Pub Date : 2024-06-26DOI: 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.
{"title":"Control of sodium appetite by hindbrain aldosterone-sensitive neurons","authors":"Ahmet Kuralay , Miriam C. McDonough , Jon M. Resch","doi":"10.1016/j.mce.2024.112323","DOIUrl":"10.1016/j.mce.2024.112323","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-26DOI: 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.
{"title":"Downregulation of CASC15 attenuates the symptoms of polycystic ovary syndrome by affecting granulosa cell proliferation and regulating ovarian follicular development","authors":"Tongwei Zhang , Junnan Fang , Jingyi Hu , Yue Kong , Ran Jiang , Huihui Wang , Guang Yang , Guidong Yao","doi":"10.1016/j.mce.2024.112322","DOIUrl":"10.1016/j.mce.2024.112322","url":null,"abstract":"<div><p>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 (<em>CASC15</em>), 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 <em>CASC15</em> expression in both <em>in vitro</em> and <em>in vivo</em> models. We explored the potential regulatory relationship between <em>CASC15</em> 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 <em>CASC15</em> expression in granulosa cells derived from patients with PCOS was significantly higher than those of the normal group (<em>P</em> < 0.001). <em>In vitro</em> experiments revealed that downregulating <em>CASC15</em> significantly inhibited cell proliferation, promoted apoptosis, induced G1-phase cell cycle arrest, and influenced cellular autophagy levels. Moreover, downregulating <em>CASC15</em> affected the follicular development process in newborn mouse ovaries. <em>In vivo</em> studies in mice demonstrated that disrupting <em>CASC15</em> expression improved PCOS-related symptoms such as polycystic changes and hyperandrogenism, and significantly affected ovulation induction and embryo implantation in pregnant mice. Overall, <em>CASC15</em> 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.</p></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-25DOI: 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。
{"title":"Replenishment of TCA cycle intermediates and long-noncoding RNAs regulation in breast cancer","authors":"Xuewei Zheng , ShunShun Zhang , HaoDi Ma , Yirui Dong , Jiayu Zheng , Li Zeng , Jiangbo Liu , Yanzhenzi Dai , Qinan Yin","doi":"10.1016/j.mce.2024.112321","DOIUrl":"10.1016/j.mce.2024.112321","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-24DOI: 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.
{"title":"Sexually dimorphic control of aggression by androgen signaling in a cichlid","authors":"Lillian R. Jackson , Beau A. Alward","doi":"10.1016/j.mce.2024.112319","DOIUrl":"10.1016/j.mce.2024.112319","url":null,"abstract":"<div><p>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 <em>Astatotilapia burtoni</em>, 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<em>.</em> However, ARα KO males showed clear deficits in attacks. Thus, in <em>A. burtoni</em> there appears to be a sexual dimorphism in the role of ARα in the control of aggression.</p></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-20DOI: 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。
{"title":"Activated AMP-protein kinase (pAMPK) is overexpressed in human somatotroph pituitary adenomas","authors":"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","doi":"10.1016/j.mce.2024.112318","DOIUrl":"10.1016/j.mce.2024.112318","url":null,"abstract":"<div><h3>Introduction</h3><p>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.</p></div><div><h3>Methods</h3><p>We studied pituitary adenoma tissue from patients with sporadic somatotroph adenomas, familial acromegaly with heterozygote germline variants in the aryl hydrocarbon receptor interacting protein (<em>AIP</em>) gene (p.Q164*, p.R304* and p.F269_H275dup) and autopsy from normal pituitary glands without structural alterations.</p></div><div><h3>Results</h3><p>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 <em>AIP</em> 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.</p></div><div><h3>Conclusion</h3><p>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 <em>AIP</em> mutations.</p></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141440684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-18DOI: 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.
{"title":"De novo synthesis of monounsaturated fatty acids modulates exosome-mediated lipid export from human granulosa cells","authors":"Shabnam Fayezi , Sophie Oehms , Helena Wolff von Gudenberg , Maharajah Ponnaiah , Marie Lhomme , Thomas Strowitzki , 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}
Pub Date : 2024-06-14DOI: 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.
{"title":"Maternal protein restriction combined with postnatal sugar consumption alters liver proteomic profile and metabolic pathways in adult male offspring rats","authors":"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.","doi":"10.1016/j.mce.2024.112316","DOIUrl":"10.1016/j.mce.2024.112316","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141331430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-13DOI: 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.
{"title":"Overexpression of MD1 ameliorates pathological myocardial remodeling in diabetic cardiomyopathy by TLR4/STAT3 signaling pathway","authors":"Caijie Shen , Shuwen Yang , Nan Wu , Wang Jian , Tingsha Du , Huimin Chu , Weiping Du","doi":"10.1016/j.mce.2024.112315","DOIUrl":"10.1016/j.mce.2024.112315","url":null,"abstract":"<div><p>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 <em>in vivo</em> and <em>in vitro</em> 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.</p></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-12DOI: 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。
{"title":"Fundamentals and recent advances in the evaluation and management of medullary thyroid carcinoma","authors":"Benjamin J. Gigliotti , Jennifer A. Brooks , Lori J. Wirth","doi":"10.1016/j.mce.2024.112295","DOIUrl":"10.1016/j.mce.2024.112295","url":null,"abstract":"<div><p>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. <em>RE</em>arranged during <em>T</em>ransfection (<em>RET)</em> 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.</p></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Knockdown of type 2 orexin receptor in adult mouse testis potentiates testosterone production and germ cell proliferation","authors":"Pratikshya Sahoo , Debarshi Sarkar , Shubhangi Sharma , Arpit Verma , Suraj Kumar Naik , Vikash Prashar , Jyoti Parkash , Shio Kumar Singh","doi":"10.1016/j.mce.2024.112312","DOIUrl":"10.1016/j.mce.2024.112312","url":null,"abstract":"<div><p>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 <em>in vivo</em> and <em>ex vivo</em> 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 <em>ex vivo</em> experiment also supported the findings of the <em>in vivo</em> study. In conclusion, OX2R may regulate testosterone production and thereby control the fine-tuning between steroidogenesis and germ cell dynamics.</p></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141311123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}