulation and tissue homeostasis. Antimicrobial peptides (AMPs) are essential components of innate immunity, not only defending against pathogens but also modulating processes such as inflammation. However, their tissue-specific regulation in response to alcohol remains poorly characterized, particularly in humans [...] Read more.

Alcohol exposure affects immune regulation and tissue homeostasis. Antimicrobial peptides (AMPs) are essential components of innate immunity, not only defending against pathogens but also modulating processes such as inflammation. However, their tissue-specific regulation in response to alcohol remains poorly characterized, particularly in humans after acute intoxication. We evaluated the expression of AMPs in the peripheral blood of patients with alcohol use disorder (AUD, n = 9), individuals with acute alcohol consumption (AAC, n = 9), and controls using quantitative polymerase chain reaction (qPCR). Additionally, we analyzed AMP expression in selected tissues of mice exposed to chronic ethanol feeding (National Institute on Alcohol Abuse and Alcoholism model for 5 days) and performed a systematic review of AMP regulation in alcohol-related disorders (2005–2025; n = 36 studies, reflecting a limited and heterogeneous body of available evidence). Human cathelicidin antimicrobial peptide (LL-37), lipopolysaccharide-binding protein (LBP), and bactericidal/permeability-increasing protein (BPI) were significantly upregulated in patients with AUD, whereas LL-37 and LBP were significantly upregulated in AAC. In the livers of ethanol-fed mice, LEP2, LCN2, and LBP levels were markedly increased, whereas LL-37 and LEP1 were downregulated. Duodenal tissue exhibited upregulation of DEFB1. In adipose tissue, DEFA2 was significantly increased in peripheral depots, whereas only LCN2 was upregulated in brain tissue. The systematic review demonstrated complex, heterogeneous, and organ-dependent AMP regulation and also highlighted the paucity of human data on AAC, a gap that our study partially addresses. Our results are consistent with the hypothesis that selected AMPs may serve as candidate markers of organ damage or microbial translocation and as possible therapeutic targets, a hypothesis that requires confirmation in larger, adequately powered studies. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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21 pages, 6543 KB

Open AccessArticle

Transplantation of Soluble Epoxide Hydrolase Inhibitor-Treated Human Brown Adipocytes Promotes Adipose Tissue Activation in High-Fat-Diet-Fed Nude Mice

by Haoying Wu, Xinyun Xu, Jiangang Chen, Christophe Morisseau, Bruce D. Hammock, Yu-Hua Tseng and Ling Zhao

Int. J. Mol. Sci. 2026, 27(3), 1440; https://doi.org/10.3390/ijms27031440 - 31 Jan 2026

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Abstract

Brown adipose tissue (BAT) plays a key role in non-shivering thermogenesis and is a promising target for enhancing energy expenditure to combat obesity. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme that catalyzes the conversion of epoxy fatty acids into less active diols. [...] Read more.

Brown adipose tissue (BAT) plays a key role in non-shivering thermogenesis and is a promising target for enhancing energy expenditure to combat obesity. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme that catalyzes the conversion of epoxy fatty acids into less active diols. We have reported that local administration of the sEH inhibitor, t-TUCB, to the endogenous interscapular BAT (iBAT) of diet-induced obese mice decreased serum triglycerides and enhanced the expression of essential genes associated with lipid metabolism. Here, the effects of sEH inhibition by t-AUCB were assessed on human brown adipocyte (HuBr) differentiation and in nude mice transplanted with t-AUCB-treated HuBr. HuBr cells were differentiated with t-AUCB (1–10 µM) or the vehicle (0.1% DMSO). HuBr differentiated with t-AUCB at 5 μM (AUCB 5) or DMSO was mixed with matrix gel and transplanted into the nude mice. The mice were then fed a high-fat diet for eight weeks. The mice receiving AUCB 5-treated HuBr exhibited markedly reduced lipid accumulation in the iBAT compared with DMSO or matrix-only controls, along with increased protein expression of thermogenic PGC1α and UCP1, fatty acid transporter CD36, and CPT1A in the iBAT, while the NFκB inflammatory pathways were suppressed in both the AUCB 5 and DMSO groups. Moreover, the PGC1α and CPT1A protein levels were elevated, and the adipocyte sizes were decreased in the epididymal white adipose tissue of the AUCB 5 group. Our findings indicate that the transplantation of HuBr treated with AUCB 5 may stimulate thermogenesis, enhance lipid metabolism, and reduce inflammation in iBAT. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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20 pages, 12327 KB

Open AccessArticle

Deletion of RhoGDI Protects Against Hepatic Steatosis via Improved Mitochondrial Metabolism in Mice

by Yongzhi Wang, Yuanqi Zhou, Yifan Xu, Chen Wang, Shuo Meng, Honglin Li, Huifang Tang and Jian Zhang

Int. J. Mol. Sci. 2026, 27(3), 1161; https://doi.org/10.3390/ijms27031161 - 23 Jan 2026

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Abstract

The global incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising alongside epidemics of diabetes and obesity. Rho GDP-dissociation inhibitor (RhoGDI) is now recognized to play dual regulatory roles in disease. A deeper understanding of its mechanistic contributions in MASLD could offer [...] Read more.

The global incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising alongside epidemics of diabetes and obesity. Rho GDP-dissociation inhibitor (RhoGDI) is now recognized to play dual regulatory roles in disease. A deeper understanding of its mechanistic contributions in MASLD could offer critical insights for developing novel therapies against this growing health burden. Immunohistochemical staining was used to examine RhoGDI expression in liver tissues from patients with MASLD. Hepatocyte-specific deletion of Arhgdia (the gene encodes RhoGDI) was generated in mice, and they subjected to NASH diets to induce hepatic steatosis. Transcriptomic sequencing was carried out to identify altered pathways in the Arhgdia-deficient mice, followed by functional investigations of downstream signaling and mitochondrial performance. Finally, the therapeutic potential of a candidate compound was evaluated in the MASLD model. The expression level of RhoGDI was significantly upregulated, and hepatocyte-specific deletion of Arhgdia (the gene encodes RhoGDI) attenuated hepatic lipid accumulation and fibrotic progression. The RNA sequencing analysis revealed that RhoGDI deficiency suppressed the hepatic steroid hormone biosynthesis pathway. It was demonstrated that RhoGDI plays a crucial role in maintaining mitochondrial function, since hepatocyte-specific knockout of Arhgdia significantly reversed mitochondrial dysfunction in mice. Furthermore, a natural compound was found to alleviate hepatic steatosis and inflammation in MASLD mice by targeting RhoGDI. This finding demonstrates that Arhgdia deletion confers protection against the progression of MASLD by reducing hepatic lipid accumulation and enhances mitochondrial β-oxidation in hepatocytes establishing RhoGDI as a critical regulator of MASLD pathogenesis and highlighting its potential as a therapeutic target for metabolic liver diseases. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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14 pages, 2008 KB

Open AccessArticle

Pilot Investigation on the Metabolic Effects of Cimicifuga racemosa Extract Ze 450 and Voluntary Physical Activity in Female Rats

by Elisabeth Habersatter, Tihomir Kostov, Nele Laing, Jürgen Drewe, Georg Boonen, Veronika Butterweck and Patrick Rene Diel

Int. J. Mol. Sci. 2026, 27(2), 977; https://doi.org/10.3390/ijms27020977 - 19 Jan 2026

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Abstract

Cimicifuga racemosa extracts, particularly the ethanolic extract Ze 450, are widely used to alleviate menopausal symptoms, such as hot flushes and excessive sweating. While their clinical efficacy is well established, the effects of these interventions on systemic energy metabolism remain unclear. This pilot [...] Read more.

Cimicifuga racemosa extracts, particularly the ethanolic extract Ze 450, are widely used to alleviate menopausal symptoms, such as hot flushes and excessive sweating. While their clinical efficacy is well established, the effects of these interventions on systemic energy metabolism remain unclear. This pilot study investigated the impact of Ze 450 on body composition, metabolic markers, and voluntary physical activity in non-ovariectomized female Wistar rats. Animals (N = 36) received Ze 450 at either 30 mg/kg or 130 mg/kg body weight, with or without access to voluntary wheel running over four weeks. Neither treatment influenced body weight gain or final body weight, indicating normal growth across all groups. Post-mortem analyses included visceral fat mass, serum cholesterol, and leptin levels. Both Ze 450 and running reduced visceral fat mass, adipocyte size, and circulating leptin levels, suggesting that they share overlapping mechanisms. Serum cholesterol was significantly lowered by running but remained unaffected by Ze 450, while liver weight and alanine aminotransferase activity were unchanged, confirming hepatic safety. Collectively, Ze 450 improved key metabolic parameters related to adiposity and appetite without affecting hepatic integrity, highlighting its potential as a safe, non-hormonal metabolic modulator complementary to physical activity. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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19 pages, 1444 KB

Open AccessArticle

Rosa x hybrida: A New Tool for Functional Food Development with Triple-Negative Breast Antitumoral Implications

by Lorenzo Rivas-Garcia, Tamara Y. Forbes-Hernández, Pablo Cristóbal-Cueto, David Tébar-García, Alfonso Salinas-Castillo, Ana Cristina Abreu, Ignacio Fernández, Pilar Aranda, Juan Llopis, Elena Nebot-Valenzuela, Eva M. Galan-Moya and Cristina Sánchez-González

Int. J. Mol. Sci. 2026, 27(2), 907; https://doi.org/10.3390/ijms27020907 - 16 Jan 2026

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Abstract

Edible flowers have garnered increasing attention due to their high content of bioactive compounds, making them promising candidates for biomedical and functional food applications. This work evaluated the metabolomic data of fresh Rosa x hybrida petals, revealing seven types of metabolites, including amino [...] Read more.

Edible flowers have garnered increasing attention due to their high content of bioactive compounds, making them promising candidates for biomedical and functional food applications. This work evaluated the metabolomic data of fresh Rosa x hybrida petals, revealing seven types of metabolites, including amino acids, organic acids, vitamins, sugars, phenolic acids, and flavonoids. Notably, quercetin, kaempferol and their derivatives were the main flavonoids determined. Furthermore, in vitro studies were conducted to evaluate the potential antiproliferative effects against triple-negative breast cancer (TNBC). Thus, the methanolic extract derived from Rosa x hybrida petals demonstrated significant antitumoral activity against both sensitive and resistant TNBC cells, as evidenced by reduced MTT metabolization, colony formation, and wound healing activity. Furthermore, the cell death mechanism associated with the petal extract was studied. The antiproliferative activity was mediated by reactive oxygen species generation, triggering cell death mechanisms such as apoptosis and autophagy. In conclusion, these results propose Rosa x hybrida could be a new tool for nutraceuticals and functional food production. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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17 pages, 2610 KB

Open AccessArticle

Cross-Expression of Thymic and Parathyroid Hormone Receptors Supports the Hypothesis of a Parathyroid–Thymus Port System

by Maria-Paula Comanescu, Otilia Boișteanu, Delia Hînganu, Ludmila Lozneanu, Fabian Cezar Lupu, Roxana Grigorovici, Alexandru Grigorovici, Tiberiu Lunguleac and Marius Valeriu Hînganu

Int. J. Mol. Sci. 2025, 26(23), 11561; https://doi.org/10.3390/ijms262311561 - 28 Nov 2025

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Abstract

The thymus and parathyroid glands share a common embryological origin from the third pharyngeal pouch, yet their potential morphological and functional interconnections remain insufficiently explored. We conducted a comparative study integrating immunohistochemistry (IHC) and SEM on human thymic tissue, parathyroid adenomas, and parathyroid [...] Read more.

The thymus and parathyroid glands share a common embryological origin from the third pharyngeal pouch, yet their potential morphological and functional interconnections remain insufficiently explored. We conducted a comparative study integrating immunohistochemistry (IHC) and SEM on human thymic tissue, parathyroid adenomas, and parathyroid tissue excised during thyroidectomy. IHC staining targeted Thymosin-α1, CaSR, and PTH1R, with semi-quantitative evaluation of staining intensity and distribution. SEM analysis was performed at multiple magnifications to assess stromal organization and microvascular relief. Non-parametric statistical tests (Kruskal–Wallis with Mann–Whitney post hoc comparisons) were applied to clinical and laboratory data across the three cohorts. Scanning electron microscopy (SEM) revealed convergent ultrastructural features between thymus and parathyroid, including reticular stromal meshes and vascular grooves suggestive of comparable microcirculatory organization. IHC demonstrated robust Thymosin expression in thymus, with heterogeneous/apical distribution in parathyroid tissue; CaSR showed strong membranous and cytoplasmic expression in parathyroid, but weak diffuse signal in thymus; PTH1R exhibited low-to-moderate expression in thymus and moderate heterogeneous expression in parathyroid, with apical accentuation in adenomas. Statistical analysis confirmed significant differences in ionized calcium, PTH, and anti-AChR titers among the three cohorts (all p < 0.001), while TSH and calcitonin did not differ significantly. Our findings strengthen the hypothesis of a morpho-functional parathyroid–thymus axis. The robust parathyroid expression of CaSR and PTH1R aligns with established roles in calcium–PTH homeostasis, while the novel detection of Thymosin in parathyroid tissue suggests an expanded functional repertoire. These results highlight a continuum between embryological proximity and adult tissue cross-talk, with potential clinical implications for parathyroid pathology and immune regulation. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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18 pages, 2611 KB

Open AccessArticle

Accessing Altered Metabolic Profile in Acute Deep Vein Thrombosis Through Nuclear Magnetic Resonance Spectroscopy

by Letícia Queiroz da Silva, Thyerre Santana da Costa, Lucas Gelain Martins, Silmara Aparecida de Lima Montalvão, Stephany Cares Huber, Sandra Martins Silva Soares, Ljubica Tasic and Joyce Maria Annichino-Bizzacchi

Int. J. Mol. Sci. 2025, 26(23), 11345; https://doi.org/10.3390/ijms262311345 - 24 Nov 2025

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Abstract

Deep venous thrombosis (DVT) is characterized by the formation of a thrombus within deep veins. The unmet need to identify new biomarkers and causal risk factors in DVT patients has led to the use of novel techniques, such as metabolite analyses. This study [...] Read more.

Deep venous thrombosis (DVT) is characterized by the formation of a thrombus within deep veins. The unmet need to identify new biomarkers and causal risk factors in DVT patients has led to the use of novel techniques, such as metabolite analyses. This study aimed to characterize metabolic alterations in acute DVT patients using ¹H-NMR spectroscopy and determine the persistence of these changes over a six-month follow-up. Metabolomics, particularly ¹H-NMR spectroscopy, was performed on serum samples from acute DVT patients (first 30 days from diagnosis) and healthy controls (HC). Additionally, 10 plasma markers were evaluated using a Luminex kit. A total of 30 patients, with a mean age of 44 ± 12.5 years, primarily women (9 males:21 females), were included. Acute DVT patients showed elevated inflammatory markers, such as IL-6, IL-8, PDGF-AB/BB, and P-selectin, which later decreased in the follow-up group. However, adhesion molecules like sVCAM-1 and sICAM-1 have increased after six months. Metabolomics analysis revealed significantly decreased levels of glutamine, glucose, and branched-chain amino acids (BCAAs), alongside increased lactate levels in acute DVT samples. Metabolomic profiles showed only partial normalization at follow-up, indicating persistent metabolic dysregulation. Overall, the reduced glucose metabolism and increased lactate levels indicate anaerobic metabolism, likely caused by tissue hypoxia due to impaired blood flow. Glutamine, essential for DNA, ATP, and protein synthesis, was notably reduced, potentially impairing endothelial cell proliferation and vascular repair. The presence of adhesion molecules in the follow-up group confirms persistent endothelial dysfunction. These findings suggest that metabolic and endothelial alterations may persist long after acute inflammation resolves in DVT patients. In conclusion, the persistence of metabolic dysregulation suggests chronic metabolic stress in these patients, potentially resulting from ongoing endothelial damage, low-grade inflammation, or altered mitochondrial function due to past tissue hypoxia. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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15 pages, 1833 KB

Open AccessArticle

Relevance of STIM/Orai Calcium Entry System Hyperactivation in Human Prostate Contractility in Benign Prostate Hyperplasia

by José M. La Fuente, Mariam El Assar, Argentina Fernández, Leocadio Rodríguez-Mañas and Javier Angulo

Int. J. Mol. Sci. 2025, 26(18), 8985; https://doi.org/10.3390/ijms26188985 - 15 Sep 2025

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Abstract

Benign prostate hyperplasia (BPH) is characterized by prostate enlargement and dynamic alterations contributing to development of lower tract urinary symptoms (LUTS). Prostate hypercontractility has been proposed to contribute to BPH-related LUTS. The aim was to evaluate the effects of inhibiting stromal interaction molecule [...] Read more.

Benign prostate hyperplasia (BPH) is characterized by prostate enlargement and dynamic alterations contributing to development of lower tract urinary symptoms (LUTS). Prostate hypercontractility has been proposed to contribute to BPH-related LUTS. The aim was to evaluate the effects of inhibiting stromal interaction molecule (STIM)/Orai calcium entry system on adrenergic and neurogenic contractions in prostate (HP) and bladder neck (HB) strips from BPH patients. Effects of STIM/Orai inhibition on adrenergic and neurogenic contractions of HP from organ donors (ODs) without BPH were also evaluated. HP and HB strips were obtained from 20 patients with BPH undergoing radical prostatectomy and from six OD at the time of organ collection for transplantation. Tissues were functionally evaluated for isometric tension recording. STIM-1, Orai1, and Orai3 protein expressions were determined in prostate tissues. STIM-1 was also localized by immunofluorescence in prostate sections. Norepinephrine-induced and neurogenic contractions were significantly reduced by STIM/Orai inhibition with YM-58483 (20 µM) in HP from BPH patients but not in tissues from ODs. STIM/Orai inhibition failed to significantly modify contraction of HB from BPH patients. Protein expression of STIM-1 was significantly elevated in HP from BPH patients. Functional contribution of STIM/Orai system to contractile tone is relevant in prostate when BPH is present, probably related to increased expression of STIM-1. Inhibition of STIM/Orai could have therapeutic implications for the management of BPH patients by alleviating prostatic hypercontraction. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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20 pages, 3854 KB

Open AccessArticle

Hepatic AhR Activation by TCDD Induces Obesity and Steatosis via Hepatic Plasminogen Activator Inhibitor-1 (PAI-1)

by Seung Jun Oh, Suyeol Im, Sora Kang, Aden Geonhee Lee, Byung Cheol Lee and Youngmi Kim Pak

Int. J. Mol. Sci. 2025, 26(17), 8452; https://doi.org/10.3390/ijms26178452 - 30 Aug 2025

Cited by 2 | Viewed by 1868

Abstract

Exposure to persistent organic pollutants such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD) increases metabolic disorder risk. In this study, we show that a single intraperitoneal injection of TCDD (10 μg/kg) in C57BL/6J mice induced body weight gain, lipid accumulation in the liver and adipose tissue, macrophage [...] Read more.

Exposure to persistent organic pollutants such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD) increases metabolic disorder risk. In this study, we show that a single intraperitoneal injection of TCDD (10 μg/kg) in C57BL/6J mice induced body weight gain, lipid accumulation in the liver and adipose tissue, macrophage infiltration, and elevated hepatic and serum triglyceride levels after 12 weeks. Despite serum aryl hydrocarbon receptor (AhR) ligand levels normalizing by 12 weeks, the persistent effects suggest TCDD sequestration in fat tissue. TCDD inhibited the expression of mitochondrial proteins (COX1, TOM20, TFAM, H2AX) and reduced mitochondrial oxygen consumption. Liver-specific AhR knockout ameliorated TCDD-induced mitochondrial dysfunction, lipid accumulation, and macrophage infiltration. Mechanistically, TCDD-induced hepatic plasminogen activator inhibitor-1 (PAI-1) promoted adipocyte hypertrophy. In the liver, PAI-1 disrupted the interaction between tissue-type plasminogen activator (tPA) and apolipoprotein B (ApoB), thereby enhancing very-low-density lipoprotein (VLDL) assembly. These findings reveal that hepatocyte-derived circulating PAI-1, upregulated via hepatic AhR activation, contributes to adipocyte hypertrophy and hepatosteatosis through the intracellular modulation of the tPA–PAI-1 axis. Thus, hepatic AhR activation drives mitochondrial dysfunction and obesity, even after a single TCDD exposure. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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Review

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22 pages, 632 KB

Open AccessReview

Therapeutic Peptides in Aesthetic, Metabolic and Endocrine Conditions: Effects, Safety, Clinical Applications, and Future Perspectives

by Guilherme Renke and Lucas Chinellato

Int. J. Mol. Sci. 2026, 27(9), 3890; https://doi.org/10.3390/ijms27093890 - 27 Apr 2026

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Abstract

Therapeutic peptides are short chains of amino acids used to treat metabolic and endocrine conditions such as obesity and type 2 diabetes. While several peptide drugs have undergone rigorous approval processes that evaluate both safety and efficacy, novel, unapproved compounds have emerged and [...] Read more.

Therapeutic peptides are short chains of amino acids used to treat metabolic and endocrine conditions such as obesity and type 2 diabetes. While several peptide drugs have undergone rigorous approval processes that evaluate both safety and efficacy, novel, unapproved compounds have emerged and are rapidly expanding into preventive medicine and performance enhancement. Our objective is to present the effects, clinical applications, safety profiles, and regulatory status of prominent peptides used to treat several conditions. We reviewed 106 articles, prioritizing systematic reviews, meta-analyses, and randomized controlled trials in the PubMed, ScienceDirect, and SciELO databases. Our results suggest that therapeutic peptides are a promising tool for treating type 2 diabetes and obesity, for skin rejuvenation, and as hormone analogs for specific diseases and conditions. Although these are strategic and innovative options that can improve health, performance, and longevity, further studies are needed before most new peptides can be used safely in humans. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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19 pages, 440 KB

Open AccessReview

Metabolomics for Preclinical Detection of Diabetic Kidney Disease: A Comprehensive Review

by Michael Garoufis, Sissy Foteini Sakkou, Christina E. Kostara, Eleni Bairaktari and Vasilios Tsimihodimos

Int. J. Mol. Sci. 2026, 27(2), 998; https://doi.org/10.3390/ijms27020998 - 19 Jan 2026

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Abstract

Diabetic kidney disease (DKD) affects up to 40% of individuals with diabetes and remains the leading cause of end-stage renal disease worldwide. Current biomarkers, such as albuminuria and estimated glomerular filtration rate, detect disease only after substantial kidney injury, limiting early intervention. Metabolomics [...] Read more.

Diabetic kidney disease (DKD) affects up to 40% of individuals with diabetes and remains the leading cause of end-stage renal disease worldwide. Current biomarkers, such as albuminuria and estimated glomerular filtration rate, detect disease only after substantial kidney injury, limiting early intervention. Metabolomics offers unique potential to identify early biochemical changes preceding the clinical onset of DKD. This review synthesizes evidence from animal and human studies in diabetes without overt kidney disease, highlighting early perturbations in energy metabolism (TCA cycle, beta-oxidation, glycolysis) as well as alterations in amino acid, nucleotide and urea cycle pathways associated with future DKD risk. We discuss methodological considerations, translational relevance, and current research gaps and outline strategies for integrating metabolomics into predictive diagnostics. Early, non-invasive metabolic biomarkers may enable more precise risk stratification and timely intervention to improve patient outcomes. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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36 pages, 2173 KB

Open AccessReview

Natural Products in Alzheimer’s Disease: A Systematic Review of Clinical Trials and Underlying Molecular Mechanisms

by Maria T. Bayo Jimenez, Lorenzo Rivas-García, Cristina Sánchez-González, Giuseppe Grosso, Vivian Lipari, Laura Vera-Ramírez, Maurizio Battino, Francesca Giampieri, José L. Quiles and Tamara Y. Forbes-Hernández

Int. J. Mol. Sci. 2025, 26(21), 10631; https://doi.org/10.3390/ijms262110631 - 31 Oct 2025

Cited by 4 | Viewed by 6685

Abstract

This systematic review included 31 clinical trial articles examining the effects of natural compounds on Alzheimer’s disease (AD) and mild cognitive impairment (MCI), involving 3582 participants aged 50–90. Treatment durations ranged from 8 weeks to 2 years, with an average of 12.5 months. [...] Read more.

This systematic review included 31 clinical trial articles examining the effects of natural compounds on Alzheimer’s disease (AD) and mild cognitive impairment (MCI), involving 3582 participants aged 50–90. Treatment durations ranged from 8 weeks to 2 years, with an average of 12.5 months. Notably, 11 studies focused on herbal extracts highlighting their prominence in current research. These extracts showed potential cognitive and neuroprotective benefits, although results varied across compounds and study designs. Other natural compounds—including flavonoids, polyphenols, omega-3 fatty acids, Aloe vera, Spirulina, and citrus phytochemicals—may provide cognitive and neuroprotective benefits, with ginseng and Ginkgo biloba combinations also showing promise. Curcumin and Melissa officinalis had limited effects, resveratrol showed mixed outcomes with some side effects, and matcha green tea may improve cognition and sleep quality. Despite generally favorable results, the studies varied considerably in design and quality; nonetheless, herbal extracts represent a prominent category of natural interventions in AD and MCI, underscoring the need for further large-scale, high-quality clinical trials to confirm their therapeutic potential. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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19 pages, 344 KB

Open AccessReview

Cushing’s Disease in the Animal Kingdom: Translational Insights for Human Medicine

by Elena Massardi, Germano Gaudenzi, Silvia Carra, Monica Oldani, Ilona Rybinska, Luca Persani and Giovanni Vitale

Int. J. Mol. Sci. 2025, 26(17), 8626; https://doi.org/10.3390/ijms26178626 - 4 Sep 2025

Viewed by 2828

Abstract

Cushing’s disease (CD) is a rare neuroendocrine disorder caused by ACTH-secreting pituitary adenomas, presenting significant diagnostic and therapeutic challenges. Given the evolutionary conservation of the hypothalamic–pituitary–adrenal axis, this review explores the translational value of spontaneous CD forms in dogs, horses, cats, small mammals, [...] Read more.

Cushing’s disease (CD) is a rare neuroendocrine disorder caused by ACTH-secreting pituitary adenomas, presenting significant diagnostic and therapeutic challenges. Given the evolutionary conservation of the hypothalamic–pituitary–adrenal axis, this review explores the translational value of spontaneous CD forms in dogs, horses, cats, small mammals, and rats, as well as of experimental models in mice, rats, and zebrafish. Dogs are the most studied, showing strong molecular and clinical similarities with human CD, making them valuable for preclinical drug and diagnostic research. While equine and feline CD are less characterized, they may provide insights into dopaminergic therapies and glucocorticoid resistance. Nevertheless, practical and ethical challenges limit the experimental use of companion animals. In preclinical research, mouse models are widely used to study hypercortisolism and test therapeutic agents via transgenic and xenograft strategies. Conversely, few studies are available on a zebrafish transgenic model for CD, displaying pituitary corticotroph expansion and partial resistance to glucocorticoid-negative feedback at the larval stage, while adults exhibit hypercortisolism resembling the human phenotype. Future transplantable systems in zebrafish may overcome several limitations observed in mice, supporting CD research. Collectively, these animal models, each offering unique advantages and limitations, provide a diverse toolkit for advancing CD research and improving human clinical outcomes. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

31 pages, 1732 KB

Open AccessReview

GLUT4 Trafficking and Storage Vesicles: Molecular Architecture, Regulatory Networks, and Their Disruption in Insulin Resistance

by Hana Drobiova, Ghadeer Alhamar, Rasheed Ahmad, Fahd Al-Mulla and Ashraf Al Madhoun

Int. J. Mol. Sci. 2025, 26(15), 7568; https://doi.org/10.3390/ijms26157568 - 5 Aug 2025

Cited by 7 | Viewed by 7502

Abstract

Insulin-regulated glucose uptake is a central mechanism in maintaining systemic glucose homeostasis, primarily occurring in skeletal muscle and adipose tissue. This process relies on the insulin-stimulated translocation of the glucose transporter, GLUT4, from specialized intracellular compartments, known as GLUT4 storage vesicles (GSVs), to [...] Read more.

Insulin-regulated glucose uptake is a central mechanism in maintaining systemic glucose homeostasis, primarily occurring in skeletal muscle and adipose tissue. This process relies on the insulin-stimulated translocation of the glucose transporter, GLUT4, from specialized intracellular compartments, known as GLUT4 storage vesicles (GSVs), to the plasma membrane. Disruption of this pathway is a hallmark of insulin resistance and a key contributor to the pathogenesis of type 2 diabetes. Recent advances have provided critical insights into both the insulin signalling cascades and the complex biogenesis, as well as the trafficking and fusion dynamics of GSVs. This review synthesizes the current understanding of the molecular mechanisms governing GSV mobilization and membrane fusion, highlighting key regulatory nodes that may become dysfunctional in metabolic disease. By elucidating these pathways, we propose new therapeutic avenues targeting GSV trafficking to improve insulin sensitivity and combat type 2 diabetes. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

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