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Indole-3-propionic acid function through PXR and AhR, molecular signaling pathways, and antitoxic role in underlying diseases 吲哚-3-丙酸通过PXR和AhR的功能、分子信号通路和潜在疾病的抗毒性作用。
IF 2.5 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-10-13 DOI: 10.1016/j.jsbmb.2025.106877
Cyrus Jalili , Foruzan Hosseinkhani , Dian Dayer , Mohammad Reza Tabandeh , Ardeshir Abbasi , Touraj Zamir Nasta
The host organism's balance within the body relies on its crucial symbiotic relationship with gut microbiota. This balance, known as homeostasis, can be influenced by various factors. One significant factor is the role of bacterial metabolites from different substrates, such as tryptophan. Recent research has revealed that these metabolites impact many biological processes. Microbial metabolites, such as Indole-3-Propionic Acid (IPA), are produced by the intestinal microbiota by converting dietary tryptophan. IPA is absorbed by intestinal epithelial cells, transported via the portal circulation, undergoes minimal hepatic metabolism, and is subsequently released into the systemic circulation to reach peripheral tissues and exert its biological effects. The Pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR) are the two main receptors of IPA which induce different gene expression profiles and subsequently diverse biological pathways in different tissues. Once absorbed by intestinal epithelial cells, IPA is released into the circulatory system and can significantly affect the immune, cardiovascular, nervous, and gastrointestinal systems. Furthermore, IPA has been found to have positive effects on a cellular level by inhibiting oxidative stress injury and preventing the synthesis of proinflammatory cytokines. Numerous studies have highlighted IPA's antioxidant, anti-inflammatory, anti-cancer, and neuroprotective effects. Therefore, dysbiosis of IPA contributes to disorders such as metabolic syndromes, inflammatory conditions, cancer, and neuropsychiatric diseases. This review provides a detailed examination of the most recent studies on indole-3-propionic acid function through PXR and AhR, outlining its molecular signaling pathways and correlation with various diseases.
宿主生物在体内的平衡依赖于它与肠道微生物群的重要共生关系。这种平衡被称为体内平衡,可以受到各种因素的影响。一个重要的因素是来自不同底物的细菌代谢物的作用,如色氨酸。最近的研究表明,这些代谢物影响许多生物过程。微生物代谢物,如吲哚-3-丙酸(IPA),是由肠道菌群通过转化膳食色氨酸产生的。IPA被肠上皮细胞吸收,经门静脉循环运输,经过最低限度的肝脏代谢,随后释放进入体循环到达外周组织,发挥其生物学作用。孕烷X受体(PXR)和芳烃受体(AhR)是IPA的两个主要受体,它们在不同的组织中诱导不同的基因表达谱和不同的生物学途径。IPA一旦被肠上皮细胞吸收,释放到循环系统,可显著影响免疫、心血管、神经和胃肠道系统。此外,IPA已被发现在细胞水平上具有抑制氧化应激损伤和防止促炎细胞因子合成的积极作用。许多研究都强调了IPA的抗氧化、抗炎、抗癌和神经保护作用。因此,IPA的失调会导致代谢综合征、炎症、癌症和神经精神疾病等疾病。本文综述了吲哚-3-丙酸通过PXR和AhR功能的最新研究进展,概述了其分子信号通路及其与多种疾病的关系。
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引用次数: 0
Corrigendum to “From lipids to glucose: Investigating the role of dyslipidemia in the risk of insulin resistance” [J. Steroid Biochem. Mol. Biol. 250 (2025) 106744] “从脂质到葡萄糖:血脂异常在胰岛素抵抗风险中的作用研究”[J]。类固醇生物化学。中华生物医学工程学报,2009(5):344 - 344。
IF 2.5 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-10-10 DOI: 10.1016/j.jsbmb.2025.106876
Mahtab Jahdkaran, Mohammad Sistanizad
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引用次数: 0
Canine aldo-keto reductase 1C3 (AKR1C3/PGFS) exhibits 17β/20α-hydroxysteroid dehydrogenase activity and is inhibited by trilostane 犬醛酮还原酶1C3 (AKR1C3/PGFS)具有17β/20α-羟基类固醇脱氢酶活性,可被三叶甾烷抑制。
IF 2.5 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-10-06 DOI: 10.1016/j.jsbmb.2025.106874
Satoshi Endo , Riri Hayashi , Yutaro Nakada , Yudai Kudo , Yoshifumi Morikawa , Yuji Sakai , Koichi Suenami , Naohito Abe , Toshiyuki Matsunaga , Akira Hara , Hiroshi Ueda
Most members of the aldo-keto reductase (AKR) 1 C subfamily are hydroxysteroid dehydrogenases (HSDs), and their numbers are more than four in many individual mammals. In contrast, there is only one gene for the AKR1C protein (AKR1C3) in dogs, which have been used as a preclinical model for human biomedical research. Here, we report that dog AKR1C3 (known as prostaglandin-F synthase) catalyzes the conversion of the 17-keto group of estrone, 4- and 5-androstenes, and 5α-androstanes to their 17β-hydroxy-metabolites with NADPH as a coenzyme. Dog AKR1C3 also exhibited 20α-HSD activity toward 20-keto-C21-steroids (deoxycorticosterone, its 5α-dihydro- and 5α-tetrahydro-derivatives, and progesterone), but, notably, did not display 3-ketosteroid reductase activity. Additionally, dog AKR1C3 reduced various nonsteroidal carbonyl compounds including endogenous 4-oxo-2-nonenal, all-trans-retinal, and isatin, of which isatin was the most excellent substrate. In the reverse reaction, the enzyme weakly oxidized 17β- and 20α-hydroxysteroids and some alicyclic alcohols. Further site-directed mutagenesis study revealed that residue M55 is responsible for the lack of 3-ketosteroid reductase activity. The enzyme was inhibited by flavonoids, nonsteroidal anti-inflammatory drugs, bile acids, benzbromarone, abiraterone, and trilostane, of which trilostane inhibited most potently (IC50 0.30 µM), and its inhibition was uncompetitive and competitive with respect to the substrates in the forward and reverse reactions, respectively. Thus, dog AKR1C3 may play a role in the metabolism of steroid hormones (as a reductive 17β/20α-HSD) and nonsteroidal carbonyl compounds, and is a novel target of trilostane that is used to treat Cushing’s disease in dogs.
醛酮还原酶(AKR) 1C亚家族的大多数成员是羟基类固醇脱氢酶(HSDs),在许多个体哺乳动物中其数量超过4个。相比之下,狗的AKR1C蛋白只有一个基因(AKR1C3),已被用作人类生物医学研究的临床前模型。在这里,我们报道狗AKR1C3(称为前列腺素- f合成酶)在NADPH作为辅酶的作用下催化17-酮组雌酮、4-和5-雄烯和5α-雄烯转化为17- β-羟基代谢物。狗AKR1C3对20-酮- c21类固醇(脱氧皮质酮及其5α-二氢和5α-四氢衍生物和孕酮)也表现出20α-HSD活性,但值得注意的是,没有表现出3-酮类固醇还原酶活性。此外,狗AKR1C3还原了多种非甾体羰基化合物,包括内源性4-氧-2-壬烯醛、全反式视网膜和isatin,其中isatin是最优秀的底物。在逆反应中,酶弱氧化17β-和20α-羟基类固醇和一些脂环醇。进一步的定点诱变研究表明,残基M55是导致3-酮类固醇还原酶活性缺乏的原因。黄酮类化合物、非甾体抗炎药、胆汁酸、苯溴马隆、阿比特龙和三洛烷对该酶均有抑制作用,其中三洛烷的抑制作用最强(IC50为0.30µM),其对正向反应底物的抑制作用为非竞争性,对逆向反应底物的抑制作用为竞争性。因此,犬AKR1C3可能在类固醇激素(作为还原性17β/20α-HSD)和非甾体羰基化合物的代谢中发挥作用,并且是用于治疗犬库欣病的三叶烷的新靶点。
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引用次数: 0
Advancements in understanding the role and mechanisms of mitochondria in diabetes: A comprehensive review 线粒体在糖尿病中的作用和机制研究进展综述
IF 2.5 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-10-06 DOI: 10.1016/j.jsbmb.2025.106875
Xia Ge , Min Ye , Aihua Fei , Qingping Zhang , Aihong Yuan
Diabetes mellitus is a global health crisis with a rising prevalence attributed to complex interactions of genetic, lifestyle, and environmental factors. This comprehensive review delves into the pivotal role of mitochondrial dysfunction in the onset and progression of diabetes. It outlines how defects in mitochondrial oxidative phosphorylation, increased free radical production, and mitochondrial DNA damage contribute to insulin resistance, β-cell apoptosis, and systemic metabolic dysfunctions. The review highlights the critical roles of mitochondria in energy metabolism, oxidative balance, and the interplay of genetic and environmental factors in diabetes. It also emphasizes the association of impaired mitochondrial function with various diabetes-related complications and organ-specific diseases, underscoring the urgent need for innovative therapeutic strategies. Potential interventions discussed include pharmacological agents promoting mitochondrial biogenesis and enhancing mitochondrial dynamics, alongside dietary and lifestyle modifications that support mitochondrial function and overall metabolic health. The review calls for intensified research into mitochondrial mechanisms and their therapeutic targets, advocating for comprehensive clinical trials and support from medical and governmental institutions to advance diabetes management strategies centered on mitochondrial health.
糖尿病是一种全球性的健康危机,由于遗传、生活方式和环境因素的复杂相互作用,其患病率不断上升。这篇综合综述深入研究了线粒体功能障碍在糖尿病发病和进展中的关键作用。它概述了线粒体氧化磷酸化缺陷、自由基产生增加和线粒体DNA损伤如何导致胰岛素抵抗、β细胞凋亡和全身代谢功能障碍。这篇综述强调了线粒体在糖尿病的能量代谢、氧化平衡以及遗传和环境因素的相互作用中的关键作用。它还强调了线粒体功能受损与各种糖尿病相关并发症和器官特异性疾病的关联,强调了迫切需要创新的治疗策略。讨论的潜在干预措施包括促进线粒体生物发生和增强线粒体动力学的药理学药物,以及支持线粒体功能和整体代谢健康的饮食和生活方式改变。该综述呼吁加强对线粒体机制及其治疗靶点的研究,倡导全面的临床试验和医疗和政府机构的支持,以推进以线粒体健康为中心的糖尿病管理策略。
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引用次数: 0
Androgen receptor inhibitory activity of dihydrocapsaicin: Insights from in vitro, in vivo and in silico studies 二氢辣椒素的雄激素受体抑制活性:来自体外、体内和计算机研究的见解
IF 2.5 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-10-02 DOI: 10.1016/j.jsbmb.2025.106872
Jingqi Zhao , Xue Liu , Yong Pang , Haoge Luo , Jie Zhang , Chen Shao
As a natural capsaicinoid from Capsicum annuum L., dihydrocapsaicin is well known for its anti-obesity property by reducing fat accumulation in adipose tissue. The androgen receptor (AR) is essential for both health and disease in humans and is the main focus for prostate cancer treatment. This study seeks to explore how dihydrocapsaicin inhibits the AR in human prostate cancer cell lines, aiming to offer a new natural product-derived AR inhibitor for the clinical management of prostate-related conditions. At first, it was observed that dihydrocapsaicin can induce proliferation suppression in human prostate cancer cells by hindering the cell cycle at the G0/G1 phase. In addition, dihydrocapsaicin probably inhibited AR activity by blocking its movement from the cytoplasm to the nucleus through binding to the AR-LBD, highlighting its potential as an effective inhibitor. From a mechanistic perspective, dihydrocapsaicin facilitated AR release from a stabilizing chaperone complex and enhanced its ubiquitination by E3 ligases, resulting in AR partial degradation via the ubiquitin-proteasome pathway. Our study on the molecular mechanisms behind dihydrocapsaicin's inhibitory effects on the AR revealed that it not only hindered the growth of prostate cancer cells but also reduced tumor growth in vivo. These results offer both experimental evidence and a theoretical basis for the thorough development of AR inhibitors, emphasizing dihydrocapsaicin's potential for application in functional foods or nutritional supplements targeting prostatic disorders.
作为一种天然辣椒素,二氢辣椒素通过减少脂肪组织中的脂肪积累而具有抗肥胖的特性。雄激素受体(AR)对人类的健康和疾病都至关重要,是前列腺癌治疗的主要焦点。本研究旨在探索二氢辣椒素如何抑制人前列腺癌细胞系的AR,旨在为前列腺相关疾病的临床治疗提供一种新的天然产物衍生的AR抑制剂。首先,我们观察到二氢辣椒素可以通过阻碍细胞周期在G0/G1期诱导人前列腺癌细胞的增殖抑制。此外,二氢辣椒素可能通过与AR- lbd结合,阻断AR从细胞质向细胞核的运动,从而抑制AR活性,这突出了其作为一种有效抑制剂的潜力。从机制角度看,二氢辣椒素促进AR从稳定伴侣复合物中释放,并通过E3连接酶增强其泛素化,导致AR通过泛素-蛋白酶体途径部分降解。我们对二氢辣椒素对AR抑制作用的分子机制的研究表明,二氢辣椒素在体内不仅能抑制前列腺癌细胞的生长,还能抑制肿瘤的生长。这些结果为AR抑制剂的深入开发提供了实验证据和理论基础,强调了二氢辣椒素在针对前列腺疾病的功能食品或营养补充剂中的应用潜力。
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引用次数: 0
Quantum biochemistry characterization of representative conformations of the sex hormone-binding globulin monomer bound to estradiol, dihydrotestosterone and testosterone 结合雌二醇、二氢睾酮和睾酮的性激素结合球蛋白单体的典型构象的量子生物化学表征
IF 2.5 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-10-01 DOI: 10.1016/j.jsbmb.2025.106873
André Hadad , Victor L.B. França , Jackson L. Amaral , Hernandes F. Carvalho , Valder N. Freire
The transport of sex steroid hormones in the plasma is largely mediated by sex-hormone binding globulin (SHBG). SHBG is a functional homodimer, meaning it can bind two sex hormones with similar affinities. This binding occurs through a complex allosteric mechanism. This globulin plays a pivotal role in regulating the availability of sex hormones within target tissues and cells. Given the established correlation between SHBG and various pathological disorders, there has been increasing interest in characterizing the interactions between SHBG and hormones as well as in identifying potential inhibitors or modulators of the SHBG function. In this regard, the present study aims to provide novel insights into the binding of SHBG with estradiol (EST), dihydrotestosterone (DHT), and testosterone (TES). To this end, molecular docking, molecular dynamics, and quantum mechanics were employed here. The analysis of representative conformations of the highest and lowest interaction energies revealed a high degree of similarity in the binding sites. The SHBG::TES interaction, for which structural data are lacking, exhibited a high degree of structural and energetic similarity to the SHBG::EST and SHBG::DHT complexes. Quantum mechanics calculations demonstrated the following order of theoretical binding affinity, from the highest to lowest: SHBG::DHT > SHBG::EST > SHBG::TES. Furthermore, SER42, PHE67, MET107, and MET139 exhibited the lowest interaction energies, thereby emphasizing the critical role of these residues in SHBG coupling and steroid hormone transport. The energetic description of these complexes contributes to a deeper understanding of steroid hormone transport and provides new insights for targeting SHBG in drug discovery.
性类固醇激素在血浆中的转运主要由性激素结合球蛋白(SHBG)介导。SHBG是一种功能性同型二聚体,这意味着它可以结合两种具有相似亲和力的性激素。这种结合通过复杂的变构机制发生。这种球蛋白在调节目标组织和细胞内性激素的可用性方面起着关键作用。鉴于SHBG与各种病理疾病之间的相关性,人们对表征SHBG与激素之间的相互作用以及确定SHBG功能的潜在抑制剂或调节剂的兴趣越来越大。在这方面,本研究旨在为SHBG与雌二醇(EST)、二氢睾酮(DHT)和睾酮(TES)的结合提供新的见解。为此,本文运用了分子对接、分子动力学和量子力学等方法。对最高和最低相互作用能的代表性构象的分析表明,它们的结合位点高度相似。SHBG::TES相互作用与SHBG::EST和SHBG::DHT复合物表现出高度的结构和能量相似性,但缺乏结构数据。量子力学计算表明,理论结合亲合力由高到低依次为:SHBG::DHT >; SHBG::EST >; SHBG::TES。此外,SER42、PHE67、MET107和MET139表现出最低的相互作用能,从而强调了这些残基在SHBG偶联和类固醇激素运输中的关键作用。这些复合物的能量描述有助于更深入地了解类固醇激素的转运,并为靶向SHBG的药物发现提供新的见解。
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引用次数: 0
Evaluation of endogenous steroid sulfates and glucuronides in urine after oral and transdermal administration of testosterone. Part I: Male participants 口服和经皮给药睾酮后尿液中内源性类固醇硫酸盐和葡萄糖醛酸苷的评价。第一部分:男性参与者。
IF 2.5 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-09-29 DOI: 10.1016/j.jsbmb.2025.106870
Sandra Pfeffer , Günter Gmeiner , Nenad Dikic , Marija Andjelkovic , Guro Forsdahl
The detection of the performance-enhancing drug testosterone (T) remains a significant challenge in doping control analysis. Longitudinal monitoring through the steroidal Athlete Biological Passport (ABP) is a valuable tool for T detection, but further research is needed to enhance its efficacy. Phase II metabolites of endogenous anabolic androgenic steroids (EAAS), including glucuronides and sulfates, have gained increasing interest as potential new biomarkers for the steroidal ABP. Notably, sulfate metabolites have demonstrated higher sensitivity to oral, transdermal, and intramuscular T administration, with extended detection windows compared to traditional biomarkers. However, before incorporating these promising biomarkers into urinary steroid profiling, it is essential to address the metabolic variations associated with different T administration methods, as well as differences related to ethnicity and sex. In this part of the study, we investigate the effects of oral and transdermal T administration on conventional biomarkers and phase II EAAS metabolites in male participants. Sulfate ratios indicated higher sensitivity to multiple administrations of testosterone undecanoate (TU) tablets and T gel, significantly prolonging detection times compared to conventional steroid profile biomarkers. Specifically, sulfate ratios such as androsterone sulfate (AS)/testosterone sulfate (TS) and epiandrosterone sulfate (EpiAS)/TS enabled detection for an average of 20 days following the last oral TU dose and at least 16 days after the last transdermal T application. These findings provide further evidence that incorporating sulfate EAAS metabolites into steroid profiling enhances detection capabilities. For advanced T doping detection, sulfate metabolites should be considered essential biomarkers in the steroid profile.
提高成绩的药物睾酮(T)的检测仍然是兴奋剂控制分析中的一个重大挑战。通过类固醇运动员生物护照(ABP)进行纵向监测是一种有价值的T检测工具,但需要进一步研究以提高其有效性。内源性合成代谢雄激素类固醇(EAAS)的II期代谢物,包括葡萄糖醛酸酯和硫酸盐,作为类固醇ABP的潜在新生物标志物越来越受到关注。值得注意的是,硫酸盐代谢物对口服、透皮和肌内给药具有更高的敏感性,与传统生物标志物相比,具有更大的检测窗口。然而,在将这些有前景的生物标志物纳入尿类固醇分析之前,有必要解决与不同T给药方法相关的代谢变化,以及与种族和性别相关的差异。在这部分研究中,我们研究了口服和透皮给药T对男性参与者常规生物标志物和II期EAAS代谢物的影响。硫酸盐比表明对多次给药十一酸睾酮(TU)片和T凝胶的敏感性更高,与传统的类固醇生物标志物相比,显著延长了检测时间。具体来说,硫酸雄酮(as)/硫酸睾酮(TS)和硫酸表雄酮(EpiAS)/TS等硫酸盐比率使最后一次口服TU剂量后平均20天和最后一次透皮T应用后至少16天的检测成为可能。这些发现提供了进一步的证据,将硫酸盐EAAS代谢物纳入类固醇谱分析可以提高检测能力。对于高级T兴奋剂检测,硫酸盐代谢物应被认为是类固醇谱中必不可少的生物标志物。
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引用次数: 0
17β-estradiol (E2) increases ciliary beat frequency via membrane estrogen receptor β 17β-雌二醇(E2)通过膜雌激素受体β增加纤毛搏动频率。
IF 2.5 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-09-29 DOI: 10.1016/j.jsbmb.2025.106871
Kouta Noriyama , Nobuhisa Todo , Nobuyo Tamiya , Masaki Shigeta , Yuki Toda , Shigekuni Hosogi , Eishi Ashihara
Estrogen receptors (ER) are expressed in various tissues, including the lungs and other respiratory tissues, independent of sex. However, the role of estrogen in the respiratory tract is not fully understood. Airway ciliated cells are important for mucociliary clearance (MCC), which protects the human airways from foreign substances, and ciliary beat frequency (CBF) is an important indicator of MCC efficiency. Although the function of estrogen in airway smooth muscle cells and goblet cells has been studied, its effects on airway ciliated cells remain unclear. Here, we investigated the effect of 17β-estradiol (E2) on CBF. E2 increased CBF and intracellular cAMP concentration ([cAMP]i) in murine airway ciliated cells, whereas it had no effect on intracellular Ca2 + concentration and intracellular pH. The selective ERβ inhibitor PHTPP suppressed the E2-induced increase in CBF and [cAMP]i. β-Estradiol 6-(O-carboxymethyl)oxime: bovine serum albumin conjugate, which activates membrane ER, also increased CBF and [cAMP]i in murine airway ciliated cells, and PHTPP suppressed these effects. The results of this study indicate that E2 increases CBF by increasing [cAMP]i via membrane ERβ in murine airway ciliated cells. These results provide new insight into the function of estrogen in airway ciliated cells.
雌激素受体(ER)在各种组织中表达,包括肺和其他呼吸组织,与性别无关。然而,雌激素在呼吸道中的作用尚不完全清楚。气道纤毛细胞在粘膜纤毛清除(mucociliary clearance, MCC)中起着重要的作用,而纤毛搏动频率(ciliary beat frequency, CBF)是MCC效率的重要指标。虽然雌激素在气道平滑肌细胞和杯状细胞中的作用已被研究,但其对气道纤毛细胞的影响尚不清楚。在这里,我们研究了17β-雌二醇(E2)对CBF的影响。E2增加小鼠气道纤毛细胞的CBF和细胞内cAMP浓度([cAMP]i),而对细胞内Ca2+浓度和细胞内ph没有影响。选择性ERβ抑制剂PHTPP抑制E2诱导的CBF和[cAMP]i的增加。β-雌二醇6-(o -羧甲基)肟:牛血清白蛋白偶联物,激活膜内质网,也增加小鼠气道纤毛细胞的CBF和[cAMP]i,而PHTPP抑制了这些作用。本研究结果表明,E2通过小鼠气道纤毛细胞膜ERβ增加[cAMP]i,从而增加CBF。这些结果为雌激素在气道纤毛细胞中的作用提供了新的认识。
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引用次数: 0
Inhibition of 14–3-3 protein enhances steroid hormone production and oxidative stress in mouse ovary: Implications for apoptosis regulation 14-3-3蛋白抑制小鼠卵巢类固醇激素产生和氧化应激:凋亡调控的意义。
IF 2.5 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-09-28 DOI: 10.1016/j.jsbmb.2025.106869
Shatrudhan Upadhyay , Namrata Dubey , Aanya Singh
The ovary is a primary reproductive organ where the fine balance between steroidogenesis, oxidative stress, and apoptosis governs female reproductive health. A highly conserved protein, 14–3–3, is known to influence steroid biosynthesis, redox balance, and cell survival; however, its integrative role in ovarian physiology remains poorly defined. This study investigated the consequences of pharmacological inhibition of 14–3–3 protein using BV02 in in vitro cultured mouse ovaries. Immunohistochemical analysis revealed strong expression of 14–3–3 in granulosa cells, with moderate expression in oocytes and theca cells. In the BV02-treated ovary (100 μM), there was significant elevation in the levels of ovarian progesterone, testosterone, and estradiol, indicating enhanced steroidogenesis. However, the treated ovaries showed decreased activity of catalase and superoxide dismutase (SOD), along with increased lipid peroxidation (TBARS), indicating increased oxidative stress. Western blot analysis showed downregulation of the anti-apoptotic protein Bcl-2 together with elevated levels of the pro-apoptotic protein Caspase-3, signifying a molecular shift toward apoptosis. Correlation analysis further established strong associations (p < 0.05) between oxidative stress markers and apoptotic regulators, highlighting a mechanistic link between impaired antioxidant defenses and apoptosis. These findings reveal that 14–3–3 protein acts as a dual regulator of ovarian physiology by restraining steroid hormone production in addition to maintaining redox balance and cell survival. Disruption of this equilibrium may lead to pathological states such as polycystic ovary syndrome (PCOS) and ovarian cancer. Thus, this study provides novel mechanistic insights into the regulatory role of 14–3–3 protein in the ovary and underscores its potential as a therapeutic target in reproductive disorders.
卵巢是主要生殖器官,甾体生成、氧化应激和细胞凋亡之间的良好平衡支配着女性生殖健康。已知高度保守的14-3-3蛋白影响类固醇生物合成、氧化还原平衡和细胞存活;然而,其在卵巢生理中的综合作用仍不明确。本研究探讨了BV02对体外培养小鼠卵巢14-3-3蛋白的药理抑制作用。免疫组化分析显示14-3-3在颗粒细胞中强表达,在卵母细胞和卵泡细胞中有中等表达。在bv02处理的卵巢(100μM)中,卵巢黄体酮、睾酮和雌二醇水平显著升高,表明类固醇生成增强。然而,处理后的卵巢过氧化氢酶和超氧化物歧化酶(SOD)活性下降,脂质过氧化(TBARS)升高,表明氧化应激增加。Western blot分析显示,抗凋亡蛋白Bcl-2下调,促凋亡蛋白Caspase-3水平升高,表明细胞向凋亡的分子转移。相关分析进一步确立了强关联(p
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引用次数: 0
Potential contribution of oxysterols and cholestanol in the vascular inflammatory process occurring in patients with Behcet’s disease 氧化甾醇和胆固醇在白塞病患者血管炎症过程中的潜在作用
IF 2.5 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-09-24 DOI: 10.1016/j.jsbmb.2025.106868
Meriam Messedi , Wassim Guidara , Mohammad Samadi , Fatma Makni-Ayadi , Gérard Lizard
Oxysterols, which are cholesterol oxidation products, can be generated by either enzymatic reactions and/or reactive oxygen species (ROS). Oxysterols considered to play key roles in health and diseases, have several physiological and biological activities. They exhibit strong immune-modulatory, pro-inflammatory and pro-oxidant properties supporting that some of them are involved in the pathogenesis of numerous chronic diseases associated with inflammation mainly cardiovascular and neurological diseases. Some oxysterols, especially those oxidized on the lateral chain, can bind to nuclear receptors such as the liver X receptors (LXR) involved in the control of transcriptional programs that regulate cell metabolism. Since Behçet’s disease (BD) is an acute systemic vasculitis leading to severe vascular damage, recent studies deem that BD could be considered a chronic immune inflammatory disease. Although BD constitutes a separate disease entity, it is still underdiagnosed, and no treatments are available. Whereas the pathophysiology of BD is not well known, the vasculitis is common to its different etiologies. Therefore, as several oxysterols are known to contribute to vascular damage, these molecules were analyzed in the plasma of BD patients. Noteworthy, altered oxysterol profiles were observed in BD patients from Tunisia. These patients were characterized by abnormal levels of 7-ketocholesterol (7KC), 25-hydroxycholesterol (25-OHC), 27-hydroxycholesterol (27-OHC), and cholestane-3β,5α,6β-triol (CT). Thus, 7KC and 25-OHC were decreased whereas 27-OHC and CT were increased. Cholesterol undergoes a rapid non enzymatic oxidation to form cholesterol-5α,6α-epoxide and cholesterol-5β,6β-epoxide, and these molecules are then converted by cholesterol 5,6 epoxide hydrolase (ChEH) and/or ROS to CT. In addition, cholestanol level was increased. Therefore, there are evidence of altered oxysterol profiles and cholestanol level in BD patients. It is proposed that oxysterols and cholestanol could be used as biomarkers to characterize BD disease i) to distinguish different forms of this disease and of its outcome, and ii) to identify efficient treatments. Based on the abnormal levels of oxysterols and cholestanol observed in the plasma of BD Tunisian patients, current data support that a rupture of oxysterol homeostasis and perturbations of cholesterol metabolism, suggested by increased cholestanol level, could both contribute to the pathophysiology of Behçet’s disease.
氧甾醇是胆固醇氧化产物,可以通过酶促反应和/或活性氧(ROS)产生。氧化甾醇被认为在健康和疾病中起着关键作用,具有多种生理和生物活性。它们表现出强大的免疫调节、促炎和促氧化特性,支持其中一些参与许多与炎症相关的慢性疾病的发病机制,主要是心血管和神经系统疾病。一些氧化甾醇,特别是那些在侧链上氧化的,可以结合核受体,如肝脏X受体(LXR),参与控制调节细胞代谢的转录程序。由于behet病(BD)是一种急性全身性血管炎,导致严重的血管损伤,近年来的研究认为BD可被认为是一种慢性免疫性炎症性疾病。虽然双相障碍是一种独立的疾病,但它仍然没有得到充分的诊断,也没有治疗方法。虽然双相障碍的病理生理学尚不清楚,但血管炎的病因不同。因此,由于已知几种氧甾醇会导致血管损伤,我们对BD患者血浆中的这些分子进行了分析。值得注意的是,在突尼斯的BD患者中观察到改变的羟甾醇谱。这些患者的特征是7-酮胆固醇(7KC)、25-羟基胆固醇(25-OHC)、27-羟基胆固醇(27-OHC)和胆固醇-3β,5α,6β-三醇(CT)水平异常。7KC和25-OHC降低,27-OHC和CT升高。胆固醇经过快速的非酶氧化形成胆固醇-5α,6α-环氧化物和胆固醇-5β,6β-环氧化物,然后这些分子被胆固醇- 5,6环氧化物水解酶(ChEH)和/或ROS转化为CT。5α-胆甾醇(胆甾醇-3β-醇)水平升高。因此,有证据表明,BD患者的羟甾醇谱和5α-胆固醇水平发生了改变。我们提出,羟甾醇和5α-胆固醇可以作为生物标志物来表征BD疾病i)区分这种疾病的不同形式及其结局,ii)确定有效的治疗方法。根据突尼斯BD患者血浆中氧甾醇和5α-胆固醇水平的异常,目前的数据支持,5α-胆固醇水平升高所提示的氧甾醇稳态的破坏和胆固醇代谢的紊乱都可能参与behet病的病理生理。
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Journal of Steroid Biochemistry and Molecular Biology
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