Differential efficacy of vitamin D2 (D2) versus vitamin D3 (D3) in improving classical functions in target organs remain incompletely understood. Previous studies show contradictory results, with limited comprehensive assessment of functional and molecular outcomes across classical target organs namely intestine, bone and kidney. This study investigated the comparative effects of D2 and D3, administered independently or in combination at different dosages, on these organs using a rat model. Weanling male Sprague-Dawley rats were subjected to a depletion-repletion study design with diets containing D2, D3, combination (D2 +D3), or vitamin D deficient (VDD) diet. Our results demonstrated that vitamin D3 supplementation elevated serum 25(OH)D levels more efficiently compared to vitamin D2, while concurrent D2 administration reduced the potential of D3 to increase 25(OH)D3 levels. Both D2 and D3 maintained serum Ca and PTH in the normal range. Intestinal 45Ca absorption was higher in groups receiving D3-based diets in a dose-dependent manner. Furthermore, D3 supplementation had superior effects on bone length, width and strength compared to D2. Vitamin D3 more effectively reduced trabecular bone area in the rehabilitation phase. Additionally, the expression of genes involved in renal calcium reabsorption (Trpv5, Calbindin-D28k, Pmca1b) and vitamin D metabolism/function (Cubilin, Vdr) were significantly altered in VDD group and better corrected with D3 than D2 during rehabilitation. These findings suggest that vitamin D3 is more efficacious than vitamin D2 in improving blood levels of 25(OH)D and majority of the classical functions. Hence vitamin D3 appears to be the superior choice for both prevention and rehabilitation purposes.
{"title":"Vitamin D3 (cholecalciferol) is more efficacious than Vitamin D2 (ergocalciferol) at regulating calcium absorption and bone quality in rats","authors":"Soumam Dutta , Athira Anilkumar Sudharma , Shabna Aboo , Surendar Jatavath , Sivaramakrishna Siginam , Pradeep B. Patil , Sai Santhosh Vadakattu , Mullapudi Venkata Surekha , G. Bhanuprakash Reddy , Ayesha Ismail","doi":"10.1016/j.jsbmb.2025.106837","DOIUrl":"10.1016/j.jsbmb.2025.106837","url":null,"abstract":"<div><div>Differential efficacy of vitamin D2 (D2) versus vitamin D3 (D3) in improving classical functions in target organs remain incompletely understood. Previous studies show contradictory results, with limited comprehensive assessment of functional and molecular outcomes across classical target organs namely intestine, bone and kidney. This study investigated the comparative effects of D2 and D3, administered independently or in combination at different dosages, on these organs using a rat model. Weanling male Sprague-Dawley rats were subjected to a depletion-repletion study design with diets containing D2, D3, combination (D2 +D3), or vitamin D deficient (VDD) diet. Our results demonstrated that vitamin D3 supplementation elevated serum 25(OH)D levels more efficiently compared to vitamin D2, while concurrent D2 administration reduced the potential of D3 to increase 25(OH)D3 levels. Both D2 and D3 maintained serum Ca and PTH in the normal range. Intestinal <sup>45</sup>Ca absorption was higher in groups receiving D3-based diets in a dose-dependent manner. Furthermore, D3 supplementation had superior effects on bone length, width and strength compared to D2. Vitamin D3 more effectively reduced trabecular bone area in the rehabilitation phase. Additionally, the expression of genes involved in renal calcium reabsorption (<em>Trpv5</em>, <em>Calbindin-D28k</em>, <em>Pmca1b</em>) and vitamin D metabolism/function (<em>Cubilin</em>, <em>Vdr</em>) were significantly altered in VDD group and better corrected with D3 than D2 during rehabilitation. These findings suggest that vitamin D3 is more efficacious than vitamin D2 in improving blood levels of 25(OH)D and majority of the classical functions. Hence vitamin D3 appears to be the superior choice for both prevention and rehabilitation purposes.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"254 ","pages":"Article 106837"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Polycystic Ovary Syndrome (PCOS) is a severe and heterogeneous endocrine disorder affecting 6-20 % of women of reproductive age globally. Despite its high prevalence, the underlying etiology and pathophysiology remain unclear, necessitating the use of animal models to study disease mechanisms and therapeutic targets. This review critically evaluates various induction agents used in PCOS animal models and their ability to mimic the clinical, metabolic, and reproductive manifestations of the human condition. Induction agents explored include androgens [Testosterone, Dihydrotestosterone (DHT), Dehydroepiandrosterone (DHEA)], estrogen (estradiol valerate), aromatase inhibitors (letrozole), endocrine disruptors (bisphenol A), and dietary modifications (high-fat or high-sugar diets). These agents, administered in species such as rats, mice, zebrafish, reproduce hallmark PCOS features, including hyperandrogenism, anovulation, polycystic ovaries, and insulin resistance. The review highlights the mechanisms, symptom profiles, and translational relevance of each model. Comparative analysis is provided to assess the strengths and limitations associated with each agent, considering factors such as hormonal balance, metabolic function, and reproductive outcomes. Animal models serve as essential tools for understanding PCOS and testing therapeutic interventions. Each inducing agent offers unique insights into specific aspects of the disorder, although none fully replicates the human syndrome. The selection of the agent and animal species based on research goals is vital for clinical relevance. Future work should focus on integrating models that reflect both reproductive and metabolic features of PCOS to improve translational value.
{"title":"Inducing agents and PCOS - A comprehensive analysis.","authors":"Dhanyaa Muthukumaran, Jayalakshmi Kumar, Rajeshkumar Shanmugam","doi":"10.1016/j.jsbmb.2025.106840","DOIUrl":"10.1016/j.jsbmb.2025.106840","url":null,"abstract":"<p><p>Polycystic Ovary Syndrome (PCOS) is a severe and heterogeneous endocrine disorder affecting 6-20 % of women of reproductive age globally. Despite its high prevalence, the underlying etiology and pathophysiology remain unclear, necessitating the use of animal models to study disease mechanisms and therapeutic targets. This review critically evaluates various induction agents used in PCOS animal models and their ability to mimic the clinical, metabolic, and reproductive manifestations of the human condition. Induction agents explored include androgens [Testosterone, Dihydrotestosterone (DHT), Dehydroepiandrosterone (DHEA)], estrogen (estradiol valerate), aromatase inhibitors (letrozole), endocrine disruptors (bisphenol A), and dietary modifications (high-fat or high-sugar diets). These agents, administered in species such as rats, mice, zebrafish, reproduce hallmark PCOS features, including hyperandrogenism, anovulation, polycystic ovaries, and insulin resistance. The review highlights the mechanisms, symptom profiles, and translational relevance of each model. Comparative analysis is provided to assess the strengths and limitations associated with each agent, considering factors such as hormonal balance, metabolic function, and reproductive outcomes. Animal models serve as essential tools for understanding PCOS and testing therapeutic interventions. Each inducing agent offers unique insights into specific aspects of the disorder, although none fully replicates the human syndrome. The selection of the agent and animal species based on research goals is vital for clinical relevance. Future work should focus on integrating models that reflect both reproductive and metabolic features of PCOS to improve translational value.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"106840"},"PeriodicalIF":2.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-08-11DOI: 10.1016/j.jsbmb.2025.106842
Weihao Huang , Jiahui Liu , Lunxuan Zhao , Huaming He
The skin is a vital organ that protects the body from external insults. Ceramides, the major lipid components of the skin, are synthesized through three main pathways: de novo synthesis, sphingomyelin hydrolysis, and the salvage pathway. Ceramides are crucial for maintaining the skin barrier and hydration, and their deficiencies are associated with various skin diseases such as atopic dermatitis, psoriasis, and Netherton's syndrome. In the cosmetic industry, ceramides are used for skin barrier repair and moisturization. However, their poor water solubility necessitates the development of effective delivery systems. Alternatively, exogenous substances can be utilized to promote ceramide synthesis in skin. Therefore, elucidating the mechanisms by which ceramides influence the skin barrier and hydration, and developing ceramide-containing cosmetic products based on these mechanisms, represent promising research directions for improving skin health.
{"title":"Function of ceramides in the skin and its relationship with skin disease","authors":"Weihao Huang , Jiahui Liu , Lunxuan Zhao , Huaming He","doi":"10.1016/j.jsbmb.2025.106842","DOIUrl":"10.1016/j.jsbmb.2025.106842","url":null,"abstract":"<div><div>The skin is a vital organ that protects the body from external insults. Ceramides, the major lipid components of the skin, are synthesized through three main pathways: <em>de novo</em> synthesis, sphingomyelin hydrolysis, and the salvage pathway. Ceramides are crucial for maintaining the skin barrier and hydration, and their deficiencies are associated with various skin diseases such as atopic dermatitis, psoriasis, and Netherton's syndrome. In the cosmetic industry, ceramides are used for skin barrier repair and moisturization. However, their poor water solubility necessitates the development of effective delivery systems. Alternatively, exogenous substances can be utilized to promote ceramide synthesis in skin. Therefore, elucidating the mechanisms by which ceramides influence the skin barrier and hydration, and developing ceramide-containing cosmetic products based on these mechanisms, represent promising research directions for improving skin health.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"254 ","pages":"Article 106842"},"PeriodicalIF":2.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144849568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-06-30DOI: 10.1016/j.jsbmb.2025.106823
Huiqian Zhang , Jiayi He , Xiuwei Shen , Congcong Wen , Yubin Xu , Feilu Wang , Shaowei Wang , Ren-shan Ge , Xiaoheng Li
The placenta contains 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1), an enzyme critical for converting estrone to estradiol. Salicylates, widely used as preservatives, may inhibit 17β-HSD1, but their inhibitory strength and structure-activity relationships (SAR) remain unclear. This study evaluated 13 structurally diverse salicylates, identifying potent inhibitors of human and rat 17β-HSD1. Menthyl salicylate showed the strongest inhibition in humans (IC50: 5.23 μM) and rats (IC50: 14.85 μM). Inhibition correlated negatively with molecular weight, volume, carbon chain length, and LogP. Mechanistic studies revealed mixed/noncompetitive inhibition in both species. 3D-QSAR and molecular docking highlighted hydrophobic, van der Waals, and hydrogen-bonding interactions at the enzyme’s active site. Key structural features, including carbon chain length and substituent patterns, determined inhibitory potency. These findings clarify SAR and suggest salicylates' potential as endocrine disruptors.
{"title":"Suppression of human and rat 17β-hydroxysteroid dehydrogenase 1 by salicylate preservatives: 3D quantitative structure-activity relationship and in silico docking analysis","authors":"Huiqian Zhang , Jiayi He , Xiuwei Shen , Congcong Wen , Yubin Xu , Feilu Wang , Shaowei Wang , Ren-shan Ge , Xiaoheng Li","doi":"10.1016/j.jsbmb.2025.106823","DOIUrl":"10.1016/j.jsbmb.2025.106823","url":null,"abstract":"<div><div>The placenta contains 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1), an enzyme critical for converting estrone to estradiol. Salicylates, widely used as preservatives, may inhibit 17β-HSD1, but their inhibitory strength and structure-activity relationships (SAR) remain unclear. This study evaluated 13 structurally diverse salicylates, identifying potent inhibitors of human and rat 17β-HSD1. Menthyl salicylate showed the strongest inhibition in humans (IC<sub>50</sub>: 5.23 μM) and rats (IC<sub>50</sub>: 14.85 μM). Inhibition correlated negatively with molecular weight, volume, carbon chain length, and LogP. Mechanistic studies revealed mixed/noncompetitive inhibition in both species. 3D-QSAR and molecular docking highlighted hydrophobic, van der Waals, and hydrogen-bonding interactions at the enzyme’s active site. Key structural features, including carbon chain length and substituent patterns, determined inhibitory potency. These findings clarify SAR and suggest salicylates' potential as endocrine disruptors.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"254 ","pages":"Article 106823"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144535774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-09-01DOI: 10.1016/j.jsbmb.2025.106848
Sarvesh Sabarathinam , Nila Ganamurali
7-Ketocholesterol (7-KC), a cytotoxic cholesterol oxidation product, drives oxidative stress, inflammation, and apoptosis in cardiovascular, neurodegenerative, and metabolic disorders. Current lipid-lowering agents, such as statins, do not eliminate pre-formed oxysterols, highlighting an unmet therapeutic need. Guggulsterone(GGS), a steroidal phytoconstituent from Commiphora mukul, exhibits dual-function potential by reducing 7-KC formation through antioxidant, anti-inflammatory, and Nrf2-activating effects, while enhancing cholesterol efflux via LDLR and ABC transporters. Additionally, it improves endothelial and neuronal resilience to oxysterol-induced apoptosis. Guggulsterone’s amphiphilic nature supports its integration into nanocarriers, enabling co-delivery with therapeutics for synergistic effects. Advanced formulations such as SEDDS, nanoparticle co-encapsulation, and solid lipid nanoparticles enhance its bioavailability, stability, and tissue targeting, including brain delivery. These properties position guggulsterone as both a therapeutic agent and bioenhancer, offering a promising strategy to mitigate oxysterol burden and improve clinical outcomes in 7-KC–related disorders.
{"title":"Guggulsterone as a dual-function steroidal scaffold: Cholesterol modulation and bioenhancement potential against 7-Ketocholesterol-Linked pathologies","authors":"Sarvesh Sabarathinam , Nila Ganamurali","doi":"10.1016/j.jsbmb.2025.106848","DOIUrl":"10.1016/j.jsbmb.2025.106848","url":null,"abstract":"<div><div>7-Ketocholesterol (7-KC), a cytotoxic cholesterol oxidation product, drives oxidative stress, inflammation, and apoptosis in cardiovascular, neurodegenerative, and metabolic disorders. Current lipid-lowering agents, such as statins, do not eliminate pre-formed oxysterols, highlighting an unmet therapeutic need. Guggulsterone(GGS), a steroidal phytoconstituent from <em>Commiphora mukul</em>, exhibits dual-function potential by reducing 7-KC formation through antioxidant, anti-inflammatory, and Nrf2-activating effects, while enhancing cholesterol efflux via LDLR and ABC transporters. Additionally, it improves endothelial and neuronal resilience to oxysterol-induced apoptosis. Guggulsterone’s amphiphilic nature supports its integration into nanocarriers, enabling co-delivery with therapeutics for synergistic effects. Advanced formulations such as SEDDS, nanoparticle co-encapsulation, and solid lipid nanoparticles enhance its bioavailability, stability, and tissue targeting, including brain delivery. These properties position guggulsterone as both a therapeutic agent and bioenhancer, offering a promising strategy to mitigate oxysterol burden and improve clinical outcomes in 7-KC–related disorders.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"254 ","pages":"Article 106848"},"PeriodicalIF":2.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elucidating the mechanisms of action of natural metabolites may be promising in the emergence of alternative candidate therapeutics. In the present study, the combined approaches of in silico molecular docking (MD) and in vitro analyses were conducted to investigate the interacting partners of 24-epibrassinolide (EBR) as a steroid-derived phytohormone in cancer cells and evaluate the cell death mechanisms associated with these partners. EBR scoring functions were initially calculated against the selected 35 functional target proteins, which may interact with steroids, for tumor biology using AutoDock Tools-1.5.7 receptor-ligand MD software. Molecular analyses were carried out in breast, pancreatic, and hepatocellular carcinoma cell lines. Our results showed that the retinoic acid nuclear receptor γ (RARγ) was the most stable interacting partner with a binding energy (BE). Furthermore, the secondary simulation analyses obtained the lowest BE score for EBR among RARγ selective agonistic compounds. According to our data, EBR was significantly inhibited the cell viability of MDA-MB-231, MIA-PaCa-2, and Hep-G2 cells, and diminished the colony formation potential. We showed that RARγ was inhibited after increasing concentration of EBR, by affecting the downstream target’s expressions including p21, p16, p27, p57 and cyclin D1 detected by qRT-PCR. We also investigated the effect of EBR treatment on the expression levels of the proteins linked to nuclear hormone receptor (NHR) expressions, apoptosis, endoplasmic reticulum stress, and Hippo-Yes-associated protein (YAP)/ Transcriptional coactivator with PDZ-binding motif (TAZ) signaling pathways. Our findings indicated that EBR is a strong ER stress modulator, apoptosis inducer in a caspase-dependent manner, and effector for the modulation of Hippo-YAP-TAZ signaling pathways through the interaction with retinoic acid receptor.
{"title":"In silico multitargeted molecular docking study of interacting partners of epibrassinolide in cancer cells and in vitro evaluation of cell death mechanisms associated with these partners","authors":"Leila Mehdizadehtapeh , Zeynep Demirel , Esranur Kopal , Elif Damla Arısan , Tugba Taşkın Tok , Pınar Obakan Yerlikaya","doi":"10.1016/j.jsbmb.2025.106845","DOIUrl":"10.1016/j.jsbmb.2025.106845","url":null,"abstract":"<div><div>Elucidating the mechanisms of action of natural metabolites may be promising in the emergence of alternative candidate therapeutics. In the present study, the combined approaches of <em>in silico</em> molecular docking (MD) and <em>in vitro</em> analyses were conducted to investigate the interacting partners of 24-epibrassinolide (EBR) as a steroid-derived phytohormone in cancer cells and evaluate the cell death mechanisms associated with these partners. EBR scoring functions were initially calculated against the selected 35 functional target proteins, which may interact with steroids, for tumor biology using AutoDock Tools-1.5.7 receptor-ligand MD software. Molecular analyses were carried out in breast, pancreatic, and hepatocellular carcinoma cell lines. Our results showed that the retinoic acid nuclear receptor γ (RARγ) was the most stable interacting partner with a binding energy (BE). Furthermore, the secondary simulation analyses obtained the lowest BE score for EBR among RARγ selective agonistic compounds. According to our data, EBR was significantly inhibited the cell viability of MDA-MB-231, MIA-PaCa-2, and Hep-G2 cells, and diminished the colony formation potential. We showed that RARγ was inhibited after increasing concentration of EBR, by affecting the downstream target’s expressions including p21, p16, p27, p57 and cyclin D1 detected by qRT-PCR. We also investigated the effect of EBR treatment on the expression levels of the proteins linked to nuclear hormone receptor (NHR) expressions, apoptosis, endoplasmic reticulum stress, and Hippo-Yes-associated protein (YAP)/ Transcriptional coactivator with PDZ-binding motif (TAZ) signaling pathways. Our findings indicated that EBR is a strong ER stress modulator, apoptosis inducer in a caspase-dependent manner, and effector for the modulation of Hippo-YAP-TAZ signaling pathways through the interaction with retinoic acid receptor.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"254 ","pages":"Article 106845"},"PeriodicalIF":2.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-07-01DOI: 10.1016/j.jsbmb.2025.106824
Maryam Mahjoubin-Tehran , Ali H. Eid , Tannaz Jamialahmadi , Saheem Ahmad , Safia Obaidur Rab , Prashant Kesharwani , Amirhossein Sahebkar
Obesity is currently recognized as a serious global health problem, which accounts for a considerable morbidity and mortality burden. Bariatric surgery is widely accepted as one of the most effective treatments for severe obesity. Roux-en-Y Gastric Bypass (RYGB) is a common type of bariatric surgery. Although the clinical impact of RYGB has been widely studied, the effects of this intervention at the molecular and genetic levels remain largely unknown. In this study, we aimed to identify differentially expressed genes in gastric mucosa after bariatric surgery vs. before in order to recognize genes and pathways influenced by surgery. Data of GSE76762 was downloaded from GEO (NCBI) database. Gene expression of after surgery samples were compared with before. Genes with a │Log fold change (LFC) │ > 1 and adjusted p-value < 0.05 were defined as differentially expressed genes. It was found that 11 genes were differentially upregulated and 6 genes were differentially downregulated after bariatric surgery. Protein-protein interactions assessed using STRNG online database was significant (p-value: 0.000202). SCD, INSIG1, CYP51A1, and LDLR have strong protein-protein interactions. Gene-gene interaction was investigated using GeneMANIA which showed the high co-expression score (97.78 %). GO and pathway enrichment analysis was investigated using EnrichR. Cholesterol Homeostasis, Sterol Homeostasis, and Cellular Response to Sterol are the best results of biological process. Metabolism of steroids, Steroid regulatory element binding proteins signaling, and Bile secretion are the best results of Reactome, WikiPathway, and KEGG, respectively. Importantly, associations of LDLR, KCNJ13, and PMP22 with Familial hypercholesterolemia, Hyperlipoproteinemia, Charcot-marie-tooth disease type 1 and 4, and Leber congenital amaurosis were discovered.
{"title":"Gastric mucosal differentially expressed genes after bariatric surgery: Effects on sterol-related pathways","authors":"Maryam Mahjoubin-Tehran , Ali H. Eid , Tannaz Jamialahmadi , Saheem Ahmad , Safia Obaidur Rab , Prashant Kesharwani , Amirhossein Sahebkar","doi":"10.1016/j.jsbmb.2025.106824","DOIUrl":"10.1016/j.jsbmb.2025.106824","url":null,"abstract":"<div><div>Obesity is currently recognized as a serious global health problem, which accounts for a considerable morbidity and mortality burden. Bariatric surgery is widely accepted as one of the most effective treatments for severe obesity. Roux-en-Y Gastric Bypass (RYGB) is a common type of bariatric surgery. Although the clinical impact of RYGB has been widely studied, the effects of this intervention at the molecular and genetic levels remain largely unknown. In this study, we aimed to identify differentially expressed genes in gastric mucosa after bariatric surgery <em>vs.</em> before in order to recognize genes and pathways influenced by surgery. Data of GSE76762 was downloaded from GEO (NCBI) database. Gene expression of after surgery samples were compared with before. Genes with a │Log fold change (LFC) │ > 1 and adjusted p-value < 0.05 were defined as differentially expressed genes. It was found that 11 genes were differentially upregulated and 6 genes were differentially downregulated after bariatric surgery. Protein-protein interactions assessed using STRNG online database was significant (p-value: 0.000202). SCD, INSIG1, CYP51A1, and LDLR have strong protein-protein interactions. Gene-gene interaction was investigated using GeneMANIA which showed the high co-expression score (97.78 %). GO and pathway enrichment analysis was investigated using EnrichR. Cholesterol Homeostasis, Sterol Homeostasis, and Cellular Response to Sterol are the best results of biological process. Metabolism of steroids, Steroid regulatory element binding proteins signaling, and Bile secretion are the best results of Reactome, WikiPathway, and KEGG, respectively. Importantly, associations of LDLR, KCNJ13, and PMP22 with Familial hypercholesterolemia, Hyperlipoproteinemia, Charcot-marie-tooth disease type 1 and 4, and Leber congenital amaurosis were discovered.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"254 ","pages":"Article 106824"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144561938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-07-16DOI: 10.1016/j.jsbmb.2025.106836
Nila Ganamurali , Varsha S B , Sarvesh Sabarathinam
Alzheimer’s disease (AD) is characterized by amyloid-β deposition and neuroinflammation. Emerging evidence implicates gut microbiota dysbiosis and gut–brain axis dysfunction in AD pathogenesis, while phytosterols—plant sterols similar to cholesterol—modulate microbiota composition, lipid metabolism, and inflammatory pathways. To review evidence of phytosterols as modulators of the gut–brain axis and neuroinflammation in AD, outlining mechanisms, therapeutic potential, and delivery approaches. A literature search of PubMed, Scopus, and Web of Science identified studies on phytosterols, gut microbiota modulation, neuroinflammation, and AD. Mechanistic data on sterol structure–activity relationships, microbiota-derived metabolites, and in vivo AD outcomes were extracted and synthesized. Phytosterols lower systemic cholesterol, cross the blood–brain barrier, and accumulate in neural tissue. They enrich short-chain fatty acid–producing gut microbes, suppress pathogens, and increase secondary bile acids that activate FXR and TGR5 signaling, attenuating neuroinflammation. Preclinical AD models show reduced amyloid-β, decreased microglial activation, and improved cognition. Nanoencapsulation and esterification strategies enhance CNS bioavailability. Phytosterols modulate cholesterol, gut microbiota, and neuroinflammatory pathways through FXR- and TGR5-mediated signaling. Advanced delivery systems and microbiome-informed dosing strategies may enhance their therapeutic precision and uptake. Future studies should focus on stratified human trials to validate efficacy and enable personalized interventions in Alzheimer’s disease.
阿尔茨海默病（AD）以淀粉样蛋白-β沉积和神经炎症为特征。新出现的证据表明，肠道菌群失调和肠-脑轴功能障碍在阿尔茨海默病的发病机制中，而植物甾醇-类似于胆固醇的植物甾醇-调节微生物群组成、脂质代谢和炎症途径。回顾植物甾醇作为AD患者肠-脑轴和神经炎症调节剂的证据，概述其机制、治疗潜力和给药途径。PubMed， Scopus和Web of Science的文献检索确定了植物甾醇，肠道微生物群调节，神经炎症和AD的研究。提取并合成了有关甾醇结构-活性关系、微生物衍生代谢物和体内AD结果的机制数据。植物甾醇降低全身胆固醇，穿过血脑屏障，并在神经组织中积累。它们丰富了产生短链脂肪酸的肠道微生物，抑制了病原体，增加了激活FXR和TGR5信号的次级胆汁酸，减轻了神经炎症。临床前AD模型显示淀粉样蛋白-β减少，小胶质细胞激活减少，认知能力改善。纳米胶囊化和酯化策略提高中枢神经系统的生物利用度。植物甾醇通过FXR-和tgr5介导的信号通路调节胆固醇、肠道菌群和神经炎症通路。先进的给药系统和微生物组信息的给药策略可以提高它们的治疗精度和摄取。未来的研究应侧重于分层人体试验，以验证阿尔茨海默病的疗效，并实现个性化干预。
{"title":"Phytosterols as modulators of gut-brain axis and neuroinflammation in Alzheimer’s disease: A novel therapeutic avenue in aging research","authors":"Nila Ganamurali , Varsha S B , Sarvesh Sabarathinam","doi":"10.1016/j.jsbmb.2025.106836","DOIUrl":"10.1016/j.jsbmb.2025.106836","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is characterized by amyloid-β deposition and neuroinflammation. Emerging evidence implicates gut microbiota dysbiosis and gut–brain axis dysfunction in AD pathogenesis, while phytosterols—plant sterols similar to cholesterol—modulate microbiota composition, lipid metabolism, and inflammatory pathways. To review evidence of phytosterols as modulators of the gut–brain axis and neuroinflammation in AD, outlining mechanisms, therapeutic potential, and delivery approaches. A literature search of PubMed, Scopus, and Web of Science identified studies on phytosterols, gut microbiota modulation, neuroinflammation, and AD. Mechanistic data on sterol structure–activity relationships, microbiota-derived metabolites, and in vivo AD outcomes were extracted and synthesized. Phytosterols lower systemic cholesterol, cross the blood–brain barrier, and accumulate in neural tissue. They enrich short-chain fatty acid–producing gut microbes, suppress pathogens, and increase secondary bile acids that activate FXR and TGR5 signaling, attenuating neuroinflammation. Preclinical AD models show reduced amyloid-β, decreased microglial activation, and improved cognition. Nanoencapsulation and esterification strategies enhance CNS bioavailability. Phytosterols modulate cholesterol, gut microbiota, and neuroinflammatory pathways through FXR- and TGR5-mediated signaling. Advanced delivery systems and microbiome-informed dosing strategies may enhance their therapeutic precision and uptake. Future studies should focus on stratified human trials to validate efficacy and enable personalized interventions in Alzheimer’s disease.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"254 ","pages":"Article 106836"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144655671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-07-01DOI: 10.1016/j.jsbmb.2025.106822
Ellen Roy Elias
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive genetic disorder associated with complex anatomic abnormalities, accompanied by medical, developmental and behavioral challenges. It was the first human disorder identified to be caused by an error in the complex cholesterol biosynthetic pathway, more than thirty years ago. This review will cover the clinical and developmental phenotype of patients with SLOS, and the understanding of how cholesterol deficiency, accumulation of the cholesterol precursors 7- and 8-dehydrocholesterol (7-DHC and 8-DHC), and the oxidation of these precursors into toxic oxysterols, are now known to cause this complex phenotype. There is a wide range of severity in patients with SLOS. The most severely affected babies may be miscarried or die in the newborn period due to lethal congenital anomalies. The most mildly impacted patients may show few anatomic abnormalities other than 2–3 toe syndactyly, but still display cognitive and behavioral challenges along the autism spectrum. The review will also cover the medical evaluation and interventions which are recommended in caring for patients with SLOS. There is no cure for this devastating disease, but certain interventions can lead to an improved quality of life, and stabilization of progressive problems for these complex patients.
{"title":"The role of cholesterol biosynthesis and metabolism causing medical complexity in patients with Smith-Lemli-Opitz Syndrome (SLOS)","authors":"Ellen Roy Elias","doi":"10.1016/j.jsbmb.2025.106822","DOIUrl":"10.1016/j.jsbmb.2025.106822","url":null,"abstract":"<div><div>Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive genetic disorder associated with complex anatomic abnormalities, accompanied by medical, developmental and behavioral challenges. It was the first human disorder identified to be caused by an error in the complex cholesterol biosynthetic pathway, more than thirty years ago. This review will cover the clinical and developmental phenotype of patients with SLOS, and the understanding of how cholesterol deficiency, accumulation of the cholesterol precursors 7- and 8-dehydrocholesterol (7-DHC and 8-DHC), and the oxidation of these precursors into toxic oxysterols, are now known to cause this complex phenotype. There is a wide range of severity in patients with SLOS. The most severely affected babies may be miscarried or die in the newborn period due to lethal congenital anomalies. The most mildly impacted patients may show few anatomic abnormalities other than 2–3 toe syndactyly, but still display cognitive and behavioral challenges along the autism spectrum. The review will also cover the medical evaluation and interventions which are recommended in caring for patients with SLOS. There is no cure for this devastating disease, but certain interventions can lead to an improved quality of life, and stabilization of progressive problems for these complex patients.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"254 ","pages":"Article 106822"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144561937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-08-25DOI: 10.1016/j.jsbmb.2025.106846
Sarvesh Sabarathinam , Nila Ganamurali
7-Ketocholesterol (7-KC), a prominent oxysterol found in oxidized LDL, plays a central role in atherosclerosis through mechanisms involving oxidative stress, NF-κB activation, and mitochondrial dysfunction. Guggulsterone (GGS), a bioactive steroid from Commiphora mukul, exhibits antioxidant, anti-inflammatory, and FXR-antagonistic properties. This work highlights guggulsterone’s ability to counteract 7-KC-induced endothelial injury by inhibiting NF-κB translocation, reducing reactive oxygen species (ROS), and modulating apoptosis. These multimodal effects suggest guggulsterone as a promising natural agent for vascular protection. A systems-based pharmacological approach may further define its therapeutic utility in oxysterol-driven cardiovascular diseases.
{"title":"Targeting 7-ketocholesterol-induced oxidative stress and inflammation: Guggulsterone as a novel vascular protectant","authors":"Sarvesh Sabarathinam , Nila Ganamurali","doi":"10.1016/j.jsbmb.2025.106846","DOIUrl":"10.1016/j.jsbmb.2025.106846","url":null,"abstract":"<div><div>7-Ketocholesterol (7-KC), a prominent oxysterol found in oxidized LDL, plays a central role in atherosclerosis through mechanisms involving oxidative stress, NF-κB activation, and mitochondrial dysfunction. Guggulsterone (GGS), a bioactive steroid from <em>Commiphora mukul</em>, exhibits antioxidant, anti-inflammatory, and FXR-antagonistic properties. This work highlights guggulsterone’s ability to counteract 7-KC-induced endothelial injury by inhibiting NF-κB translocation, reducing reactive oxygen species (ROS), and modulating apoptosis. These multimodal effects suggest guggulsterone as a promising natural agent for vascular protection. A systems-based pharmacological approach may further define its therapeutic utility in oxysterol-driven cardiovascular diseases.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"254 ","pages":"Article 106846"},"PeriodicalIF":2.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144895523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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