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Acute hyperglycemia induces podocyte apoptosis by monocyte TNF-α release, a process attenuated by vitamin D and GLP-1 receptor agonists 急性高血糖通过单核细胞tnf -α释放诱导足细胞凋亡,维生素d和glp-1受体激动剂可减弱这一过程。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-14 DOI: 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。
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引用次数: 0
Loss of DDB2 in type II diabetes mellitus induces dysregulated ubiquitination of KMT2A in lipid metabolism disorders 2型糖尿病中DDB2的缺失导致脂质代谢紊乱的KMT2A泛素化失调。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-09 DOI: 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.
糖脂代谢紊乱会导致严重的疾病,包括心血管疾病、糖尿病和脂肪肝。在这里,我们发现DNA损伤结合蛋白2 (DDB2),一种E3泛素连接酶,是II型糖尿病(T2DM)脂质代谢紊乱的关键调节因子。建立小鼠T2DM模型和小鼠原代肝细胞脂肪变性模型。将DDB2过表达或与赖氨酸n -甲基转移酶2A (KMT2A)过表达载体联合递送至db/db小鼠和体外肝细胞。在db/db小鼠的肝组织和原代肝细胞中,DDB2高表达,KMT2A低表达。DDB2改善了葡萄糖耐受不良和胰岛素抵抗,降低了肝/体重比,下调了肝组织和细胞中脂肪生成相关蛋白(SREBP1、FASN和SCD1)和糖异生相关蛋白(PEPCK和G6Pase)的表达,降低了脂肪变性肝细胞中的甘油三酯和总胆固醇水平。DDB2通过泛素化修饰降低KMT2A的表达。过表达KMT2A可促进葡萄糖耐受不良,减轻胰岛素抵抗,同时促进脂肪生成和脂质沉积,抑制DDB2存在下的糖原积累。总体而言,我们的数据表明,DDB2通过降解KMT2A减轻肝脏脂肪生成和脂质沉积,从而抑制T2DM的脂质代谢紊乱。
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引用次数: 0
Gut microbiome-derived metabolites and their impact on gene regulatory networks in gestational diabetes 肠道微生物衍生代谢物及其对妊娠糖尿病基因调控网络的影响。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-08 DOI: 10.1016/j.jsbmb.2025.106674
Sarvesh Sabarathinam , Akash Jayaraman , Ramesh Venkatachalapathy
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.
本研究探讨了肠道微生物代谢物在治疗妊娠期糖尿病(GDM)中的治疗潜力。通过网络药理学、分子对接和动力学模拟,我们确定了GDM的关键靶点和通路。我们筛选了135种肠道代谢物,其中8种符合药物相似和药代动力学标准。分析显示与gdm相关靶点有显著重叠,包括AKT1、IL6、TNF和STAT3。功能富集分析强调了AGE-RAGE信号和炎症通路在GDM发病机制中起着至关重要的作用。分子对接和动力学模拟显示木草素和柚皮素查尔酮两种代谢物与靶蛋白AKT1具有很强的结合亲和力和稳定的相互作用。这些发现表明,肠道微生物衍生的代谢物,特别是木犀草素和柚皮素查尔酮,可能有效地调节GDM的关键途径,为新的治疗策略提供了有希望的途径。
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引用次数: 0
Cyclocurcumin potently inhibits human aromatase as a potential therapeutic agent 环姜黄素能有效抑制人芳香化酶,是一种潜在的治疗药物。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-31 DOI: 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.
姜黄素,包括姜黄素及其衍生物,显示出对芳香化酶(CYP19A1)的有效抑制,该酶对雌二醇合成和乳腺癌转移至关重要。本研究利用胎盘微粒体评估了10种姜黄素及其代谢物对人和大鼠CYP19A1的抑制作用和机制,揭示了物种特异性的IC50值。环姜黄素(IC50, 4.43μM)和姜黄素(IC50, 3.49μM)分别是人CYP19A1和大鼠CYP19A1最有效的抑制剂。这些化合物作为混合或竞争性抑制剂,减少人BeWo细胞中雌二醇的产生。对接分析显示姜黄素与CYP19A1活性位点相互作用,与Met374形成氢键。3D-QSAR分析强调了氢键在抑制中的重要性。人类CYP19A1的pKa值与IC50值呈负相关。人类CYP19A1的最低结合能与IC50值呈正相关。这些发现强调了姜黄素作为乳腺癌治疗剂的潜力。
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引用次数: 0
Comprehensive review of phthalate exposure: Health implications, biomarker detection and regulatory standards 邻苯二甲酸盐暴露的综合评价:健康影响,生物标志物检测和监管标准。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-31 DOI: 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.
邻苯二甲酸盐是一个广泛的化学品家族,用于许多不同的工业应用,包括生产塑料,玩具,特别是儿童食品包装和医疗设备。由于其各种化学和物理性质,邻苯二甲酸盐可能对人类、动物和环境产生负面影响。因此,邻苯二甲酸盐暴露并对人类、动物和环境造成危害的可能性很高,因为它的存在令人震惊。邻苯二甲酸盐可被动物和人类摄入、吸入、局部吸收或医源性接触。本文旨在确定邻苯二甲酸盐的暴露方式、命运和检测技术,以及邻苯二甲酸盐对人类、动物和环境的有害影响。这篇综述还表明,从食物、玩具和空气等来源摄入超过规定的每日限量的邻苯二甲酸盐会造成严重危害,包括免疫功能受损、妊娠困难、生育能力丧失以及对人体肾脏、肺、心脏和大脑的损害。儿童和孕妇是受影响最大的群体,邻苯二甲酸酯也对环境和野生动物产生负面影响。本文还讨论了几种确定邻苯二甲酸盐暴露的方法,如LC和HPLC-MS/MS方法,这些方法采用人体液体或粉尘空气作为生物标志物。因此,这项全面审查的目的是对现有证据进行详细分析,这些证据表明接触邻苯二甲酸盐与可能与这种接触直接相关的后续健康结果之间存在明确联系。此外,我们回顾了已开发和验证的分析方法,并补充了部分生物监测数据的文献代谢产物。
{"title":"Comprehensive review of phthalate exposure: Health implications, biomarker detection and regulatory standards","authors":"Md. Mehedi Hasan ,&nbsp;Rahima Tanbin Tama ,&nbsp;Humayra Afroz Dona ,&nbsp;Naeema Salatia Hoque ,&nbsp;Md. Ashikur Rahaman ,&nbsp;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}
引用次数: 0
Segetalin B promotes bone formation in ovariectomized mice by activating PLD1/SIRT1 signaling to inhibit γ-secretase-mediated Notch1 overactivation Segetalin B通过激活PLD1/SIRT1信号以抑制γ-分泌酶介导的Notch1过度活化,促进卵巢切除小鼠的骨形成。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-28 DOI: 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 ,&nbsp;Furui Tang ,&nbsp;Haiping Ma ,&nbsp;Yipin Xiong ,&nbsp;Sijian Lin ,&nbsp;Zhen Yuan ,&nbsp;Jie Wu ,&nbsp;Binwu Xu ,&nbsp;Lei Xiao ,&nbsp;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}
引用次数: 0
Testosterone biosynthesis and spermatogenesis disruption by PM exposure: The hidden role of bitter taste transduction
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-28 DOI: 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 ,&nbsp;Danyu Zhao ,&nbsp;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}
引用次数: 0
Ligand-independent homo-/hetero-dimerization events of ERα and ERβ occur in the cytoplasmic compartment: Evidences from receptor dynamics in live cells
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-27 DOI: 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,&nbsp;Anjali Tripathi,&nbsp;Sheeba Rizvi,&nbsp;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}
引用次数: 0
Role of programmed cell death in mammalian ovarian follicular atresia 程序性细胞死亡在哺乳动物卵巢卵泡闭锁中的作用。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-24 DOI: 10.1016/j.jsbmb.2024.106667
Huaming Xi, Xinyu Chen, Xianglong Wang, Feng Jiang, Dong Niu
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.
细胞程序性死亡(Programmed cell death, PCD)是生物发育过程中的一个基本过程,包括细胞凋亡、自噬、铁死亡和焦亡。在哺乳动物卵巢中,99% %的卵泡闭锁,而只有1% %的卵泡成熟并排卵,这限制了哺乳动物的生殖效率。PCD过程与卵泡发育和闭锁的调控密切相关。近年来,越来越多的研究报道PCD的自噬、焦亡和铁亡参与调控颗粒细胞凋亡和滤泡闭锁。颗粒细胞凋亡是滤泡闭锁的标志。因此,了解调节PCD事件的分子机制对于未来各种卵泡闭锁疾病的诊断和治疗是必要的。本文综述了近年来PCD细胞凋亡、自噬、焦亡和铁亡对颗粒细胞存活和卵泡闭锁的影响,并进一步阐明了卵泡闭锁的机制,为提高人和动物的生殖能力提供了新的研究方向。
{"title":"Role of programmed cell death in mammalian ovarian follicular atresia","authors":"Huaming Xi,&nbsp;Xinyu Chen,&nbsp;Xianglong Wang,&nbsp;Feng Jiang,&nbsp;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}
引用次数: 0
Molecular characterization of archival adrenal tumor tissue from patients with ACTH-independent Cushing syndrome acth非依赖性库欣综合征患者档案肾上腺肿瘤组织的分子特征。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-19 DOI: 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.
库欣综合征表现出与长期和过度接触糖皮质激素相关的多种体征和症状。孤立性皮质醇生成腺瘤(CPAs)占acth非依赖性库欣综合征(CS)的大多数病例。新一代测序技术的进步大大增加了我们对cpa基因景观的了解。然而,传统的方法使用新鲜/冷冻组织样本,这不是大多数临床肾上腺腺瘤标本的常规方法。再加上CS相对罕见的事实,减少了注册会计师进行研究的可及性。为了规避这个问题,我们的团队最近开发了一种测序策略,允许使用福尔马林固定石蜡包埋(FFPE) CPA样本进行突变分析。我们的简化方法包括使用免疫组织化学(IHC)引导技术对肿瘤中皮质醇产生区域进行可视化和基因组DNA (gDNA)捕获,然后进行靶向和/或全外显子组测序分析。该方法具有前瞻性和回顾性CPA队列的优点,因为FFPE病理标本是常规储存的。这篇综述讨论了这种先进的方法,使用ihc引导的病理组织gDNA捕获,然后使用NGS作为cpa突变分析的首选方法。
{"title":"Molecular characterization of archival adrenal tumor tissue from patients with ACTH-independent Cushing syndrome","authors":"Juilee Rege ,&nbsp;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}
引用次数: 0
期刊
Journal of Steroid Biochemistry and Molecular Biology
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