Molecular and Cellular Endocrinology最新文献

{"title":"The possible regulatory role of miRNA-30c-5p, miRNA-545-3p and miRNA-125a-5p in women with polycystic ovary syndrome: A case-control study and signaling pathways","authors":"Jessica D. Pereira ,&nbsp;Fernanda M.V. Magalhães ,&nbsp;Fabiana M.S. Tameirão ,&nbsp;Frederico M. Soriani ,&nbsp;Karina T. de O. S. Jorge ,&nbsp;Fernando M. Reis ,&nbsp;Ana Lúcia Cândido ,&nbsp;Fábio V. Comim ,&nbsp;Karina B. Gomes","doi":"10.1016/j.mce.2025.112492","DOIUrl":"10.1016/j.mce.2025.112492","url":null,"abstract":"<div><h3>Introduction</h3><div>Polycystic Ovary Syndrome (PCOS) is one of the most common endocrinopathy in women of reproductive age. MicroRNA (miRNAs) are small non-coding RNAs related to the control of gene expression in biological fluids. Our study analyzed the expression of miRNAs related to inflammation in individuals with PCOS compared to controls.</div></div><div><h3>Methods</h3><div>Twenty patients with PCOS and 20 controls, matched by body mass index and age, were included in the study. The miRNAs evaluated were miRNA-30c-5p; miRNA-545-3p and miRNA-125a-5p.</div></div><div><h3>Results</h3><div>The expression of the miRNAs was similar between the two groups. A positive correlation was observed between the expression of miRNA-125a-5p and LDLc levels only in the PCOS group. Subsequent analysis of biological pathways showed that miRNA-125a -5p is significantly involved in the regulation of SREBP/SREBF pathways of cholesterol biosynthesis, glycolysis, insulin receptor signaling, oxidative stress-induced senescence and estrogen-dependent gene expression.</div></div><div><h3>Conclusion</h3><div>The results suggest that the miRNA-125a-5p shows a potential implication to the regulation of lipid biosynthesis and LDL-c levels in PCOS women.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"599 ","pages":"Article 112492"},"PeriodicalIF":3.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419093","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}

{"title":"PPM1G dephosphorylates α-catenin to maintain the integrity of adherens junctions and regulates apoptosis in Sertoli cells","authors":"Xinyao Li ,&nbsp;Qian Liu ,&nbsp;Lingling Wang ,&nbsp;Tiao Bu ,&nbsp;Xiwen Yang ,&nbsp;Sheng Gao ,&nbsp;Damin Yun ,&nbsp;Fei Sun","doi":"10.1016/j.mce.2025.112493","DOIUrl":"10.1016/j.mce.2025.112493","url":null,"abstract":"<div><div>Protein phosphatase, Mg2+/Mn2+ dependent, 1G (PPM1G) regulates protein function via dephosphorylation. PPM1G participates in the assembly of adherens junctions by dephosphorylating α-catenin. Here, we demonstrated through siRNA transfection and intratesticular injection that PPM1G is critical for maintaining blood-testis barrier function and regulating Sertoli cell apoptosis. We observed that upon knocking down Ppm1g in rat testes, the function of the blood testis barrier was compromised, and the localization of α-catenin and β-catenin became aberrant. Further investigation in rat Sertoli cells revealed that after Ppm1g knockdown, the level of phosphorylated α-catenin increased, and it failed to properly aggregate at the cell membrane; instead, it was mislocalized to the cytoplasm. The actin to which catenin is attached also exhibited a disordered arrangement in the absence of PPM1G. Additionally, through RNA sequencing and bioinformatics analysis, we identified genes associated with Sertoli cell dysfunction induced by Ppm1g knockdown and identified a set of genes involved in regulating intercellular junctions. Subsequent validation revealed that after Ppm1g knockdown, the expression of the junction-related protein JAM2 was reduced, and Sertoli cells underwent apoptosis. Overall, we identified a gene, Ppm1g, which may be involved in maintaining the normal function of the blood-testis barrier and influencing the survival of Sertoli cells by regulating apoptotic pathways.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"600 ","pages":"Article 112493"},"PeriodicalIF":3.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425817","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}

{"title":"USP7 deficiency promotes diabetic wound healing by repressing GATA3-mediated pro-inflammatory macrophage polarization","authors":"Yan Zhu ,&nbsp;Ming Zong ,&nbsp;Ling Hu ,&nbsp;Juan Wan ,&nbsp;Liyao Zong ,&nbsp;Jixiong Xu","doi":"10.1016/j.mce.2025.112489","DOIUrl":"10.1016/j.mce.2025.112489","url":null,"abstract":"<div><h3>Background</h3><div>The polarization of inflammatory macrophages is an important factor contributing to delay wound healing in diabetic foot ulcers (DFU). In this study, the role of ubiquitin-specific protease 7 (USP7) in regulating macrophage polarization during DFU progression was investigated.</div></div><div><h3>Methods</h3><div>Gene and protein expression levels were assessed using qRT-PCR and western blot. In vitro and in vivo diabetes mellitus (DM) models were established by HG treatment and STZ injection, respectively. HUVEC viability, migration, and angiogenesis were detected by CCK8 assay, wound healing assay, and tube formation assay, respectively. Flow cytometry was employed to analyze the levels of macrophage polarization markers. Co-IP assay was performed to analyze the interaction between USP7 and GATA3.</div></div><div><h3>Results</h3><div>Our results demonstrated that USP7 was overexpressed in ulcer margin tissues of DFU patients, wound tissues of DFU mice, and HG-treated macrophages. Functionally, USP7 deficiency inhibited macrophage M1 polarization and promoted wound healing in DFU mice. In vitro, USP7 knockdown promoted HUVEC proliferation, migration, and angiogenesis by inducing M2 macrophage polarization and inhibiting M1 macrophage polarization under HG condition. Mechanistically, USP7 could stabilize GATA3 protein in macrophages by deubiquitinating GATA3. Moreover, the effects of USP7 knockdown on HUVEC function and macrophage polarization under HG condition were partially reversed by GATA3 overexpression.</div></div><div><h3>Conclusion</h3><div>USP7 silencing enhanced wound healing in DFU by inhibiting M1 macrophage polarization and promoting M2 macrophage polarization through mediating GATA3 deubiquitylation.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"599 ","pages":"Article 112489"},"PeriodicalIF":3.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374018","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}

{"title":"Expression of genes involved in thyroid hormone action in human induced pluripotent stem cells during differentiation to insulin-producing cells: Effects of iopanoic acid on differentiation","authors":"Azusa Maruoka ,&nbsp;Azuma Kimura ,&nbsp;Fumiyuki Hattori ,&nbsp;Hirofumi Hitomi ,&nbsp;Kenji Osafune ,&nbsp;Ichiro Shiojima ,&nbsp;Nagaoki Toyoda","doi":"10.1016/j.mce.2025.112490","DOIUrl":"10.1016/j.mce.2025.112490","url":null,"abstract":"<div><h3>Aims</h3><div>Type 3 iodothyronine deiodinase (Dio3) converts triiodothyronine (T3) to diiodothyronine, thereby reducing intracellular T3 levels. In this study, we investigated the potential roles of Dio3 in the differentiation of human pancreatic β cells, using β cells derived from human induced pluripotent stem cells (hiPSCs).</div></div><div><h3>Main methods</h3><div>hiPSCs were differentiated to β cells in a stepwise manner over 29 days. The differentiation medium was supplemented with B27, which contains T3 but not T4, instead of serum. The T3 levels in the differentiated cells were determined based on the amount of T3 supplied to the medium and the activity of Dio3 within the cells. Iopanoic acid (IOP) was used as the Dio3 inhibitor.</div></div><div><h3>Key findings</h3><div>Dio3 expression is substantially altered during differentiation. IOP treatment reduced Dio3 activity on day 4 and increased T3 levels in the medium on day 29. To investigate the involvement of Dio3 during differentiation, we used IOP, in which cells differentiated in the presence of IOP (+IOP) were compared to those differentiated without IOP (−IOP). On day 29, the proportion of β cells expressing C-peptide, NKX6 homeobox 1, and both markers was considerably higher in the presence than in the absence of IOP. Furthermore, on day 29, the insulin content of differentiated + IOP cells was considerably higher than that of differentiated −IOP cells.</div></div><div><h3>Conclusions</h3><div>An increase in intracellular T3 content promoted via the inhibition of Dio3 activity by IOP from day 0–29 enhances the differentiation of hiPSCs to β cells.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"599 ","pages":"Article 112490"},"PeriodicalIF":3.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitronectin stimulates hepatic gluconeogenesis by activating the cAMP/PKA/CREB axis in the liver","authors":"Yuejun Ju ,&nbsp;Runze Wu ,&nbsp;Guanyi Wang ,&nbsp;Ting Shen ,&nbsp;Ji Hu ,&nbsp;Yinghong Kong","doi":"10.1016/j.mce.2025.112485","DOIUrl":"10.1016/j.mce.2025.112485","url":null,"abstract":"<div><div>Vitronectin, a protein derived the human placenta, has been identified as an inducer of insulin resistance in trophoblast cells in gestational diabetes mellitus (GDM). As a secreted protein, vitronectin may have systemic effects on dysregulated glucose metabolism in GDM. To address this speculation, we generated a GDM mouse model using high-fat diet-induced obese mice. Consistent with findings in placentas of GDM patients, GDM mouse placentas showed higher vitronectin expression, accompanied by increased serum vitronectin levels. Reduced insulin signaling transduction was observed in both the placentas and livers of GDM mice, along with enhanced hepatic gluconeogenesis. To further explore the role of vitronectin in hepatic gluconeogenesis, we constructed an adeno-associated virus expressing <em>Vtn</em> (AAV-VTN), which was administered to mice via tail vein injection. In AAV-VTN-treated mice, glucose production from exogenous pyruvate increased, and the expression of gluconeogenic genes in the liver was upregulated, indicating that hepatic gluconeogenesis was stimulated by vitronectin. Mechanistically, vitronectin binds to its receptor CD51/61, activating the cAMP/PKA/CREB axis in hepatocytes, thereby promoting hepatic gluconeogenesis. In summary, our findings suggest that placenta-derived vitronectin plays a critical role in inducing insulin resistance in the liver in GDM. Moreover, vitronectin stimulates hepatic gluconeogenesis through activation of the cAMP/PKA/CREB axis. These results point to vitronectin as a potential therapeutic target for managing hyperglycemia in GDM.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"599 ","pages":"Article 112485"},"PeriodicalIF":3.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255843","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}

{"title":"p75NTR antagonist THX-B increases mature nerve growth factor secretion by bladder cells through decreased activity of matrix metalloproteinase-9","authors":"Aalya Hamouda ,&nbsp;Stephanie Sirmakesyan ,&nbsp;Aya Hajj ,&nbsp;Philippe G. Cammisotto ,&nbsp;H. Uri Saragovi ,&nbsp;Lysanne Campeau","doi":"10.1016/j.mce.2025.112487","DOIUrl":"10.1016/j.mce.2025.112487","url":null,"abstract":"<div><div>In urine samples from an aging female cohort with overactive bladder syndrome (OAB), the proteolytic activity of matrix metalloproteinase-9 (MMP-9), an enzyme which degrades mature NGF, was elevated and associated with low levels of nerve growth factor (NGF). Given that a substantial portion of urine constituents originate from bladder cellular processes, we examined the synthesis of NGF and MMP-9 in rat urothelial (UROs) and smooth muscle (SMCs) cells in culture. NGF and proNGF were found expressed and released by both cell types while UROs were the major source of secreted MMP-9. THX-B, a highly specific p75^NTR antagonist, decreased the expression of MMP-9 resulting in increased mature NGF levels in culture medium of UROs while displaying minor effects on SMCs. Likewise, CRISPR-cas9 genomic deletion of MMP-9 potently increased mature NGF levels in both cell types. On the other hand, THX-B decreased the synthesis and release of α2 Macroglobulin (α2M), a protein that stabilizes proNGF in UROs but increased it in SMCs. THX-B also increased the activity of enzymes furin and matrix metalloproteinase-7 (MMP-7), that convert proNGF to mature NGF in UROs, yielding a net increase in mature NGF and a decrease of proNGF. We conclude that p75^NTR is involved in the control of proNGF and mature NGF secretion from bladder cells through modulation of proteolytic activities. Since neurotrophins and binding to their receptors are relevant to pathologies, inhibition of p75^NTR by THX-B may be exploited in a therapeutic strategy.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"599 ","pages":"Article 112487"},"PeriodicalIF":3.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255826","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}

{"title":"Liraglutide promotes osteogenic differentiation of mesenchymal stem cells by inhibiting M1 macrophage polarization and CXCL9 release in vitro","authors":"Yilin He ,&nbsp;Wenpeng Song ,&nbsp;Yinxin Deng ,&nbsp;Xiao Lin ,&nbsp;Zhenhua Gao ,&nbsp;Pan Ma","doi":"10.1016/j.mce.2024.112441","DOIUrl":"10.1016/j.mce.2024.112441","url":null,"abstract":"<div><div>As a GLP-1 receptor agonist widely used in treating type 2 diabetes, liraglutide shows potential applications in bone tissue engineering. This study investigated liraglutide's direct effects on rat bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation and its regulatory mechanism through macrophage polarization. Results showed that liraglutide significantly enhanced BMSC migration and osteogenic differentiation. Additionally, liraglutide markedly inhibited M1 macrophage polarization induced by LPS and IFN-γ, reducing inflammatory factors CXCL9 and TNF-α secretion, possibly by partially reversing M1 macrophage regulatory signals (AMPK and NF-κB pathways). Compared to M1 macrophage-conditioned medium (M1-CM), conditioned medium from liraglutide-treated macrophages showed stronger promotion of BMSC osteogenic differentiation, though this effect was reversed by CXCL9 addition. The study demonstrates that liraglutide enhances BMSC osteogenic capacity both directly and by inhibiting M1 macrophage polarization and CXCL9 secretion, offering a new therapeutic option for severe bone defects with inflammatory responses.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"597 ","pages":"Article 112441"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872520","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}

{"title":"NAT10 drives endometriosis progression through acetylation and stabilization of TGFB1 mRNA","authors":"Na Liu ,&nbsp;Jing YangOu ,&nbsp;Chenxuan Wei,&nbsp;Guojing Li,&nbsp;Ruoer Yu,&nbsp;Yu Lin,&nbsp;Hong Xu","doi":"10.1016/j.mce.2024.112447","DOIUrl":"10.1016/j.mce.2024.112447","url":null,"abstract":"<div><div>Endometriosis, a gynecological disorder marked by pelvic pain and infertility, has its pathogenesis and pathophysiology significantly influenced by epigenetics, as these factors have been well characterized. However, the role of RNA-mediated epigenetic regulation in endometriosis remains to be elucidated. In our study, we found that N4-acetylcytidine (ac⁴C) RNA modification and N-acetyltransferase 10 (NAT10) were significantly upregulated in endometrial lesions compared to eutopic endometrium. Knockdown of NAT10 suppressed endometrial epithelial cell proliferation, epithelial-to-mesenchymal transition (EMT), and cell cycle processes in vitro. RNA-seq and acRIP-seq analyses revealed that the knockdown of NAT10 impaired cell proliferation and the TGF-beta signaling pathway. We further identified that ac⁴C RNA modification enhanced TGFB1 mRNA stability and expression levels, and inhibition of NAT10 activity by Remodelin effectively suppressed the growth of ectopic lesions in an endometriosis mouse model. Collectively, our findings reveal that increased NAT10-mediated ac⁴C modification enhances TGFB1 mRNA stability, thereby promoting the development of endometriosis. This discovery lays the molecular foundation for future therapeutic approaches targeting endometriosis.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"597 ","pages":"Article 112447"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896076","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}

{"title":"Melatonin induces white-to-beige adipocyte transdifferentiation through melatonin receptor 1-mediated direct browning and indirect M2 polarization","authors":"Seong Mi Ji ,&nbsp;Hana Yoo ,&nbsp;Jea Il Kim ,&nbsp;Mi Jin Choi ,&nbsp;Hyae Gyeong Cheon","doi":"10.1016/j.mce.2024.112439","DOIUrl":"10.1016/j.mce.2024.112439","url":null,"abstract":"<div><div>Previous studies have shown that melatonin induces adipocyte browning <em>in vivo</em>. However, the underlying mechanisms of melatonin action at the cellular level remain elusive. In this study, we investigated the mechanisms underlying melatonin-induced browning in 3T3-L1 adipocytes and RAW 264.7 macrophages. Melatonin caused the transdifferentiation of fully differentiated white adipocytes into beige adipocytes, which involves the activation of melatonin receptor 1, followed by increased phosphorylation of p38 MAPK and Akt. Both luzindole (LZ), a non-selective melatonin receptor antagonist, and selective melatonin receptor 1 knockdown attenuated the browning effects of melatonin. Melatonin also induced M2 polarization in RAW 264.7, involving the melatonin receptor 1-Src-STAT3/STAT6 phosphorylation signaling cascade. Melatonin-treated M2-conditioned medium (CM) contained increased levels of catecholamine (CA) and induced beige adipocytes when treated with differentiated 3T3-L1 white adipocytes. <em>In vivo</em> oral administration of melatonin to high-fat diet (HFD)-induced obese (DIO) mice reduced body weight, accompanied by increased expression of uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in subcutaneous adipose tissues. Moreover, arginase-1 (Arg1) and mannose receptor C type-1 (MRC1) levels were markedly higher in the melatonin-treated groups, suggesting that melatonin induces adipose browning and M2 polarization <em>in vivo</em>. Collectively, melatonin-induced adipocyte browning appeared to be reflected by the sum of melatonin receptor 1-activated direct browning effects and indirect M2 polarization-mediated effects.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"597 ","pages":"Article 112439"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801752","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}

{"title":"Maternal protein restriction and postnatal sugar consumption increases inflammatory response and deregulates metabolic pathways in the liver of male offspring rats with aging","authors":"Isabelle Tenori Ribeiro ,&nbsp;Matheus Naia Fioretto ,&nbsp;Sérgio Alexandre Alcantara dos Santos ,&nbsp;Marcus Vinicius Niz Alvarez ,&nbsp;Luiz Marcos Frediani Portela ,&nbsp;Renato Mattos ,&nbsp;Hecttor Baptista Sebastian ,&nbsp;Pedro Menchini Vitali ,&nbsp;Fábio Rodrigues Ferreira Seiva ,&nbsp;Luís Fernando Barbisan ,&nbsp;Clélia Akiko Hiruma Lima ,&nbsp;Débora Cristina Damasceno ,&nbsp;Elena Zambrano ,&nbsp;Luis Antonio Justulin","doi":"10.1016/j.mce.2025.112484","DOIUrl":"10.1016/j.mce.2025.112484","url":null,"abstract":"<div><div>This study investigated the late effects of maternal protein restriction (MPR) and early postnatal sugar consumption on liver health in male Sprague-Dawley rat offspring, focusing on changes observed throughout the aging process. The animals were divided into the following groups: Control (CTR): Male offspring whose dams consumed a normal protein diet (NPD, 17% protein) and water <em>ad libitum</em> during gestation and lactation, and then fed a NPD and water until PND 540; Control + Sugar (CTR + SUG): The same treatment as CTR, but consuming a sugar solution (10% diluted in water) from postnatal day (PND) 21–90, and then fed a NPD and water until PND 540; Gestational and Lactational Low Protein (GLLP): Male offspring whose dams consumed a low-protein diet (LPD, 6% protein) during gestation and lactation and, then fed a NPD and water <em>ad libitum</em> until PND 540; Gestational and Lactational Low Protein + Sugar (GLLP + SUG): male offspring whose dams consumed a LPD during gestation and lactation, and then fed a NPD and a sugar solution (10% diluted in water) <em>ad libitum</em> from PND 21 to 90. On PND 540, the animals were anesthetized, weighed, and euthanized, and their livers were collected for morphological and molecular analyses. The GLLP and GLLP + SUG groups showed lower body weight and lower retroperitoneal fat weight compared to the CTR and CTR + SUG groups. Morphological analysis revealed inflammatory foci in the liver from the CTR + SUG, GLLP, and GLLP + SUG groups, compared to the CTR group. Hepatic activities of CAT, SOD, and GSH-Px were increased in the GLLP + SUG group and decreased in the GLLP group, compared to the CTR group. Immunohistochemistry showed a significant increase in occupied area per foci de hepatocytes positive for GSTpi (placental form) in the CTR + SUG, GLLP, and GLLP + SUG groups, compared to the CTR group. Proteomic analysis of the groups revealed significant changes in hepatic metabolic and inflammatory pathways. In the CTR + SUG group, upregulated pathways associated with non-alcoholic fatty liver disease (NAFLD) and downregulated pathways related to autophagy were observed. In the GLLP and GLLP + SUG groups, there was a significant impact on metabolic pathways, including glucose metabolism, gluconeogenesis, glycogenesis, and cellular stress responses. An upregulation of pathways associated with chemokine- and cytokine-mediated inflammatory processes was also identified, indicating activation of the immune system in the liver during aging. Therefore, MPR, with or without postnatal sugar consumption, resulted in hepatic changes in metabolism and the antioxidant defense in old male offspring.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"599 ","pages":"Article 112484"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123380","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}