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Control of sodium appetite by hindbrain aldosterone-sensitive neurons 后脑醛固酮敏感神经元控制钠食欲
IF 3.8 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-26 DOI: 10.1016/j.mce.2024.112323
Ahmet Kuralay , Miriam C. McDonough , Jon M. Resch

Mineralocorticoids play a key role in hydromineral balance by regulating sodium retention and potassium wasting. Through favoring sodium, mineralocorticoids can cause hypertension from fluid overload under conditions of hyperaldosteronism, such as aldosterone-secreting tumors. An often-overlooked mechanism by which aldosterone functions to increase sodium is through stimulation of salt appetite. To drive sodium intake, aldosterone targets neurons in the hindbrain which uniquely express 11β-hydroxysteroid dehydrogenase type 2 (HSD2). This enzyme is a necessary precondition for aldosterone-sensing cells as it metabolizes glucocorticoids – preventing their activation of the mineralocorticoid receptor. In this review, we will consider the role of hindbrain HSD2 neurons in regulating sodium appetite by discussing HSD2 expression in the brain, regulation of hindbrain HSD2 neuron activity, and the circuitry mediating the effects of these aldosterone-sensitive neurons. Reducing the activity of hindbrain HSD2 neurons may be a viable strategy to reduce sodium intake and cardiovascular risk, particularly for conditions of hyperaldosteronism.

矿皮质激素通过调节钠潴留和钾消耗,在水矿物质平衡中发挥着关键作用。在醛固酮分泌过多(如分泌醛固酮的肿瘤)的情况下,矿物质皮质激素通过增加钠,可导致体液超负荷引起高血压。醛固酮增加钠含量的一个经常被忽视的机制是刺激食盐欲。为了促进钠的摄入,醛固酮以后脑中独特表达 11β- 羟基类固醇脱氢酶 2 型(HSD2)的神经元为目标。这种酶是醛固酮传感细胞的必要先决条件,因为它能代谢糖皮质激素,阻止其激活矿质类固醇受体。在本综述中,我们将通过讨论 HSD2 在大脑中的表达、后脑 HSD2 神经元活性的调节以及介导这些醛固酮敏感神经元效应的回路,探讨后脑 HSD2 神经元在调节钠食欲中的作用。降低后脑 HSD2 神经元的活性可能是减少钠摄入量和心血管风险的一种可行策略,尤其是对于醛固酮过多症。
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引用次数: 0
Downregulation of CASC15 attenuates the symptoms of polycystic ovary syndrome by affecting granulosa cell proliferation and regulating ovarian follicular development 通过影响颗粒细胞增殖和调节卵泡发育,下调 CASC15 可减轻多囊卵巢综合征的症状。
IF 3.8 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-26 DOI: 10.1016/j.mce.2024.112322
Tongwei Zhang , Junnan Fang , Jingyi Hu , Yue Kong , Ran Jiang , Huihui Wang , Guang Yang , Guidong Yao

Polycystic ovary syndrome (PCOS) is a type of follicular dysplasia with an unclear pathogenesis, posing certain challenges in its diagnosis and treatment. Cancer susceptibility candidate 15 (CASC15), a long non-coding RNA closely associated with tumour development, has been implicated in PCOS onset and development. Therefore, this study aimed to investigate the molecular mechanisms underlying PCOS by downregulating CASC15 expression in both in vitro and in vivo models. We explored the potential regulatory relationship between CASC15 expression and PCOS by examining cell proliferation, cell cycle dynamics, cell autophagy, steroid hormone secretion capacity, and overall ovarian function in mice. We found that CASC15 expression in granulosa cells derived from patients with PCOS was significantly higher than those of the normal group (P < 0.001). In vitro experiments revealed that downregulating CASC15 significantly inhibited cell proliferation, promoted apoptosis, induced G1-phase cell cycle arrest, and influenced cellular autophagy levels. Moreover, downregulating CASC15 affected the follicular development process in newborn mouse ovaries. In vivo studies in mice demonstrated that disrupting CASC15 expression improved PCOS-related symptoms such as polycystic changes and hyperandrogenism, and significantly affected ovulation induction and embryo implantation in pregnant mice. Overall, CASC15 was highly expressed in granulosa cells of patients with PCOS and its downregulation improved PCOS-related symptoms by influencing granulosa cell function and follicular development in mice.

多囊卵巢综合征(PCOS)是一种卵泡发育不良,发病机制尚不清楚,给诊断和治疗带来了一定的挑战。癌症易感性候选基因 15(CASC15)是一种与肿瘤发生密切相关的长非编码 RNA,它与多囊卵巢综合征的发病和发展有一定关系。因此,本研究旨在通过在体外和体内模型中下调 CASC15 的表达来研究 PCOS 的分子机制。我们通过检测小鼠的细胞增殖、细胞周期动态、细胞自噬、类固醇激素分泌能力和整体卵巢功能,探索了 CASC15 表达与多囊卵巢综合征之间的潜在调控关系。我们发现,CASC15 在多囊卵巢综合症患者颗粒细胞中的表达明显高于正常组(P<0.05)。
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引用次数: 0
Replenishment of TCA cycle intermediates and long-noncoding RNAs regulation in breast cancer 乳腺癌中 TCA 循环中间产物的补充和长非编码 RNA 的调控。
IF 3.8 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-25 DOI: 10.1016/j.mce.2024.112321
Xuewei Zheng , ShunShun Zhang , HaoDi Ma , Yirui Dong , Jiayu Zheng , Li Zeng , Jiangbo Liu , Yanzhenzi Dai , Qinan Yin

The tricarboxylic acid (TCA) cycle is an essential interface that coordinates cellular metabolism and is as a primary route determining the fate of a variety of fuel sources, including glucose, fatty acid and glutamate. The crosstalk of nutrients replenished TCA cycle regulates breast cancer (BC) progression by changing substrate levels-induced epigenetic alterations, especially the methylation, acetylation, succinylation and lactylation. Long non-coding RNAs (lncRNA) have dual roles in inhibiting or promoting energy reprogramming, and so altering the metabolic flux of fuel sources to the TCA cycle, which may regulate epigenetic modifications at the cellular level of BC. This narrative review discussed the central role of the TCA cycle in interconnecting numerous fuels and the induced epigenetic modifications, and the underlying regulatory mechanisms of lncRNAs in BC.

三羧酸(TCA)循环是协调细胞新陈代谢的重要界面,是决定葡萄糖、脂肪酸和谷氨酸等多种燃料来源去向的主要途径。营养物质补充的 TCA 循环通过改变底物水平引起的表观遗传学改变,特别是甲基化、乙酰化、琥珀酰化和乳酰化,从而调节乳腺癌(BC)的进展。长非编码 RNA(lncRNA)具有双重作用,可抑制或促进能量重编程,从而改变 TCA 循环燃料源的代谢通量,这可能会调控 BC 细胞水平的表观遗传学改变。这篇叙述性综述讨论了TCA循环在连接众多燃料和诱导表观遗传修饰方面的核心作用,以及lncRNAs在BC中的潜在调控机制。
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引用次数: 0
Sexually dimorphic control of aggression by androgen signaling in a cichlid 慈鲷体内雄性激素信号对攻击行为的性双态控制
IF 3.8 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-24 DOI: 10.1016/j.mce.2024.112319
Lillian R. Jackson , Beau A. Alward

Innate social behaviors like aggression are modulated by sex steroid hormones such as androgens and estrogens. However, we know little about how the same hormone regulates similar behaviors in both sexes. We investigated the role of androgenic signaling in the regulation of aggression in Astatotilapia burtoni, a social fish in which males and females perform similar aggressive behaviors. We used androgen receptor (AR) α knockout (KO) animals for this study since this gene was recently shown to be required for male-typical aggression and mating. Surprisingly, ARα KO females did not show deficits in aggression. We also determined that females lacking the other AR, ARβ, showed normal levels of aggression. Blocking both ARs pharmacologically confirmed that neither AR is necessary for aggression in females. However, ARα KO males showed clear deficits in attacks. Thus, in A. burtoni there appears to be a sexual dimorphism in the role of ARα in the control of aggression.

攻击等天生的社会行为受雄激素和雌激素等性甾体激素的调节。然而,我们对同一种激素如何调节两性的类似行为知之甚少。我们研究了雄激素信号在调控布氏鲶(Astatotilapia burtoni)攻击行为中的作用,布氏鲶是一种社会性鱼类,雌雄都有类似的攻击行为。我们使用雄激素受体(AR)α基因敲除(KO)动物进行这项研究,最近的研究表明雄激素受体α是雄性典型攻击行为和交配所必需的。令人惊讶的是,ARα KO雌性动物并没有表现出攻击性缺陷。我们还发现,缺乏另一种AR(ARβ)的雌性也表现出正常水平的攻击性。通过药理学方法阻断这两个AR,证实了雌性动物的攻击行为都不需要AR。然而,ARα KO雄性在攻击方面表现出明显的缺陷。因此,在伯顿猿中,ARα在控制攻击方面的作用似乎存在性二态性。
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引用次数: 0
Activated AMP-protein kinase (pAMPK) is overexpressed in human somatotroph pituitary adenomas 活化的 AMP 蛋白激酶(pAMPK)在人类嗜体细胞垂体腺瘤中过度表达。
IF 3.8 3区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-20 DOI: 10.1016/j.mce.2024.112318
Mariana Ferreira Bizzi , Juliana Beaudette Drummond , Sergio Veloso Brant Pinheiro , Eduardo Paulino , Stanley Almeida Araújo , Beatriz Santana Soares , Alexandre V. Giannetti , Júnia Ribeiro de Oliveira Longo Schweizer , Sayka Barry , Márta Korbonits , Antonio Ribeiro-Oliveira

Introduction

AMPK (AMP-activated protein kinase) is an enzyme that acts as a metabolic sensor and regulates multiple pathways via phosphorylating proteins in metabolic and proliferative pathways. The aim of this work was to study the activated cellular AMPK (phosphorylated-AMPK at Thr172, pAMPK) levels in pituitary tumor samples from patients with sporadic and familial acromegaly, as well as in samples from normal human pituitary gland.

Methods

We studied pituitary adenoma tissue from patients with sporadic somatotroph adenomas, familial acromegaly with heterozygote germline variants in the aryl hydrocarbon receptor interacting protein (AIP) gene (p.Q164*, p.R304* and p.F269_H275dup) and autopsy from normal pituitary glands without structural alterations.

Results

Cellular levels of pAMPK were significantly higher in patients with sporadic acromegaly compared to normal pituitary glands (p < 0.0001). Tissues samples from patients with germline AIP mutations also showed higher cellular levels of pAMPK compared to normal pituitary glands. We did not observe a significant difference in cellular levels of pAMPK according to the cytokeratin (CAM5.2) pattern (sparsely or densely granulated) for tumor samples of sporadic acromegaly.

Conclusion

Our data show, for the first time in human cells, an increase of cellular levels of pAMPK in sporadic somatotropinomas, regardless of cytokeratin pattern, as well as in GH-secreting adenomas from patients with germline AIP mutations.

简介:AMPK(AMP-活化蛋白激酶)是一种作为代谢传感器的酶,通过磷酸化代谢和增殖途径中的蛋白质调节多种途径。这项工作的目的是研究散发性和家族性肢端肥大症患者垂体瘤样本以及正常人垂体样本中活化的细胞 AMPK(磷酸化-AMPK at Thr172,pAMPK)水平:我们研究了散发性嗜体细胞腺瘤患者的垂体腺瘤组织、家族性肢端肥大症患者的芳基烃受体相互作用蛋白(AIP)基因杂合子种系变异(p.Q164*、p.R304*和p.F269_H275dup)以及无结构改变的正常垂体的尸检样本:结果:与正常垂体相比,散发性肢端肥大症患者的细胞中pAMPK水平明显更高(pConclusion):我们的数据首次在人体细胞中显示,无论细胞角蛋白形态如何,散发性体细胞瘤以及来自AIP基因突变患者的GH分泌腺瘤中的pAMPK细胞水平均有所增加。
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引用次数: 0
De novo synthesis of monounsaturated fatty acids modulates exosome-mediated lipid export from human granulosa cells 单不饱和脂肪酸的新合成调节外泌体介导的人类颗粒细胞脂质输出。
IF 3.8 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-18 DOI: 10.1016/j.mce.2024.112317
Shabnam Fayezi , Sophie Oehms , Helena Wolff von Gudenberg , Maharajah Ponnaiah , Marie Lhomme , Thomas Strowitzki , Ariane Germeyer

Background

Ovarian somatic cells support the maturation and fertility of oocytes. Metabolic desaturation of fatty acids in these cells has a positive paracrine impact on the maturation of oocytes. We hypothesized that the enzyme stearoyl-CoA desaturase 1 (SCD1) in granulosa cells regulates the lipid cargo of exosomes secreted from these cells by maintaining the balance between saturated and unsaturated lipids. We investigated the effect of SCD1 on exosome lipid content in a cumulus-granulosa cell model under physiologically relevant in vitro conditions.

Methods

Non-luteinized human COV434 granulosa cells were subjected to treatment with an inhibitor of SCD1 (SCDinhib) alone, in combination with oleic acid, or under control conditions. Subsequently, the exosomes were isolated and characterized via nanoparticle tracking analysis, transmission electron microscopy, and Western blotting. We used liquid chromatography mass spectrometry to investigate the lipidomic profiles. We used quantitative PCR with TaqMan primers to assess the expression of genes involved in lipogenesis and control of cell cycle progression.

Results

A trend toward exosome production was observed with a shift toward smaller exosome sizes in cells treated with SCD1inhib. This trend reached statistical significance when SCDinhib was combined with oleic acid supplementation. SCD1 inhibition led to the accumulation of saturated omega-6 lipids in exosomes. The latter effect was reversed by oleic acid supplementation, which also improved exosome production and suppressed the expression of fatty acid synthase and Cyclin D2.

Conclusion

These findings underscore the critical role of de novo fatty acid desaturation in the regulation of the export of specific lipids through exosomes, with potential implications for controlling intercellular communication within the ovary.

背景:卵巢体细胞支持卵母细胞的成熟和生育。这些细胞中脂肪酸的代谢去饱和对卵母细胞的成熟有积极的旁分泌影响。我们假设颗粒细胞中的硬脂酰-CoA 去饱和酶 1(SCD1)通过维持饱和与不饱和脂质之间的平衡来调节这些细胞分泌的外泌体的脂质货物。我们研究了在与生理相关的体外条件下,SCD1对积液-颗粒细胞模型中外泌体脂质含量的影响:方法:对非黄体化的人 COV434 颗粒细胞单独使用 SCD1 抑制剂(SCDinhib)、与油酸联合使用或在对照条件下进行处理。随后,外泌体被分离出来,并通过纳米颗粒追踪分析、透射电子显微镜和 Western 印迹法进行表征。我们使用液相色谱质谱法研究了脂质体概况。我们使用 TaqMan 引物进行定量 PCR,以评估参与脂肪生成和控制细胞周期进程的基因的表达:结果:在使用SCD1抑制剂处理的细胞中,观察到外泌体产生的趋势,而且外泌体的体积变小。当 SCDinhib 与油酸补充剂结合使用时,这一趋势达到统计学意义。抑制 SCD1 会导致外泌体中饱和欧米加 6 脂类的积累。补充油酸可逆转后一种效应,补充油酸还能改善外泌体的生成,抑制脂肪酸合成酶和细胞周期蛋白 D2 的表达:这些发现强调了新脂肪酸脱饱和在调节特定脂质通过外泌体输出中的关键作用,对控制卵巢内的细胞间通讯具有潜在影响。
{"title":"De novo synthesis of monounsaturated fatty acids modulates exosome-mediated lipid export from human granulosa cells","authors":"Shabnam Fayezi ,&nbsp;Sophie Oehms ,&nbsp;Helena Wolff von Gudenberg ,&nbsp;Maharajah Ponnaiah ,&nbsp;Marie Lhomme ,&nbsp;Thomas Strowitzki ,&nbsp;Ariane Germeyer","doi":"10.1016/j.mce.2024.112317","DOIUrl":"10.1016/j.mce.2024.112317","url":null,"abstract":"<div><h3>Background</h3><p>Ovarian somatic cells support the maturation and fertility of oocytes. Metabolic desaturation of fatty acids in these cells has a positive paracrine impact on the maturation of oocytes. We hypothesized that the enzyme stearoyl-CoA desaturase 1 (SCD1) in granulosa cells regulates the lipid cargo of exosomes secreted from these cells by maintaining the balance between saturated and unsaturated lipids. We investigated the effect of SCD1 on exosome lipid content in a cumulus-granulosa cell model under physiologically relevant in vitro conditions.</p></div><div><h3>Methods</h3><p>Non-luteinized human COV434 granulosa cells were subjected to treatment with an inhibitor of SCD1 (SCDinhib) alone, in combination with oleic acid, or under control conditions. Subsequently, the exosomes were isolated and characterized via nanoparticle tracking analysis, transmission electron microscopy, and Western blotting. We used liquid chromatography mass spectrometry to investigate the lipidomic profiles. We used quantitative PCR with TaqMan primers to assess the expression of genes involved in lipogenesis and control of cell cycle progression.</p></div><div><h3>Results</h3><p>A trend toward exosome production was observed with a shift toward smaller exosome sizes in cells treated with SCD1inhib. This trend reached statistical significance when SCDinhib was combined with oleic acid supplementation. SCD1 inhibition led to the accumulation of saturated omega-6 lipids in exosomes. The latter effect was reversed by oleic acid supplementation, which also improved exosome production and suppressed the expression of fatty acid synthase and Cyclin D2.</p></div><div><h3>Conclusion</h3><p>These findings underscore the critical role of de novo fatty acid desaturation in the regulation of the export of specific lipids through exosomes, with potential implications for controlling intercellular communication within the ovary.</p></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0303720724001734/pdfft?md5=4f3b36da263703d7053f5197cb16fe97&pid=1-s2.0-S0303720724001734-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Maternal protein restriction combined with postnatal sugar consumption alters liver proteomic profile and metabolic pathways in adult male offspring rats 母体蛋白质限制与产后糖摄入会改变成年雄性后代大鼠的肝脏蛋白质组图谱和代谢途径
IF 3.8 3区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-14 DOI: 10.1016/j.mce.2024.112316
Isabelle Tenori Ribeiro , Matheus Naia Fioretto , Sérgio Alexandre Alcantara dos Santos , Ketlin Thassiani Colombelli , Luiz Marcos Frediani Portela , Marcus Vinicius Niz Alvarez , Pedro de Magalhães Padilha , Aislan Quintiliano Delgado , Marcus Vinicius Lage Silva Giaculi Marques , José Roberto Bosqueiro , Fábio Rodrigues Ferreira Seiva , Luís Fernando Barbisan , Antonio Marcus de Andrade Paes , Elena Zambrano , Luis Antonio Justulin Jr.

This study investigated the impact of maternal protein restriction (MPR) and early postnatal sugar consumption (SUG) on the liver health of adult male descendant rats. Male offspring of mothers fed a normal protein diet (NPD) or a low protein diet (LPD) were divided into four groups: Control (CTR), Sugar Control (CTR + SUG), LPD during gestation and lactation (GLLP), and LPD with sugar (GLLP + SUG). Sugar consumption (10% glucose diluted in water) began after weaning on day 21 (PND 21), and at 90 days (PND 90), rats were sacrificed for analysis. Sugar intake reduced food intake and increased water consumption in CTR + SUG and GLLP + SUG compared to CTR and GLLP. GLLP and GLLP + SUG groups showed lower body weight and total and retroperitoneal fat compared to CTR and CTR + SUG. CTR + SUG and GLLP + SUG groups exhibited hepatocyte vacuolization associated with increased hepatic glycogen content compared to CTR and GLLP. Hepatic catalase activity increased in GLLP compared to CTR. Proteomic analysis identified 223 differentially expressed proteins (DEPs) among experimental groups. While in the GLLP group, the DEPs enriched molecular pathways related to cellular stress, glycogen metabolic pathways were enriched in the GLLP + SUG and CTR + SUG groups. The association of sugar consumption amplifies the effects of MPR, deregulating molecular mechanisms related to metabolism and the antioxidant system.

本研究调查了母体蛋白质限制(MPR)和产后早期糖摄入量(SUG)对成年雄性后代大鼠肝脏健康的影响。母鼠以正常蛋白质饮食(NPD)或低蛋白饮食(LPD)喂养的雄性后代分为四组:对照组(CTR)、糖控制组(CTR+SUG)、妊娠期和哺乳期低蛋白饮食组(GLLP)和含糖低蛋白饮食组(GLLP+SUG)。大鼠断奶后第 21 天(PND 21)开始摄入糖(10% 葡萄糖稀释水),90 天(PND 90)后将大鼠处死以进行分析。与 CTR 和 GLLP 相比,CTR+SUG 和 GLLP+SUG 的糖摄入量减少了食物摄入量,增加了耗水量。与 CTR 和 CTR+SUG 相比,GLLP 和 GLLP+SUG 组的体重、总脂肪和腹膜后脂肪含量较低。与 CTR 和 GLLP 相比,CTR+SUG 组和 GLLP+SUG 组表现出与肝糖原含量增加有关的肝细胞空泡化。与 CTR 相比,GLLP 组的肝过氧化氢酶活性增加。蛋白质组学分析在各实验组中发现了 223 个差异表达蛋白 (DEPs)。在 GLLP 组,差异表达蛋白富集了与细胞应激有关的分子通路,而在 GLLP+SUG 组和 CTR+SUG 组,则富集了糖代谢通路。与糖消费相关联会放大 MPR 的影响,解除与新陈代谢和抗氧化系统相关的分子机制。
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引用次数: 0
Overexpression of MD1 ameliorates pathological myocardial remodeling in diabetic cardiomyopathy by TLR4/STAT3 signaling pathway 过表达 MD1 可通过 TLR4/STAT3 信号通路改善糖尿病心肌病的病理性心肌重塑。
IF 4.1 3区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-13 DOI: 10.1016/j.mce.2024.112315
Caijie Shen , Shuwen Yang , Nan Wu , Wang Jian , Tingsha Du , Huimin Chu , Weiping Du

Diabetic cardiomyopathy (DCM) is characterized by oxidative damage and inflammatory responses. Myeloid differentiation protein 1 (MD1) exhibits antioxidant and anti-inflammatory properties. However, the specific role of MD1 in DCM has yet to be elucidated. This study aims to investigate the role of MD1 in DCM and to elucidate the underlying mechanisms. We utilized a gain-of-function approach to explore the involvement of MD1 in DCM. Diabetes was induced in MD1-transgenic (MD1-TG) mice and their wild-type (WT) counterparts via streptozotocin (STZ) injection. Additionally, a diabetes cell model was established using H9c2 cells exposed to high glucose levels. We conducted comprehensive evaluations, including pathological analyses, echocardiography, electrocardiography, and molecular assessments, to elucidate the underlying mechanisms of MD1 in DCM. Notably, MD1 expression was reduced in the hearts of STZ-induced diabetic mice. Overexpression of MD1 significantly improved cardiac function and markedly inhibited ventricular pathological hypertrophy and fibrosis in these mice. Furthermore, MD1 overexpression resulted in a substantial decrease in myocardial reactive oxygen species (ROS) accumulation, mitigating myocardial oxidative stress and reducing the levels of inflammation-related markers such as IL-1β, IL-6, and TNF-α. Mechanistically, MD1 overexpression inhibited the activation of the TLR4/STAT3 signaling pathway, as demonstrated in both in vivo and in vitro experiments. The overexpression of MD1 significantly impeded pathological cardiac remodeling and improved cardiac function in STZ-induced diabetic mice. This effect was primarily attributed to a reduction in ROS accumulation and mitigation of myocardial oxidative stress and inflammation, facilitated by the inhibition of the TLR4/STAT3 signaling pathway.

糖尿病心肌病(DCM)的特点是氧化损伤和炎症反应。髓系分化蛋白 1(MD1)具有抗氧化和抗炎特性。然而,MD1 在 DCM 中的具体作用仍有待阐明。本研究旨在探讨 MD1 在 DCM 中的作用并阐明其潜在机制。我们采用功能增益法来探讨 MD1 在 DCM 中的参与。通过注射链脲佐菌素(STZ)诱导 MD1 转基因(MD1-TG)小鼠及其野生型(WT)小鼠患糖尿病。此外,我们还利用暴露于高葡萄糖水平的 H9c2 细胞建立了糖尿病细胞模型。我们进行了全面的评估,包括病理分析、超声心动图、心电图和分子评估,以阐明 MD1 在 DCM 中的潜在机制。值得注意的是,MD1在STZ诱导的糖尿病小鼠心脏中表达减少。过表达 MD1 能显著改善这些小鼠的心功能,并明显抑制心室病理性肥厚和纤维化。此外,MD1 的过表达导致心肌活性氧(ROS)积累大幅减少,减轻了心肌氧化应激,降低了炎症相关标志物(如 IL-1β、IL-6 和 TNF-α)的水平。从机理上讲,MD1的过表达抑制了TLR4/STAT3信号通路的激活,这在体内和体外实验中均得到了证实。在 STZ 诱导的糖尿病小鼠体内,MD1 的过表达能显著抑制病理性心脏重塑并改善心脏功能。这种效应主要归因于抑制 TLR4/STAT3 信号通路减少了 ROS 的积累,减轻了心肌氧化应激和炎症反应。
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引用次数: 0
Fundamentals and recent advances in the evaluation and management of medullary thyroid carcinoma 甲状腺髓样癌评估和管理的基础与最新进展。
IF 3.8 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-12 DOI: 10.1016/j.mce.2024.112295
Benjamin J. Gigliotti , Jennifer A. Brooks , Lori J. Wirth

Medullary thyroid carcinoma (MTC) is a rare primary neuroendocrine thyroid carcinoma that is distinct from other thyroid or neuroendocrine cancers. Most cases of MTC are sporadic, although MTC exhibits a high degree of heritability as part of the multiple endocrine neoplasia syndromes. REarranged during Transfection (RET) mutations are the primary oncogenic drivers and advances in molecular profiling have revealed that MTC is enriched in druggable alterations. Surgery at an early stage is the only chance for cure, but many patients present with or develop metastases. C-cell-specific calcitonin trajectory and structural doubling times are critical biomarkers to inform prognosis, extent of surgery, likelihood of residual disease, and need for additional therapy. Recent advances in the role of active surveillance, regionally directed therapies for localized disease, and systemic therapy with multi-kinase and RET-specific inhibitors for progressive/metastatic disease have significantly improved outcomes for patients with MTC.

甲状腺髓样癌(MTC)是一种罕见的原发性神经内分泌甲状腺癌,与其他甲状腺癌或神经内分泌癌不同。大多数 MTC 病例为散发性,但作为多发性内分泌肿瘤综合征的一部分,MTC 具有高度遗传性。RET突变是主要的致癌驱动因素,分子图谱分析的进展显示,MTC富含可药物治疗的改变。早期手术是治愈的唯一机会,但许多患者会出现或发展为转移瘤。C细胞特异性降钙素轨迹和结构倍增时间是重要的生物标志物,可为预后、手术范围、残留疾病的可能性以及是否需要额外治疗提供依据。最近,积极监测、针对局部疾病的区域定向疗法以及针对进展性/转移性疾病的多激酶和 RET 特异性抑制剂全身疗法的作用都取得了进展,从而显著改善了 MTC 患者的预后。
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引用次数: 0
Knockdown of type 2 orexin receptor in adult mouse testis potentiates testosterone production and germ cell proliferation 敲除成年小鼠睾丸中的 2 型奥曲肽受体可促进睾酮生成和生殖细胞增殖。
IF 4.1 3区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-10 DOI: 10.1016/j.mce.2024.112312
Pratikshya Sahoo , Debarshi Sarkar , Shubhangi Sharma , Arpit Verma , Suraj Kumar Naik , Vikash Prashar , Jyoti Parkash , Shio Kumar Singh

Orexins (OXs) are neuropeptides which regulate various physiological processes. OXs exist in two different forms, mainly orexin A (OXA) and orexin B (OXB) and their effects are mediated via OX1R and OX2R. Presence of OXB and OX2R in mouse testis is also reported. However, the role of OXB/OX2R in the male gonad remains unexplored. Herein we investigated the role of OXB/OX2R system in testicular physiology under in vivo and ex vivo conditions. Adult mice were given a single dose of bilateral intratesticular injection of siRNA targeting OX2R and were sacrificed 96 h post-injection. OX2R-knockdown potentiated serum and intratesticular testosterone levels with up-regulation in the expressions of major steroidogenic proteins. Germ cell proliferation also increased in siRNA-treated mice. Results of the ex vivo experiment also supported the findings of the in vivo study. In conclusion, OX2R may regulate testosterone production and thereby control the fine-tuning between steroidogenesis and germ cell dynamics.

奥曲肽是一种神经肽,可调节各种生理过程。OXs 以两种不同的形式存在,主要是 OXin A(OXA)和 OXin B(OXB),其作用通过 OX1R 和 OX2R 介导。也有报道称小鼠睾丸中存在 OXB 和 OX2R。然而,OXB/OX2R在雄性性腺中的作用仍未得到探索。在此,我们研究了体内和体外条件下 OXB/OX2R 系统在睾丸生理中的作用。成年小鼠接受单剂量双侧睾丸内注射靶向 OX2R 的 siRNA,注射后 96 小时处死。OX2R敲除可提高血清和睾丸内睾酮水平,并上调主要类固醇生成蛋白的表达。经 siRNA 处理的小鼠生殖细胞增殖也有所增加。体内外实验的结果也支持了体内研究的发现。总之,OX2R 可调节睾酮的产生,从而控制类固醇生成和生殖细胞动态之间的微调。
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