Pub Date : 2025-10-17DOI: 10.1016/j.mce.2025.112689
Ana Paula de Paula Alves , Emanuelle Barreto-Reis , Beatriz Gouvêa de Luca , Thaís de Souza Carvalho , Giovanna Palermo de Andrade , Vinicius Sepúlveda-Fragoso , Beatriz Alexandre-Santos , Ana Beatriz Proença Souza , Ana Lívia Ladislau de Souza Vieira , Milena Barcza Stockler-Pinto , Eliete Dalla Corte Frantz , Clarice Machado-Santos , Denise Pires de Carvalho , Leandro Miranda-Alves , D'Angelo Carlo Magliano
Obesity is a chronic inflammatory disease linked to several comorbidities. Bisphenol S (BPS), a BPA substitute, is an endocrine disruptor that may impact pancreas and white adipose tissue (WAT) morphology and metabolism. This study investigated the obesogenic effects of BPS, alone or with a high-fat diet (HF), on pancreas and epididymal WAT (eWAT) morphology. Male C57BL/6 mice (n = 12) were divided into four groups: standard chow (SC), standard chow + BPS (SCB), HF diet (HF), and HF diet + BPS (HFB). BPS exposure (25 μg/kg/day) occurred via drinking water for 12 weeks. Body mass, pancreas and eWAT weights, plasma parameters, insulin resistance, morphometry, stereology, eWAT mRNA levels and protein expression of ER stress markers were analyzed. All interventions increased body and tissue masses, pancreatic α-cells and β-cells, Pparγ mRNA level, GRP78, ERO1 and ATF4 protein expression, epididymal adipocyte size, and insulin, glucose, and cholesterol levels. HF and HFB groups also showed increased Grp78 mRNA level, p-eIF2α and CHOP expression, pancreatic islet diameter, inflammatory infiltrate, and triacylglycerol levels. BPS combined with HF diet worsened insulin resistance. These findings suggest that BPS has obesogenic activity, affecting metabolism and remodeling pancreatic islets and eWAT, even at low doses, independently of a HF diet.
{"title":"Bisphenol S chronic exposure impairs pancreatic function and induces obesity in male mice independently of high-fat diet intake","authors":"Ana Paula de Paula Alves , Emanuelle Barreto-Reis , Beatriz Gouvêa de Luca , Thaís de Souza Carvalho , Giovanna Palermo de Andrade , Vinicius Sepúlveda-Fragoso , Beatriz Alexandre-Santos , Ana Beatriz Proença Souza , Ana Lívia Ladislau de Souza Vieira , Milena Barcza Stockler-Pinto , Eliete Dalla Corte Frantz , Clarice Machado-Santos , Denise Pires de Carvalho , Leandro Miranda-Alves , D'Angelo Carlo Magliano","doi":"10.1016/j.mce.2025.112689","DOIUrl":"10.1016/j.mce.2025.112689","url":null,"abstract":"<div><div>Obesity is a chronic inflammatory disease linked to several comorbidities. Bisphenol S (BPS), a BPA substitute, is an endocrine disruptor that may impact pancreas and white adipose tissue (WAT) morphology and metabolism. This study investigated the obesogenic effects of BPS, alone or with a high-fat diet (HF), on pancreas and epididymal WAT (eWAT) morphology. Male C57BL/6 mice (n = 12) were divided into four groups: standard chow (SC), standard chow + BPS (SCB), HF diet (HF), and HF diet + BPS (HFB). BPS exposure (25 μg/kg/day) occurred via drinking water for 12 weeks. Body mass, pancreas and eWAT weights, plasma parameters, insulin resistance, morphometry, stereology, eWAT mRNA levels and protein expression of ER stress markers were analyzed. All interventions increased body and tissue masses, pancreatic α-cells and β-cells, <em>Pparγ</em> mRNA level, GRP78, ERO1 and ATF4 protein expression, epididymal adipocyte size, and insulin, glucose, and cholesterol levels. HF and HFB groups also showed increased <em>Grp7</em>8 mRNA level, p-eIF2α and CHOP expression, pancreatic islet diameter, inflammatory infiltrate, and triacylglycerol levels. BPS combined with HF diet worsened insulin resistance. These findings suggest that BPS has obesogenic activity, affecting metabolism and remodeling pancreatic islets and eWAT, even at low doses, independently of a HF diet.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112689"},"PeriodicalIF":3.6,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145321936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-16DOI: 10.1016/j.mce.2025.112679
S. Maurotti , B. Scopacasa , F. Scionti , R. Pujia , M. Frosina , A. Mirarchi , N. Geirola , R. Mare , T. Montalcini , P. Candeloro , L. Tirinato , A. Pujia
Primary hypothyroidism has been associated with metabolic dysfunction-associated steatotic liver disease and, potentially, increased liver fibrosis risk. Although T4-analog drug is one of the standard treatments, its molecular effects on the liver are not fully understood.
To elucidate drug-induced hepatic metabolic changes, chronic human 2D and 3D hypothyroid models were developed. The effects of T4 were assessed by Raman spectroscopy and complementary biological techniques to observe lipid and fibrotic changes. In vitro chronic hypothyroidism caused lipid droplet (LDs) accumulation in liver cells which was unaffected by T4 therapy. Notably, TSH and T4 influenced TG fatty acid saturation in different ways: T4-exposed cells accumulated monounsaturated fatty acids at the expense of saturated fatty acids. In the case of liver fibrosis, TSH treatment activated hepatic stellate cells as evidenced by increased collagen secretion and decreased LD content, regardless of T4 co-treatment. Data confirmed that TSH induced pro-inflammatory changes leading to higher inflammasome levels in a 3D liver model.
These findings indicate the detrimental effects of elevated TSH levels, and it is worth noting that T4 administration does not reverse the excess of hepatic lipid overload but has the ability to alter its lipid composition. Furthermore, T4 administration did not reverse TSH-induced hepatic fibrogenesis in the hypothyroid cell models. Because micro-Raman spectroscopy is currently restricted to 2D/3D in-vitro systems, further validation in intact tissue and in vivo is warranted. In conclusion, our results highlight the importance of further research into the molecular pathways associated with chronic liver injury in patients with chronic hypothyroidism.
{"title":"Raman spectroscopic characterization of liver steatosis and fibrosis in a 2D and 3D in vitro thyroxine-treated hypothyroid cellular model","authors":"S. Maurotti , B. Scopacasa , F. Scionti , R. Pujia , M. Frosina , A. Mirarchi , N. Geirola , R. Mare , T. Montalcini , P. Candeloro , L. Tirinato , A. Pujia","doi":"10.1016/j.mce.2025.112679","DOIUrl":"10.1016/j.mce.2025.112679","url":null,"abstract":"<div><div>Primary hypothyroidism has been associated with metabolic dysfunction-associated steatotic liver disease and, potentially, increased liver fibrosis risk. Although T4-analog drug is one of the standard treatments, its molecular effects on the liver are not fully understood.</div><div>To elucidate drug-induced hepatic metabolic changes, chronic human 2D and 3D hypothyroid models were developed. The effects of T4 were assessed by Raman spectroscopy and complementary biological techniques to observe lipid and fibrotic changes. <em>In vitro</em> chronic hypothyroidism caused lipid droplet (LDs) accumulation in liver cells which was unaffected by T4 therapy. Notably, TSH and T4 influenced TG fatty acid saturation in different ways: T4-exposed cells accumulated monounsaturated fatty acids at the expense of saturated fatty acids. In the case of liver fibrosis, TSH treatment activated hepatic stellate cells as evidenced by increased collagen secretion and decreased LD content, regardless of T4 co-treatment. Data confirmed that TSH induced pro-inflammatory changes leading to higher inflammasome levels in a 3D liver model.</div><div>These findings indicate the detrimental effects of elevated TSH levels, and it is worth noting that T4 administration does not reverse the excess of hepatic lipid overload but has the ability to alter its lipid composition. Furthermore, T4 administration did not reverse TSH-induced hepatic fibrogenesis in the hypothyroid cell models. Because micro-Raman spectroscopy is currently restricted to 2D/3D <em>in-vitro</em> systems, further validation in intact tissue and <em>in vivo</em> is warranted. In conclusion, our results highlight the importance of further research into the molecular pathways associated with chronic liver injury in patients with chronic hypothyroidism.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112679"},"PeriodicalIF":3.6,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-15DOI: 10.1016/j.mce.2025.112678
Carlos Alberto de Carvalho Fraga , Catarina Rosa e Silva Santos , Kayo Felipe Barbosa Lima , Gustavo Henrique Brasil Rodrigues , Caio Cesar Fernandes Nobre Porto , Maria Nathália de Menezes , Gabriel Victor Lucena da Silva , Adriana Simizo , Ana Kelly da Silva Fernandes Duarte , Jussara Almeida de Oliveira Baggio , Amanda Karine Barros Ferreira Rodrigues , Karol Fireman de Farias , Elaine Virginia Martins de Souza Figueiredo , Carolinne de Sales Marques , Pedro Luiz Serrano Uson Junior , Paulo Vidal Campregher , Helder I. Nakaya
Perineural invasion (PNI) is a hallmark of pancreatic ductal adenocarcinoma (PDAC) associated with poor prognosis. Despite its clinical significance, the specific cellular and molecular mechanisms driving PNI in PDAC remain poorly defined. In this study, we analyzed transcriptomic data from approximately 60,000 single cells across 24 PDAC biopsy specimens to characterize the cellular composition and signaling networks associated with PNI. We found that pancreatic stellate cells (PSCs) expressing high levels of Periostin (POSTN), collagens, and metalloproteinases are enriched in PNI-positive samples, suggesting an active role in extracellular matrix remodeling and tumor invasion. Spatial transcriptomics revealed that these POSTN + PSCs are located adjacent to tumor cells in invasive regions but are more distant in non-invasive samples. Invasive tumors show a coordinated expression pattern involving ANXA1 in tumor cells, SPP1 and PLAU in PSCs, and their receptors in myeloid cells, supporting a signaling axis that promotes perineural invasion. This spatial arrangement indicates that POSTN + PSCs are not merely bystanders but active participants in driving tumor infiltration and perineural dissemination. Together, these findings reveal coordinated multicellular programs that underlie tumor invasion and spread in PDAC, offering new insights into its aggressive biology.
{"title":"Periostin-positive stellate cells associated with perineural invasion in pancreatic adenocarcinoma","authors":"Carlos Alberto de Carvalho Fraga , Catarina Rosa e Silva Santos , Kayo Felipe Barbosa Lima , Gustavo Henrique Brasil Rodrigues , Caio Cesar Fernandes Nobre Porto , Maria Nathália de Menezes , Gabriel Victor Lucena da Silva , Adriana Simizo , Ana Kelly da Silva Fernandes Duarte , Jussara Almeida de Oliveira Baggio , Amanda Karine Barros Ferreira Rodrigues , Karol Fireman de Farias , Elaine Virginia Martins de Souza Figueiredo , Carolinne de Sales Marques , Pedro Luiz Serrano Uson Junior , Paulo Vidal Campregher , Helder I. Nakaya","doi":"10.1016/j.mce.2025.112678","DOIUrl":"10.1016/j.mce.2025.112678","url":null,"abstract":"<div><div>Perineural invasion (PNI) is a hallmark of pancreatic ductal adenocarcinoma (PDAC) associated with poor prognosis. Despite its clinical significance, the specific cellular and molecular mechanisms driving PNI in PDAC remain poorly defined. In this study, we analyzed transcriptomic data from approximately 60,000 single cells across 24 PDAC biopsy specimens to characterize the cellular composition and signaling networks associated with PNI. We found that pancreatic stellate cells (PSCs) expressing high levels of Periostin (POSTN), collagens, and metalloproteinases are enriched in PNI-positive samples, suggesting an active role in extracellular matrix remodeling and tumor invasion. Spatial transcriptomics revealed that these POSTN + PSCs are located adjacent to tumor cells in invasive regions but are more distant in non-invasive samples. Invasive tumors show a coordinated expression pattern involving ANXA1 in tumor cells, SPP1 and PLAU in PSCs, and their receptors in myeloid cells, supporting a signaling axis that promotes perineural invasion. This spatial arrangement indicates that POSTN + PSCs are not merely bystanders but active participants in driving tumor infiltration and perineural dissemination. Together, these findings reveal coordinated multicellular programs that underlie tumor invasion and spread in PDAC, offering new insights into its aggressive biology.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112678"},"PeriodicalIF":3.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14DOI: 10.1016/j.mce.2025.112681
Gisela Soledad Bracho , María Virginia Acosta , Inri Iñiguez , Gabriela Anahí Altamirano , Laura Kass , Verónica Lis Bosquiazzo
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. In this study, we aimed to investigate the long-term effects of PCOS. We assessed fertility at 3 months of age and uterine histomorphology along with endocrine status at 6 and 24 months of age in an experimental model. PCOS was induced in female Wistar rats from 21 to 40 days of age by subcutaneous injection of dehydroepiandrosterone (6 mg/100 g bw). After treatment, rats were separated into groups and euthanized on gestational day 18 (GD18), 6 months and 24 months of age. Fertility test was performed on GD18 and no changes were observed in the PCOS rats. At 6 months of age, PCOS rats showed uterine lesions associated with a higher serum 17-β estradiol (E2)/progesterone (P4) ratio. At 24 months of age, PCOS rats had a higher incidence of luminal hyperplasia and a greater number of glands with metaplasia and conglomerates of glands. This was associated with increased serum E2/P4 ratio, uterine steroidogenic enzymes (steroid sulfatase, 5α-reductase type I) and estrogen receptor alpha expression. In addition, an increased infiltration of eosinophils in the uterus was observed, suggesting an estrogenic effect. These results show that PCOS induced early in life alters the uterine endocrine status in the long term, suggesting increased uterine exposure and sensitivity to estrogens. Taken together, these findings may explain the increased incidence/multiplicity of uterine lesions observed in the PCOS group.
{"title":"Polycystic ovary syndrome: Long-term effects on fertility and uterine lesions","authors":"Gisela Soledad Bracho , María Virginia Acosta , Inri Iñiguez , Gabriela Anahí Altamirano , Laura Kass , Verónica Lis Bosquiazzo","doi":"10.1016/j.mce.2025.112681","DOIUrl":"10.1016/j.mce.2025.112681","url":null,"abstract":"<div><div>Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. In this study, we aimed to investigate the long-term effects of PCOS. We assessed fertility at 3 months of age and uterine histomorphology along with endocrine status at 6 and 24 months of age in an experimental model. PCOS was induced in female Wistar rats from 21 to 40 days of age by subcutaneous injection of dehydroepiandrosterone (6 mg/100 g bw). After treatment, rats were separated into groups and euthanized on gestational day 18 (GD18), 6 months and 24 months of age. Fertility test was performed on GD18 and no changes were observed in the PCOS rats. At 6 months of age, PCOS rats showed uterine lesions associated with a higher serum 17-β estradiol (E2)/progesterone (P4) ratio. At 24 months of age, PCOS rats had a higher incidence of luminal hyperplasia and a greater number of glands with metaplasia and conglomerates of glands. This was associated with increased serum E2/P4 ratio, uterine steroidogenic enzymes (s<em>teroid sulfatase</em>, <em>5α-reductase type I)</em> and estrogen receptor alpha expression. In addition, an increased infiltration of eosinophils in the uterus was observed, suggesting an estrogenic effect. These results show that PCOS induced early in life alters the uterine endocrine status in the long term, suggesting increased uterine exposure and sensitivity to estrogens. Taken together, these findings may explain the increased incidence/multiplicity of uterine lesions observed in the PCOS group.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112681"},"PeriodicalIF":3.6,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-10DOI: 10.1016/j.mce.2025.112677
Ke Wang , Jing-Hua Zhang , Xiao-Ning Cui , Yan-Jun Niu , Jing-Jing Liu , Shi-Qi Lu , Xiao-Mei Liu , Zheng Zhu , Zhen-Bo Cao
Vitamin D deficiency is a global public health problem associated with intramyocellular lipid (IMCL) accumulation, leading to insulin resistance. Aerobic exercise improves lipid metabolism, insulin sensitivity, and vitamin D levels. However, the mechanism by which aerobic exercise regulates IMCL remains unclear. C57BL/6J male mice were randomly divided into four groups: control (CON), vitamin D-deficient (VDD), control exercise, and vitamin D-deficient exercise (VDDE). Moreover, we generated skeletal muscle-specific vitamin D receptor (VDR)-knockout (mVDR−/−) mice and classified them into four groups: VDRflox/flox control (FC); mVDR−/−; exercise and VDRflox/flox control; and exercise and mVDR−/− (emVDR−/−). All exercise mice underwent a 12-week aerobic exercise program on a treadmill at speeds progressively increasing from 10 to 17 m/min. The VDD group mice exhibited decreased VDR expression, lipolysis factors (ATGL and Hormone-sensitive lipase (HSL)), and fatty acid oxidation (SIRT1 and PGC1α), and increased expression of lipid synthesis factors (DGAT1 and FATP1) compared with the CON group. Conversely, the VDDE group mice showed a significant increase in VDR, ATGL, HSL, SIRT1 and PGC1α expression, alongside a decrease in DGAT1, DGAT2, FATP1 and CD36 expression compared with the VDD group. Moreover, mVDR−/− mice exhibited impaired lipid metabolism (FATP1, CD36, SREBP1C, DGAT1, DGAT2 and ATGL) and fatty acid oxidation (SIRT1 and PGC1α) compared with the FC group mice. However, emVDR−/− mice did not show improved lipid metabolism or fatty acid oxidation related factors compared with mVDR−/− mice. Therefore, aerobic exercise attenuates IMCL accumulation may by upregulating VDR associated with restored SIRT1/PGC1α signaling mediated lipid metabolism in skeletal muscle.
{"title":"Aerobic exercise attenuates intramyocellular lipid accumulation by upregulating vitamin D receptor","authors":"Ke Wang , Jing-Hua Zhang , Xiao-Ning Cui , Yan-Jun Niu , Jing-Jing Liu , Shi-Qi Lu , Xiao-Mei Liu , Zheng Zhu , Zhen-Bo Cao","doi":"10.1016/j.mce.2025.112677","DOIUrl":"10.1016/j.mce.2025.112677","url":null,"abstract":"<div><div>Vitamin D deficiency is a global public health problem associated with intramyocellular lipid (IMCL) accumulation, leading to insulin resistance. Aerobic exercise improves lipid metabolism, insulin sensitivity, and vitamin D levels. However, the mechanism by which aerobic exercise regulates IMCL remains unclear. C57BL/6J male mice were randomly divided into four groups: control (CON), vitamin D-deficient (VDD), control exercise, and vitamin D-deficient exercise (VDDE). Moreover, we generated skeletal muscle-specific vitamin D receptor (VDR)-knockout (mVDR<sup>−/−</sup>) mice and classified them into four groups: VDR<sup>flox/flox</sup> control (FC); mVDR<sup>−/−</sup>; exercise and VDR<sup>flox/flox</sup> control; and exercise and mVDR<sup>−/−</sup> (emVDR<sup>−/−</sup>). All exercise mice underwent a 12-week aerobic exercise program on a treadmill at speeds progressively increasing from 10 to 17 m/min. The VDD group mice exhibited decreased VDR expression, lipolysis factors (ATGL and Hormone-sensitive lipase (HSL)), and fatty acid oxidation (SIRT1 and PGC1α), and increased expression of lipid synthesis factors (DGAT1 and FATP1) compared with the CON group. Conversely, the VDDE group mice showed a significant increase in VDR, ATGL, HSL, SIRT1 and PGC1α expression, alongside a decrease in DGAT1, DGAT2, FATP1 and CD36 expression compared with the VDD group. Moreover, mVDR<sup>−/−</sup> mice exhibited impaired lipid metabolism (FATP1, CD36, SREBP1C, DGAT1, DGAT2 and ATGL) and fatty acid oxidation (SIRT1 and PGC1α) compared with the FC group mice. However, emVDR<sup>−/−</sup> mice did not show improved lipid metabolism or fatty acid oxidation related factors compared with mVDR<sup>−/−</sup> mice. Therefore, aerobic exercise attenuates IMCL accumulation may by upregulating VDR associated with restored SIRT1/PGC1α signaling mediated lipid metabolism in skeletal muscle.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112677"},"PeriodicalIF":3.6,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-10DOI: 10.1016/j.mce.2025.112676
Rodrigo Valenzuela , Camila Farías , Yasna Muñoz , Jessica Zúñiga-Hernández , Luis A. Videla
Alcoholism and overnutrition both contribute to the development of hepatic steatosis in humans. In alcoholic liver disease, steatosis is driven by (i) alcohol oxidation via alcohol dehydrogenase (ADH), which increases the NADH/NAD+ ratio, and (ii) induction of cytochrome P450 2E1 (CYP2E1), which elevates oxidative stress. Both pathways generate toxic acetaldehyde. Overnutrition is characterized by excessive energy intake, high consumption of refined carbohydrates and saturated fatty acids (FAs), and low intake of dietary fiber, fruits, vegetables, and n-3 polyunsaturated fatty acids (n-3 PUFAs). The increased NADH/NAD+ ratio inhibits the Krebs cycle and FA β-oxidation, redirecting acetyl-CoA toward de novo lipogenesis. This process is mainly regulated by insulin-mediated activation of sterol regulatory element-binding protein-1c (SREBP-1c) and suppression of peroxisome proliferator-activated receptor-α (PPAR-α) related to n-3 PUFA depletion, which further impairs FA β-oxidation and upregulates citrate carrier expression, promoting lipogenesis. Chronic exposure to either alcohol or overnutrition independently promotes steatosis; however, co-exposure significantly exacerbates the condition, as shown in emerging preclinical studies. In humans, the relationship remains complex and inconsistent. Several anti-steatotic agents have been explored, including n-3 PUFAs, vitamins (E, C, D), polyphenols (curcumin, resveratrol, anthocyanins), anti-craving medications (disulfiram, naltrexone, nalmefene, acamprosate), and appetite suppressants (e.g., topiramate), as well as combination therapies such as naltrexone with bupropion. Despite the range of available interventions, inconsistent outcomes in past clinical trials hinder the establishment of standardized protocols. This underscores the urgent need to investigate synergistic effects of combined risk factors to better guide therapeutic strategies for hepatic steatosis prevention and reversal, and inform the health professionals on these aspects.
{"title":"Interrelationship between alcohol consumption, overnutrition, and pharmacotherapy for liver steatosis: Considerations and proposals","authors":"Rodrigo Valenzuela , Camila Farías , Yasna Muñoz , Jessica Zúñiga-Hernández , Luis A. Videla","doi":"10.1016/j.mce.2025.112676","DOIUrl":"10.1016/j.mce.2025.112676","url":null,"abstract":"<div><div>Alcoholism and overnutrition both contribute to the development of hepatic steatosis in humans. In alcoholic liver disease, steatosis is driven by (i) alcohol oxidation via alcohol dehydrogenase (ADH), which increases the NADH/NAD<sup>+</sup> ratio, and (ii) induction of cytochrome P450 2E1 (CYP2E1), which elevates oxidative stress. Both pathways generate toxic acetaldehyde. Overnutrition is characterized by excessive energy intake, high consumption of refined carbohydrates and saturated fatty acids (FAs), and low intake of dietary fiber, fruits, vegetables, and n-3 polyunsaturated fatty acids (n-3 PUFAs). The increased NADH/NAD<sup>+</sup> ratio inhibits the Krebs cycle and FA β-oxidation, redirecting acetyl-CoA toward <em>de novo</em> lipogenesis. This process is mainly regulated by insulin-mediated activation of sterol regulatory element-binding protein-1c (SREBP-1c) and suppression of peroxisome proliferator-activated receptor-α (PPAR-α) related to n-3 PUFA depletion, which further impairs FA β-oxidation and upregulates citrate carrier expression, promoting lipogenesis. Chronic exposure to either alcohol or overnutrition independently promotes steatosis; however, co-exposure significantly exacerbates the condition, as shown in emerging preclinical studies. In humans, the relationship remains complex and inconsistent. Several anti-steatotic agents have been explored, including n-3 PUFAs, vitamins (E, C, D), polyphenols (curcumin, resveratrol, anthocyanins), anti-craving medications (disulfiram, naltrexone, nalmefene, acamprosate), and appetite suppressants (e.g., topiramate), as well as combination therapies such as naltrexone with bupropion. Despite the range of available interventions, inconsistent outcomes in past clinical trials hinder the establishment of standardized protocols. This underscores the urgent need to investigate synergistic effects of combined risk factors to better guide therapeutic strategies for hepatic steatosis prevention and reversal, and inform the health professionals on these aspects.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112676"},"PeriodicalIF":3.6,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01Epub Date: 2025-08-07DOI: 10.1016/j.mce.2025.112634
Laurens W H J Heling, Jolieke van der Veen, Adam Rofe, Eric West, Alba Jiménez-Panizo, Andrea Alegre-Martí, Vahid Sheikhhassani, Julian Ng, Thomas Schmidt, Eva Estébanez-Perpiñá, Iain J McEwan, Alireza Mashaghi
The androgen receptor (AR) plays a pivotal role in male physiological development and is implicated in the pathogenesis of various diseases, including prostate cancer. Its N-terminal domain (NTD), characterized by intrinsic disorder, is essential for transcriptional activation. Despite its importance, the precise mechanisms by which the NTD regulates AR's DNA-binding activity remain incompletely understood. This research elucidates the allosteric control mediated by specific NTD subregions-the N-terminal region (NR) and the C-terminal region (CR)-over the DNA binding properties of a truncated AR construct comprising the DNA-binding and ligand-binding domains (ΔNTD-AR). Microscale Thermophoresis (MST) and single-molecule fluorescence imaging were employed to investigate these interactions. This study demonstrates that the NTD subregions exert differential modulatory effects on the kinetics and affinity of ΔNTD-AR binding to DNA. MST analyses indicated that CR reduces ΔNTD-AR DNA binding affinity concentration-dependently, whereas NR did not significantly alter affinity. Single-molecule investigations revealed NR accelerates dissociation, while CR markedly diminishes binding frequency and accelerates dissociation. Combined NR and CR exerted complex effects, synergistically reducing affinity at high concentrations and altering kinetics distinctively compared to individual subregions. Collectively, these results delineate distinct functional roles for the NR and CR subregions in allosterically modulating AR-DNA interactions. This detailed understanding of intrinsic AR regulation offers mechanistic insights into receptor function and highlights potential allosteric sites for therapeutic intervention.
{"title":"Deciphering the allosteric control of androgen receptor DNA binding by its disordered N-terminal domain.","authors":"Laurens W H J Heling, Jolieke van der Veen, Adam Rofe, Eric West, Alba Jiménez-Panizo, Andrea Alegre-Martí, Vahid Sheikhhassani, Julian Ng, Thomas Schmidt, Eva Estébanez-Perpiñá, Iain J McEwan, Alireza Mashaghi","doi":"10.1016/j.mce.2025.112634","DOIUrl":"10.1016/j.mce.2025.112634","url":null,"abstract":"<p><p>The androgen receptor (AR) plays a pivotal role in male physiological development and is implicated in the pathogenesis of various diseases, including prostate cancer. Its N-terminal domain (NTD), characterized by intrinsic disorder, is essential for transcriptional activation. Despite its importance, the precise mechanisms by which the NTD regulates AR's DNA-binding activity remain incompletely understood. This research elucidates the allosteric control mediated by specific NTD subregions-the N-terminal region (NR) and the C-terminal region (CR)-over the DNA binding properties of a truncated AR construct comprising the DNA-binding and ligand-binding domains (ΔNTD-AR). Microscale Thermophoresis (MST) and single-molecule fluorescence imaging were employed to investigate these interactions. This study demonstrates that the NTD subregions exert differential modulatory effects on the kinetics and affinity of ΔNTD-AR binding to DNA. MST analyses indicated that CR reduces ΔNTD-AR DNA binding affinity concentration-dependently, whereas NR did not significantly alter affinity. Single-molecule investigations revealed NR accelerates dissociation, while CR markedly diminishes binding frequency and accelerates dissociation. Combined NR and CR exerted complex effects, synergistically reducing affinity at high concentrations and altering kinetics distinctively compared to individual subregions. Collectively, these results delineate distinct functional roles for the NR and CR subregions in allosterically modulating AR-DNA interactions. This detailed understanding of intrinsic AR regulation offers mechanistic insights into receptor function and highlights potential allosteric sites for therapeutic intervention.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112634"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01Epub Date: 2025-08-06DOI: 10.1016/j.mce.2025.112639
Li Chen, Linhu Hui, Yueping Shi, Anwei Wang, Yueheng Zhang, Xinsheng Yao, Jun Li
Polycystic ovary syndrome (PCOS) is often linked with immune dysregulation and chronic inflammation, where immune responses play a significant role. Recent studies have identified IGFBP7 involvement in immune processes, suggesting its potential role in modulating immune function. However, the involvement of IGFBP7 in immune modulation within the context of PCOS remains underexplored. In this study, we utilized a Dehydroepiandrosterone (DHEA)-induced PCOS mouse model, including both wild-type and IGFBP7 knockout (KO) mice, to investigate the involvement of IGFBP7 in immune regulation related to PCOS. We performed spleen transcriptome sequencing and TCR β CDR3 repertoire sequencing to assess changes in immune gene expression and T cell receptor diversity. Our findings demonstrate that IGFBP7-/- significantly mitigates PCOS-like symptoms, normalizing estrous cycles and improving ovarian morphology. Transcriptome analysis revealed a substantial downregulated genes in the spleen of IGFBP7-/- mice, with enrichment in pathways associated with immune function. Additionally, in the DHEA-induced PCOS mouse model, TCR β CDR3 repertoire analysis indicated increased clonality and decreased diversity, alongside alterations in V and J gene usage in IGFBP7-/- mice. These results highlight the critical role of IGFBP7 in immune regulation within the context of PCOS, offering new insights into the immune mechanisms underlying PCOS pathology.
{"title":"The role of IGFBP7 in the immune regulation of PCOS-like symptoms based on spleen transcriptome and TCR β CDR3 repertoire analysis.","authors":"Li Chen, Linhu Hui, Yueping Shi, Anwei Wang, Yueheng Zhang, Xinsheng Yao, Jun Li","doi":"10.1016/j.mce.2025.112639","DOIUrl":"10.1016/j.mce.2025.112639","url":null,"abstract":"<p><p>Polycystic ovary syndrome (PCOS) is often linked with immune dysregulation and chronic inflammation, where immune responses play a significant role. Recent studies have identified IGFBP7 involvement in immune processes, suggesting its potential role in modulating immune function. However, the involvement of IGFBP7 in immune modulation within the context of PCOS remains underexplored. In this study, we utilized a Dehydroepiandrosterone (DHEA)-induced PCOS mouse model, including both wild-type and IGFBP7 knockout (KO) mice, to investigate the involvement of IGFBP7 in immune regulation related to PCOS. We performed spleen transcriptome sequencing and TCR β CDR3 repertoire sequencing to assess changes in immune gene expression and T cell receptor diversity. Our findings demonstrate that IGFBP7<sup>-/-</sup> significantly mitigates PCOS-like symptoms, normalizing estrous cycles and improving ovarian morphology. Transcriptome analysis revealed a substantial downregulated genes in the spleen of IGFBP7<sup>-/-</sup> mice, with enrichment in pathways associated with immune function. Additionally, in the DHEA-induced PCOS mouse model, TCR β CDR3 repertoire analysis indicated increased clonality and decreased diversity, alongside alterations in V and J gene usage in IGFBP7<sup>-/-</sup> mice. These results highlight the critical role of IGFBP7 in immune regulation within the context of PCOS, offering new insights into the immune mechanisms underlying PCOS pathology.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112639"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01Epub Date: 2025-07-29DOI: 10.1016/j.mce.2025.112628
Natalia Fossas De Mello, Wendy B Bollag
The mineralocorticoid receptor (MR) plays a pivotal role in skin homeostasis, inflammation, and repair, interacting closely with the glucocorticoid receptor (GR) to regulate various physiological and pathological processes. Dysregulation of MR signaling has been implicated in several skin disorders, including psoriasis, atopic dermatitis, and impaired wound healing. Furthermore, studies have shown that patients with primary hyperaldosteronism exhibit epidermal hyperplasia, impaired differentiation, increased immune cell infiltrates, and elevated pro-inflammatory cytokines due to MR overactivation. Pharmacological studies demonstrate that MR antagonists can mitigate glucocorticoid-induced skin barrier dysfunction, epidermal atrophy, and delayed wound healing. Additionally, skin sodium storage and water conservation mechanisms are emerging as key factors in systemic fluid balance and blood pressure regulation, with skin glycosaminoglycans (GAGs) thought to serve as sodium reservoirs. Mouse models of psoriasis further reveal how the disrupted skin barrier activates systemic protective mechanisms, including water retention processes in the skin that can lead to increased blood pressure; psoriasis in humans is also associated with hypertension. These findings and additional data are discussed in this review and underscore the dual role of cutaneous MR in both maintaining epidermal integrity and contributing to inflammatory skin disorders, and potentially hypertension, when dysregulated. Targeting MR signaling pathways may offer novel therapeutic strategies for skin diseases while enhancing our understanding of the skin's role in systemic homeostasis.
{"title":"The role of the mineralocorticoid receptor in skin.","authors":"Natalia Fossas De Mello, Wendy B Bollag","doi":"10.1016/j.mce.2025.112628","DOIUrl":"10.1016/j.mce.2025.112628","url":null,"abstract":"<p><p>The mineralocorticoid receptor (MR) plays a pivotal role in skin homeostasis, inflammation, and repair, interacting closely with the glucocorticoid receptor (GR) to regulate various physiological and pathological processes. Dysregulation of MR signaling has been implicated in several skin disorders, including psoriasis, atopic dermatitis, and impaired wound healing. Furthermore, studies have shown that patients with primary hyperaldosteronism exhibit epidermal hyperplasia, impaired differentiation, increased immune cell infiltrates, and elevated pro-inflammatory cytokines due to MR overactivation. Pharmacological studies demonstrate that MR antagonists can mitigate glucocorticoid-induced skin barrier dysfunction, epidermal atrophy, and delayed wound healing. Additionally, skin sodium storage and water conservation mechanisms are emerging as key factors in systemic fluid balance and blood pressure regulation, with skin glycosaminoglycans (GAGs) thought to serve as sodium reservoirs. Mouse models of psoriasis further reveal how the disrupted skin barrier activates systemic protective mechanisms, including water retention processes in the skin that can lead to increased blood pressure; psoriasis in humans is also associated with hypertension. These findings and additional data are discussed in this review and underscore the dual role of cutaneous MR in both maintaining epidermal integrity and contributing to inflammatory skin disorders, and potentially hypertension, when dysregulated. Targeting MR signaling pathways may offer novel therapeutic strategies for skin diseases while enhancing our understanding of the skin's role in systemic homeostasis.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112628"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01Epub Date: 2025-08-05DOI: 10.1016/j.mce.2025.112633
Jixiang Dong, Tianyu Ma, Yichen Qu, Runquan Ye, Jia Feng, Ge Bai, An Hong, Yi Ma
High-fat diet (HFD)-induced obesity leads endothelial dysfunction and contributes to cardiovascular diseases. NLRP3-mediated pyroptosis plays a key role in endothelial injury induced by HFD. Pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide belonging to the secretin family, has demonstrated diverse beneficial effects. However, its impact on a high-fat-induced pyroptosis remains unexplored. The purpose of this study is to evaluate the effect of PACAP in alleviating high-fat-induced pyroptosis of human umbilical vein endothelial cells (HUVECs) and to elucidate its potential mechanisms. The results show that palmitic acid (PA) induces HUVECs injury and pyroptosis, while PACAP alleviates PA-induced HUVECs injury and pyroptosis. In addition, PACAP also has a protective effect on vascular damage in the thoracic aorta of obese mice. We further found that PACAP reduced PA-induced intracellular Reactive Oxygen Species (ROS) in HUVECs, while also mitigating PA-induced HUVECs pyroptosis. Moreover, PACAP can inhibit PA-induced ROS and pyroptosis through activation of SIRT1, and the effects of PACAP are reversed by a SIRT1 inhibitor. In conclusion, our study demonstrates that PACAP can inhibit PA-induced oxidative stress and pyroptosis in HUVECs, and its action is closely related to the SIRT1 pathway.
{"title":"PACAP inhibits high fat-induced NLRP3 inflammasome-mediated pyroptosis in vascular endothelial cells by regulating the SIRT1/ROS pathway.","authors":"Jixiang Dong, Tianyu Ma, Yichen Qu, Runquan Ye, Jia Feng, Ge Bai, An Hong, Yi Ma","doi":"10.1016/j.mce.2025.112633","DOIUrl":"10.1016/j.mce.2025.112633","url":null,"abstract":"<p><p>High-fat diet (HFD)-induced obesity leads endothelial dysfunction and contributes to cardiovascular diseases. NLRP3-mediated pyroptosis plays a key role in endothelial injury induced by HFD. Pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide belonging to the secretin family, has demonstrated diverse beneficial effects. However, its impact on a high-fat-induced pyroptosis remains unexplored. The purpose of this study is to evaluate the effect of PACAP in alleviating high-fat-induced pyroptosis of human umbilical vein endothelial cells (HUVECs) and to elucidate its potential mechanisms. The results show that palmitic acid (PA) induces HUVECs injury and pyroptosis, while PACAP alleviates PA-induced HUVECs injury and pyroptosis. In addition, PACAP also has a protective effect on vascular damage in the thoracic aorta of obese mice. We further found that PACAP reduced PA-induced intracellular Reactive Oxygen Species (ROS) in HUVECs, while also mitigating PA-induced HUVECs pyroptosis. Moreover, PACAP can inhibit PA-induced ROS and pyroptosis through activation of SIRT1, and the effects of PACAP are reversed by a SIRT1 inhibitor. In conclusion, our study demonstrates that PACAP can inhibit PA-induced oxidative stress and pyroptosis in HUVECs, and its action is closely related to the SIRT1 pathway.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112633"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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