Journal of Steroid Biochemistry and Molecular Biology最新文献

{"title":"Prostaglandin E₂ activates the brain-pituitary axis via olfactory pathways in male Bostrychus sinensis","authors":"Ke Wei ,&nbsp;Ke Jiang ,&nbsp;Shi Xi Chen","doi":"10.1016/j.jsbmb.2025.106703","DOIUrl":"10.1016/j.jsbmb.2025.106703","url":null,"abstract":"<div><div>Prostaglandin E₂ (PGE₂) has been identified as a key sex pheromone in male <em>Bostrychus sinensis</em>, yet its molecular and neural mechanisms remain unclear. Here, we performed transcriptome sequencing on male <em>B. sinensis</em> brains following exposure to 50 nM PGE₂ to uncover genes and pathways involved in reproductive regulation. RNA-seq analysis revealed significant upregulation of key genes associated with the activation of the brain-pituitary axis. RT-PCR validation further confirmed the significant upregulation the expression of <em>gnrh1</em> and <em>kiss2</em> in the brain, as well as <em>lhβ</em> mRNA levels in the pituitary, supporting activation of the reproductive axis. To further elucidate the role of <em>kiss2</em> in this regulatory pathway, we synthesized the core peptide of BsKiss2–12 and examined its functional effects. Administration of BsKiss2–12 (1μg/g) significantly increased the <em>gnrh1</em> and <em>kiss1ra</em> mRNA levels in the brain, along with <em>lhβ</em> expression in the pituitary. Additionally, c-fos induction and DiI tracing experiments demonstrated that PGE₂ activated olfactory sensory neurons, relaying signals from the olfactory epithelium to the olfactory bulb and higher brain centers implicated in reproductive behavior. Collectively, our findings reveal that key molecular and neural mechanisms by which the sex pheromone PGE₂ modulates the reproductive axis in male <em>B. sinensis</em>.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"249 ","pages":"Article 106703"},"PeriodicalIF":2.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520620","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}

{"title":"Facing challenges in modern steroid research.","authors":"Jerzy Adamski","doi":"10.1016/j.jsbmb.2025.106715","DOIUrl":"https://doi.org/10.1016/j.jsbmb.2025.106715","url":null,"abstract":"","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"106715"},"PeriodicalIF":2.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517419","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}

{"title":"Targeted quantitative analysis of urinary bile acids by liquid chromatography-tandem mass spectrometry: Method development and application to healthy and obese children","authors":"M. Schauermann ,&nbsp;R. Wang ,&nbsp;J. Pons-Kuehnemann ,&nbsp;M.F. Hartmann ,&nbsp;T. Remer ,&nbsp;Y. Hua ,&nbsp;A. Bereket ,&nbsp;M. Wasniewska ,&nbsp;M. Shmoish ,&nbsp;Z. Hochberg ,&nbsp;A. Gawlik ,&nbsp;S.A. Wudy","doi":"10.1016/j.jsbmb.2025.106712","DOIUrl":"10.1016/j.jsbmb.2025.106712","url":null,"abstract":"<div><div>Bile acids (BA) are C24 steroids synthesized from cholesterol in liver. Hardly any data exist on BA in the most accessible human biofluid urine. As bile acids bear great potential as future biomarkers in diagnosis and monitoring of metabolic diseases, we aimed at developing and implementing a new method for the quantification of urinary bile acids using targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). A second goal consisted in creating first reference values of urinary bile acids during childhood and to investigate their excretion patterns in obese children and adolescents.</div><div>Our method required 2 mL of urine and sample preparation consisting of protein precipitation and solid phase extraction. Stable isotopes of BA were included as internal standards (IS).</div><div>Our method is capable of simultaneously determining 18 BA: the primary BA cholic acid (CA) and chenodeoxycholic acid (CDCA), and the secondary BA deoxycholic acid (DCA) and lithocholic acid (LCA) as well as glycine and taurine conjugates of these four BA. Furthermore, ursodeoxycholic acid (UDCA) and five BA in their sulfated forms (LCA-S, GLCA-S, TLCA-S, GCDCA-S, GDCA-S) were analyzed.</div><div>After successful validation (intra-day precision 1.02 % - 11.07 %; inter-day precision 0.42–11.47 %.; intra-day accuracy 85.75 % - 108.90 %; inter-day accuracy 86.76 % - 110.99 %; no significant matrix effect; recovery 90.49 % - 113.99 %)., the method was applied to samples of 80 healthy children as well as 237 obese children of various age groups.</div><div>Sulfated BA showed the highest concentrations, with GCDCA-S (nmol/L, medians, controls vs. obese 588.4 vs. 360.2) being the most abundant among all BA, followed by GLCA-S (353.9 vs. 344.8) and GDCA-S (319,3 vs. 323.9). CA (135.1 vs. 174.6) and GCA (100.2 vs. 92.4) were the two dominant non-sulfated BA.</div><div>In conclusion, we developed a LC-MS/MS method for the simultaneous determination of 18 urinary bile acids in children and adolescents. We created reference values and investigated obese children. Sulfated bile acids dominated in both study groups. Lower bile acid sulfation and amidation in obese children point to limitations in their hepatic metabolic capacity.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"249 ","pages":"Article 106712"},"PeriodicalIF":2.7,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitamin D receptor in osteoblast lineage cells mediates increased sclerostin circulation and decreased bone formation in hypervitaminosis D","authors":"Ziyang Liu ,&nbsp;Zhifeng He ,&nbsp;Linan Shi ,&nbsp;Tomoki Mori ,&nbsp;Yoshihiro Tamamura ,&nbsp;Nobuyuki Udagawa ,&nbsp;Yuko Nakamichi","doi":"10.1016/j.jsbmb.2025.106711","DOIUrl":"10.1016/j.jsbmb.2025.106711","url":null,"abstract":"<div><div>Hypervitaminosis D is induced iatrogenically or endogenously. We previously reported that the vitamin D receptor (VDR) in osteoblast lineage cells mediates bone resorption and soft-tissue calcification in hypervitaminosis D. However, bone formation in hypervitaminosis D remains understudied. Here, we show that abundant 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] suppresses bone formation through VDR in osteoblast lineage cells. High-dose 1,25(OH)₂D₃ suppressed bone formation and increased serum sclerostin, a bone formation inhibitor, in <em>Control</em> but not osteoblast lineage-specific VDR-cKO [<em>Osterix (Osx)-VDR-cKO</em>] mice. However, <em>Sost</em> mRNA expression in bone was downregulated by 1,25(OH)₂D₃ in <em>Control</em> but not <em>Osx-VDR-cKO</em> mice. Meanwhile, mRNA expression of β-1,4-N-acetyl-galactosaminyltransferase 3 (B4GALNT3), whose function is reported to decrease circulating sclerostin, was suppressed by 1,25(OH)₂D₃ in bone in <em>Control</em> but not <em>Osx-VDR-cKO</em> mice. Overexpressed <em>B4galnt3</em> in rodent osteoblast-lineage cell lines increased GalNAcβ1→4GlcNAc- (LDN-) glycosylated sclerostin, suggesting that this modification can explain the discordance between serum sclerostin levels and mRNA in bone. Although excessive 1,25(OH)₂D₃ increased mRNA levels of <em>Fibroblast growth factor 23</em> (<em>Fgf23)</em>, another osteotropic factor, by 10-fold through VDR in osteoblast lineage cells, it was previously shown to increase serum FGF23 levels by several hundred-fold. 1,25(OH)₂D₃-induced changes of FGF23-degradation regulators, such as furin, polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), and family with sequence similarity member 20 C (FAM20C), did not match the markedly high FGF23 levels, suggesting the existence of other regulators of FGF23. These findings suggest that VDR plays pivotal roles in the suppression of bone formation in hypervitaminosis D, possibly by increasing circulations of sclerostin and FGF23 through post-translational or post-transcriptional mechanisms.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"249 ","pages":"Article 106711"},"PeriodicalIF":2.7,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"COVID-19 and our understanding of vitamin D and immune function","authors":"Martin Hewison","doi":"10.1016/j.jsbmb.2025.106710","DOIUrl":"10.1016/j.jsbmb.2025.106710","url":null,"abstract":"<div><div>The interaction between vitamin D and the immune system is perhaps the most well recognised extraskeletal facet of vitamin D, encompassing early studies of therapy for TB and leprosy through to more recent links with autoimmune disease. However, the spotlight on vitamin D and immune function has been particularly intense in the last five years following the COVID-19 pandemic. This was due, in part, to the many association studies of vitamin D status and COVID-19 infection and disease prognosis, as well as the smaller number of clinical trials of vitamin D supplementation. However, a potential role for vitamin D in COVID-19 also stemmed from the basic biology of vitamin D that provides a plausible mechanistic rationale for beneficial effects of vitamin D for improved immune health in the setting of respiratory infection. The aim of this review is to summarise the different strands of mechanistic evidence supporting a beneficial effect of vitamin D in COVID-19, how this was modified during the pandemic itself, and the potential new aspects of vitamin D and immune function that are likely to arise in the near future. Key topics that feature in this review are: antibacterial versus antiviral innate immune responses to 1,25-dihydroxyvitamin D (1,25(OH)₂D); the function of immune 1α-hydroxylase (CYP27B1) activity and metabolism of 25-hydroxyvitamin D (25(OH)D) beyond antigen-presenting cells; advances in immune cell target gene responses to 1,25-dihydroxyvitamin D (notably changes in metabolic profile). Whilst much of the interest during the COVID-19 era has focused on vitamin D and public health, the continued evolution of our understanding of how vitamin D interacts with different components of the immune system continues to support a beneficial role for vitamin D in immune health.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"249 ","pages":"Article 106710"},"PeriodicalIF":2.7,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling 2-isopropyl-5-methylphenol’s immunomodulatory potential in breast cancer: A synergistic computational and laboratory investigation","authors":"Mehr Un Nissa Bashir ,&nbsp;Muhammad Usman Rashid ,&nbsp;Naila Malkani","doi":"10.1016/j.jsbmb.2025.106702","DOIUrl":"10.1016/j.jsbmb.2025.106702","url":null,"abstract":"<div><div>Tumor cells evade immune surveillance and promote their growth by modulating immune checkpoint molecules (ICMs). Various breast cancer subtypes have demonstrated the involvement of these molecules, promoting the investigation of natural compounds for immunomodulatory potential. 2-Isopropyl-5-methylphenol, a bioactive monoterpenoid found in several plant species, was evaluated for its impact on breast cancer immunomodulation. Computational and <em>in-vitro</em> studies were conducted to evaluate 2-Isopropyl-5-methylphenol’s immunomodulatory potential. Molecular docking of ICMs (CTLA-4, PD-1, and PD-L1) with 2-Isopropyl-5-methylphenol was performed using AutoDock Vina. Additional tools utilized were BIOVIA Discovery Studio 2021, PyMOL, and LigPlot⁺. The mRNA expression of ICMs upon treatment of breast cancer cells (MDA-MB-231) with varying concentrations (50, 100, and 200 µg) of 2-Isopropyl-5-methylphenol was measured by qPCR. Docking complexes of CTLA-4, PD-1, and PD-L1 with 2-Isopropyl-5-methylphenol showed binding free energies of −4.3 kcal/mol, −5.2 kcal/mol and −4.4 kcal/mol, respectively. Involvement of different key amino acid residues strengthened 2-Isopropyl-5-methylphenol’s binding with ICMs. Expression analysis revealed 2-Isopropyl-5-methylphenol downregulated <em>CTLA-4</em> expression while upregulated <em>PD-1</em> and <em>PD-L1</em> expression. This study highlights the immunomodulatory potential of the bioactive monoterpene 2-Isopropyl-5-methylphenol. Supported by computational and <em>in-vitro</em> findings, 2-Isopropyl-5-methylphenol could be considered as a potential target for anti-tumor drug development.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"248 ","pages":"Article 106702"},"PeriodicalIF":2.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419622","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}

{"title":"Impact of copper nanoparticles (CuNPs) on hypothalamic GnRH and pituitary gonadotropins secretions in a male mouse: An immunohistochemical study","authors":"Vanrohlu Nicy,&nbsp;Guruswami Gurusubramanian,&nbsp;Vikas Kumar Roy","doi":"10.1016/j.jsbmb.2025.106700","DOIUrl":"10.1016/j.jsbmb.2025.106700","url":null,"abstract":"<div><div>The copper nanoparticles (CuNPs) have widely been used for human welfare in the various applications. Despite its uses for beneficial purposes, CuNPs has been known to cause toxicity in the various organ based on the size, dose and duration. Both male and female reproductive functions have been to be compromised under CuNPs toxicity. The aim of this study is to investigate the effects of CuNPs after prolonged duration on the hypothalamus and pituitary in relation to the neuroendocrine regulation of reproduction in male mice since it has not been done before. Due to which the mice were orally treated with three doses of CuNPs viz. 10,100 and 200 mg/kg for 70 consecutive days to examines its adverse effects. The circulating GnRH levels and its abundance in the median eminence did not change in the CuNPs treated groups. However, circulating FSH showed significant decline in all the CuNPs treated groups, while LH was decline only in higher doses of CuNPs. The immunolocalization of LH and FSH also showed decreased abundance in the pituitary. Thus, pituitary function showed severely affected by CuNPs; the architecture of anterior pituitary also showed sign of degeneration such a presence of vacuoles and it was also shown that CuNPs treated groups have higher level of MDA which is an oxidative stress marker as indicated by the MDA staining. Moreover, the abundance of GnRHR and AR exhibited less abundance in the pituitary of higher dose of CuNPs treated groups. Thus, it can be concluded that pituitary becomes less responsive for hypothalamic GnRH and gonadal steroid, which could be reason of suppressed gonadotropin in the CuNPs treated mice.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"248 ","pages":"Article 106700"},"PeriodicalIF":2.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419624","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}

{"title":"Antiepileptic drugs carbamazepine and valproic acid mediate transcriptional activation of CYP1A1 via aryl hydrocarbon receptor and regulation of estrogen metabolism","authors":"Neha Kanojia ,&nbsp;Samiksha Kukal ,&nbsp;Nitin Machahary ,&nbsp;Shivangi Bora ,&nbsp;Ankit Srivastava ,&nbsp;Priyanka Rani Paul ,&nbsp;Shakti Sagar ,&nbsp;Reema Kumar ,&nbsp;Gurpreet Kaur Grewal ,&nbsp;Srishti Sharma ,&nbsp;Binukumar B.K. ,&nbsp;Ritushree Kukreti","doi":"10.1016/j.jsbmb.2025.106699","DOIUrl":"10.1016/j.jsbmb.2025.106699","url":null,"abstract":"<div><div>Cytochrome P450 1A1 (<em>CYP1A1</em>) actively catalyzes estrogen hydroxylation reactions and maintains the levels of neuroactive steroid estradiol. The widely prescribed first-line anti-epileptic drugs (AEDs) are considered to be a potent inducer of <em>CYP1A1</em> and have also been observed to affect serum estradiol and calcium levels in patients with epilepsy. However, the ability of AEDs to interfere with CYP enzyme function and estrogen disposition is a relatively unexplored area. Here we investigate the effect of widely prescribed AEDs (carbamazepine and valproic acid) on <em>CYP1A1</em> regulation and the levels of estradiol and calcium in cell supernatants of hepatocellular, HepG2, and neuronal, SH-SY5Y cells. We observed that both the AEDs significantly increased <em>CYP1A1</em> expression and enzyme activity, which was accompanied by a decrease in estradiol and calcium levels in HepG2 cells. This induction of <em>CYP1A1</em> mRNA and protein was fully prevented by aryl hydrocarbon receptor (<em>AHR</em>) knockdown and StemRegenin 1 (SR1) antagonism. Notably, the AEDs did not affect the <em>AHR</em> expression but regulated its nuclear translocation, potentially driving the transcriptional upregulation of <em>CYP1A1</em>. Furthermore, the knockdown of <em>CYP1A1</em> in HepG2 cells elucidated a marked increase in estradiol and calcium levels. Later, this increase subsided upon AED exposure. Lastly, we observed a similar trend in estradiol and calcium alterations in SH-SY5Y cells on AED exposure, speculating the involvement of <em>CYP1A1</em> induction via AEDs at neuronal sites. This work demonstrates that AEDs mediate the upregulation of <em>CYP1A1</em> via an AHR-dependent mechanism and influence estrogen and calcium homeostasis.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"248 ","pages":"Article 106699"},"PeriodicalIF":2.7,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426572","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}

{"title":"The effect of vitamin D supplementation on mental and functional health outcomes in African Americans with type 2 diabetes","authors":"Kai E. Jones ,&nbsp;Amy E. Riek ,&nbsp;Esmeralda Castelblanco ,&nbsp;Jisu Oh ,&nbsp;Daniela Porta ,&nbsp;Claudia Villatoro ,&nbsp;Robert M. Carney ,&nbsp;Adriana S. Dusso ,&nbsp;Carlos Bernal-Mizrachi","doi":"10.1016/j.jsbmb.2025.106698","DOIUrl":"10.1016/j.jsbmb.2025.106698","url":null,"abstract":"<div><div>In patients with type 2 diabetes (T2DM), depression increases the risk of poor glycemic control and decreases adherence to medications, exercise, and diet. Studies have shown an inverse relationship between plasma vitamin D (VD) level and depression risk. However, there are few interventional trials of African Americans (AAs), a demographic with higher prevalence of diabetes, depression, and VD deficiency. This randomized controlled trial evaluated the efficacy of vitamin D₃ supplementation [4000 vs. 600 international units (IU)/day] for one year on mental and functional health outcomes in 75 adult AAs with T2DM with serum 25-hydroxy vitamin D (25(OH)D) level &lt; 25 ng/mL. PHQ-9 and PROMIS questionnaires evaluated mental health outcomes, and 6-minute walk test estimated the ability to perform daily activities. At baseline, groups had similar levels of 25(OH)D, calcium, parathyroid hormone, hemoglobin A1c, and body mass index, and 25(OH)D levels correlated positively with a 6-minute walk distance. Surprisingly, both supplementation strategies increased 25(OH)D to &gt; 30 ng/mL by 6 months with a plateau thereafter. Vitamin D₃ 4000 IU/day in AAs with T2DM did not produce significant difference in mental and functional health scores compared to 600 IU/day. Post-hoc analysis of those with baseline VD deficiency [25(OH)D &lt; 20 ng/mL] demonstrated trends towards worsening pain interference and higher depression and fatigue scores throughout the study, plus consistently shorter 6-minute walk distances, most of which were independent of vitamin D supplementation group. These results suggest that VD deficient AAs with T2DM may be refractory to supplementation for improvement in mental and functional health outcomes.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"248 ","pages":"Article 106698"},"PeriodicalIF":2.7,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419623","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}

{"title":"Mechanistic insights into the anti-fibrotic effects of estrogen via the PI3K-Akt pathway in frozen shoulder","authors":"Zhuo Wang ,&nbsp;Xinhao Li ,&nbsp;Xiaoshan Liu ,&nbsp;Yitao Yang ,&nbsp;Yan Yan ,&nbsp;Dedong Cui ,&nbsp;Chenyang Meng ,&nbsp;Maslah Idiris Ali ,&nbsp;Jinming Zhang ,&nbsp;Zeyu Yao ,&nbsp;Yi Long ,&nbsp;Rui Yang","doi":"10.1016/j.jsbmb.2025.106701","DOIUrl":"10.1016/j.jsbmb.2025.106701","url":null,"abstract":"<div><div>The development of frozen shoulder (FS) is primarily characterized by pathological fibrosis, yet clinical treatment options remain limited. Recent studies have identified estrogen depletion during perimenopause as a significant contributor to the onset of FS and fibrosis. This study investigates the role of estradiol (E2) and the estrogen-related receptor (GPER) in fibrotic processes associated with FS to elucidate the underlying mechanisms. The functional relationship between E2, GPER, and FS progression was examined using a rat immobilization model and synovial-derived fibroblasts (SFs) from FS patients. E2’s effects on GPER expression, fibroblast activation, and tissue fibrosis were evaluated through Western blotting, immunofluorescence staining, collagen contraction assays, wound healing assays, and histological staining. RNA sequencing identified signaling pathways and key regulators involved in E2 treatment. Both E2 and the GPER activator G1 exhibited antifibrotic effects, improving shoulder mobility, reducing extracellular matrix (ECM) deposition in the periarticular capsule, and decreasing the expression of fibrosis-related genes, including fibronectin, α-SMA, and COL3. In contrast, the GPER inhibitor G15 reversed these effects, suggesting that E2 mediates its antifibrotic action through GPER activation. Mechanistically, KEGG pathway analysis revealed that E2 suppresses the PI3K/AKT signaling pathway by inhibiting PI3K and AKT phosphorylation, thereby preventing fibroblast activation and reversing FS-associated fibrosis. These findings provide mechanistic insights into the previously unrecognized role of GPER in FS progression and may open new avenues for research to optimize future clinical therapies.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"249 ","pages":"Article 106701"},"PeriodicalIF":2.7,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416249","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}