Pub Date : 2025-01-14DOI: 10.1016/j.jsbmb.2025.106676
Rong M. Zhang , Jisu Oh , Burton M. Wice , Adriana Dusso , Carlos Bernal-Mizrachi
Targeting optimal glycemic control based on hemoglobin A1c (A1c) values reduces but does not abolish the onset of diabetic kidney disease and its progression to chronic kidney disease (CKD). This suggests that factors other than the average glucose contribute to the residual risk. Vitamin D deficiency and frequent episodes of acute hyperglycemia (AH) are associated with the onset of albuminuria and CKD progression in diabetes. This study aimed to determine if moderate levels of AH harm podocytes directly or promote a pro-inflammatory monocyte/macrophage phenotype that leads to podocyte apoptosis, and whether vitamin D deficiency accelerates these processes. We found that AH (16.7 mM D- glucose) didn't induce podocyte apoptosis directly, but it did promote a pro-inflammatory response in human monocytes and macrophages, resulting in an increased TNF-α secretion causing podocyte apoptosis. The AH-induced monocyte TNF-α secretion was inversely correlated with healthy donors' serum 25(OH)D levels. AH induced monocyte TNF-α release by increasing oxidative and ER stress, which in turn increased ADAM17 (A Disintegrin And Metalloprotease 17) and iRhom2 (inactive Rhomboid protein 2) expression, both essential for TNF-α secretion. Additionally, monocyte activation of glucagon-like peptide-1 receptor (GLP-1R), using a GLP-1R agonist, downregulated ADAM17/iRhom2 expression, decreasing TNF-α release and reducing podocyte apoptosis. These results show that a normal vitamin D status may attenuate a mechanism by which AH contributes to podocyte apoptosis and CKD progression and might enhance a novel anti-inflammatory role of GLP-1 to prevent AH-driven CKD progression in diabetes.
以糖化血红蛋白（A1c）值为基础的最佳血糖控制可减少但不能消除糖尿病肾病的发病及其向慢性肾病（CKD）的进展。这表明，除了平均血糖水平外，其他因素也会导致剩余风险。维生素D缺乏和急性高血糖症（AH）的频繁发作与糖尿病中蛋白尿和CKD进展的发生有关。本研究旨在确定中等水平的AH是否直接损害足细胞或促进促炎单核细胞/巨噬细胞表型导致足细胞凋亡，以及维生素D缺乏是否加速了这些过程。我们发现，AH （16.7mM D-葡萄糖）不直接诱导足细胞凋亡，但确实促进了人单核细胞和巨噬细胞的促炎反应，导致TNF-α分泌增加，导致足细胞凋亡。ah诱导的单核细胞TNF-α分泌与健康供者血清25(OH)D水平呈负相关。AH通过增加氧化应激和内质网应激诱导单核细胞TNF-α释放，从而增加ADAM17 （A Disintegrin and Metalloprotease 17）和iRhom2 （inactive Rhomboid protein 2）的表达，两者都是TNF-α分泌所必需的。此外，单核细胞激活胰高血糖素样肽-1受体（GLP-1R），使用GLP-1R激动剂，下调ADAM17/iRhom2表达，减少TNF-α释放，减少足细胞凋亡。这些结果表明，正常的维生素D状态可能减弱AH促进足细胞凋亡和CKD进展的机制，并可能增强GLP-1的新型抗炎作用，以防止糖尿病AH驱动的CKD进展。
{"title":"Acute hyperglycemia induces podocyte apoptosis by monocyte TNF-α release, a process attenuated by vitamin D and GLP-1 receptor agonists","authors":"Rong M. Zhang , Jisu Oh , Burton M. Wice , Adriana Dusso , Carlos Bernal-Mizrachi","doi":"10.1016/j.jsbmb.2025.106676","DOIUrl":"10.1016/j.jsbmb.2025.106676","url":null,"abstract":"<div><div>Targeting optimal glycemic control based on hemoglobin A1c (A1c) values reduces but does not abolish the onset of diabetic kidney disease and its progression to chronic kidney disease (CKD). This suggests that factors other than the average glucose contribute to the residual risk. Vitamin D deficiency and frequent episodes of acute hyperglycemia (AH) are associated with the onset of albuminuria and CKD progression in diabetes. This study aimed to determine if moderate levels of AH harm podocytes directly or promote a pro-inflammatory monocyte/macrophage phenotype that leads to podocyte apoptosis, and whether vitamin D deficiency accelerates these processes. We found that AH (16.7 mM D- glucose) didn't induce podocyte apoptosis directly, but it did promote a pro-inflammatory response in human monocytes and macrophages, resulting in an increased TNF-α secretion causing podocyte apoptosis. The AH-induced monocyte TNF-α secretion was inversely correlated with healthy donors' serum 25(OH)D levels. AH induced monocyte TNF-α release by increasing oxidative and ER stress, which in turn increased ADAM17 (A Disintegrin And Metalloprotease 17) and iRhom2 (inactive Rhomboid protein 2) expression, both essential for TNF-α secretion. Additionally, monocyte activation of glucagon-like peptide-1 receptor (GLP-1R), using a GLP-1R agonist, downregulated ADAM17/iRhom2 expression, decreasing TNF-α release and reducing podocyte apoptosis. These results show that a normal vitamin D status may attenuate a mechanism by which AH contributes to podocyte apoptosis and CKD progression and might enhance a novel anti-inflammatory role of GLP-1 to prevent AH-driven CKD progression in diabetes.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106676"},"PeriodicalIF":2.7,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015853","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}
Pub Date : 2025-01-09DOI: 10.1016/j.jsbmb.2025.106673
Lvqiu Li , Maogeng Yang , Longqiao Tan , Yanhong Ni , Yang Wu
The disorders of glucose and lipid metabolism contribute to severe diseases, including cardiovascular disease, diabetes, and fatty liver. Here, we identified DNA damage-binding protein 2 (DDB2), an E3 ubiquitin ligase, as a pivotal regulator of lipid metabolism disorders in type II diabetes mellitus (T2DM). A mouse model of T2DM and primary mouse hepatocytes with steatosis were induced. DDB2 overexpression alone or in combination with lysine N-methyltransferase 2 A (KMT2A) overexpression vectors were delivered into db/db mice and in vitro hepatocytes. DDB2 was expressed poorly, while KMT2A was expressed highly in liver tissues and primary hepatocytes of db/db mice. DDB2 ameliorated glucose intolerance and insulin resistance, decreased liver/body weight ratio, downregulated expression of lipogenesis-associated proteins (SREBP1, FASN, and SCD1) and gluconeogenesis-related proteins (PEPCK and G6Pase) in liver tissues and cells, and decreased triglyceride and total cholesterol levels in steatotic hepatocytes. DDB2 reduced KMT2A expression through ubiquitination modification. Overexpression of KMT2A promoted insulin resistance, lipogenesis and lipid deposition, and glycogen accumulation in the presence of DDB2. Overall, our data demonstrate that DDB2 alleviates hepatic lipogenesis and lipid deposition via degradation of KMT2A, thereby repressing lipid metabolism disorders in T2DM.
{"title":"Loss of DDB2 in type II diabetes mellitus induces dysregulated ubiquitination of KMT2A in lipid metabolism disorders","authors":"Lvqiu Li , Maogeng Yang , Longqiao Tan , Yanhong Ni , Yang Wu","doi":"10.1016/j.jsbmb.2025.106673","DOIUrl":"10.1016/j.jsbmb.2025.106673","url":null,"abstract":"<div><div>The disorders of glucose and lipid metabolism contribute to severe diseases, including cardiovascular disease, diabetes, and fatty liver. Here, we identified DNA damage-binding protein 2 (DDB2), an E3 ubiquitin ligase, as a pivotal regulator of lipid metabolism disorders in type II diabetes mellitus (T2DM). A mouse model of T2DM and primary mouse hepatocytes with steatosis were induced. DDB2 overexpression alone or in combination with lysine N-methyltransferase 2 A (KMT2A) overexpression vectors were delivered into db/db mice and <em>in vitro</em> hepatocytes. DDB2 was expressed poorly, while KMT2A was expressed highly in liver tissues and primary hepatocytes of db/db mice. DDB2 ameliorated glucose intolerance and insulin resistance, decreased liver/body weight ratio, downregulated expression of lipogenesis-associated proteins (SREBP1, FASN, and SCD1) and gluconeogenesis-related proteins (PEPCK and G6Pase) in liver tissues and cells, and decreased triglyceride and total cholesterol levels in steatotic hepatocytes. DDB2 reduced KMT2A expression through ubiquitination modification. Overexpression of KMT2A promoted insulin resistance, lipogenesis and lipid deposition, and glycogen accumulation in the presence of DDB2. Overall, our data demonstrate that DDB2 alleviates hepatic lipogenesis and lipid deposition via degradation of KMT2A, thereby repressing lipid metabolism disorders in T2DM.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106673"},"PeriodicalIF":2.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142973176","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}
This study explored the therapeutic potential of gut microbiota metabolites in managing Gestational Diabetes Mellitus (GDM). Using network pharmacology, molecular docking, and dynamics simulations, we identified key targets and pathways involved in GDM. We screened 135 gut-derived metabolites, with 8 meeting drug-likeness and pharmacokinetic criteria. Analysis revealed significant overlap with GDM-related targets, including AKT1, IL6, TNF, and STAT3. Functional enrichment analysis highlighted the AGE-RAGE signaling and inflammatory pathways as crucial in GDM pathogenesis. Molecular docking and dynamics simulations showed strong binding affinities and stable interactions between two metabolites, luteolin and naringenin chalcone, and the target protein AKT1. These findings suggest that gut microbiota-derived metabolites, particularly luteolin and naringenin chalcone, may effectively modulate key pathways in GDM, offering promising avenues for novel treatment strategies.
{"title":"Gut microbiome-derived metabolites and their impact on gene regulatory networks in gestational diabetes","authors":"Sarvesh Sabarathinam , Akash Jayaraman , Ramesh Venkatachalapathy","doi":"10.1016/j.jsbmb.2025.106674","DOIUrl":"10.1016/j.jsbmb.2025.106674","url":null,"abstract":"<div><div>This study explored the therapeutic potential of gut microbiota metabolites in managing Gestational Diabetes Mellitus (GDM). Using network pharmacology, molecular docking, and dynamics simulations, we identified key targets and pathways involved in GDM. We screened 135 gut-derived metabolites, with 8 meeting drug-likeness and pharmacokinetic criteria. Analysis revealed significant overlap with GDM-related targets, including AKT1, IL6, TNF, and STAT3. Functional enrichment analysis highlighted the AGE-RAGE signaling and inflammatory pathways as crucial in GDM pathogenesis. Molecular docking and dynamics simulations showed strong binding affinities and stable interactions between two metabolites, luteolin and naringenin chalcone, and the target protein AKT1. These findings suggest that gut microbiota-derived metabolites, particularly luteolin and naringenin chalcone, may effectively modulate key pathways in GDM, offering promising avenues for novel treatment strategies.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106674"},"PeriodicalIF":2.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-31DOI: 10.1016/j.jsbmb.2024.106672
Han Lu , Jingyi Zheng , Chunnan Hu , Jiayi He , Shaowei Wang , Zhuoqi Chen , Yiyan Wang , Huitao Li , Ren-shan Ge , Yunbing Tang , Yingfen Ying
Curcuminoids, including curcumin and its derivatives, show potent inhibition of aromatase (CYP19A1), crucial for estradiol synthesis and breast cancer metastasis. Our study evaluated the efficacy and mechanism of 10 curcuminoids and their metabolites against human and rat CYP19A1 using placental microsomes, revealing species-specific IC50 values. Cyclocurcumin (IC50, 4.43 μM) and curcumin (IC50, 3.49 μM) were the most effective inhibitors for human and rat CYP19A1, respectively. These compounds acted as mixed or competitive inhibitors, reducing estradiol production in human BeWo cells. Docking analysis showed that curcuminoids interact with CYP19A1 active site, forming a hydrogen bond with Met374. 3D-QSAR analysis highlighted the importance of hydrogen bonding in inhibition. A negative correlation was observed between the pKa values and IC50 values for human CYP19A1. A positive correlation was observed between the lowest binding energy and IC50 values for human CYP19A1. These findings underscore the potential of curcuminoids as therapeutic agents against breast cancer.
{"title":"Cyclocurcumin potently inhibits human aromatase as a potential therapeutic agent","authors":"Han Lu , Jingyi Zheng , Chunnan Hu , Jiayi He , Shaowei Wang , Zhuoqi Chen , Yiyan Wang , Huitao Li , Ren-shan Ge , Yunbing Tang , Yingfen Ying","doi":"10.1016/j.jsbmb.2024.106672","DOIUrl":"10.1016/j.jsbmb.2024.106672","url":null,"abstract":"<div><div>Curcuminoids, including curcumin and its derivatives, show potent inhibition of aromatase (CYP19A1), crucial for estradiol synthesis and breast cancer metastasis. Our study evaluated the efficacy and mechanism of 10 curcuminoids and their metabolites against human and rat CYP19A1 using placental microsomes, revealing species-specific IC<sub>50</sub> values. Cyclocurcumin (IC<sub>50</sub>, 4.43 μM) and curcumin (IC<sub>50</sub>, 3.49 μM) were the most effective inhibitors for human and rat CYP19A1, respectively. These compounds acted as mixed or competitive inhibitors, reducing estradiol production in human BeWo cells. Docking analysis showed that curcuminoids interact with CYP19A1 active site, forming a hydrogen bond with Met374. 3D-QSAR analysis highlighted the importance of hydrogen bonding in inhibition. A negative correlation was observed between the pKa values and IC<sub>50</sub> values for human CYP19A1. A positive correlation was observed between the lowest binding energy and IC<sub>50</sub> values for human CYP19A1. These findings underscore the potential of curcuminoids as therapeutic agents against breast cancer.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106672"},"PeriodicalIF":2.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-31DOI: 10.1016/j.jsbmb.2024.106671
Md. Mehedi Hasan , Rahima Tanbin Tama , Humayra Afroz Dona , Naeema Salatia Hoque , Md. Ashikur Rahaman , Md. Ashraful Alam
Phthalates are a wide family of chemicals that are used in many different industrial applications used in many different industrial applications, including the production of plastics, toys, food packaging particularly for kids, and medical equipment. Due to their various chemical and physical properties, phthalates may negatively impact humans, animals, and the environment. Thus the potential for phthalate exposure and harm to humans, animals, and the environment is high because its presence is alarming. Phthalates can be ingested, inhaled, absorbed topically, or via iatrogenic exposure in animals and humans. This article aimed to ascertain the modes of exposure, fate and detection techniques, and harmful effects of phthalates on humans, animals, and the environment. This review also shows that the intake of phthalate above the established daily limit from sources such as food, toys, and air causes serious harm, including impaired immune function, difficulties in pregnancy, loss of reproduction, and damage to the kidneys, lungs, heart, and brain in humans. Children and pregnant women are the most impacted groups and phthalates also negatively affect the environment and wildlife. A few methods to determine phthalate exposure, such as the LC and the HPLC-MS/MS methods, which employ human fluid or dust air as a biomarker, are also addressed here. Consequently, this comprehensive review aims to provide a detailed analysis of the existing evidence regarding explicit links between exposure to phthalates and subsequent health outcomes that may be directly related to this exposure. Additionally, we reviewed the developed and validated analytical methods and supplemented the literature with partial biomonitoring data on their metabolites.
{"title":"Comprehensive review of phthalate exposure: Health implications, biomarker detection and regulatory standards","authors":"Md. Mehedi Hasan , Rahima Tanbin Tama , Humayra Afroz Dona , Naeema Salatia Hoque , Md. Ashikur Rahaman , Md. Ashraful Alam","doi":"10.1016/j.jsbmb.2024.106671","DOIUrl":"10.1016/j.jsbmb.2024.106671","url":null,"abstract":"<div><div>Phthalates are a wide family of chemicals that are used in many different industrial applications used in many different industrial applications, including the production of plastics, toys, food packaging particularly for kids, and medical equipment. Due to their various chemical and physical properties, phthalates may negatively impact humans, animals, and the environment. Thus the potential for phthalate exposure and harm to humans, animals, and the environment is high because its presence is alarming. Phthalates can be ingested, inhaled, absorbed topically, or via iatrogenic exposure in animals and humans. This article aimed to ascertain the modes of exposure, fate and detection techniques, and harmful effects of phthalates on humans, animals, and the environment. This review also shows that the intake of phthalate above the established daily limit from sources such as food, toys, and air causes serious harm, including impaired immune function, difficulties in pregnancy, loss of reproduction, and damage to the kidneys, lungs, heart, and brain in humans. Children and pregnant women are the most impacted groups and phthalates also negatively affect the environment and wildlife. A few methods to determine phthalate exposure, such as the LC and the HPLC-MS/MS methods, which employ human fluid or dust air as a biomarker, are also addressed here. Consequently, this comprehensive review aims to provide a detailed analysis of the existing evidence regarding explicit links between exposure to phthalates and subsequent health outcomes that may be directly related to this exposure. Additionally, we reviewed the developed and validated analytical methods and supplemented the literature with partial biomonitoring data on their metabolites.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106671"},"PeriodicalIF":2.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-28DOI: 10.1016/j.jsbmb.2024.106669
Huixian Du , Furui Tang , Haiping Ma , Yipin Xiong , Sijian Lin , Zhen Yuan , Jie Wu , Binwu Xu , Lei Xiao , Xiaoyong Lan
Segetalin B (SB) has shown promise in mitigating osteoporosis in ovariectomized (OVX) mice, though its underlying mechanisms remain unclear. This study investigates how SB promotes bone formation through Phospholipase D1 (PLD1) activation in OVX models. In vitro, bone marrow-derived mesenchymal stem cells (BMSCs) from OVX mice were cultured for osteogenic differentiation. The effects of SB, PLD1 inhibitor VU0359595, SIRT1 inhibitor EX527, and γ-secretase inhibitor LY-411575 were examined. In vivo, the impact of SB and LY-411575 on osteoporosis in OVX mice was evaluated. SB significantly increased PLD1 phosphorylation, enhancing osteogenic differentiation and SIRT1 activity. Blocking PLD1 with VU0359595 reversed these effects. Inhibiting SIRT1 with EX527 restored γ-secretase activity and Notch1 signaling but did not alter PLD1 activation. Notch1 overexpression weakened SB’s promotion of osteogenesis and activation of the Wnt/β-catenin pathway. In vivo, SB combined with LY-411575 showed stronger anti-bone loss effects compared to SB alone. These findings suggest that SB may directly activates PLD1, which enhances SIRT1 activity and suppresses Notch1 signaling overactivation via γ-secretase inhibition. This cascade promotes bone formation by upregulating Wnt/β-catenin signaling. Combining SB with LY-411575 may offer a novel therapeutic strategy for postmenopausal osteoporosis.
Segetalin B （SB）在卵巢切除（OVX）小鼠中显示出减轻骨质疏松症的希望，尽管其潜在机制尚不清楚。本研究探讨SB如何通过激活OVX模型中的磷脂酶D1 （PLD1）促进骨形成。体外培养OVX小鼠骨髓间充质干细胞（BMSCs）进行成骨分化。检测SB、PLD1抑制剂VU0359595、SIRT1抑制剂EX527、γ-分泌酶抑制剂LY-411575的作用。在体内，我们评估了SB和LY-411575对OVX小鼠骨质疏松症的影响。SB显著增加PLD1磷酸化，促进成骨分化和SIRT1活性。用VU0359595阻断PLD1逆转了这些效应。用EX527抑制SIRT1可以恢复γ-分泌酶活性和Notch1信号，但不改变PLD1的激活。Notch1过表达减弱了SB促进成骨和激活Wnt/β-catenin通路的作用。在体内，SB联合LY-411575比单独使用SB具有更强的抗骨质流失作用。这些发现表明SB可能直接激活PLD1，通过抑制γ-分泌酶增强SIRT1活性，抑制Notch1信号的过度激活。这个级联通过上调Wnt/β-catenin信号传导促进骨形成。SB联合LY-411575可能为绝经后骨质疏松症提供新的治疗策略。
{"title":"Segetalin B promotes bone formation in ovariectomized mice by activating PLD1/SIRT1 signaling to inhibit γ-secretase-mediated Notch1 overactivation","authors":"Huixian Du , Furui Tang , Haiping Ma , Yipin Xiong , Sijian Lin , Zhen Yuan , Jie Wu , Binwu Xu , Lei Xiao , Xiaoyong Lan","doi":"10.1016/j.jsbmb.2024.106669","DOIUrl":"10.1016/j.jsbmb.2024.106669","url":null,"abstract":"<div><div>Segetalin B (SB) has shown promise in mitigating osteoporosis in ovariectomized (OVX) mice, though its underlying mechanisms remain unclear. This study investigates how SB promotes bone formation through Phospholipase D1 (PLD1) activation in OVX models. <em>In vitro</em>, bone marrow-derived mesenchymal stem cells (BMSCs) from OVX mice were cultured for osteogenic differentiation. The effects of SB, PLD1 inhibitor VU0359595, SIRT1 inhibitor EX527, and γ-secretase inhibitor LY-411575 were examined. <em>In vivo</em>, the impact of SB and LY-411575 on osteoporosis in OVX mice was evaluated. SB significantly increased PLD1 phosphorylation, enhancing osteogenic differentiation and SIRT1 activity. Blocking PLD1 with VU0359595 reversed these effects. Inhibiting SIRT1 with EX527 restored γ-secretase activity and Notch1 signaling but did not alter PLD1 activation. Notch1 overexpression weakened SB’s promotion of osteogenesis and activation of the Wnt/β-catenin pathway. <em>In vivo</em>, SB combined with LY-411575 showed stronger anti-bone loss effects compared to SB alone. These findings suggest that SB may directly activates PLD1, which enhances SIRT1 activity and suppresses Notch1 signaling overactivation via γ-secretase inhibition. This cascade promotes bone formation by upregulating Wnt/β-catenin signaling. Combining SB with LY-411575 may offer a novel therapeutic strategy for postmenopausal osteoporosis.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106669"},"PeriodicalIF":2.7,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-28DOI: 10.1016/j.jsbmb.2024.106670
Siwei Jiao , Danyu Zhao , Huilan Yi
Male infertility, a major global reproductive health concern, has been linked to increased particulate air pollution and inflammatory response. Bitter taste transduction, involved in sensing bitterness, inflammation, and immune regulation, remains understudied in male reproductive damage. This research investigated how particulate matter (PM) impacts male reproductive health and the involvement of bitter taste transduction in reproductive toxicity. A PM exposure mouse model was established via aerosol inhalation of ovalbumin (OVA) following intraperitoneal injection of OVA. Results showed that PM exposure reduced sperm count, increased sperm malformation rate, decreased seminiferous epithelium height and tubular diameter, and caused disordered spermatogenic cell arrangement, along with decreased Johnsen scores, suggesting testicular structural damage and spermatogenesis disorders. Furthermore, PM exposure reduced serum testosterone levels and diminished the mRNA expression of genes involved in testosterone synthesis, transport, and spermatogenesis, including luteinizing hormone receptor (LHR), steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage enzyme (P450scc), 17-beta-hydroxysteroid dehydrogenase (17β-HSD), androgen-binding protein (ABP), and DEAD-box helicase 3 Y-linked (Ddx3y). Meanwhile, pro-inflammatory cytokine gene TNF-α and inflammatory genes IL-4Rα, JAK1, JAK2, JAK3, STAT3, and STAT6 were significantly upregulated in testes of PM-exposed mice. This was accompanied by inhibited expression of Th1 cytokine gene IFN-γ and enhanced expression of Th2 cytokine genes IL-4, IL-5, and IL-13. Twenty-four out of thirty-five bitter taste receptor (T2R) genes, along with their downstream signaling molecules α-gustducin and transient receptor potential cation channel subfamily M member 5 (TRPM5) genes exhibited transcriptional repression in testes of PM-treated mice. The bitter compound baicalin alleviated PM-induced male reproductive damage accompanied with activating testis-specific T2R cluster (T2R102, T2R109, T2R113, T2R117, T2R119, T2R124, T2R135, T2R136), α-gustducin and Trpm5. In conclusion, PM inhalation affects testosterone biosynthesis and spermatogenesis, induces inflammatory response and immune imbalance, and causes testicular injury, all of which are associated with the inhibition of bitter taste transduction. The results indicate that bitter signaling molecules could serve as potential targets for preventing and managing infertility in men.
{"title":"Testosterone biosynthesis and spermatogenesis disruption by PM exposure: The hidden role of bitter taste transduction","authors":"Siwei Jiao , Danyu Zhao , Huilan Yi","doi":"10.1016/j.jsbmb.2024.106670","DOIUrl":"10.1016/j.jsbmb.2024.106670","url":null,"abstract":"<div><div>Male infertility, a major global reproductive health concern, has been linked to increased particulate air pollution and inflammatory response. Bitter taste transduction, involved in sensing bitterness, inflammation, and immune regulation, remains understudied in male reproductive damage. This research investigated how particulate matter (PM) impacts male reproductive health and the involvement of bitter taste transduction in reproductive toxicity. A PM exposure mouse model was established via aerosol inhalation of ovalbumin (OVA) following intraperitoneal injection of OVA. Results showed that PM exposure reduced sperm count, increased sperm malformation rate, decreased seminiferous epithelium height and tubular diameter, and caused disordered spermatogenic cell arrangement, along with decreased Johnsen scores, suggesting testicular structural damage and spermatogenesis disorders. Furthermore, PM exposure reduced serum testosterone levels and diminished the mRNA expression of genes involved in testosterone synthesis, transport, and spermatogenesis, including luteinizing hormone receptor (<em>LHR</em>), steroidogenic acute regulatory protein (<em>StAR</em>), cytochrome P450 side-chain cleavage enzyme (<em>P450scc</em>), 17-beta-hydroxysteroid dehydrogenase (<em>17β-HSD</em>), androgen-binding protein (<em>ABP</em>), and DEAD-box helicase 3 Y-linked (<em>Ddx3y</em>). Meanwhile, pro-inflammatory cytokine gene <em>TNF-α</em> and inflammatory genes <em>IL-4Rα</em>, <em>JAK1</em>, <em>JAK2</em>, <em>JAK3</em>, <em>STAT3</em>, and <em>STAT6</em> were significantly upregulated in testes of PM-exposed mice. This was accompanied by inhibited expression of Th1 cytokine gene <em>IFN-γ</em> and enhanced expression of Th2 cytokine genes <em>IL-4</em>, <em>IL-5</em>, and <em>IL-13</em>. Twenty-four out of thirty-five bitter taste receptor (T2R) genes, along with their downstream signaling molecules α-gustducin and transient receptor potential cation channel subfamily M member 5 (TRPM5) genes exhibited transcriptional repression in testes of PM-treated mice. The bitter compound baicalin alleviated PM-induced male reproductive damage accompanied with activating testis-specific T2R cluster (<em>T2R102</em>, <em>T2R109</em>, <em>T2R113</em>, <em>T2R117</em>, <em>T2R119</em>, <em>T2R124</em>, <em>T2R135</em>, <em>T2R136</em>), <em>α-gustducin</em> and <em>Trpm5</em>. In conclusion, PM inhalation affects testosterone biosynthesis and spermatogenesis, induces inflammatory response and immune imbalance, and causes testicular injury, all of which are associated with the inhibition of bitter taste transduction. The results indicate that bitter signaling molecules could serve as potential targets for preventing and managing infertility in men.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106670"},"PeriodicalIF":2.7,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143154565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-27DOI: 10.1016/j.jsbmb.2024.106668
Ayushi Chhabra, Anjali Tripathi, Sheeba Rizvi, Rakesh K. Tyagi
Estrogen receptor α/β (ERα/β), are members of the steroid/nuclear receptor superfamily. They function as a ligand-inducible transcriptional regulator and are targets for the treatment of several endocrine diseases. Irrespective of the ligand binding status, ERα/β are primarily localized in the nucleus. However, when activated, they bind to specific DNA response elements as homo-/hetero-dimers to transactivate their target genes. Homo-/hetero-dimerization of ERα/β is crucial in ER-mediated regulation of gene expression and cellular responses. However, the cellular site that hosts the receptor homo-/hetero-dimerization, essential for its physiological function, is poorly explored. Here, using a comprehensive approach, we show that the initial intermolecular interaction between ERα/β monomers occurs in the cytoplasmic compartment of the cell in a ligand-independent manner. To explore the site of homo-/hetero-dimerization of ERα/β in living cells, we created GFP-ERα/β and mCherry-ERα constructs to perform co-receptor interaction studies through fluorescence microscopy and live-cell imaging. The study revealed that ERα/β monomers dimerize in the cytoplasmic compartment, facilitating the nuclear import of the complex. We also observed that ligand-independent homodimerization requires a functional nuclear localization signal in at least one of the ER monomers. Finally, it has also been shown that the ligand-binding domain of ERα plays a key role in ligand-independent homodimerization. Understanding the intricacies of ER homo-/hetero-dimerization events and their disease-associated dysregulation paves the way for potential therapeutic interventions.
{"title":"Ligand-independent homo-/hetero-dimerization events of ERα and ERβ occur in the cytoplasmic compartment: Evidences from receptor dynamics in live cells","authors":"Ayushi Chhabra, Anjali Tripathi, Sheeba Rizvi, Rakesh K. Tyagi","doi":"10.1016/j.jsbmb.2024.106668","DOIUrl":"10.1016/j.jsbmb.2024.106668","url":null,"abstract":"<div><div>Estrogen receptor α/β (ERα/β), are members of the steroid/nuclear receptor superfamily. They function as a ligand-inducible transcriptional regulator and are targets for the treatment of several endocrine diseases. Irrespective of the ligand binding status, ERα/β are primarily localized in the nucleus. However, when activated, they bind to specific DNA response elements as homo-/hetero-dimers to transactivate their target genes. Homo-/hetero-dimerization of ERα/β is crucial in ER-mediated regulation of gene expression and cellular responses. However, the cellular site that hosts the receptor homo-/hetero-dimerization, essential for its physiological function, is poorly explored. Here, using a comprehensive approach, we show that the initial intermolecular interaction between ERα/β monomers occurs in the cytoplasmic compartment of the cell in a ligand-independent manner. To explore the site of homo-/hetero-dimerization of ERα/β in living cells, we created GFP-ERα/β and mCherry-ERα constructs to perform co-receptor interaction studies through fluorescence microscopy and live-cell imaging. The study revealed that ERα/β monomers dimerize in the cytoplasmic compartment, facilitating the nuclear import of the complex. We also observed that ligand-independent homodimerization requires a functional nuclear localization signal in at least one of the ER monomers. Finally, it has also been shown that the ligand-binding domain of ERα plays a key role in ligand-independent homodimerization. Understanding the intricacies of ER homo-/hetero-dimerization events and their disease-associated dysregulation paves the way for potential therapeutic interventions.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106668"},"PeriodicalIF":2.7,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143154566","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}
Programmed cell death (PCD) is a fundamental process in the development process of organisms, including apoptosis, autophagy, ferroptosis, and pyroptosis. In mammalian ovaries, 99 % of follicles undergo atresia, while only 1 % mature and ovulate, which limits the reproductive efficiency of mammals. The PCD process is closely related to the regulation of follicle development and atresia. Recently, an increasing number of studies have reported that autophagy, pyroptosis, and ferroptosis of PCD are involved in regulating granulosa cell apoptosis and follicular atresia. Granulosa cell apoptosis is a hallmark of follicular atresia. Therefore, an understanding of molecular mechanisms regulating PCD events is required for future advances in the diagnosis and management of various disorders of follicular atresia. This review summarizes recent work on apoptosis, autophagy, pyroptosis, and ferroptosis of PCD that affect granulosa cell survival and follicular atresia, and further elucidating the mechanisms of follicular atresia and providing new directions for improving the reproductive capacity of humans and animals.
{"title":"Role of programmed cell death in mammalian ovarian follicular atresia","authors":"Huaming Xi, Xinyu Chen, Xianglong Wang, Feng Jiang, Dong Niu","doi":"10.1016/j.jsbmb.2024.106667","DOIUrl":"10.1016/j.jsbmb.2024.106667","url":null,"abstract":"<div><div>Programmed cell death (PCD) is a fundamental process in the development process of organisms, including apoptosis, autophagy, ferroptosis, and pyroptosis. In mammalian ovaries, 99 % of follicles undergo atresia, while only 1 % mature and ovulate, which limits the reproductive efficiency of mammals. The PCD process is closely related to the regulation of follicle development and atresia. Recently, an increasing number of studies have reported that autophagy, pyroptosis, and ferroptosis of PCD are involved in regulating granulosa cell apoptosis and follicular atresia. Granulosa cell apoptosis is a hallmark of follicular atresia. Therefore, an understanding of molecular mechanisms regulating PCD events is required for future advances in the diagnosis and management of various disorders of follicular atresia. This review summarizes recent work on apoptosis, autophagy, pyroptosis, and ferroptosis of PCD that affect granulosa cell survival and follicular atresia, and further elucidating the mechanisms of follicular atresia and providing new directions for improving the reproductive capacity of humans and animals.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106667"},"PeriodicalIF":2.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-19DOI: 10.1016/j.jsbmb.2024.106666
Juilee Rege , Aaron M. Udager
Cushing syndrome represents a multitude of signs and symptoms associated with long-term and excessive exposure to glucocorticoids. Solitary cortisol-producing adenomas (CPAs) account for most cases of ACTH-independent Cushing syndrome (CS). Technological advances in next-generation sequencing have significantly increased our understanding about the genetic landscape of CPAs. However, the conventional approach utilizes fresh/frozen tissue samples, which are not routinely available for most clinical adrenal adenoma specimens. This coupled with the fact that CS is relatively rare reduces the accessibility to CPAs for research. In order to circumvent this issue, our group recently developed a sequencing strategy that allowed the use of formalin-fixed paraffin-embedded (FFPE) CPA samples for mutation analysis. Our streamlined approach includes the visualization and genomic DNA (gDNA) capture of the cortisol-producing regions in the tumor using immunohistochemistry (IHC)-guided techniques followed by targeted and/or whole-exome sequencing analysis. This approach has the advantage of using both prospective and retrospective CPA cohorts since FFPE pathologic specimens are routinely banked. This review discusses this advanced approach using IHC-guided gDNA capture of pathologic tissue followed by NGS as a preferred method for mutational analysis of CPAs.
{"title":"Molecular characterization of archival adrenal tumor tissue from patients with ACTH-independent Cushing syndrome","authors":"Juilee Rege , Aaron M. Udager","doi":"10.1016/j.jsbmb.2024.106666","DOIUrl":"10.1016/j.jsbmb.2024.106666","url":null,"abstract":"<div><div>Cushing syndrome represents a multitude of signs and symptoms associated with long-term and excessive exposure to glucocorticoids. Solitary cortisol-producing adenomas (CPAs) account for most cases of ACTH-independent Cushing syndrome (CS). Technological advances in next-generation sequencing have significantly increased our understanding about the genetic landscape of CPAs. However, the conventional approach utilizes fresh/frozen tissue samples, which are not routinely available for most clinical adrenal adenoma specimens. This coupled with the fact that CS is relatively rare reduces the accessibility to CPAs for research. In order to circumvent this issue, our group recently developed a sequencing strategy that allowed the use of formalin-fixed paraffin-embedded (FFPE) CPA samples for mutation analysis. Our streamlined approach includes the visualization and genomic DNA (gDNA) capture of the cortisol-producing regions in the tumor using immunohistochemistry (IHC)-guided techniques followed by targeted and/or whole-exome sequencing analysis. This approach has the advantage of using both prospective and retrospective CPA cohorts since FFPE pathologic specimens are routinely banked. This review discusses this advanced approach using IHC-guided gDNA capture of pathologic tissue followed by NGS as a preferred method for mutational analysis of CPAs.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106666"},"PeriodicalIF":2.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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