Molecular and Cellular Endocrinology最新文献_第7页

Puerarin reduces diabetic nephropathy-induced podocyte pyroptosis by modulating the SIRT1/NLRP3/caspase-1 pathway 葛根素通过调节SIRT1/NLRP3/caspase-1途径减少糖尿病肾病诱导的荚膜细胞脓毒症

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-11-06 DOI: 10.1016/j.mce.2024.112409

Lu Wang , Xiaohai Xie , Qiuyan Chen , Yulin Chen , Xiaohui Xu , Tao Liang

Background

Chronic kidney inflammation and podocyte injury are key pathological features of Diabetic Nephropathy (DN). Puerarin has been shown to inhibit podocyte pyroptosis and provide renal protection, although its molecular mechanism remains unclear.

Methods

The effects and mechanisms of puerarin on podocyte pyroptosis were investigated in a DN mouse model. In vivo, a DN model was established using streptozotocin (STZ) and treated with puerarin, a SIRT1 agonist, or a SIRT1 inhibitor. In vitro, a podocyte pyroptosis model was induced under high glucose (HG) conditions, and lentivirus transfection was used to either silence or overexpress SIRT1. Techniques including ELISA, transmission electron microscopy, flow cytometry, PCR, and Western blotting were employed to explore the molecular mechanisms by which puerarin inhibits podocyte pyroptosis.

Results

The study showed that SIRT1 expression was significantly downregulated in STZ-induced DN mice and HG-induced MPC-5 cell pyroptosis models. Overexpression of SIRT1 decreased the secretion of inflammatory factors, reduced reactive oxygen species (ROS) release, improved podocyte injury, restored podocyte function, and inhibited the expression of the NLRP3 inflammasome and its downstream factors. Furthermore, puerarin increased SIRT1 expression in DN mice and HG-treated MPC-5 cells, inhibited the activation of the NLRP3/Caspase-1 pathway, reduced podocyte pyroptosis, and alleviated renal inflammatory damage.

Conclusion

These findings suggest that puerarin may inhibit podocyte pyroptosis, reduce podocyte injury, and mitigate renal inflammatory damage by modulating the SIRT1/NLRP3/Caspase-1 pathway.

背景：慢性肾脏炎症和荚膜细胞损伤是糖尿病肾病（DN）的主要病理特征。葛根素已被证明可抑制荚膜细胞脓毒症并提供肾脏保护，但其分子机制仍不清楚：方法：在 DN 小鼠模型中研究葛根素对荚膜细胞脓毒症的影响和机制。在体内，使用链脲佐菌素（STZ）建立 DN 模型，并用葛根素、SIRT1 激动剂或 SIRT1 抑制剂治疗。在体外，在高糖（HG）条件下诱导荚膜细胞热解模型，并使用慢病毒转染来沉默或过表达 SIRT1。采用酶联免疫吸附、透射电子显微镜、流式细胞术、PCR和Western印迹等技术探讨葛根素抑制荚膜细胞脓毒症的分子机制：结果：研究表明，SIRT1在STZ诱导的DN小鼠和HG诱导的MPC-5细胞脓毒症模型中表达明显下调。过表达 SIRT1 可减少炎症因子的分泌，降低活性氧（ROS）的释放，改善荚膜细胞损伤，恢复荚膜细胞功能，抑制 NLRP3 炎性体及其下游因子的表达。此外，葛根素还能增加 DN 小鼠和经 HG 处理的 MPC-5 细胞中 SIRT1 的表达，抑制 NLRP3/Caspase-1 通路的激活，减少荚膜细胞的脓毒症，减轻肾脏炎症损伤：这些研究结果表明，葛根素可通过调节SIRT1/NLRP3/Caspase-1通路，抑制荚膜细胞脓毒症，减少荚膜细胞损伤，减轻肾脏炎症损伤。

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引用次数: 0

Female C57BL/6 mice exhibit protection against nonalcoholic fatty liver disease and diabesity accompanied by differential regulation of hepatic lipocalin prostaglandin D2 synthase 雌性 C57BL/6 小鼠对非酒精性脂肪肝和肥胖症的保护作用伴随着肝脏脂联素前列腺素 D2 合成酶的不同调节。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-11-04 DOI: 10.1016/j.mce.2024.112404

Md Asrarul Islam , Rhema Khairnar , Joshua Fleishman , Sandra E. Reznik , Louis Ragolia , Shruthi Gobbooru , Sunil Kumar

引用次数: 0

PRDM16 in thermogenic adipocytes mediates an inter-organ protective signaling against alcohol-associated liver disease 发热脂肪细胞中的 PRDM16 介导器官间保护信号，防止酒精相关性肝病。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-11-04 DOI: 10.1016/j.mce.2024.112407

Shanshan Liu , Kezhou Zhu , Yunying Huang , Weilai Ye , Jun Wu

Alcohol-associated liver disease (ALD) is one of the major chronic liver diseases and despite the dire clinical needs and extensive research efforts, no effective therapies are available for late-stages of ALD except for liver transplantation. Adipose tissue dysfunction has been implicated in the progression of ALD. Furthermore, it has been previously suggested that thermogenic fat can be activated after alcohol consumption. In this study, increased thermogenic gene expression was detected in both classical brown adipose tissue and beige adipocytes in mice that were given alcohol challenges even when housed at thermoneutrality. In particular, higher expression level of Prdm16, the key transcriptional co-component for beige fat function, was observed in the subcutaneous fat of mice after alcohol challenges. The objective of the present study is to explore the functional significance of adipocyte PRDM16 in the context of ALD. Even though Prdm16 adipocyte-specific-deleted mice (Prdm16-adKO) did not show liver defects at the basal level, following two different alcohol challenge regimens, exacerbated ALD phenotypes were observed in Prdm16-adKO mice compared to that of the control Prdm16 ^fl/fl mice. Mechanistic investigation suggests that adipose dysfunction after alcohol abuse, including alcohol-induced changes in adipose lipolytic activity, fatty acid oxidation and adipokine levels, may render the worsened ALD phenotype in Prdm16-adKO mice. These results indicate PRDM16-mediated signaling in fat plays a protective role against liver injury caused by alcohol abuse, suggesting it may represent a potential therapeutic target against ALD.

酒精相关性肝病（ALD）是主要的慢性肝病之一，尽管临床需求迫切，研究工作也十分广泛，但除了肝脏移植外，目前还没有针对ALD晚期的有效疗法。脂肪组织功能障碍与 ALD 的进展有关。此外，有研究表明，饮酒后可激活生热脂肪。在本研究中，即使小鼠在恒温饲养条件下接受酒精挑战，也能在其经典棕色脂肪组织和米色脂肪细胞中检测到生热基因表达的增加。特别是，在酒精挑战后的小鼠皮下脂肪中，观察到米色脂肪功能的关键转录辅成分 Prdm16 表达水平较高。本研究旨在探讨脂肪细胞 PRDM16 在 ALD 中的功能意义。尽管Prdm16脂肪细胞特异性缺失小鼠（Prdm16-adKO）在基础水平上没有表现出肝脏缺陷，但在两种不同的酒精挑战方案后，与对照组Prdm16fl/fl小鼠相比，Prdm16-adKO小鼠的ALD表型加剧了。机理研究表明，酒精滥用后的脂肪功能障碍，包括酒精诱导的脂肪分解活性、脂肪酸氧化和脂肪因子水平的变化，可能导致 Prdm16-adKO 小鼠的 ALD 表型恶化。这些结果表明，PRDM16介导的脂肪信号传导对酗酒引起的肝损伤具有保护作用，表明它可能是ALD的潜在治疗靶点。

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引用次数: 0

NLRP3 inhibitor alleviates glycemic variability-induced cognitive impairment in aged rats with type 2 diabetes mellitus NLRP3抑制剂可缓解血糖变化诱发的2型糖尿病老年大鼠认知功能障碍

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-11-01 DOI: 10.1016/j.mce.2024.112406

Wei Yang, Si-Cong Si, Jing Li, Yi-Xin Ma, Huan Zhao, Jia Liu

Glycemic variability (GV) markedly exacerbates cognitive impairment in elderly patients with type 2 diabetes mellitus (T2DM), in part through chronic inflammation. This study investigated the therapeutic efficacy of the NLRP3 inflammasome inhibitor MCC950 in mitigating GV-induced cognitive impairment in an aged rat model of T2DM. Aged Sprague-Dawley rats with induced T2DM were subjected to GV conditions, and the effects of MCC950 were evaluated through measurement of body weight, blood glucose, lipid profiles, insulin level, inflammatory markers, and cognitive function. Transcriptomic analysis was performed on the hippocampus and prefrontal cortex. Treatment with MCC950 significantly alleviated weight loss and hyperglycemia in the GV group compared with the control group. MCC950 also reduced the levels of cholesterol, triglycerides, and pro-inflammatory markers (interleukin-1β (IL-1β) and interleukin-18 (IL-18)). Most notably, MCC950 improved spatial learning and memory retention in the GV group. Immunohistochemical analysis indicated a reduction in inflammasome activation and an increase in the expression level of the neuronal marker NeuN in the hippocampus. Transcriptomic analysis revealed that MCC950 altered neuroactive ligand-receptor interaction pathways in the hippocampus and influenced receptor binding and cell adhesion processes in the prefrontal cortex. These findings validated the efficacy of NLRP3 inhibitor in mitigating GV-induced cognitive impairment in elderly rats with T2DM and provided the basis for subsequent clinical studies exploring the broader potential of NLRP3-targeted interventions in addressing diabetes-associated cognitive impairment.

血糖变异（GV）会明显加剧老年 2 型糖尿病（T2DM）患者的认知障碍，部分原因是慢性炎症。本研究调查了 NLRP3 炎性体抑制剂 MCC950 在老年 T2DM 大鼠模型中减轻 GV 引起的认知障碍的疗效。将诱导 T2DM 的老年 Sprague-Dawley 大鼠置于龙胆紫条件下，通过测量体重、血糖、血脂、胰岛素水平、炎症标志物和认知功能来评估 MCC950 的效果。对海马和前额叶皮层进行了转录组分析。与对照组相比，MCC950能明显减轻龙胆紫组的体重减轻和高血糖症状。MCC950还降低了胆固醇、甘油三酯和促炎标志物（白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18））的水平。最值得注意的是，MCC950能改善龙胆紫组的空间学习能力和记忆保持能力。免疫组化分析表明，炎性体激活减少，海马中神经元标志物 NeuN 的表达水平升高。转录组分析表明，MCC950改变了海马中神经活性配体与受体的相互作用途径，并影响了前额叶皮质中受体结合和细胞粘附过程。这些发现验证了 NLRP3 抑制剂在减轻 GV 诱导的 T2DM 老年大鼠认知功能损害方面的功效，并为后续临床研究提供了基础，以探索 NLRP3 靶向干预在解决糖尿病相关认知功能损害方面的更广泛潜力。

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引用次数: 0

Status of sperm mitochondrial functions and DNA methylation in infertile men with clinical varicocele before and after treatment 临床精索静脉曲张不育男性精子线粒体功能和 DNA 甲基化治疗前后的状况。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-10-30 DOI: 10.1016/j.mce.2024.112393

Deepshikha Arya , Prakash Pawar , Rahul Gajbhiye , Deepti Tandon , Priyank Kothari , Reshma Goankar , Dipty Singh

Varicocele has been associated with reduced male fertility potential. Treatment modalities for varicocele improve semen parameters, yet more than 50% of cases remain infertile. Varicocele-induced heat and hypoxia stress may affect sperm mitochondrial functions, possibly leading to aberrant epigenetic modifications. This study includes 30 fertile men and 40 infertile men with clinical varicocele. The effect of varicocele treatment (antioxidant supplementation and or varicocelectomy) was evaluated after 3 months of treatment. Mitochondrial membrane potential (MMP) and intracellular reactive oxygen species (iROS) were measured by flow cytometry using JC-1 and DCFDA, respectively. mtDNA copy number and deletions were determined by PCR. DNA methylation was analysed by pyrosequencing. Present investigations suggest that infertile men with varicocele have abnormal semen parameters; significantly low MMP, high iROS, and high mtDNA copy number. Semen parameters were improved in a subset of men of both the treatment modalities; however, it was noted that varicocelectomy helped better in improving sperm parameters compared to antioxidant treatment. Both treatment modalities helped in reducing iROS and mtDNA copy number significantly; however, they were noneffective in improving MMP. Altered DNA methylation at mitochondria D loop and mitochondrial structure and function genes UQCRC2, MIC60, TOM22, and LETM1 (promoter region) were observed in varicocele group. The DNA methylation levels were restored after varicocele treatment; however, the restoration was not consistent at all CpG sites. Both the treatment modalities helped in restoring the altered DNA methylation levels of mitochondrial genes but the restoration is nonhomogeneous across the studied CpG sites.

精索静脉曲张与男性生育能力下降有关。精索静脉曲张的治疗方法可改善精液参数，但仍有 50%以上的病例无法生育。精索静脉曲张诱发的热和缺氧应激可能会影响精子线粒体的功能，从而可能导致异常的表观遗传修饰。这项研究包括 30 名可育男性和 40 名患有临床精索静脉曲张的不育男性。治疗 3 个月后，对精索静脉曲张治疗（补充抗氧化剂和或进行精索静脉曲张切除术）的效果进行了评估。线粒体膜电位（MMP）和细胞内活性氧（iROS）分别通过使用 JC-1 和 DCFDA 的流式细胞术进行测量。DNA甲基化采用热测序法进行分析。目前的研究表明，患有精索静脉曲张的不育男性精液参数异常；MMP明显偏低，iROS偏高，mtDNA拷贝数偏高。两种治疗方法都能改善部分男性的精液参数；但与抗氧化剂治疗相比，精索静脉曲张切除术更有助于改善精子参数。两种治疗方法都有助于显著降低iROS和mtDNA拷贝数，但对改善MMP无效。在精索静脉曲张组中，线粒体 D 环和线粒体结构与功能基因 UQCRC2、MIC60、TOM22 和 LETM1（启动子区域）的 DNA 甲基化发生了改变。精索静脉曲张治疗后，DNA 甲基化水平得到了恢复，但并非所有 CpG 位点的甲基化水平都得到了恢复。两种治疗方式都有助于恢复线粒体基因已改变的 DNA 甲基化水平，但在所研究的 CpG 位点上，恢复情况并不一致。

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引用次数: 0

An optimized fractionation method reveals insulin-induced membrane surface localization of GLUT1 to increase glycolysis in LβT2 cells 优化的分馏方法揭示了胰岛素诱导的 GLUT1 膜表面定位增加 LβT2 细胞中的糖酵解。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-10-29 DOI: 10.1016/j.mce.2024.112405

Olivia Molinar-Inglis , Kiara Wiggins , Anjali Varma , Zena Del Mundo , Jose M. Adame , Alyssa Cozzo , Oscar Muñoz , Uyen-Vy Le , Davina Trinh , Alexis C. Garcia , Metztli Cisneros-Aguirre , Monica L. Gonzalez Ramirez , Jeremiah Keyes , Jin Zhang , Mark A. Lawson , JoAnn Trejo , Dequina A. Nicholas

Insulin is an important regulator of whole-body glucose homeostasis. In insulin sensitive tissues such as muscle and adipose, insulin induces the translocation of glucose transporter 4 (GLUT4) to the cell membrane, thereby increasing glucose uptake. However, insulin also signals in tissues that are not generally associated with glucose homeostasis. In the human reproductive endocrine axis, hyperinsulinemia suppresses the secretion of gonadotropins from gonadotrope cells of the anterior pituitary, thereby linking insulin dysregulation to suboptimal reproductive health. In the mouse, gonadotropes express the insulin receptor which has the canonical signaling response of IRS, AKT, and mTOR activation. However, the functional outcomes of insulin action on gonadotropes are unclear. Here, we demonstrate through use of an optimized cell fractionation protocol that insulin stimulation of the LβT2 gonadotropic cell line results in the unexpected translocation of GLUT1 to the plasma membrane. Using our high purity fractionation protocol, we further demonstrate that though Akt signaling in response to insulin is intact, insulin-induced translocation of GLUT1 occurs independently of Akt activation in LβT2 cells.

胰岛素是全身葡萄糖平衡的重要调节剂。在肌肉和脂肪等对胰岛素敏感的组织中，胰岛素会诱导葡萄糖转运体 4（GLUT4）转运到细胞膜上，从而增加葡萄糖的摄取。然而，胰岛素也会在通常与葡萄糖平衡无关的组织中发出信号。在人类生殖内分泌轴中，高胰岛素血症会抑制垂体前叶促性腺激素细胞分泌促性腺激素，从而将胰岛素失调与生殖健康不良联系起来。在小鼠体内，促性腺激素表达胰岛素受体，而胰岛素受体具有激活 IRS、AKT 和 mTOR 的典型信号反应。然而，胰岛素作用于促性腺激素的功能结果尚不清楚。在这里，我们通过使用优化的细胞分馏方案证明，胰岛素刺激 LβT2 促性腺激素细胞系会导致 GLUT1 意外地转位到质膜上。利用我们的高纯度分馏方案，我们进一步证明，尽管对胰岛素做出反应的 Akt 信号是完整的，但胰岛素诱导的 GLUT1 转位在 LβT2 细胞中的发生与 Akt 激活无关。

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引用次数: 0

FSH increases lipid droplet content by regulating the expression of genes related to lipid storage in Rat Sertoli cells FSH 通过调节大鼠 Sertoli 细胞中脂质储存相关基因的表达增加脂滴含量

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-10-28 DOI: 10.1016/j.mce.2024.112403

Marina Ercilia Dasso, Cecilia Lucia Centola, Maria Noel Galardo, Maria Fernanda Riera, Silvina Beatriz Meroni

Sertoli cells (SCs) are essential for appropriate spermatogenesis. From a metabolic standpoint, they catabolize glucose and provide germ cells with lactate, which is their main energy source. SCs also oxidize fatty acids (FAs), which are stored as triacylglycerides (TAGs) within lipid droplets (LDs), to fulfill their own energy requirements. On the other hand, it has been demonstrated that FSH regulates some of SCs functions, but little is known about its effect on lipid metabolism. In the present study, we aimed to analyze FSH-mediated regulation of (1) lipid storage in LDs and (2) the expression of genes involved in FAs activation and TAG synthesis and storage in SCs. SCs obtained from 20-day-old rats were cultured for different incubation periods with FSH (100 ng/ml). It was observed that FSH increased LD content and TAG levels in SCs. There were also increments in the expression of Plin1, Fabp5, Acsl1, Acsl4, Gpat3, and Dgat1, which suggests that these proteins may mediate the increase in TAGs and LDs elicited by FSH. Regarding the signaling involved in FSH actions, it was observed that dbcAMP increased LD, and H89, a PKA inhibitor, inhibited FSH stimulus. Also, dbcAMP increased Plin2, Fabp5, Acsl1, Acsl4, and Dgat1 mRNA levels, confirming a role of the cAMP/PKA pathway in the regulation of lipid storage in SCs. Altogether, these results suggest that FSH, via the cAMP/PKA pathway, regulates lipid storage in SCs ensuring the availability of substrates to satisfy their energy requirements.

正常的精子发生离不开肥大细胞（SC）。从新陈代谢的角度来看，它们分解葡萄糖并为生殖细胞提供乳酸，这是它们的主要能量来源。生精细胞还会氧化脂肪酸（FA），以三酰甘油（TAG）的形式储存在脂滴（LD）中，以满足自身的能量需求。另一方面，已有研究表明 FSH 可调节 SCs 的某些功能，但对其对脂质代谢的影响却知之甚少。在本研究中，我们旨在分析 FSH 介导的（1）LDs 脂质储存和（2）SCs 中参与 FAs 激活和 TAG 合成及储存的基因表达的调控。用 FSH（100 毫微克/毫升）培养 20 天龄大鼠的 SCs 不同孵育期。结果发现，FSH 增加了 SCs 中的 LD 含量和 TAG 水平。Plin1、Fabp5、Acsl1、Acsl4、Gpat3和Dgat1的表达也有所增加，这表明这些蛋白可能介导了FSH引起的TAG和LD的增加。关于参与 FSH 作用的信号传导，观察到 dbcAMP 增加了 LD，而 PKA 抑制剂 H89 抑制了 FSH 的刺激。此外，dbcAMP 还增加了 Plin2、Fabp5、Acsl1、Acsl4 和 Dgat1 的 mRNA 水平，证实了 cAMP/PKA 通路在调节 SCs 脂质储存中的作用。总之，这些结果表明，FSH通过cAMP/PKA途径调节SCs的脂质储存，确保底物的可用性以满足其能量需求。

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引用次数: 0

Selenoprotein M protects cardiac endothelial cell integrity against high-glucose stress via enhancing Parkin-mediated mitophagy 硒蛋白M通过增强Parkin介导的有丝分裂来保护心脏内皮细胞的完整性，使其免受高葡萄糖应激的影响。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-10-23 DOI: 10.1016/j.mce.2024.112392

Bin Zhao , Wen-Liang Tan , Bing-Bo Yu , Jun Fan , Chang Liu , Jian Liu , Zhen Liu

Selenoprotein M (SELENOM) has emerged as a crucial factor in maintaining cellular redox homeostasis and mitigating oxidative damage. This study aims to investigate its protective role in cardiac endothelial cells under hyperglycemic stress, a condition commonly associated with diabetes mellitus and its cardiovascular complications. Diabetic mice model and human umbilical vein endothelial cells (HUVECs) were applied for in vivo and in vitro studies. Results reveal that hyperglycemia significantly downregulates SELENOM expression in both diabetic mouse hearts and primary cultured cardiac endothelial cells. Overexpression of SELENOM in HUVECs mitigated high-glucose-induced FITC-Dextran diffusion and the loss of transendothelial electrical resistance. Additionally, SELENOM overexpression decreased reactive oxygen species (ROS) levels, preserved tight junction protein expression, and maintained cellular structural integrity under hyperglycemic conditions. Furthermore, SELENOM overexpression attenuated high-glucose-induced mitochondrial apoptosis. High-glucose conditions decreased Parkin and increased p62 and Beclin1 expressions. SELENOM overexpression restored Parkin levels and promoted co-localization of LAMP1 and TOMM20. Knockdown of Parkin significantly attenuated these protective effects, suggesting the importance of Parkin in Selenoprotein M-mediated mitophagy. Collectively, these findings suggest that Selenoprotein M enhances Parkin-mediated mitophagy to protect endothelial cells from hyperglycemic stress, offering potential therapeutic insights for diabetic cardiovascular complications.

硒蛋白M（SELENOM）已成为维持细胞氧化还原平衡和减轻氧化损伤的关键因素。本研究旨在探讨硒蛋白 M 在高血糖应激状态下对心脏内皮细胞的保护作用，高血糖应激状态通常与糖尿病及其心血管并发症有关。研究采用糖尿病小鼠模型和人脐静脉内皮细胞（HUVECs）进行体内和体外研究。结果发现，高血糖会显著下调糖尿病小鼠心脏和原代培养的心脏内皮细胞中SELENOM的表达。SELENOM在HUVECs中的过表达减轻了高血糖诱导的FITC-二聚体扩散和跨内皮电阻的损失。此外，SELENOM的过表达降低了活性氧（ROS）水平，保护了紧密连接蛋白的表达，并在高血糖条件下保持了细胞结构的完整性。此外，SELENOM的过表达还减轻了高血糖诱导的线粒体凋亡。高血糖条件减少了Parkin的表达，增加了p62和Beclin1的表达。SELENOM的过表达恢复了Parkin的水平，并促进了LAMP1和TOMM20的共定位。敲除Parkin能明显减弱这些保护作用，表明Parkin在硒蛋白M介导的有丝分裂中的重要性。总之，这些研究结果表明，硒蛋白M能增强Parkin介导的有丝分裂，保护内皮细胞免受高血糖应激，为糖尿病心血管并发症提供了潜在的治疗思路。

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引用次数: 0

HSF1/HSP25 system protects mitochondria function from heat stress and assists steroidogenesis in MA-10 Leydig cells HSF1/HSP25 系统可保护线粒体功能免受热应力影响，并协助 MA-10 Leydig 细胞的类固醇生成。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-10-22 DOI: 10.1016/j.mce.2024.112391

Shintaro Oka , Ryosuke Takii , Mitsuaki Fujimoto , Akira Nakai , Koji Shiraishi

Heat shock response is characterized by the induction of heat shock proteins (HSPs) or molecular chaperones that maintain protein homeostasis. Heat shock transcription factor 1 (HSF1) plays a central role in heat shock response in mammalian cells. To investigate the impact of the heat shock response mechanism on steroidogenesis, we generated MA-10 mouse Leydig tumor cells deficient in HSF1 using CRISPR-Cas9 genome editing. Under heat stress conditions, the levels of StAR protein, but not its mRNA, decreased more in HSF1-knockout cells than in wild-type cells, confirming that HSF1 stabilizes StAR protein. Simultaneously, HSP110, HSP70, and HSP25 were markedly upregulated in a manner dependent on HSF1. Mitochondrial membrane potential (MMP) and ATP synthesis were decreased in HSF1-knockout cells under heat stress conditions, and mitochondrial fragmentation was enhanced. Furthermore, treatment with carbonyl cyanide 3-chlorophenylhydrazone (CCCP), a disruptor of MMP, reduced the levels of StAR protein to a greater extent in HSF1-knockout cells than in wild-type cells, which was associated with decreased MMP and ATP synthesis. Unexpectedly, HSP25 expression was markedly increased in wild-type cells following CCCP treatment. HSP25 knockdown reduces MMP under heat stress conditions and decreases StAR protein levels and progesterone synthesis. HSP25 overexpression in HSF1KO cells restored StAR protein levels. These results show that the HSF1/HSP25 pathway protects mitochondrial function and maintains StAR synthesis.

热休克反应的特点是诱导热休克蛋白（HSP）或分子伴侣，以维持蛋白质的平衡。热休克转录因子 1（HSF1）在哺乳动物细胞的热休克反应中发挥着核心作用。为了研究热休克反应机制对类固醇生成的影响，我们利用 CRISPR-Cas9 基因组编辑技术生成了缺失 HSF1 的 MA-10 小鼠雷迪格肿瘤细胞。在热应激条件下，与野生型细胞相比，HSF1基因敲除细胞中的StAR蛋白（而非其mRNA）水平下降更多，这证实了HSF1能稳定StAR蛋白。与此同时，HSP110、HSP70 和 HSP25 以依赖 HSF1 的方式显著上调。在热应激条件下，HSF1 基因敲除细胞的线粒体膜电位（MMP）和 ATP 合成减少，线粒体破碎增强。此外，用羰基氰-3-氯苯基腙（CCCP）（一种 MMP 破坏剂）处理后，HSF1-基因敲除细胞中 StAR 蛋白水平的降低程度大于野生型细胞，这与 MMP 和 ATP 合成的减少有关。出乎意料的是，在 CCCP 处理后，野生型细胞中 HSP25 的表达明显增加。敲除 HSP25 可减少热应激条件下的 MMP，降低 StAR 蛋白水平和孕酮合成。在 HSF1KO 细胞中过表达 HSP25 可恢复 StAR 蛋白水平。这些结果表明，HSF1/HSP25途径可保护线粒体功能并维持StAR的合成。

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引用次数: 0

Vasopressinergic sexual dimorphism: Sex chromosome complement and organizational hormonal effects 血管加压素能性双态性：性染色体互补和组织荷尔蒙效应

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-10-18 DOI: 10.1016/j.mce.2024.112390

Florencia María Dadam , Lihue Gonzalez , Laura Vivas, Andrea Godino, Ximena E. Caeiro

This study aimed to analyze the role of the sex chromosomes (SCC: XX/XY) and the interaction with organizational hormonal effects on Avp gene expression at the supraoptic (SON) and paraventricular nuclei (PVN) due to water deprivation, as well as on the vasopressinergic sexually dimorphic antidiuretic and pressor responses. For this purpose, we used gonadectomized (GDX) transgenic mice of the "four core genotypes" model, in which the effect of gonadal sex and SCC are dissociated.

A significant interaction between treatment and SCC on Avp gene expression at the SON was observed. Regardless of sex, XX mice showed higher basal expression than those with XY; however after water deprivation no changes in mRNA Avp expression were observed in the XX group, while an increase for XY was reported. At the PVN an interaction of SCC, organizational hormonal, and treatment factors was observed, revealing an increase in Avp gene expression in the XY-GDX male DEP group.

Although no SCC or organizational hormonal effects were observed on the demopressin-antidiuretic response and renal Avpr2 mRNA expression, an interplay of organizational hormonal and SCC factors in short and medium-term vasopressin-blood pressure regulation were reported. XX-GDX females showed a facilitated vasopressin-bradycardic baroreflex response when compared to the other genotypes. Furthermore, although vasopressin continuous infusion resulted initially in the expected increase in the percentage change in MAP in all genotypes, in XX-GDX male and female this increase was sustained until the 30-min infusion, while in XY-GDX male and in XY-GDX female mice a decrease in MAP was observed.

本研究旨在分析性染色体（SCC：XX/XXY）的作用，以及与组织激素的相互作用对缺水导致的视上核（SON）和室旁核（PVN）Avp基因表达的影响，以及对血管加压素能性双态抗利尿和加压反应的影响。为此，我们使用了性腺切除（GDX）转基因小鼠的 "四核心基因型 "模型，在该模型中，性腺性别和SCC的影响是分离的。我们观察到处理和 SCC 对 SON 的 Avp 基因表达有明显的交互作用。无论性别如何，XX 组小鼠的基础表达量均高于 XY 组小鼠；但在缺水后，XX 组小鼠的 mRNA Avp 表达量没有发生变化，而 XY 组小鼠的表达量则有所增加。在 PVN，观察到 SCC、组织激素和治疗因素之间的相互作用，显示 XY-GDX 雄性 DEP 组的 Avp 基因表达增加。虽然没有观察到 SCC 或组织激素对去甲加压素-抗利尿反应和肾脏 Avpr2 mRNA 表达的影响，但报告了组织激素和 SCC 因素在中短期血管加压素-血压调节中的相互作用。与其他基因型相比，XX-GDX 女性显示出血管加压素-心动过缓-血压反射反应的促进作用。此外，虽然持续输注血管加压素最初会导致所有基因型小鼠的血压变化百分比出现预期的增加，但在 XX-GDX 雄性和雌性小鼠中，这种增加一直持续到输注 30 分钟，而在 XY-GDX 雄性和 XY-GDX 雌性小鼠中，则观察到血压下降。

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