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Curr. Issues Mol. Biol., Volume 47, Issue 10 (October 2025) – 86 articles

Cover Story (view full-size image): Alterations in gut microbiota composition are emerging as a key link between metabolic dysfunction-associated steatohepatitis and inflammatory bowel disease. Both conditions share a loss of protective short-chain fatty acid-producing bacteria and an enrichment of pro-inflammatory taxa, leading to disruption of epithelial barrier integrity and immune–metabolic balance. These shared microbial and molecular pathways reveal the gut–liver–immune axis as a central hub connecting metabolic and inflammatory disorders, opening the way to innovative microbiota-based therapeutic strategies. View this paper
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22 pages, 7790 KB  
Article
The Tumor-Suppressive Role of SAT2 in Pancreatic Cancer: Involvement in PI3K/Akt-MAPK Pathways and Immune Modulation
by Ben Zhao, Lu Wang, Rui Fang, Xiaoxiao Luo and Lu Zhang
Curr. Issues Mol. Biol. 2025, 47(10), 872; https://doi.org/10.3390/cimb47100872 - 21 Oct 2025
Viewed by 444
Abstract
Spermidine/spermine N1-Acetyltransferase 2 (SAT2), belonging to the spermidine/spermine N1-Acetyltransferase family, has been increasingly recognized for its potential effects on tumor occurrence and development. Nonetheless, little is known about its biological function and clinical value for pancreatic cancer (PC). The present work focused on [...] Read more.
Spermidine/spermine N1-Acetyltransferase 2 (SAT2), belonging to the spermidine/spermine N1-Acetyltransferase family, has been increasingly recognized for its potential effects on tumor occurrence and development. Nonetheless, little is known about its biological function and clinical value for pancreatic cancer (PC). The present work focused on investigating its expression pattern, prognostic value, molecular mechanisms, and immune relevance in PC. SAT2 expression within PC samples and its prognostic significance were analyzed by retrieving the relevant data from the TCGA, CPTAC, and HPA databases. The biological function of SAT2 was investigated through GO and KEGG enrichment analyses. The association of SAT2 with immune cell infiltration in tumors was assessed by CIBERSORT. Additionally, in vitro experiments were performed to examine how SAT2 expression affected the PC cell proliferation, invasion, and migration abilities. An in vivo xenograft tumor model was employed for investigating how SAT2 expression affected the PC cell-derived tumor growth. The expression of SAT2 within the PC tissue exhibited a significant decrease in comparison with a non-carcinoma sample. Such observation was validated within PC cells. In addition, SAT2 expression showed a close relation to both tumor growth (T stage) and prognosis. SAT2 primarily participates in pathways, including the PI3K/Akt and MAPK pathways. Furthermore, we demonstrated a significant association between SAT2 expression and immune cell infiltration into tumors. The in vitro experiments confirmed that elevated SAT2 expression significantly suppressed PC cell viability, invasion, and migration through modulating the PI3K/Akt and MAPK pathways. The in vivo experimental results suggested the role of SAT2 overexpression in inhibiting xenograft tumor growth. Our investigation confirms the role of SAT2 in PC development through involvement in the PI3K/Akt and MAPK pathways. The correlation between SAT2 expression levels, immune infiltration, and checkpoint regulation provides valuable insights for immunotherapy strategies targeting PC. Full article
(This article belongs to the Section Molecular Medicine)
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14 pages, 1713 KB  
Article
Study on Autophagy Death of Alpha TC1 Clone 6 (αTC1-6) Cells Induced by Trametenolic Acid Through PI3K/AKT Pathway
by Wangyang Ye, Shangling Pan, Hongqi Zhang, Xiaolan Zhang and Junzhi Wang
Curr. Issues Mol. Biol. 2025, 47(10), 871; https://doi.org/10.3390/cimb47100871 - 21 Oct 2025
Viewed by 467
Abstract
Glucagonoma, a rare neuroendocrine tumor, lacks targeted treatment drugs. Excessive secretion of glucagon is the main cause of its clinical syndrome. To explore targeted therapeutic drugs that can inhibit glucagon secretion and tumor proliferation, we investigated the effect of Trametenolic Acid (TA) on [...] Read more.
Glucagonoma, a rare neuroendocrine tumor, lacks targeted treatment drugs. Excessive secretion of glucagon is the main cause of its clinical syndrome. To explore targeted therapeutic drugs that can inhibit glucagon secretion and tumor proliferation, we investigated the effect of Trametenolic Acid (TA) on mouse pancreatic alpha TC1 clone 6 (αTC1-6) cells and its regulatory role in the PI3K/AKT signaling pathway. Cell viability of αTC1-6 cells was assessed via the MTT assay. Glucagon content in cell culture supernatants was measured using an Enzyme-Linked Immunosorbent Assay (ELISA). Autophagic vacuoles were visualized through Monodansylcadaverine (MDC) staining. The expression of autophagy-related proteins including Atg7, LC3 Ⅱ and PI3K/AKT signaling pathway-related proteins mTOR and FoxO1 were determined by Western blot. The results showed that the proliferation of αTC1-6 cells was significantly inhibited by TA in a dose- and time-dependent manner, and the IC50 was 140.71, 26.77 and 1.99 μM after treatment of 12, 24, and 48 h, respectively. The secretion of glucagon was significantly inhibited by TA. The MDC staining results showed that the fluorescent labeled autophagic vesicles in the TA group were increased. The Western blot results showed that the expression of Atg7 and LC3 Ⅱ was promoted by TA in a dose-dependent manner, the phosphorylation of PI3K, AKT, mTOR and FoxO1 was significantly inhibited, and the expression of FoxO1 protein was increased. These results demonstrated that TA can inhibit glucagon secretion, induce autophagy, and suppress cell proliferation in αTC1-6 cells. The mechanism may be associated with the PI3K/AKT signaling pathway. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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24 pages, 7640 KB  
Article
Ethacridine Targets Bacterial Biofilms in Diabetic Foot Ulcers: A Multi-Target Mechanism Revealed by Network Pharmacology, Molecular Docking, Molecular Dynamics Simulation, and Clinical RT-qPCR Validation
by Tianbo Li, Yuming Zhuang, Jiangning Wang and Lei Gao
Curr. Issues Mol. Biol. 2025, 47(10), 870; https://doi.org/10.3390/cimb47100870 - 21 Oct 2025
Viewed by 451
Abstract
Objective: This study aimed to systematically investigate the potential antibacterial mechanisms of ethacridine in the treatment of diabetic foot ulcers (DFUs) by integrating network pharmacology, molecular docking, and molecular dynamics simulation approaches. Methods: The potential targets of ethacridine were predicted using the SwissTargetPrediction [...] Read more.
Objective: This study aimed to systematically investigate the potential antibacterial mechanisms of ethacridine in the treatment of diabetic foot ulcers (DFUs) by integrating network pharmacology, molecular docking, and molecular dynamics simulation approaches. Methods: The potential targets of ethacridine were predicted using the SwissTargetPrediction and PharmMapper databases and subsequently converted to gene symbols via the UniProt database. DFU-related and antibacterial-related targets were retrieved from the GeneCards and OMIM databases. The overlapping targets among ethacridine, DFU, and antibacterial-related genes were identified as candidate therapeutic targets. A “drug–disease–target” network was constructed using Cytoscape, while protein–protein interaction (PPI) networks were built through the STRING database. GO and KEGG enrichment analyses were performed using R software. Molecular docking was conducted to evaluate the binding affinities between core compounds and hub targets. Furthermore, molecular dynamics (MD) simulation was applied to assess the binding stability of the top-ranked compound–target complex. Finally, RT-qPCR was conducted on wound edge tissue samples from DFU patients treated with ethacridine to experimentally validate the mRNA expression of predicted hub genes. Results: A total of 302 potential ethacridine-related targets, 4264 DFU-related targets, and 1942 antibacterial-related targets were identified. Intersection analysis revealed 105 common targets potentially involved in the antibacterial effects of ethacridine against DFU. PPI network analysis highlighted 10 hub targets, including AKT1, EGFR, SRC, HSP90AA1, and MMP9. GO enrichment indicated significant involvement in responses to reactive oxygen species, regulation of inflammatory responses, responses to lipopolysaccharide, and bacterial molecular patterns. KEGG pathway analysis identified 157 relevant pathways, including the lipid and atherosclerosis, TNF signaling, IL-17 signaling, and the AGE–RAGE signaling pathways in diabetic complications. Molecular docking demonstrated favorable binding affinities (all < −5.0 kcal/mol) between ethacridine and the hub targets, with the strongest binding observed between MMP9 and ethacridine (−9.8 kcal/mol). These docking results suggest possible interaction tendencies that may contribute indirectly to Ethacridine’s network-level regulatory effects, rather than direct binding to all targets in vivo. Molecular dynamics simulation further confirmed the stable interaction between MMP9 and ethacridine. RT-qPCR validation in clinical DFU tissue samples demonstrated expression trends of key genes consistent with in silico predictions. These results reflect transcriptional regulation consistent with pathway modulation predicted by the network analysis, rather than direct protein–ligand binding across all targets. Conclusion: Ethacridine may exert antibacterial effects against bacterial biofilms in DFU through multi-target and multi-pathway mechanisms. These findings highlight ethacridine’s translational potential as a safe, readily available, and mechanistically validated topical agent for the clinical management of biofilm-associated diabetic foot infections. Full article
(This article belongs to the Section Bioinformatics and Systems Biology)
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16 pages, 5225 KB  
Article
Determination of the Phylogenetic Relationship of Dendrobium linawianum (Orchidaceae) Based on Comparative Analysis of Complete Chloroplast Genomes
by Fengping Zhang, Qiyong Huang, Yaqiong Zhang, Dongqin Lǚ, Rui Chen, Yanshu Jia and Qiongchao Li
Curr. Issues Mol. Biol. 2025, 47(10), 869; https://doi.org/10.3390/cimb47100869 - 21 Oct 2025
Viewed by 353
Abstract
Dendrobium is an orchid genus with high economic and ecological importance, but its taxonomy based on morphology remains controversial. Dendrobium linawianum, a critically endangered species with both ornamental and medicinal value, represents a key taxon within this genus. However, its phylogenetic relationship [...] Read more.
Dendrobium is an orchid genus with high economic and ecological importance, but its taxonomy based on morphology remains controversial. Dendrobium linawianum, a critically endangered species with both ornamental and medicinal value, represents a key taxon within this genus. However, its phylogenetic relationship has long been unplaced due to similar morphological traits. Despite its conservation and taxonomic importance, its complete chloroplast genome has not been previously characterized. Here, we newly sequenced and assembled the complete chloroplast genome of D. linawianum. The 150,497 bp genome exhibits a typical quadripartite structure, encoding 119 genes. A total of 161 simple sequence repeats (SSRs) were identified, predominantly mononucleotide and dinucleotide motifs. Condon usage analysis revealed leucine as the most abundant amino acid. Phylogenetic analysis based on complete chloroplast genome sequences strongly supported the close relationship of D. linawianum with D. hercoglossum, D. thyrsiflorum, and D. moniliforme, resolving its taxonomic position within the genus. The complete chloroplast genomes successfully resolved the phylogenetic relationships among 35 Dendrobium species, demonstrating their efficacy as powerful molecular markers for resolving taxonomic ambiguities within this morphologically complex genus. Our findings provide a genomic foundation for precise species identification and molecular breeding of D. linawianum, and enhance understanding of phylogenetic relationships in this taxonomically challenging group. Full article
(This article belongs to the Section Molecular Plant Sciences)
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27 pages, 2977 KB  
Article
Neurobiological Correlates of Coping Strategies in PTSD: The Role of IGF-1, CASP-9, nNOS, and IL-10 Based on Brief-COPE Assessment
by Barbara Paraniak-Gieszczyk and Ewa Alicja Ogłodek
Curr. Issues Mol. Biol. 2025, 47(10), 868; https://doi.org/10.3390/cimb47100868 - 21 Oct 2025
Viewed by 389
Abstract
Post-traumatic stress disorder (PTSD) is associated with long-term disturbances in stress regulation, neuroinflammation, and oxidative stress and reduced psychological coping capacity. The aim of the study was to assess the relationship between selected neurobiological biomarkers (Insulin-like Growth Factor 1—IGF-1; Caspase-9—CASP-9; Neuronal Nitric Oxide [...] Read more.
Post-traumatic stress disorder (PTSD) is associated with long-term disturbances in stress regulation, neuroinflammation, and oxidative stress and reduced psychological coping capacity. The aim of the study was to assess the relationship between selected neurobiological biomarkers (Insulin-like Growth Factor 1—IGF-1; Caspase-9—CASP-9; Neuronal Nitric Oxide Synthase—nNOS; and Interleukin-10—IL-10) and coping styles evaluated using the Brief Coping Orientation to Problems Experienced (Brief-COPE) questionnaire in men with trauma experience. Particular emphasis was placed on analyzing the effect of PTSD chronicity (≤5 years vs. >5 years) on these relationships. The study included 92 adult men with a history of life-threatening situations. Participants were divided into three groups: PTSD within the past ≤5 years (n = 33), PTSD within the past >5 years (n = 31), and a No PTSD group (n = 28). Biomarkers were measured in blood serum. Coping strategies were assessed using the Brief-COPE questionnaire, which includes four subscales: task-oriented, emotion-oriented, avoidant, and general coping. Due to the lack of normal distribution, the Kruskal–Wallis test and Dunn’s post hoc test were used. Correlations between biomarkers and Brief-COPE subscales were calculated using Spearman’s Rank Correlation Coefficient (Rho). Significant differences between groups were found in all four biomarkers (p < 0.001). IGF-1 and IL-10 reached the highest values in the No PTSD group and the lowest in the PTSD ≤ 5 years group, indicating neuroprotective and anti-inflammatory deficits in PTSD. Conversely, CASP-9 and nNOS levels (markers of apoptosis and oxidative stress) were highest in PTSD ≤ 5 years, with partial normalization in the PTSD > 5 years group. In terms of coping strategies, the No PTSD group displayed a highly adaptive profile (task-oriented: 30/32; emotion-oriented: 43/48; and avoidant: 12/32). Individuals with PTSD ≤ 5 years presented a maladaptive pattern (task-oriented: 13/32; avoidant: 26/32; and emotion-oriented: 27/48), while in PTSD > 5 years, a further decline in emotion-oriented (21/48) and general coping (59/112) was observed, suggesting progressive depletion of psychological resources. The strongest correlations between biomarkers and coping strategies occurred in PTSD groups. Low IGF-1 levels in PTSD ≤ 5 years correlated negatively with emotion-oriented coping (Rho = −0.39) and general coping (Rho = −0.35). High CASP-9 levels were associated with reduced task-oriented coping in PTSD > 5 years (Rho = −0.29). Similar trends were observed for nNOS and IL-10, indicating a disturbance in neurobiological balance that favors persistence of PTSD symptoms. PTSD, both in its acute and chronic phases, is associated with an abnormal profile of neuroprotective, apoptotic, and inflammatory biomarkers, which correlates with impaired adaptive coping capacity. Although partial normalization of biological parameters is observed in chronic PTSD, deficits in emotion-oriented and task-oriented coping persist. The Brief-COPE questionnaire, combined with biomarker analysis, may serve as a useful clinical tool for assessing psychophysiological balance and designing early interventions. These results highlight the potential of IGF-1, CASP-9, nNOS, and IL-10 as biomarkers of stress adaptation and therapeutic targets in PTSD. Full article
(This article belongs to the Section Molecular Medicine)
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13 pages, 14057 KB  
Article
Genome-Wide Identification and Functional Evolution of NLR Gene Family in Capsicum annuum
by Chong Feng, Qi Chen, Wenhao Liu, Tengfei Li and Tuo Ji
Curr. Issues Mol. Biol. 2025, 47(10), 867; https://doi.org/10.3390/cimb47100867 - 21 Oct 2025
Viewed by 391
Abstract
Capsicum annuum (pepper) is a globally significant Solanaceous crop vulnerable to devastating pathogens such as Phytophthora capsici. Nucleotide-binding leucine-rich repeat (NLRs) proteins are crucial intracellular immune receptors mediating effector-triggered immunity (ETI). This study presents the comprehensive genome-wide identification and analysis of the [...] Read more.
Capsicum annuum (pepper) is a globally significant Solanaceous crop vulnerable to devastating pathogens such as Phytophthora capsici. Nucleotide-binding leucine-rich repeat (NLRs) proteins are crucial intracellular immune receptors mediating effector-triggered immunity (ETI). This study presents the comprehensive genome-wide identification and analysis of the NLR gene family in pepper using the high-quality ‘Zhangshugang’ reference genome. We identified 288 high-confidence canonical NLR genes. Chromosomal distribution analysis showed significant clustering, particularly near telomeric regions, with Chr09 harboring the highest density (63 NLRs). Evolutionary analysis demonstrated that tandem duplication is the primary driver of NLR family expansion, accounting for 18.4% of NLR genes (53/288), predominantly on Chr08 and Chr09. Analysis of promoter cis-regulatory elements (CREs) revealed enrichment in defense-related motifs, with 82.6% of promoters (238 genes) containing binding sites for salicylic acid (SA) and/or jasmonic acid (JA) signaling. Transcriptome profiling of Phytophthora capsici-infected resistant (C. annuum cv. CM334) and susceptible (C. annuum cv. NMCA10399) cultivars identified 44 significantly differentially expressed NLR genes, and protein–protein interaction (PPI) network analysis predicted key interactions among them, with Caz01g22900 and Caz09g03820 as potential hubs. This study elucidates the tandem-duplication-driven expansion, domain-specific functional implications, and expression dynamics of the pepper NLR family. It identifies conserved and lineage-specific candidate NLR genes, including Caz03g40070, Caz09g03770, Caz10g20900, and Caz10g21150. These findings provide valuable candidate gene targets for the development of molecular markers for pepper resistance to Phytophthora capsici. Full article
(This article belongs to the Section Molecular Plant Sciences)
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13 pages, 6536 KB  
Article
Comparison of Gut Microbial Structure and Function Changes in Sichuan–Tibetan Black Pigs at Different Growth Stages Based on Metagenomic Analysis
by Lichun Jiang, Yi Qing, Kaiyuan Huang, Huiling Huang, Chengmin Li, Qinggang Mei and Qian Wu
Curr. Issues Mol. Biol. 2025, 47(10), 866; https://doi.org/10.3390/cimb47100866 - 21 Oct 2025
Viewed by 349
Abstract
The gut microbiota plays a crucial role in maintaining swine health and understanding its stage-specific variations provides a scientific basis for health assessment. This study investigated the structural changes in intestinal microbiota during the development of Sichuan–Tibetan black pigs (n = 15) [...] Read more.
The gut microbiota plays a crucial role in maintaining swine health and understanding its stage-specific variations provides a scientific basis for health assessment. This study investigated the structural changes in intestinal microbiota during the development of Sichuan–Tibetan black pigs (n = 15) by collecting fecal samples at three growth stages: the nursery period (1 month), growing period (3 months), and finishing period (10 months). Microbial profiling was performed using 16S rRNA sequencing. Results showed no significant difference in the Shannon index between the nursery and growing periods, while the finishing period exhibited distinct ACE and Chao 1 indices compared to other stages. PCoA and NMDS analyses revealed significant structural divergence in the finishing period microbiota, with greater intra-group variability observed in the nursery and growing periods. At the phylum level, Firmicutes abundance increased progressively with growth, becoming the absolute dominant phylum, whereas Bacteroidota showed a declining trend. These characteristics are particularly prominent during the finishing period. At the family level, Lactobacillaceae abundance increased continuously. Oscillospiraceae remained stable during the early stages but decreased significantly in the finishing period. Genus-level analysis shows that Lactobacillus, especially L. amylovorus and L. reuteri, become dominant bacterial species during the finishing period. A total of 84 differentially abundant core microbiota were identified, with the finishing period containing the highest number. Functional annotation revealed 19 significantly different metabolic pathways across the three stages. The most significant is the enhanced activity of microorganisms during the finishing period in pathogen-related metabolism and exogenous degradation, reflecting their adaptability to complex feed. These findings demonstrate stage-dependent variations in the gut microbiota of Sichuan–Tibetan black pigs, providing valuable references for nutritional regulation and feeding management practices. Full article
(This article belongs to the Section Molecular Microbiology)
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20 pages, 1698 KB  
Review
Systematic Review: Exosomes as Molecular Messengers in the Development of Obesity-Related Complications in Children
by Kamila Szeliga, Dominika Krakowczyk, Marcin Chyra, Monika Pietrowska, Tomasz Koszutski, Aneta Monika Gawlik-Starzyk and Lidia Hyla-Klekot
Curr. Issues Mol. Biol. 2025, 47(10), 865; https://doi.org/10.3390/cimb47100865 - 20 Oct 2025
Viewed by 620
Abstract
Emerging evidence highlights extracellular vesicles (EVs), especially exosomes, as critical molecular messengers linking pediatric obesity to multi-organ complications. This scoping review synthesizes current knowledge on EVs-mediated intercellular communication that exacerbates inflammation, insulin resistance, endothelial dysfunction and organ-specific damage. Data demonstrate that adipose- and [...] Read more.
Emerging evidence highlights extracellular vesicles (EVs), especially exosomes, as critical molecular messengers linking pediatric obesity to multi-organ complications. This scoping review synthesizes current knowledge on EVs-mediated intercellular communication that exacerbates inflammation, insulin resistance, endothelial dysfunction and organ-specific damage. Data demonstrate that adipose- and endothelial-derived EVs carry bioactive cargo, microRNAs, proteins, and lipids, that modulate key pathways driving metabolic derangements and vascular injury, often preceding detectable clinical biomarkers. Notably, maternal obesity influences EVs composition in breast milk, shaping early-life metabolic programming and offspring risk of obesity. Recent studies underscore the diagnostic and therapeutic potential of EVs in obesity-related conditions such as metabolic-associated fatty liver disease (MAFLD), early renal injury, and cardiovascular dysfunction in children. Furthermore, EVs released in response to exercise or bariatric surgery may mediate systemic metabolic improvements, offering a novel window into personalized interventions. Despite promising findings, standardization of EV isolation and profiling in pediatric research is lacking, and large-scale longitudinal studies are urgently needed. By deepening our understanding of EVs biology, clinicians may advance early detection, risk stratification, and targeted therapies to interrupt the progression from childhood obesity to lifelong metabolic and cardiovascular disease. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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14 pages, 6616 KB  
Article
Integrating Multiple Methods to Validate Key Genes Driving the Progression of Breast Ductal Carcinoma In Situ
by Minjie Zhong, Shengkai Zheng, Yahui Wen, Juansi Zhang, Jiahui Zhang, Hanwei Wang, Caiqin Mo, Sunwang Xu and Xiangjin Chen
Curr. Issues Mol. Biol. 2025, 47(10), 864; https://doi.org/10.3390/cimb47100864 - 20 Oct 2025
Viewed by 344
Abstract
Background: Ductal carcinoma in situ (DCIS) is a precursor to breast cancer. The mechanisms by which the stroma of DCIS affects disease progression remain elusive. Thus, the aim of this study is to identify key stroma genes that affect DCIS progression and to [...] Read more.
Background: Ductal carcinoma in situ (DCIS) is a precursor to breast cancer. The mechanisms by which the stroma of DCIS affects disease progression remain elusive. Thus, the aim of this study is to identify key stroma genes that affect DCIS progression and to define high-risk DCIS cases. Method: Gene expression matrix files from the Gene Expression Omnibus (GEO) database were selected to identify candidate genes associated with the stromal transition from DCIS to invasive ductal carcinoma (IDC). An integrative approach was employed to identify and functionally characterize driver genes of DCIS progression. In vitro experiments were performed to validate the role of these genes. Results: We identified 13 differentially expressed genes (DEGs), of which 5 were selected as candidate drivers. Gene set enrichment analysis (GSEA) revealed the biological functions of RAMP2 and ADM2, while in vitro functional assays demonstrated that ADM2 knockdown and RAMP2 overexpression in breast cancer cell lines significantly suppressed cellular proliferation and invasion. Conclusion: This study identified and validated the roles and functions of ADM2 and RAMP2 and revealed their function as key driver genes in the progression of ductal carcinoma in situ (DCIS). Collectively, our findings elucidate critical genetic mechanisms underlying DCIS progression and provide novel insights for the development of personalized therapeutic strategies. Full article
(This article belongs to the Section Molecular Medicine)
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23 pages, 4305 KB  
Article
Epigenetic Remodeling in Thyroid Cancer: New Dimensions of Targeted Therapy Through lncRNA Modulation
by Adrian Albulescu, Alina Fudulu, Mirela Antonela Mihaila, Iulia Iancu, Adriana Plesa, Marinela Bostan, Anca Botezatu, Lorelei Irina Brasoveanu and Camelia Mia Hotnog
Curr. Issues Mol. Biol. 2025, 47(10), 863; https://doi.org/10.3390/cimb47100863 - 18 Oct 2025
Viewed by 399
Abstract
Thyroid carcinomas are phenotypically heterogeneous malignancies. Advances in molecular and cellular technologies have revealed genetic, epigenetic, and nongenetic factors underlying this heterogeneity. Our study aimed to assess the impact of single and combined treatments with anticancer agents (Carboplatin, Doxorubicin, Paclitaxel, Avastin), natural compounds [...] Read more.
Thyroid carcinomas are phenotypically heterogeneous malignancies. Advances in molecular and cellular technologies have revealed genetic, epigenetic, and nongenetic factors underlying this heterogeneity. Our study aimed to assess the impact of single and combined treatments with anticancer agents (Carboplatin, Doxorubicin, Paclitaxel, Avastin), natural compounds (Quercetin), and epigenetic modulators (suberoylanilide hydroxamic acid and 5-Azacytidine) on the expression of long noncoding RNAs, methylation regulators, and functional features in the human thyroid cancer cell line K1. Methods: Treated and untreated K1 cells were used throughout experiments to evaluate the drug-induced cytotoxicity, apoptosis, cell cycle distribution, cytokine release, gene expression, and global DNA methylation levels. Results: Some single- and combined-drug treatments modulated both cell cycle progression and apoptotic events, demonstrating anti-tumor activity of the tested compounds. Gene expression analysis showed treatment-specific regulation of target genes and lncRNAs, including both upregulation and downregulation across different drug combinations. All treatments resulted in increased global DNA methylation levels compared to the untreated controls. Several combinations significantly upregulated DNMT1 and DNMT3B, while concomitantly decreased EZH2 levels. Conclusions: These coordinated epigenetic changes highlight the therapeutic potential of combining epigenetic modulators with chemotherapeutic agents, suggesting a strategy to prevent or reverse treatment resistance and improve outcomes in thyroid cancer patients. Full article
(This article belongs to the Special Issue Molecular Functions of Long Non-Coding RNAs: Implications for Diseases and Therapy)
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3 pages, 153 KB  
Editorial
Editorial for Special Issue “Mental Disorder: Focus on Pathogenesis to Treatment”
by Fabrizio Bella, Cecilia Chiarenza and Carmen Concerto
Curr. Issues Mol. Biol. 2025, 47(10), 862; https://doi.org/10.3390/cimb47100862 - 18 Oct 2025
Viewed by 262
Abstract
In recent years, advances in molecular biology have enabled the investigation of previously inaccessible mechanisms at the cellular and immunological levels that underlie the pathogenesis of numerous conditions affecting the central nervous system [...] Full article
(This article belongs to the Special Issue Mental Disorder: Focus on Pathogenesis to Treatment)
18 pages, 3947 KB  
Article
Contributions of Retinoid Signaling to Autism-like Behaviors Induced by Early Postnatal Lead Exposure in the Mouse Cerebellum
by Xiaochun Xia, Xulan Zhou, Zihan Ma, Li Liu, Yaqi Wang, Yongli Wu, Ying Zhang and Juan Wang
Curr. Issues Mol. Biol. 2025, 47(10), 861; https://doi.org/10.3390/cimb47100861 - 18 Oct 2025
Viewed by 316
Abstract
Autism spectrum disorder (ASD) is a group of neurodevelopmental dysfunctions characterized by a heterogeneous etiology that involves gene–environment interactions. Early postnatal lead (Pb) exposure has been found to be associated with the etiology of ASD, but the mechanisms remain unclear. The present study [...] Read more.
Autism spectrum disorder (ASD) is a group of neurodevelopmental dysfunctions characterized by a heterogeneous etiology that involves gene–environment interactions. Early postnatal lead (Pb) exposure has been found to be associated with the etiology of ASD, but the mechanisms remain unclear. The present study aims to investigate the effects of early Pb exposure on the emergence of ASD-like behaviors in offspring and to evaluate its potential relationship with morphological changes and underlying mechanisms in the cerebellum. The study established a mouse model to study early postnatal Pb exposure and examined ASD-like behaviors through the open field test, novel object recognition test, marble burying test, and three-chamber social test. Quantification of Pb levels was performed in cerebellar tissue, examination of Purkinje cell morphology was carried out, and identification of differential protein expression was conducted using TMT-based quantitative proteomics. The study revealed that the offspring of Pb-exposed mice showed significant social deficits, increased repetitive behaviors, and cognitive impairments. The cerebellum showed both elevated Pb levels and a reduction in Purkinje cells. Proteomic analysis identified 45 proteins that were differentially expressed, showing disruption in the retinoid signaling pathway. These findings demonstrate that early postnatal Pb exposure leads to ASD traits and that retinoid signaling may be a key pathway in the cerebellum, at least in part. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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23 pages, 5795 KB  
Article
In Silico Network Pharmacology, Molecular Docking, and Molecular Dynamics Analysis of Rosemary-Derived Compounds as Potential HSP90 Inhibitors for Cancer Therapy
by Radhia Mazri, Mebarka Ouassaf, Afaf Zekri, Shafi Ullah Khan, Kannan R. R. Rengasamy and Bader Y. Alhatlani
Curr. Issues Mol. Biol. 2025, 47(10), 860; https://doi.org/10.3390/cimb47100860 - 18 Oct 2025
Viewed by 455
Abstract
Cancer remains a major global health challenge, emphasizing the need for new and effective therapies. This study investigates the anticancer potential of bioactive compounds from rosemary (Rosmarinus officinalis) using an integrative network pharmacology and computational approach. Twelve phytochemicals with favorable pharmacological profiles, optimal [...] Read more.
Cancer remains a major global health challenge, emphasizing the need for new and effective therapies. This study investigates the anticancer potential of bioactive compounds from rosemary (Rosmarinus officinalis) using an integrative network pharmacology and computational approach. Twelve phytochemicals with favorable pharmacological profiles, optimal pharmacokinetics, and acceptable toxicological properties were evaluated, revealing 178 putative cancer-related targets. Protein–protein interaction (PPI) analysis highlighted ten key genes—EGFR, ESR1, HIF1A, HSP90AA1, MAPK1, BCL2, STAT3, TP53, CASP3, and SRC—implicated in the progression of various cancers, including breast, colorectal, liver, and lung tumors. Functional enrichment analysis demonstrated their involvement in multiple cancer-associated pathways. Among these, HSP90AA1 emerged as a critical target. Molecular docking revealed Rosmanol, Chlorogenic acid, and Carnosol as the most promising HSP90AA1 binders with strong predicted affinities. ADMET profiling confirmed their excellent drug-likeness and safety profiles, while molecular dynamics simulations validated the stability of the compound–protein complexes, further supporting their potential as HSP90 inhibitors. These findings suggest that rosemary-derived compounds may represent valuable candidates for anticancer drug development, though experimental validation is required to confirm their therapeutic efficacy. Full article
(This article belongs to the Collection Bioinformatics Approaches to Biomedicine)
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15 pages, 816 KB  
Article
The Linkage Between Inflammation and the Progression of Type 2 Diabetes Mellitus
by Lucy Baldeón-Rojas, Valeria Alulema, Francisco Barrera-Guarderas, Diana Aguirre-Villacís, Cristina Cañadas-Herrera, Ricardo Bedón-Galarza, Francisco Pérez-Tasigchana and Jorge Pérez-Galarza
Curr. Issues Mol. Biol. 2025, 47(10), 859; https://doi.org/10.3390/cimb47100859 - 17 Oct 2025
Viewed by 1405
Abstract
Type 2 diabetes mellitus (T2D) is a chronic metabolic disorder in which inflammation plays a central role in its onset, progression, and complications. Identifying reliable biomarkers is essential to improve risk prediction, disease monitoring, and early intervention. A total of 169 Ecuadorian participants [...] Read more.
Type 2 diabetes mellitus (T2D) is a chronic metabolic disorder in which inflammation plays a central role in its onset, progression, and complications. Identifying reliable biomarkers is essential to improve risk prediction, disease monitoring, and early intervention. A total of 169 Ecuadorian participants were stratified into four clinical groups: non-diabetic controls (NDC), controlled T2D (C-T2D), uncontrolled T2D (NC-T2D), and diabetic kidney disease (DKD). Circulating levels of cytokines (IL-6, IL-8, TNF-α), adipokines (leptin, adiponectin), and PBMC-derived microRNAs (miR-146a, miR-155) were quantified. Associations with disease stage were evaluated using ROC curve analysis and logistic regression. Leptin showed the strongest association with T2D (OR = 13.76, 95% CI: 6.47–29.26), followed by IL-8 (OR = 6.73, 95% CI: 3.30–13.70) and IL-6 (OR = 4.43, 95% CI: 2.26–8.97). Adiponectin distinguished NC-T2D from DKD (OR = 4.15, 95% CI: 1.77–9.71), underscoring its potential as an indicator of renal complications. Interestingly, TNF-α levels declined across disease stages, possibly reflecting subclinical inflammation in Ecuadorian NDC with high rates of obesity and dyslipidemia. PBMC-derived miR-146a was upregulated in T2D patients, contrasting with prior serum-based studies and emphasizing the importance of compartment-specific analysis. miR-155 was elevated in C-T2D, suggesting a compensatory immune-regulatory mechanism that diminishes with poor glycemic control and advanced disease. Inflammatory cytokines, adipokines, and microRNAs act in distinct yet complementary ways in T2D. Leptin, IL-6, and IL-8 emerge as strong predictors of disease, while miR-146a and miR-155 provide additional insight into immune-inflammatory regulation. Integrated biomarker panels may enhance patient stratification and support personalized monitoring of T2D progression. Full article
(This article belongs to the Section Molecular Medicine)
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17 pages, 5417 KB  
Article
Pennisetum glaucum (L.) Oral Supplementation Mitigates Multi-Organic Dysfunction Associated with Carcinogenesis in HPV16-Transgenic Mice
by Paula A. Oliveira, Latifa Hajri, Armando V. Pinto Moreno, Carlos E. Dias Santos, Haissa O. Brito, Margarida M. S. M. Bastos, Rui Medeiros, Soumaya Ghodbane, Mohamed Ammari, Rui M. Gil da Costa and Ana I. Faustino-Rocha
Curr. Issues Mol. Biol. 2025, 47(10), 858; https://doi.org/10.3390/cimb47100858 - 17 Oct 2025
Viewed by 341
Abstract
Cancers induced by human papillomavirus are often associated with systemic inflammation and cachexia. This study aimed to determine the interference of Pennisetum glaucum oral supplementation over multi-organic dysfunction in HPV16-transgenic mice. The experimental groups included (1) wildtype (WT) mice with standard diet, (2) [...] Read more.
Cancers induced by human papillomavirus are often associated with systemic inflammation and cachexia. This study aimed to determine the interference of Pennisetum glaucum oral supplementation over multi-organic dysfunction in HPV16-transgenic mice. The experimental groups included (1) wildtype (WT) mice with standard diet, (2) WT mice with 36% Pennisetum, (3) transgenic mice with standard diet, (4) transgenic mice with 29% Pennisetum, and (5) transgenic mice with 36% Pennisetum. During the 4-week experimental protocol, body weight, food and water intake, and humane endpoints were recorded. At sacrifice, blood and tissue samples were collected for analysis. Oral supplementation with millet was shown to be safe and well tolerated by both WT and transgenic mice, with no adverse effects on behavior, food or water intake, or general animal welfare. In HPV16-transgenic animals, millet supplementation was associated with an improved health status, reduced serum glucose levels, enhanced antioxidant responses, and a notable reduction in the severity of HPV-induced skin and organ lesions. Overall, Pennisetum glaucum was safe under these experimental conditions and is a promising functional food for patients suffering from systemic paraneoplastic syndromes. Longer exposure periods and doses should be evaluated experimentally before proceeding to clinical trials of Pennisetum-containing diets. Full article
(This article belongs to the Section Molecular Pharmacology)
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15 pages, 1470 KB  
Article
Biphasic Slc2a4 Gene Expression in 3T3-L1 Adipocytes in Response to Treatment with Low and High Concentrations of Daidzein and Genistein
by Karen Cristina Rego Gregorio, Caroline Pancera Laurindo, Helayne Soares Freitas, Maristela Mitiko Okamoto, Patricia Monteiro Seraphim and Ubiratan Fabres Machado
Curr. Issues Mol. Biol. 2025, 47(10), 857; https://doi.org/10.3390/cimb47100857 - 17 Oct 2025
Viewed by 293
Abstract
Daidzein and genistein are abundant in soy-rich foods, whose supplementation has been proposed to have beneficial effects on several diseases, including diabetes mellitus and obesity. 17β-estradiol (E2) enhances the expression of the Slc2a4 gene and GLUT4 protein in adipose tissue, increasing glucose consumption [...] Read more.
Daidzein and genistein are abundant in soy-rich foods, whose supplementation has been proposed to have beneficial effects on several diseases, including diabetes mellitus and obesity. 17β-estradiol (E2) enhances the expression of the Slc2a4 gene and GLUT4 protein in adipose tissue, increasing glucose consumption and contributing to glycemic control. We investigated, in 3T3-L1 adipocytes, the effect of low and high doses of daidzein and genistein on Slc2a4/GLUT4 expression and the participation of estrogen receptors 1/2 (ESR1/ESR2) in the regulations observed. Differentiated adipocytes were cultivated, for 24 h, in the presence of 17β-estradiol (E2, 10 nM), daidzein (10 nM–150 μM) and genistein (10 nM–50 μM), with or without ESR1 or ESR2 antagonists. Daidzein/genistein at a low dose (10 nM) increased Slc2a4/GLUT4 expression (50%, p < 0.05), an effect abrogated by an ESR1 antagonist, mimicking the effect of E2. However, maximal doses of daidzein and genistein reduced, in a ESR1-mediated mechanism, the expression of mRNA (by 47% and 60%, p < 0.001) and the protein (by 29% and 36%, p < 0.01), respectively, for daidzein and genistein, as compared to E2. In conclusion, in adipocytes, daidzein and genistein have a biphasic ESR1-mediated effect: while low concentrations increase the expression of Slc2a4/GLUT4, high concentrations decrease it, the former predisposing to an adipogenic effect, the latter to a diabetogenic condition. Full article
(This article belongs to the Special Issue Molecular Insights into Food-Derived Natural Products and Their Biological Activities—2nd Edition)
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13 pages, 1530 KB  
Article
GPX4 Inhibition Enhances the Pro-Oxidant and ER Stress Effects of Tempol in Colon and Gastric Cancer Cell Lines
by Gorkem Ozdemir and Halil Mahir Kaplan
Curr. Issues Mol. Biol. 2025, 47(10), 856; https://doi.org/10.3390/cimb47100856 - 16 Oct 2025
Viewed by 407
Abstract
Tempol, a synthetic nitroxide, exhibits dual antioxidant and pro-oxidant activity, requiring millimolar concentrations to induce oxidative stress, which limits its therapeutic use. Glutathione Peroxidase 4 (GPX4) is a critical lipid peroxidase that prevents ferroptosis, and its inhibition has emerged as a strategy to [...] Read more.
Tempol, a synthetic nitroxide, exhibits dual antioxidant and pro-oxidant activity, requiring millimolar concentrations to induce oxidative stress, which limits its therapeutic use. Glutathione Peroxidase 4 (GPX4) is a critical lipid peroxidase that prevents ferroptosis, and its inhibition has emerged as a strategy to sensitize cancer cells to oxidative stress. To enhance Tempol’s efficacy, we investigated its interaction with ML210, a GPX4 inhibitor, in human colon (HT29) and gastric (CRL-1739) cancer cell lines. We quantified cell viability, oxidative stress markers (H2O2, Total Oxidant Status (TOS), and Total Antioxidant Status (TAS)) and endoplasmic reticulum (ER) stress proteins (ATF6, GRP78, and IRE1α) in in vitro assays. Synergy was assessed using Bliss independence analysis. The combination of Tempol (2 mM) and ML210 (0.05 μM) markedly reduced viability in both cell lines. Bliss analysis revealed slight/moderate synergy for cytotoxicity (Δ = +0.15 in HT29; Δ = +0.26 in CRL-1739) and strong synergy for H2O2 accumulation (Δ = +1.92–2.23 across replicates). In contrast, TOS showed moderate-to-strong antagonism across both cell lines, and TAS demonstrated slight synergistic or antagonistic effects. ER stress markers exhibited marker and cell line specific synergy: ATF6 showed strong synergy, IRE1α slight synergy in both lines, and GRP78 activation was highly variable, showing strong synergy in CRL-1739 cells but moderate antagonism in HT29 cells. These findings indicate that the cooperative action of Tempol and ML210 is ROS-pool–specific and pathway-selective in the ER. These findings demonstrate that ML210 potentiates Tempol’s pro-oxidant pressure by targeting GPX4, selectively amplifying H2O2 accumulation and ER stress engagement without collapsing global redox balance. This study provides mechanistic rationale for redox–proteostasis co-targeting in gastric and colon cancers and establishes a foundation for in vivo validation. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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26 pages, 1268 KB  
Review
Epigenetic Mechanisms in Fabry Disease: A Thematic Analysis Linking Differential Methylation Profiles and Genetic Modifiers to Disease Phenotype
by Jatinder Singh, Paramala Santosh and Uma Ramaswami
Curr. Issues Mol. Biol. 2025, 47(10), 855; https://doi.org/10.3390/cimb47100855 - 16 Oct 2025
Viewed by 410
Abstract
Background/Objectives: Fabry disease is an X-linked lysosomal storage disorder. It is characterised by impaired metabolism of glycosphingolipids whose accumulation causes irreversible organ damage and life-threatening complications. Genotype–phenotype correlations have a limited scope in Fabry disease as the disorder presents with wide-ranging [...] Read more.
Background/Objectives: Fabry disease is an X-linked lysosomal storage disorder. It is characterised by impaired metabolism of glycosphingolipids whose accumulation causes irreversible organ damage and life-threatening complications. Genotype–phenotype correlations have a limited scope in Fabry disease as the disorder presents with wide-ranging clinical variability. In other X-linked disorders, epigenetic profiling has identified methylation patterns and disease modifiers that may explain clinical heterogeneity. In this narrative review and thematic analysis, the role of DNA methylation and epigenetics on the clinical phenotype in Fabry disease was investigated. Methods: Embase, PubMed, and PsycINFO were searched to identify literature on DNA methylation and epigenetics in Fabry disease. Based on the eligibility criteria, 20 articles were identified, and a thematic analysis was performed on the extracted data to identify themes. Results: Three themes emerged: (I) genetic modifiers, (II) methylation profiling, and (III) insights into X chromosome inactivation (XCI). The evidence synthesis revealed that telomere length, especially in early disease stages, bidirectional promoter (BDP) methylation by sphingolipids, epigenetic reader proteins, mitochondrial DNA haplogroups, and DNA methylation of the promoter region of the calcitonin receptor gene are potential genetic modifiers in Fabry disease. Methylation patterns also reveal episignatures in Fabry disease evolution and genes implicated in the maintenance of basement membranes. Studies on XCI further emphasise disease heterogeneity and draw attention to methodological issues in the assessment of XCI. Conclusions: This thematic review shows that DNA methylation and genetic modifiers are key factors modifying clinical variability in Fabry disease. More broadly, it underscores a crucial role for epigenetic processes in driving disease onset, progression, and severity in X-linked disorders. Full article
(This article belongs to the Special Issue Latest Review Papers in Molecular Biology 2025)
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16 pages, 587 KB  
Review
Pathophysiological Links Between Stroke and Prediabetes: A Systematic Review
by Yerushka Naicker and Andile Khathi
Curr. Issues Mol. Biol. 2025, 47(10), 854; https://doi.org/10.3390/cimb47100854 - 16 Oct 2025
Viewed by 380
Abstract
Prediabetes is an intermediate stage between normoglycaemia and type 2 diabetes mellitus (T2DM), affecting over 425 million people globally and contributing to vascular damage and increased stroke risk. Despite the severity of both conditions, their association remains underexplored. This review examines the literature [...] Read more.
Prediabetes is an intermediate stage between normoglycaemia and type 2 diabetes mellitus (T2DM), affecting over 425 million people globally and contributing to vascular damage and increased stroke risk. Despite the severity of both conditions, their association remains underexplored. This review examines the literature on stroke-related biomarkers in normoglycaemia, prediabetes and T2DM to identify potential links between prediabetes and stroke. This systematic review followed PRISMA-2020 guidelines. PubMed, Google Scholar, Scopus, Web of Science and Science Direct were searched for studies (2003–2023) on stroke biomarkers in prediabetes. Eligible studies were original human research in English, with defined diagnostic criteria (ADA or WHO) for glycaemic status and reported biomarker associations or stroke risk. Studies with major comorbidities were excluded. Data were extracted and bias was assessed using the Newcastle–Ottawa Scale. Meta-analysis was not performed due to limited studies per biomarker. Eight studies (n = 3003) were included. NSE was examined in three studies, all reporting significant elevations in hyperglycaemic individuals. Interleukin-6 (IL-6) was assessed in two studies; one showed a significant increase in diabetes, while the other found a non-significant upward trend. D-dimer and GFAP were each reported in separate single studies, both showing significant elevations in hyperglycaemic individuals with stroke or neurocognitive impairment. S100B was investigated in two studies, with divergent findings: one showed a positive association with glycaemic status, while the other reported lower levels in hyperglycaemia. Findings indicate biomarker alterations in T2DM, suggesting that early changes may occur in prediabetes. Our review suggests that individuals with prediabetes may show alterations in inflammatory (IL-6), coagulation (D-dimer), and neurovascular (S100B, GFAP, NSE) markers, though some findings are inconsistent, reflecting early pathophysiological changes that may increase stroke risk. Further well-designed studies are needed to clarify these associations and establish biomarker-based tools for earlier stroke risk detection and prevention in individuals with prediabetes. Full article
(This article belongs to the Special Issue Cerebrovascular Diseases: From Pathogenesis to Treatment)
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31 pages, 1423 KB  
Review
The Pathogenesis of Chronic Kidney Disease (CKD) and the Preventive and Therapeutic Effects of Natural Products
by Yuxin Dong and Yanqing Tong
Curr. Issues Mol. Biol. 2025, 47(10), 853; https://doi.org/10.3390/cimb47100853 - 16 Oct 2025
Viewed by 760
Abstract
Chronickidney disease (CKD) poses a major global public health challenge, driven by a complex pathogenesis involving multiple interconnected processes—including metabolic disturbances, chronic inflammation, oxidative stress, endoplasmic reticulum stress, and ferroptosis—which collectively contribute to progressive and often irreversible loss of renal function. Although current [...] Read more.
Chronickidney disease (CKD) poses a major global public health challenge, driven by a complex pathogenesis involving multiple interconnected processes—including metabolic disturbances, chronic inflammation, oxidative stress, endoplasmic reticulum stress, and ferroptosis—which collectively contribute to progressive and often irreversible loss of renal function. Although current standard therapies can ameliorate CKD progression, a substantial number of patients still advance to end-stage renal disease, highlighting the urgent need for innovative treatment strategies. Natural products have shown great promise in the prevention and management of CKD, largely attributable to their multi-target and multi-pathway synergistic effects. This review systematically outlines the core pathogenic mechanisms underlying CKD and elucidates the molecular mechanisms through which bioactive natural compounds exert renoprotective effects. Despite robust preclinical evidence, the clinical translation of these compounds remains hindered by limitations such as poor bioavailability and a lack of large-scale clinical trials. Moving forward, research should prioritize clinical translation of these compounds, aiming to provide novel therapeutic perspectives for CKD management. Full article
(This article belongs to the Special Issue Applications of Natural and Pseudo-Natural Products in Drug Discovery and Development 2025)
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13 pages, 1826 KB  
Article
IL-6 Inhibition Partially Ameliorates Maternal Immune Activation-Induced Autism-Like Behavioral Abnormalities in Mice
by Xiaoyun Zhang, Weili Luo, Kaiyue He, Yuping Li, Yan Chen, Zhipeng Xu and Zi-Kai Zhou
Curr. Issues Mol. Biol. 2025, 47(10), 852; https://doi.org/10.3390/cimb47100852 - 16 Oct 2025
Viewed by 526
Abstract
Prenatal maternal immune activation (MIA) has been implicated in autism spectrum disorder (ASD) pathogenesis, with interleukin-6 (IL-6) identified as a key inflammatory mediator. We investigated the therapeutic potential of IL-6 inhibition in an MIA mouse model induced by Toxoplasma gondii soluble tachyzoite antigen [...] Read more.
Prenatal maternal immune activation (MIA) has been implicated in autism spectrum disorder (ASD) pathogenesis, with interleukin-6 (IL-6) identified as a key inflammatory mediator. We investigated the therapeutic potential of IL-6 inhibition in an MIA mouse model induced by Toxoplasma gondii soluble tachyzoite antigen (STAg). Adult MIA offspring received systemic administration of the IL-6-neutralizing antibody (MP5-20F3) or isotype control, followed by behavioral assessments one week later. Open field and elevated plus maze tests revealed heightened anxiety-like behaviors in the STAg offspring, which were largely reversed by IL-6 inhibition. Reciprocal social interaction tests showed diminished sociability in the STAg offspring, which was partially restored by IL-6 inhibition. However, core ASD-like features, including impaired social preference and recognition in the three-chamber test, as well as increased repetitive behaviors, remained resistant to IL-6 inhibition. These findings demonstrate that STAg-induced MIA elicits anxiety-like and ASD-like phenotypes in adult offspring, with IL-6 playing an important role in anxiety-like behaviors and social interaction deficits. Systemic IL-6 inhibition partially ameliorates behavioral abnormalities. This study suggests that IL-6-targeted therapies may address a subset of ASD-related symptoms, and comprehensive strategies are needed for broader efficacy. Full article
(This article belongs to the Section Molecular Medicine)
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58 pages, 3255 KB  
Review
Pro-Angiogenic Bioactive Molecules in Vascular Morphogenesis: Integrating Endothelial Cell Dynamics
by Claudiu N. Lungu, Gabriela Gurau and Mihaela C. Mehedinti
Curr. Issues Mol. Biol. 2025, 47(10), 851; https://doi.org/10.3390/cimb47100851 - 15 Oct 2025
Viewed by 683
Abstract
During embryonic development, angiogenesis and arteriogenesis are responsible for vast growth and remodeling. These processes have distinct mechanisms, like budding, cord hollowing, cell hollowing, cell wrapping, and intussusception. This review discusses the diversity of morphogenetic mechanisms contributing to vessel assembly and angiogenic sprouting [...] Read more.
During embryonic development, angiogenesis and arteriogenesis are responsible for vast growth and remodeling. These processes have distinct mechanisms, like budding, cord hollowing, cell hollowing, cell wrapping, and intussusception. This review discusses the diversity of morphogenetic mechanisms contributing to vessel assembly and angiogenic sprouting in blood vessels and how molecular pathways regulate some complex cell behaviors concerning the VEGFR pathway. Also, a particular part is dedicated to the HIF 1α gene. The key components of the VEGFR pathway are VEGF receptors VEGFR1, VEGFR2, and VEGFR3. VEGFR2 plays a central role in vascular morphogenesis. VEGF is the primary ligand involved in angiogenesis and arteriogenesis. Various types of VEGF are being studied in terms of their therapeutic use. The ultimate goal of the vascular morphogenesis study is to enable the development of organized vascular tissue that presumably might be used to replace the diseased one. Cellular chirality—the intrinsic “handedness” of cells in movement, structure, and organization—plays a crucial role in angiogenesis, the process by which new blood vessels develop from old ones. This chiral activity is essential for the directed and patterned organization of endothelial cells during vascular formation and remodeling. In angiogenesis, cellular chirality directs endothelial cells to adopt specific orientations and migratory patterns, which are crucial for the formation of functionally organized blood vessels that provide tissues with the necessary nutrients and oxygen. Cellular chirality in this environment is affected by multiple mechanisms, including VEGF/VEGFR signaling, mechanical pressures, interactions with the extracellular matrix (ECM), and cytoskeletal movements. Lately, researchers have focused on the molecular control of blood vessel morphogenesis, the study of signaling circuitry implied in vascular morphogenesis, the emerging mechanism of vascular stabilization, and helical vasculogenesis driven by cell chirality. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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12 pages, 629 KB  
Review
Significant Association Between Glucokinase Regulatory Protein Variants and Genetic and Metabolic Diseases
by Ke Xu, Peng Chen, Yujing Su, Yanghui Chen, Xiuli Song, Bo Yu and Hong Wang
Curr. Issues Mol. Biol. 2025, 47(10), 850; https://doi.org/10.3390/cimb47100850 - 15 Oct 2025
Viewed by 440
Abstract
As next-generation sequencing develops, there are significant associations between glucokinase regulatory protein (GCKR) variants and many diseases, especially metabolic diseases. However, there is a lack of solid descriptions and summaries of how GCKR variants lead to diseases and a lack of successful translations [...] Read more.
As next-generation sequencing develops, there are significant associations between glucokinase regulatory protein (GCKR) variants and many diseases, especially metabolic diseases. However, there is a lack of solid descriptions and summaries of how GCKR variants lead to diseases and a lack of successful translations of drugs targeting this molecular variant. We searched literature datasets, mainly including PubMed and Web of Science, with “GCKR” or “GKRP”, “Variants”, “Hypertriglyceridemia”, “NAFLD”, and “Metabolic diseases” as the search terms. Our review firstly introduces the biological function of the GCKR gene and its encoding protein GKRP and then describes the GCKR variants in different diseases, such as hypertriglyceridemia and NAFLD, revealing that GCKR/GKPR is strongly associated with metabolic diseases. GKPR might be a potential target for T2D and other metabolic diseases. One drug for interfering with the GCK-GKRP complex has been developed and has shown its effectiveness in preclinical studies, with some possible side effects. More and more different-structured drugs should be developed to improve side effects, and more clinical trials should be carried out to determine the best intervention window and timing points to improve prognosis. Taken together, these insights show that GCKR/GKRP is significantly associated with many metabolic diseases via its complex metabolism system and is a potential target in many metabolic diseases. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Advances in Hypertension Management and Vascular Health)
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15 pages, 1786 KB  
Article
Identification and Association of CYP2R1, CYP27B1, and GC Gene Polymorphisms with Vitamin D Deficiency in Apparently Healthy Population and in Silico Analysis of the Binding Pocket of Vitamin D3
by Saima Manzoor, Asifa Majeed, Palvasha Waheed and Amir Rashid
Curr. Issues Mol. Biol. 2025, 47(10), 849; https://doi.org/10.3390/cimb47100849 - 15 Oct 2025
Viewed by 429
Abstract
Vitamin D deficiency is highly prevalent in Pakistan, but there is limited data on its genetic aspects. This case–control pilot study aimed to determine the association of rs782153744, rs200183599, rs118204011, and rs28934604 with vitamin D deficiency along rs7041 which has been studied in [...] Read more.
Vitamin D deficiency is highly prevalent in Pakistan, but there is limited data on its genetic aspects. This case–control pilot study aimed to determine the association of rs782153744, rs200183599, rs118204011, and rs28934604 with vitamin D deficiency along rs7041 which has been studied in our population. The DNA of a total of 600 subjects (300 cases and 300 controls) was extracted and genotyped by tetra ARMS PCR, followed by Sanger DNA sequencing of exon 4 of the CYP2R1 and CYP27B1 genes and exon 8 of the GC gene. SNP Stat was employed to analyze the data, while logistic regression was used to calculate the p-values and odds ratios (ORs). The R package version R studio (2025.05.1) Build 513 was used to statistically analyze rs782153744. In silico modeling of wild and mutant CYP2R1 and GC proteins was performed in Swiss-Model, Swiss-Dock, Discovery Studio, and PyMol using 3c6g and IJ78 as templates to perform binding pocket analysis of vitamin D3. The rs782153744 showed a protective association in the additive (OR: 0.15, 95% CI: 0.08–0.27, p-value < 0.001), recessive (OR: 0.19, 95% CI: 0.10–0.33, p-value < 0.001), and dominant (OR: 0.19, CI = 0.10–0.33, p-value < 0.001) models, while GC rs7041 (T > A, T > G) displayed a p-value < 0.0001 across all genetic models. Sanger sequencing yielded insignificant results, and the SNPs rs200183599, rs118204011, and rs28934604 had no significant association with vitamin D deficiency. The molecular pocket analysis of wild and mutant CYP2R1 proteins carrying rs782153744 polymorphisms revealed no changes. GC proteins carrying the rs7041 polymorphism revealed a shift in their 3D and 2D configuration, as well as a change in the amino acid residue of the binding pocket of VD3. The risk-associated rs7041 and protective rs782153744 variants back genetic screening for vitamin D deficiency risk stratification, allowing targeted supplementation in predisposed subjects and assisting in formulating a genotype-specific therapeutic approach. Full article
(This article belongs to the Collection Bioinformatics Approaches to Biomedicine)
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25 pages, 6158 KB  
Article
Hydrogen Sulfide and Nitric Oxide Improve Renal Function and α-Adrenergic Responsiveness in Rats with Left Ventricular Hypertrophy
by Tabinda Fatima, Latifah Al Shammari, Mohamed Ibrahim Lazhari, Waad Alrohily, Tan Yong Chia, Nimer Alsabeelah, Eid Fahad Alanazi, Khalid Abdulrahman Almutairi, Sultan Mujahid Alhabradi, Naif Saleh Alharbi and Ashfaq Ahmad
Curr. Issues Mol. Biol. 2025, 47(10), 848; https://doi.org/10.3390/cimb47100848 - 15 Oct 2025
Viewed by 378
Abstract
In left ventricular hypertrophy (LVH), the combined external administration of hydrogen sulfide (H2S) and nitric oxide (NO) has been shown to reverse LVH by activating the endothelial nitric oxide synthase pathway (eNOS/NO), independent of the cystathionine γ-lyase (CSE/H2S) pathway. [...] Read more.
In left ventricular hypertrophy (LVH), the combined external administration of hydrogen sulfide (H2S) and nitric oxide (NO) has been shown to reverse LVH by activating the endothelial nitric oxide synthase pathway (eNOS/NO), independent of the cystathionine γ-lyase (CSE/H2S) pathway. Individually, both H2S and NO have also been reported to significantly improve RCBP, restore renal excretory performance, and enhance α-adrenergic receptor responsiveness in rats. The induction of LVH was performed over a period of two weeks using drinking water with caffeine and isoprenaline. Five weeks later, the rats were fed with L-arginine (1.25 g/L) as a nitrogen oxide donor. Vascular reactions to methoxamine, phenylephrine, and noradrenaline were assessed in presences and absence of 5-methylurapidil (5-MeU), BMY7378, and chloroethylclonidine (CeC) and α1-adrenoceptor antagonists. In both the Control WKY and LVH-WKY groups, combined H2S+NO therapy significantly (p < 0.05) upregulated the renal mRNA of CSE and eNOS when compared with untreated LVH rats. The treatment also markedly increased RCBP in LVH-H2S+NO rats relative to LVH controls. Furthermore, H2S+NO administration enhanced the activity of α1A, α1B, and α1D adrenergic receptors in mediating renal vasoconstriction. Even under receptor blockade with high doses (HDs) of 5-MeU, CeC, and BMY 7378, renal vasoconstriction responses to adrenergic agonists like NA, PE, and ME in the LVH-H2S+NO group remained comparable to those observed in the counterpart Control-H2S+NO group. The findings of current study suggest that simultaneous exogenous administration of H2S and NO donors improve renal cortical blood flow, support renal function, and augment α1A, α1B, and α1D adrenergic receptor responsiveness to adrenergic agonists like NA, PE, and ME in LVH rats. This effect appears to rely primarily on the eNOS/NO pathway, with partial contribution from the CSE/H2S pathway. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Underlying Cardiorenal Diseases)
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15 pages, 751 KB  
Review
Gut Microbiota Changes in Metabolic Dysfunction-Associated Steatohepatitis and Inflammatory Bowel Disease: Common Pathogenic Features
by Giuseppe Guido Maria Scarlata, Domenico Morano, Abdulrahman Ismaiel, Rocco Spagnuolo, Francesco Luzza, Dan Lucian Dumitrascu and Ludovico Abenavoli
Curr. Issues Mol. Biol. 2025, 47(10), 847; https://doi.org/10.3390/cimb47100847 - 15 Oct 2025
Viewed by 691
Abstract
Gut microbiota changes have emerged as central players in the pathogenesis of both metabolic dysfunction-associated steatohepatitis (MASH) and inflammatory bowel disease (IBD). Although these diseases affect distinct primary organs, they share converging mechanisms driven by dysbiosis, including loss of beneficial short-chain fatty acid-producing taxa [...] Read more.
Gut microbiota changes have emerged as central players in the pathogenesis of both metabolic dysfunction-associated steatohepatitis (MASH) and inflammatory bowel disease (IBD). Although these diseases affect distinct primary organs, they share converging mechanisms driven by dysbiosis, including loss of beneficial short-chain fatty acid-producing taxa such as Faecalibacterium prausnitzii and Roseburia, enrichment of pro-inflammatory Enterobacteriaceae, and disruption of bile acid and tryptophan metabolism. These shifts compromise epithelial barrier integrity, promote the translocation of microbial products such as lipopolysaccharide, and trigger toll-like receptor 4-mediated activation of inflammatory cascades dominated by tumor necrosis factor-alpha, interleukin-6, and transforming growth factor-beta. In MASH, this dysbiotic environment fuels hepatic inflammation, insulin resistance, and fibrogenesis, while in IBD it sustains chronic mucosal immune activation. Shared features include impaired butyrate availability, altered bile acid pools affecting farnesoid X receptor and Takeda G protein-coupled Receptor 5 signaling, and defective aryl hydrocarbon receptor activation, all of which link microbial dysfunction to host metabolic and immune dysregulation. Understanding these overlapping pathways provides a deeper understanding of the role of the gut-liver and gut-immune axes as unifying frameworks in disease progression. This narrative review synthesizes current evidence on gut microbiota in MASH and IBD, underscoring the need for longitudinal, multi-omics studies and microbiome-targeted strategies to guide personalized therapeutic approaches. Full article
(This article belongs to the Special Issue Intestinal Inflammation: From Molecular Mechanisms to Therapeutic Strategies)
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14 pages, 2237 KB  
Article
Empagliflozin Attenuates Liver Inflammation and Fibrosis in NAFLD: Evidence from Mendelian Randomization and Mouse Experiments
by Chao Fu, Lijiao Deng, Xiaochan Zhu, Bin Wang, Bin Hu, Huan Xue, Qingxuan Zeng and Yi Zhang
Curr. Issues Mol. Biol. 2025, 47(10), 846; https://doi.org/10.3390/cimb47100846 - 15 Oct 2025
Viewed by 560
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disorder and a major global health challenge, yet effective pharmacological therapies are lacking. Empagliflozin, a sodium–glucose cotransporter-2 (SGLT2) inhibitor, has shown systemic metabolic and anti-inflammatory benefits, but its liver-specific molecular mechanisms remain incompletely [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disorder and a major global health challenge, yet effective pharmacological therapies are lacking. Empagliflozin, a sodium–glucose cotransporter-2 (SGLT2) inhibitor, has shown systemic metabolic and anti-inflammatory benefits, but its liver-specific molecular mechanisms remain incompletely understood. In this study, we evaluated the therapeutic effects of empagliflozin in a diet-induced mouse model of NAFLD, supported by Mendelian randomization analysis. Histological examination, serum biochemistry, and hepatic triglyceride quantification demonstrated that empagliflozin markedly attenuated hepatic steatosis and improved liver injury indices. At the molecular level, empagliflozin suppressed NF-κB-mediated inflammatory signaling and significantly downregulated fibrotic markers including α-SMA and COL1A1, while modulating TIMP-1 and MMP-9 expression. Collectively, these findings reveal that empagliflozin ameliorates NAFLD by inhibiting inflammatory and fibrotic molecular pathways, highlighting its potential as a mechanism-based therapeutic option for NAFLD. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Fatty Liver Disease: From Pathogenesis to Treatment, 2nd Edition)
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16 pages, 4440 KB  
Article
Action of Carnosic Acid Against Melanoma: A Strategy for Selective Radiosensitization with Protection of Non-Tumoral Cells
by Amparo Olivares, Isabel de la Fuente, Daniel Gyingiri Achel, Ana María Mercado, José Antonio Garcia-Gamuz, María del Rosario Tudela and Miguel Alcaraz
Curr. Issues Mol. Biol. 2025, 47(10), 845; https://doi.org/10.3390/cimb47100845 - 14 Oct 2025
Viewed by 320
Abstract
Carnosic acid (CA) is a phenolic diterpene with high antioxidant activity that supports its radioprotective capacity. This study aims to determine whether the radiosensitizing effect of CA established in B16F10 melanoma cells also occurs in other melanin-producing cells. Cell survival analysis, apoptosis, intracellular [...] Read more.
Carnosic acid (CA) is a phenolic diterpene with high antioxidant activity that supports its radioprotective capacity. This study aims to determine whether the radiosensitizing effect of CA established in B16F10 melanoma cells also occurs in other melanin-producing cells. Cell survival analysis, apoptosis, intracellular glutathione levels, and cell cycle progression were evaluated by comparing radiosensitive cells (PNT2) with radioresistant melanin-producing cells (MELAN A, SK-MEL-1, and B16F10). In PNT2 cells, CA exhibited radioprotective capacity, with 100% cell survival after exposure to 20 Gy of X-rays (p < 0.001), decreasing apoptosis (p < 0.001) and increasing the GSH/GSSG ratio (p < 0.01), without significant modification in cell cycle progression. However, CA administration to irradiated cells failed to exert radioprotection in MELAN A and SK-MEL-1 cells, and even doubled cell death in B16F10 cells (p < 0.001). Specifically, CA did not alter apoptosis or prevent the decrease in GSH/GSSG ratio in MELAN A and SK-MEL-1 cells, while it intensified radiation-induced cell cycle disruptions in all melanin-producing cells. All of these led to a loss of radioprotective capacity in the melanin-producing cells (MELAN A and SK-MEL-1) and even induced a radiosensitizing effect in B16F10 cells. Understanding the mechanisms of action of substances such as CA could promote new applications that protect healthy cells and exclusively damage neoplastic cells when both are present within the same irradiated volume in cancer patients requiring radiotherapy. Full article
(This article belongs to the Special Issue Molecular Insights into Radiation Oncology)
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19 pages, 914 KB  
Review
Epigenetic Factors in Pathogenesis of Retinoblastoma: DNA Methylation and Histone Acetylation
by Georgios Kiosis, Kanellos Skourtsidis, Despoina Ioannou, Vasilis-Spyridon Tseriotis, Konstantinos Stergiou, Fani Akritidou, Theodora Papamitsou, Maria Kourti and Sofia Karachrysafi
Curr. Issues Mol. Biol. 2025, 47(10), 844; https://doi.org/10.3390/cimb47100844 - 14 Oct 2025
Viewed by 436
Abstract
(Background) Retinoblastoma is the most common intraocular malignancy in childhood, primarily caused by mutations in the RB1 gene. However, increasing evidence highlights the significant role of epigenetic mechanisms, particularly DNA methylation and histone acetylation, in tumor initiation and progression. This review aims to [...] Read more.
(Background) Retinoblastoma is the most common intraocular malignancy in childhood, primarily caused by mutations in the RB1 gene. However, increasing evidence highlights the significant role of epigenetic mechanisms, particularly DNA methylation and histone acetylation, in tumor initiation and progression. This review aims to summarize and critically assess recent findings on how DNA methylation and histone acetylation contribute to the pathogenesis of retinoblastoma, and to explore their potential role as diagnostic biomarkers and therapeutic targets. (Methods) We searched the databases PubMed, Scopus, and ScienceDirect following PRISMA guidelines. Eligible studies were English-language, open-access articles published within the last ten years, including cohort studies, research articles, and case reports. After rigorous screening, 18 studies were included in the final analysis. (Results) Aberrant DNA methylation was found to inactivate tumor suppressor genes (RB1, RASSF1A, p16INK4A, MGMT) and promote oncogenesis through hypermethylation of regulatory elements. Similarly, histone acetylation’s dysregulation contributed to chromatin remodeling and overexpression of oncogenic factors such as SYK, GALNT8, and lincRNA-ROR. Elevated histone deacetylase (HDAC) activity was also linked to tumor cell proliferation, metastasis, and treatment resistance. Epigenetic inhibitors targeting these pathways demonstrated promising therapeutic potential. (Conclusions) DNA methylation and histone acetylation play a crucial role in the epigenetic regulation of genes implicated in retinoblastoma. Their dysregulation promotes tumorigenesis, and targeting these mechanisms represents a promising avenue for novel diagnostic and therapeutic strategies in pediatric oncology. Full article
(This article belongs to the Section Molecular Medicine)
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28 pages, 12490 KB  
Article
Joint Transcriptomic Analysis of the Effect of Iron Concentration on Piglet Liver and Functional Validation of Iron Regulatory Genes
by Haiming Qian, Ping Wang, Tengchuan Li, Chunyong Zhang, Jintao Li, Qingliang Wang, Haiyang Ren, Fanyu Jin, Jie Huang, Jun Yao, Hongbin Pan, Rongfu Guo and Qingcong An
Curr. Issues Mol. Biol. 2025, 47(10), 843; https://doi.org/10.3390/cimb47100843 - 14 Oct 2025
Viewed by 372
Abstract
Iron plays a key role in oxygen transport, hematopoiesis, and hypoxia adaptation. This study aimed to explore the dynamic response mechanism of the iron regulatory network and key genes in Duroc piglets. Eighteen weaned piglets were randomly divided into three dietary intervention groups: [...] Read more.
Iron plays a key role in oxygen transport, hematopoiesis, and hypoxia adaptation. This study aimed to explore the dynamic response mechanism of the iron regulatory network and key genes in Duroc piglets. Eighteen weaned piglets were randomly divided into three dietary intervention groups: low iron (0 mg/kg), conventional (100 mg/kg), and high iron (200 mg/kg). Transcriptomics technology was used to screen key liver iron regulatory genes under the influence of different dietary iron concentrations, and the expression of related genes was verified using primary pig liver cells. Fasting serum iron metabolism parameters were detected and iron content in organs was quantified. The results show, enrichment analysis highlighted immune–metabolic signaling, including NF-κB, PI3K-Akt, and TGF-β, and a total of 14 candidate genes (such as FGF21, SAA2/3, FNDC1, ETNPPL, TFR1) were identified. The study observed that these genes showed obvious dosage differentiation and nonlinear patterns. However, findings reflect mRNA-level changes and GO/KEGG over-representation, protein-level validation is planned in follow-up studies. Through the integration of in vitro and in vivo data, this study discovered new liver genes that may be related to pig iron homeostasis function, providing a theoretical basis for analyzing the regulatory mechanism of piglet iron response. Full article
(This article belongs to the Collection Feature Papers in Current Issues in Molecular Biology)
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