Pub Date : 2024-11-21DOI: 10.1016/j.mce.2024.112419
Yi Zhang , Ting Pan , Yanting Yang , Xingzhao Xu , Yao Liu
Oridonin (Ori) possesses anti-inflammatory properties. However, its potential to treat diabetic retinopathy (DR) remains unclear. This study aimed to investigate the retinal protective function of Ori and the underlying mechanism. In streptozotocin-induced mice, Ori alleviated visual impairment, reduced retinal and vascular lesions, protected the neuroretinal structure, reversed retinal nerve layer thickening. Addtionnally, Ori reduced TNF-α and IL-1β levels in the peripheral blood, and suppressed retinal NLRP3 inflammasome-related inflammatory factor. In vitro, human retinal endothelial cells (hRECs) were stimulated by high glucose (HG). HG-stimulated hRECs activated the NLRP3 inflammasome, whereas Ori significantly alleviated pyroptosis by enhancing cell viability and reducing IL-1β levels in the supernatant. Ori also inhibited NF-κB/NLRP3 inflammasome pathway. NEK7 depletion alleviated NLRP3 inflammasome activation and, to some extent, mimicked the role of Ori. Indeed, Ori reversed NLRP3 inflammasome activation by suppressing NEK7–NLRP3 interaction. Therefore, Ori may serve as a potential therapeutic agent for attenuating DR progression.
奥利多宁（Ori）具有抗炎特性。然而，它治疗糖尿病视网膜病变（DR）的潜力仍不清楚。本研究旨在探究Ori的视网膜保护功能及其内在机制。在链脲佐菌素诱导的小鼠中，Ori减轻了视力损伤，减少了视网膜和血管病变，保护了神经视网膜结构，逆转了视网膜神经层增厚。此外，Ori还能降低外周血中TNF-α和IL-1β的水平，抑制视网膜NLRP3炎症相关因子。在体外，人视网膜内皮细胞（hRECs）受到高糖（HG）的刺激。HG刺激的hRECs激活了NLRP3炎性体，而Ori通过提高细胞活力和降低上清液中的IL-1β水平，显著缓解了细胞的脓毒症。Ori 还能抑制 NF-κB/NLRP3 炎性体通路。NEK7 的耗竭减轻了 NLRP3 炎性体的激活，并在一定程度上模拟了 Ori 的作用。事实上，Ori通过抑制NEK7-NLRP3的相互作用逆转了NLRP3炎性体的激活。因此，Ori可作为一种潜在的治疗药物，用于减轻DR的进展。
{"title":"Oridonin attenuates diabetic retinopathy progression by suppressing NLRP3 inflammasome pathway","authors":"Yi Zhang , Ting Pan , Yanting Yang , Xingzhao Xu , Yao Liu","doi":"10.1016/j.mce.2024.112419","DOIUrl":"10.1016/j.mce.2024.112419","url":null,"abstract":"<div><div>Oridonin (Ori) possesses anti-inflammatory properties. However, its potential to treat diabetic retinopathy (DR) remains unclear. This study aimed to investigate the retinal protective function of Ori and the underlying mechanism. In streptozotocin-induced mice, Ori alleviated visual impairment, reduced retinal and vascular lesions, protected the neuroretinal structure, reversed retinal nerve layer thickening. Addtionnally, Ori reduced TNF-α and IL-1β levels in the peripheral blood, and suppressed retinal NLRP3 inflammasome-related inflammatory factor. In vitro, human retinal endothelial cells (hRECs) were stimulated by high glucose (HG). HG-stimulated hRECs activated the NLRP3 inflammasome, whereas Ori significantly alleviated pyroptosis by enhancing cell viability and reducing IL-1β levels in the supernatant. Ori also inhibited NF-κB/NLRP3 inflammasome pathway. NEK7 depletion alleviated NLRP3 inflammasome activation and, to some extent, mimicked the role of Ori. Indeed, Ori reversed NLRP3 inflammasome activation by suppressing NEK7–NLRP3 interaction. Therefore, Ori may serve as a potential therapeutic agent for attenuating DR progression.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"596 ","pages":"Article 112419"},"PeriodicalIF":3.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693219","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 : 2024-11-21DOI: 10.1016/j.mce.2024.112420
Corrine F. Monaco , Chloe M. Jones , Harlan R. Sayles , Brooke Rudloff , Renee McFee , Andrea S. Cupp , John S. Davis
The corpus luteum is a temporary endocrine gland that is crucial for pregnancy, as it produces the progesterone needed to maintain optimal uterine conditions for implantation. In the absence of a conceptus, the corpus luteum becomes non-functional and undergoes rapid tissue remodeling to regress into a fibrotic corpus albicans. Early luteal regression is characterized by increased cytokine release. Because the role of fibroblasts in the bovine corpus luteum remains to be elucidated, the aim of this study was to elucidate the response of bovine luteal fibroblasts to inflammatory cytokines, tumor necrosis factor α (TNFα), and interleukin 1β (IL1β). Both cytokines induced canonical mitogen activated protein kinase (MAPK) signaling in luteal fibroblasts by phosphorylation of ERK1/2, p38 MAPK, and JNK. IL1β elevated expression and phosphorylation of cytosolic phospholipase A2 (cPLA2), an enzyme that mobilizes arachidonic acid for prostanoid synthesis. IL1β also elevated expression of prostaglandin-endoperoxide synthase 2 (PTGS2), another enzyme needed to synthesize prostanoids. IL1β increased PGF2α and PGE2 levels in the culture medium over 20-fold. Inhibition of MAPKs with small-molecule inhibitors abrogated the stimulatory effects of IL1β. IL1β also induced prostaglandin production in steroidogenic cells; however, there was no elevation in cPLA2. Therefore, actions of IL1β differ based on ovarian cell type. All together, we have identified luteal fibroblasts as potential inflammatory mediators during luteal regression.
{"title":"Luteal fibroblasts produce prostaglandins in response to IL1β in a MAPK-mediated manner","authors":"Corrine F. Monaco , Chloe M. Jones , Harlan R. Sayles , Brooke Rudloff , Renee McFee , Andrea S. Cupp , John S. Davis","doi":"10.1016/j.mce.2024.112420","DOIUrl":"10.1016/j.mce.2024.112420","url":null,"abstract":"<div><div>The corpus luteum is a temporary endocrine gland that is crucial for pregnancy, as it produces the progesterone needed to maintain optimal uterine conditions for implantation. In the absence of a conceptus, the corpus luteum becomes non-functional and undergoes rapid tissue remodeling to regress into a fibrotic corpus albicans. Early luteal regression is characterized by increased cytokine release. Because the role of fibroblasts in the bovine corpus luteum remains to be elucidated, the aim of this study was to elucidate the response of bovine luteal fibroblasts to inflammatory cytokines, tumor necrosis factor α (TNFα), and interleukin 1β (IL1β). Both cytokines induced canonical mitogen activated protein kinase (MAPK) signaling in luteal fibroblasts by phosphorylation of ERK1/2, p38 MAPK, and JNK. IL1β elevated expression and phosphorylation of cytosolic phospholipase A2 (cPLA<sub>2</sub>), an enzyme that mobilizes arachidonic acid for prostanoid synthesis. IL1β also elevated expression of prostaglandin-endoperoxide synthase 2 (PTGS2), another enzyme needed to synthesize prostanoids. IL1β increased PGF2α and PGE<sub>2</sub> levels in the culture medium over 20-fold. Inhibition of MAPKs with small-molecule inhibitors abrogated the stimulatory effects of IL1β. IL1β also induced prostaglandin production in steroidogenic cells; however, there was no elevation in cPLA<sub>2</sub>. Therefore, actions of IL1β differ based on ovarian cell type. All together, we have identified luteal fibroblasts as potential inflammatory mediators during luteal regression.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"596 ","pages":"Article 112420"},"PeriodicalIF":3.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693203","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 : 2024-11-17DOI: 10.1016/j.mce.2024.112415
Sayantan Sur , Calum Stewart , Timothy A. Liddle , Ana Maria Monteiro , Irem Denizli , Gaurav Majumdar , Tyler J. Stevenson
Seasonal rhythms in photoperiod are a predictive cue used by many temperate-zone animals to time cycles of lipid accumulation. The neuroendocrine regulation of seasonal energy homeostasis and rheostasis are widely studied. However, the molecular pathways underlying tissue-specific adaptations remain poorly described. We conducted two experiments to examine long-term rheostatic changes in energy stability using the well-characterized photoperiodic response of the Japanese quail. In experiment 1, we exposed quails to photoperiodic transitions simulating the annual photic cycle and examined the morphology and fat deposition in liver, muscle, and adipose tissue. To identify changes in gene expression and molecular pathways during the vernal transition in lipid accumulation, we conducted transcriptomic analyses of adipose and liver tissues. Experiment 2 assessed whether the changes observed in Experiment 1 reflected constitutive levels or were due to time-of-day sampling. We identified increased expression of transcripts involved in adipocyte growth, such as Cysteine Rich Angiogenic Inducer 61 and Very Low-Density Lipoprotein Receptor, and in obesity-linked disease resistance, such as Insulin-Like Growth Factor Binding Protein 2 and Apolipoprotein D, in anticipation of body mass gain. Under long photoperiods, hepatic transcripts involved in fatty acid (FA) synthesis (FA Synthase, FA Desaturase 2) were down-regulated. Parallel upregulation of hepatic FA Translocase and Pyruvate Dehydrogenase Kinase 4 expression suggests increased FA uptake and inhibition of the pyruvate dehydrogenase complex. Our findings demonstrate tissue-specific biochemical and molecular changes that drive photoperiod-induced adipogenesis. These findings can be used to determine conserved pathways that enable animals to accumulate fat without developing metabolic diseases.
{"title":"Molecular basis of photoinduced seasonal energy rheostasis in Japanese quail (Coturnix japonica)","authors":"Sayantan Sur , Calum Stewart , Timothy A. Liddle , Ana Maria Monteiro , Irem Denizli , Gaurav Majumdar , Tyler J. Stevenson","doi":"10.1016/j.mce.2024.112415","DOIUrl":"10.1016/j.mce.2024.112415","url":null,"abstract":"<div><div>Seasonal rhythms in photoperiod are a predictive cue used by many temperate-zone animals to time cycles of lipid accumulation. The neuroendocrine regulation of seasonal energy homeostasis and rheostasis are widely studied. However, the molecular pathways underlying tissue-specific adaptations remain poorly described. We conducted two experiments to examine long-term rheostatic changes in energy stability using the well-characterized photoperiodic response of the Japanese quail. In experiment 1, we exposed quails to photoperiodic transitions simulating the annual photic cycle and examined the morphology and fat deposition in liver, muscle, and adipose tissue. To identify changes in gene expression and molecular pathways during the vernal transition in lipid accumulation, we conducted transcriptomic analyses of adipose and liver tissues. Experiment 2 assessed whether the changes observed in Experiment 1 reflected constitutive levels or were due to time-of-day sampling. We identified increased expression of transcripts involved in adipocyte growth, such as <em>Cysteine Rich Angiogenic Inducer 61</em> and <em>Very Low-Density Lipoprotein Receptor</em>, and in obesity-linked disease resistance, such as <em>Insulin-Like Growth Factor Binding Protein 2</em> and <em>Apolipoprotein D</em>, in anticipation of body mass gain. Under long photoperiods, hepatic transcripts involved in fatty acid (FA) synthesis (<em>FA Synthase</em>, <em>FA Desaturase 2</em>) were down-regulated. Parallel upregulation of hepatic <em>FA Translocase</em> and <em>Pyruvate Dehydrogenase Kinase 4</em> expression suggests increased FA uptake and inhibition of the pyruvate dehydrogenase complex. Our findings demonstrate tissue-specific biochemical and molecular changes that drive photoperiod-induced adipogenesis. These findings can be used to determine conserved pathways that enable animals to accumulate fat without developing metabolic diseases.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"595 ","pages":"Article 112415"},"PeriodicalIF":3.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676333","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 : 2024-11-16DOI: 10.1016/j.mce.2024.112418
Yiyun Xi , Ming Yang , Zebin Deng , Xiaofeng Xiong , Ling Wei , Juan Cai , Chengyuan Tang , Lin Sun
Background
Lipoapoptosis in Proximal tubular epithelial cells (PTCs) are substantial in the etiology of diabetic kidney disease (DKD), yet the underlying mechanisms warrant further investigation. Acyl-CoA synthetase long-chain family member 5 (ACSL5) facilitates the formation of acyl-CoA, however, the precise role of ACSL5 in lipoapoptosis of PTCs in DKD remains inconclusive.
Methods
Transcriptomic data analysis identified the hub gene Acsl5 associated with lipid metabolism in DKD. The expression of ACSL5 was examined in high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mice and high glucose/palmitic acid (HGPA)-induced mouse proximal tubular epithelial cell (BUMPT). Oil Red O staining, free fatty acids (FFA) ELISA assay, Western Blot, and morphological changes were employed to assess lipid deposition and lipoapoptosis. Furthermore, knockdown and overexpression of ACSL5 were conducted in BUMPT cells, followed by morphological assessment, Oil Red O staining, FFA ELISA assay and Western Blot analysis. Using the ChEA3 database, we predicted that STAT3 may transcriptionally regulate ACSL5. Subsequently, we knocked down STAT3 and evaluated Acsl5 expression via RT-qPCR. Additionally, we investigated whether STAT3 modulates the impact of ACSL5 on lipoapoptosis through Western Blot analysis.
Results
We demonstrated, for the first time, a notable upregulation of ACSL5 expression in PTCs in HFD/STZ-induced diabetic mice, accompanied by increased the expression of FATP2, lipid accumulation and heightened lipoapoptosis. In HGPA-treated BUMPT cells, ACSL5 knockdown reduced the expression of FATP2, lipid deposition and lipoapoptosis, whereas its overexpression elevated the expression of FATP2 and exacerbated these effects. These findings strongly suggest that ACSL5 may exacerbate lipoapoptosis in PTCs within a diabetic milieu. From a molecular mechanism perspective, ACSL5 expression decreased after Stat3 knockdown. Concurrent knockdown of Stat3 and overexpression of Acsl5 led to a mitigation of lipoapoptosis compared to sole Acsl5 overexpression. Furthermore, STAT3 promotes the activation of ACSL5 promoter under HGPA conditions.
Conclusions
In summary, our research identified ACSL5 as an important contributor exacerbating lipoapoptosis in the renal proximal tubules within diabetic environments. In addition, we found that ACSL5 is transcriptionally regulated by STAT3.
{"title":"ACSL5 promotes lipid deposition and lipoapoptosis in proximal tubular epithelial cells of diabetic kidney disease","authors":"Yiyun Xi , Ming Yang , Zebin Deng , Xiaofeng Xiong , Ling Wei , Juan Cai , Chengyuan Tang , Lin Sun","doi":"10.1016/j.mce.2024.112418","DOIUrl":"10.1016/j.mce.2024.112418","url":null,"abstract":"<div><h3>Background</h3><div>Lipoapoptosis in Proximal tubular epithelial cells (PTCs) are substantial in the etiology of diabetic kidney disease (DKD), yet the underlying mechanisms warrant further investigation. Acyl-CoA synthetase long-chain family member 5 (ACSL5) facilitates the formation of acyl-CoA, however, the precise role of ACSL5 in lipoapoptosis of PTCs in DKD remains inconclusive.</div></div><div><h3>Methods</h3><div>Transcriptomic data analysis identified the hub gene <em>Acsl5</em> associated with lipid metabolism in DKD. The expression of ACSL5 was examined in high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mice and high glucose/palmitic acid (HGPA)-induced mouse proximal tubular epithelial cell (BUMPT). Oil Red O staining, free fatty acids (FFA) ELISA assay, Western Blot, and morphological changes were employed to assess lipid deposition and lipoapoptosis. Furthermore, knockdown and overexpression of ACSL5 were conducted in BUMPT cells, followed by morphological assessment, Oil Red O staining, FFA ELISA assay and Western Blot analysis. Using the ChEA3 database, we predicted that STAT3 may transcriptionally regulate ACSL5. Subsequently, we knocked down STAT3 and evaluated <em>Acsl5</em> expression via RT-qPCR. Additionally, we investigated whether STAT3 modulates the impact of ACSL5 on lipoapoptosis through Western Blot analysis.</div></div><div><h3>Results</h3><div>We demonstrated, for the first time, a notable upregulation of ACSL5 expression in PTCs in HFD/STZ-induced diabetic mice, accompanied by increased the expression of FATP2, lipid accumulation and heightened lipoapoptosis. In HGPA-treated BUMPT cells, ACSL5 knockdown reduced the expression of FATP2, lipid deposition and lipoapoptosis, whereas its overexpression elevated the expression of FATP2 and exacerbated these effects. These findings strongly suggest that ACSL5 may exacerbate lipoapoptosis in PTCs within a diabetic milieu. From a molecular mechanism perspective, ACSL5 expression decreased after <em>Stat3</em> knockdown. Concurrent knockdown of <em>Stat3</em> and overexpression of <em>Acsl5</em> led to a mitigation of lipoapoptosis compared to sole <em>Acsl5</em> overexpression. Furthermore, STAT3 promotes the activation of <em>ACSL5</em> promoter under HGPA conditions.</div></div><div><h3>Conclusions</h3><div>In summary, our research identified ACSL5 as an important contributor exacerbating lipoapoptosis in the renal proximal tubules within diabetic environments. In addition, we found that ACSL5 is transcriptionally regulated by STAT3.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"595 ","pages":"Article 112418"},"PeriodicalIF":3.8,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668471","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 : 2024-11-16DOI: 10.1016/j.mce.2024.112417
Zhaoqing Xi , Ling Shu , Lingling Xiao , Xuesheng Fang , Mingyan Dai , Jing Wang , Yuan Wu , Junxia Zhang , Mingwei Bao
Obesity-associated cardiac remodeling is characterized by cardiac sympathetic nerve over-activation and pro-inflammatory macrophage infiltration. We identified norepinephrine (NE), a sympathetic neurotransmitter, as a pro-inflammatory effector to activate macrophage NLRP3 inflammasome, which contributed to cardiac inflammation. In vivo, Sprague-Dawley (SD) rats were fed a high-fat diet (HFD) for 12 weeks to establish obese rat models. Obese rats exhibited marked cardiac hypertrophy compared to normal rats. The expression of NLRP3 and interleukin (IL)-1β was upregulated, accompanied by CD68+NLRP3+ macrophage infiltration in the hearts of the obese rats. The obese rats also showed increased sympathetic nerve activity. β-adrenergic receptor (AR) inhibition mitigated these changes. In vitro, sympathetic neurotransmitter NE significantly exacerbated palmitic acid (PA)-induced macrophage polarization toward pro-inflammatory type and NLRP3 inflammasome activation in THP-1 macrophages. It was further found that the pro-inflammatory role of NE is dependent on the activation of protein kinase A (PKA) and subsequently inhibition of β-arrestin2, which is an important regulator of the nuclear factor-kappa B (NF-κB) pathway.
This study identifies the neuro-immune axis as an important mediator in obesity-associated cardiac remodeling. Targeting the neuro-immune system may open therapeutic opportunities for the treatment of cardiac remodeling in obesity.
{"title":"Macrophage NLRP3 inflammasome mediates the effects of sympathetic nerve on cardiac remodeling in obese rats","authors":"Zhaoqing Xi , Ling Shu , Lingling Xiao , Xuesheng Fang , Mingyan Dai , Jing Wang , Yuan Wu , Junxia Zhang , Mingwei Bao","doi":"10.1016/j.mce.2024.112417","DOIUrl":"10.1016/j.mce.2024.112417","url":null,"abstract":"<div><div>Obesity-associated cardiac remodeling is characterized by cardiac sympathetic nerve over-activation and pro-inflammatory macrophage infiltration. We identified norepinephrine (NE), a sympathetic neurotransmitter, as a pro-inflammatory effector to activate macrophage NLRP3 inflammasome, which contributed to cardiac inflammation. In vivo, Sprague-Dawley (SD) rats were fed a high-fat diet (HFD) for 12 weeks to establish obese rat models. Obese rats exhibited marked cardiac hypertrophy compared to normal rats. The expression of NLRP3 and interleukin (IL)-1β was upregulated, accompanied by CD68<sup>+</sup>NLRP3<sup>+</sup> macrophage infiltration in the hearts of the obese rats. The obese rats also showed increased sympathetic nerve activity. β-adrenergic receptor (AR) inhibition mitigated these changes. In vitro, sympathetic neurotransmitter NE significantly exacerbated palmitic acid (PA)-induced macrophage polarization toward pro-inflammatory type and NLRP3 inflammasome activation in THP-1 macrophages. It was further found that the pro-inflammatory role of NE is dependent on the activation of protein kinase A (PKA) and subsequently inhibition of β-arrestin2, which is an important regulator of the nuclear factor-kappa B (NF-κB) pathway.</div><div>This study identifies the neuro-immune axis as an important mediator in obesity-associated cardiac remodeling. Targeting the neuro-immune system may open therapeutic opportunities for the treatment of cardiac remodeling in obesity.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"596 ","pages":"Article 112417"},"PeriodicalIF":3.8,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668473","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 : 2024-11-16DOI: 10.1016/j.mce.2024.112416
Giovanni Levate , Yuan Wang , Riada McCredie , Megan Fenwick , Michael T. Rae , W. Colin Duncan , Katarzyna J. Siemienowicz
Adipose tissue dysfunction is one of the features of Polycystic Ovary Syndrome (PCOS) with dysregulated adipogenesis, altered functional pathways and increased inflammation. It is increasingly clear that there are also male correlates of the hormonal and metabolic features of PCOS. We hypothesised that the effects of adipose tissue dysfunction are not sex-specific but rather fat depot-specific and independent of obesity. We used a clinically realistic ovine model of PCOS where pregnant sheep are injected with 100 mg of testosterone propionate twice weekly from day 62 to day 102 of gestation. We studied control and prenatally androgenised (PA) female and male offspring during adolescence and weight-matched control and PA female sheep during adulthood. We examined subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and in adult female sheep bone marrow adipose tissue (BMAT). Adipogenesis related gene expression in SAT was similar in adolescent female and male controls and the reduction in adipogenesis related gene expression by PA in female adipose tissue was not observed in males. Differences in expression of genes associated with adipose tissue function in adolescence in SAT driven by PA were found in both sexes. In adulthood, the changes seen in adolescent females were absent or reversed but there was an increase in inflammatory markers that was weight independent. In addition, BMAT showed increased inflammatory markers. Adipose dysfunction evolves with time and is focussed on SAT rather than VAT and is generally sex-specific although there are also effects of prenatal androgenisation on male SAT. In female adults, the inflammation seen in SAT is also present in BMAT and the development of blood cells in an inflammatory environment may have systemic implications.
脂肪组织功能障碍是多囊卵巢综合症（PCOS）的特征之一，表现为脂肪生成失调、功能途径改变和炎症增加。越来越清楚的是，多囊卵巢综合症的激素和代谢特征也与男性有关。我们假设，脂肪组织功能障碍的影响不是性别特异性的，而是脂肪库特异性的，并且与肥胖无关。我们使用了一个符合临床实际的多囊卵巢综合症绵羊模型，即从妊娠的第 62 天到第 102 天，每周两次向妊娠绵羊注射 100 毫克丙酸睾酮。我们对对照组和产前雄激素化（PA）雌性和雄性后代的青春期以及体重匹配的对照组和PA雌性绵羊的成年期进行了研究。我们检测了皮下脂肪组织（SAT）、内脏脂肪组织（VAT）以及成年雌羊的骨髓脂肪组织（BMAT）。在青春期雌性对照组和雄性对照组中，皮下脂肪组织中与脂肪生成相关的基因表达相似，而在雄性对照组中则未观察到 PA 会降低雌性脂肪组织中与脂肪生成相关的基因表达。在 PA 的作用下，青春期 SAT 中与脂肪组织功能相关的基因表达在男女两性中均存在差异。成年后，青春期女性的变化消失或逆转，但炎症标志物增加，且与体重无关。此外，BMAT 也显示出炎症标志物的增加。脂肪功能障碍会随着时间的推移而发生变化，主要集中在SAT而非VAT上，而且一般具有性别特异性，但产前雄激素化也会对男性SAT产生影响。在女性成年人中，SAT 中的炎症也存在于 BMAT 中，血细胞在炎症环境中的发育可能会产生全身性影响。
{"title":"Insights into the effects of sex and tissue location on the evolution of adipocyte dysfunction in an ovine model of polycystic ovary syndrome (PCOS)","authors":"Giovanni Levate , Yuan Wang , Riada McCredie , Megan Fenwick , Michael T. Rae , W. Colin Duncan , Katarzyna J. Siemienowicz","doi":"10.1016/j.mce.2024.112416","DOIUrl":"10.1016/j.mce.2024.112416","url":null,"abstract":"<div><div>Adipose tissue dysfunction is one of the features of Polycystic Ovary Syndrome (PCOS) with dysregulated adipogenesis, altered functional pathways and increased inflammation. It is increasingly clear that there are also male correlates of the hormonal and metabolic features of PCOS. We hypothesised that the effects of adipose tissue dysfunction are not sex-specific but rather fat depot-specific and independent of obesity. We used a clinically realistic ovine model of PCOS where pregnant sheep are injected with 100 mg of testosterone propionate twice weekly from day 62 to day 102 of gestation. We studied control and prenatally androgenised (PA) female and male offspring during adolescence and weight-matched control and PA female sheep during adulthood. We examined subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and in adult female sheep bone marrow adipose tissue (BMAT). Adipogenesis related gene expression in SAT was similar in adolescent female and male controls and the reduction in adipogenesis related gene expression by PA in female adipose tissue was not observed in males. Differences in expression of genes associated with adipose tissue function in adolescence in SAT driven by PA were found in both sexes. In adulthood, the changes seen in adolescent females were absent or reversed but there was an increase in inflammatory markers that was weight independent. In addition, BMAT showed increased inflammatory markers. Adipose dysfunction evolves with time and is focussed on SAT rather than VAT and is generally sex-specific although there are also effects of prenatal androgenisation on male SAT. In female adults, the inflammation seen in SAT is also present in BMAT and the development of blood cells in an inflammatory environment may have systemic implications.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"595 ","pages":"Article 112416"},"PeriodicalIF":3.8,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668472","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 : 2024-11-13DOI: 10.1016/j.mce.2024.112410
Daniela Rosendo-Silva , Eduardo Lopes , Tamaeh Monteiro-Alfredo , Inês Falcão-Pires , Hans Eickhoff , Sofia Viana , Flávio Reis , Ana Salomé Pires , Ana Margarida Abrantes , Maria Filomena Botelho , Raquel Seiça , Paulo Matafome
{"title":"Corrigendum to “The adipose tissue melanocortin 3 receptor is targeted by ghrelin and leptin and may be a therapeutic target in obesity” [Mol. Cell. Endocrinol. 594 (2024), 112367]","authors":"Daniela Rosendo-Silva , Eduardo Lopes , Tamaeh Monteiro-Alfredo , Inês Falcão-Pires , Hans Eickhoff , Sofia Viana , Flávio Reis , Ana Salomé Pires , Ana Margarida Abrantes , Maria Filomena Botelho , Raquel Seiça , Paulo Matafome","doi":"10.1016/j.mce.2024.112410","DOIUrl":"10.1016/j.mce.2024.112410","url":null,"abstract":"","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"595 ","pages":"Article 112410"},"PeriodicalIF":3.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623849","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 : 2024-11-13DOI: 10.1016/j.mce.2024.112408
Chen Liu , Limin Zhang , Siqi Li , Ruixi Zhou , Wenbo Wu , Yumei Liu , Ming Shu , Wanwei Li , Xiaohong Li
Epidemiological studies have indicated that exposure to hexavalent chromium (Cr(VI)) is associated with increased morbidity in the population. Resveratrol (Res) is a polyphenolic compound known for its role in mitigating oxidative stress and inflammation. In this study, we investigated the effects of resveratrol on Cr(VI)-induced disorders of glycolipid metabolism and elucidated its mechanisms. Male C57BL/6 mice were exposed to resveratrol and Cr(VI) for 45 days. Cr(VI) exposure led to elevated blood glucose levels, impaired glucose tolerance and insulin resistance, oxidative and inflammatory responses, and alterations in glycolipid metabolism molecules such as PCK1 and SREBP1, along with inhibition of HNF1b and GPX1. Resveratrol pretreatment increased the expression of HNF1b and GPX1, reduced oxidative and inflammatory responses, and ultimately ameliorated Cr(VI)-induced glycolipid metabolism disorders. These findings suggest potential new targets for the prevention and treatment of dysglycolipidosis.
{"title":"Resveratrol attenuates Cr(VI)-induced disorders of glycolipid metabolism by regulating HNF1b/GPX1 in mice","authors":"Chen Liu , Limin Zhang , Siqi Li , Ruixi Zhou , Wenbo Wu , Yumei Liu , Ming Shu , Wanwei Li , Xiaohong Li","doi":"10.1016/j.mce.2024.112408","DOIUrl":"10.1016/j.mce.2024.112408","url":null,"abstract":"<div><div>Epidemiological studies have indicated that exposure to hexavalent chromium (Cr(VI)) is associated with increased morbidity in the population. Resveratrol (Res) is a polyphenolic compound known for its role in mitigating oxidative stress and inflammation. In this study, we investigated the effects of resveratrol on Cr(VI)-induced disorders of glycolipid metabolism and elucidated its mechanisms. Male C57BL/6 mice were exposed to resveratrol and Cr(VI) for 45 days. Cr(VI) exposure led to elevated blood glucose levels, impaired glucose tolerance and insulin resistance, oxidative and inflammatory responses, and alterations in glycolipid metabolism molecules such as PCK1 and SREBP1, along with inhibition of HNF1b and GPX1. Resveratrol pretreatment increased the expression of HNF1b and GPX1, reduced oxidative and inflammatory responses, and ultimately ameliorated Cr(VI)-induced glycolipid metabolism disorders. These findings suggest potential new targets for the prevention and treatment of dysglycolipidosis.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"595 ","pages":"Article 112408"},"PeriodicalIF":3.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623974","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 : 2024-11-13DOI: 10.1016/j.mce.2024.112414
Batoul Abi Zamer , Jasmin Shafarin , BasmaM. Sharaf , HamzaM. Al Hroub , Nelson C. Soares , Mohammad H. Semreen , Mawieh Hamad , Jibran Sualeh Muhammad
Purine metabolism is upregulated in various cancers including colorectal cancer (CRC). While previous work has elucidated the role of estrogen (E2) in metabolic reprogramming and ATP production, the effect of E2 on purine metabolism remains largely unknown. Herein, the impact of E2 signalling on purine metabolism in CRC cells was investigated using metabolome and transcriptome profiling of cell extracts derived from E2-treated HCT-116 cells with intact or silenced estrogen receptor alpha (ERα). Purine metabolic pathway enrichment analysis showed that 27 genes in the de novo purine synthesis pathway were downregulated in E2-treated CRC cells. Downstream consequences of E2 treatment including the induction of DNA damage, cell cycle arrest, and apoptosis were all shown to be ERα-dependent. These findings demonstrate, for the first time, that E2 exerts a significant anti-growth and survival effect in CRC cells by targeting the purine synthesis pathway in a ERα-dependent manner, meriting further investigation of the therapeutic utility of E2 signalling in CRC.
嘌呤代谢在包括结直肠癌（CRC）在内的各种癌症中都会上调。虽然以前的研究已经阐明了雌激素（E2）在代谢重编程和 ATP 生成中的作用，但 E2 对嘌呤代谢的影响在很大程度上仍然未知。在此，研究人员使用代谢组和转录组图谱分析法研究了E2信号对CRC细胞中嘌呤代谢的影响，这些细胞提取物来自经E2处理的HCT-116细胞，这些细胞具有完整或沉默的雌激素受体α（ERα）。嘌呤代谢通路富集分析表明，E2 处理的 CRC 细胞中，27 个新嘌呤合成通路基因下调。E2处理的下游结果，包括诱导DNA损伤、细胞周期停滞和细胞凋亡，均显示为ERα依赖性。这些研究结果首次证明，E2通过靶向嘌呤合成途径，以ERα依赖性方式对CRC细胞产生显著的抗生长和存活作用，值得进一步研究E2信号在CRC中的治疗作用。
{"title":"Estrogen-mediated inhibition of purine metabolism and cell cycle arrest as a novel therapeutic approach in colorectal cancer","authors":"Batoul Abi Zamer , Jasmin Shafarin , BasmaM. Sharaf , HamzaM. Al Hroub , Nelson C. Soares , Mohammad H. Semreen , Mawieh Hamad , Jibran Sualeh Muhammad","doi":"10.1016/j.mce.2024.112414","DOIUrl":"10.1016/j.mce.2024.112414","url":null,"abstract":"<div><div>Purine metabolism is upregulated in various cancers including colorectal cancer (CRC). While previous work has elucidated the role of estrogen (E2) in metabolic reprogramming and ATP production, the effect of E2 on purine metabolism remains largely unknown. Herein, the impact of E2 signalling on purine metabolism in CRC cells was investigated using metabolome and transcriptome profiling of cell extracts derived from E2-treated HCT-116 cells with intact or silenced estrogen receptor alpha (ERα). Purine metabolic pathway enrichment analysis showed that 27 genes in the <em>de novo</em> purine synthesis pathway were downregulated in E2-treated CRC cells. Downstream consequences of E2 treatment including the induction of DNA damage, cell cycle arrest, and apoptosis were all shown to be ERα-dependent. These findings demonstrate, for the first time, that E2 exerts a significant anti-growth and survival effect in CRC cells by targeting the purine synthesis pathway in a ERα-dependent manner, meriting further investigation of the therapeutic utility of E2 signalling in CRC.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"596 ","pages":"Article 112414"},"PeriodicalIF":3.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639275","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 : 2024-11-12DOI: 10.1016/j.mce.2024.112412
Gang-Qing Yao, Meiling Zhu, Karl Insogna
Parathyroid hormone (PTH) receptor agonists promote bone formation but also increase osteoclastogenesis, in part by increasing expression of the receptor activator of nuclear factor kappa-Β ligand (RANKL). In addition to activation of transcription, regulation of mRNA stability is another important molecular mechanism controlling mRNA abundance. PTH treatment for 6 h resulted in a 7.4-fold elevation in RANKL mRNA expression in UAMS-32P cells, despite prior inhibition of cellular transcription by thiophosphoryl (TPL). RANKL mRNA, like other TNF family members, contains AU-Rich Elements (AREs) in the 3’ UTR. AU-Rich Element Binding Proteins (ABPs including KSRP, TTP, AUF1 and HuR) bind to AREs and regulate mRNA stability. There was significantly more KSRP bound to RANKL mRNA than any of the other ABPs. PTH did not increase the amount of ABPs bound to the RANKL transcript. However, the level of cellular phosphorylated KSRP was significantly increased in UAMS-32P cells pre-treated with TPL followed by PTH exposure, compared to cells treated with vehicle following TPL. The extent of phosphorylation of cellular AUF1, HuR, and TTP did not increase with PTH treatment. There were no significant changes in the cellular content of total Pin1 and phospho-Pin1 protein with PTH treatment. We conclude that increases in cellular phospho-KSRP following PTH treatment, together with fact that the total amount of the KSRP bound to the RANKL mRNA did not change with PTH-treatment, may indicate that phospho-KSRP plays some role in stabilizing the RANKL transcript.
{"title":"PTH-dependent stabilization of RANKL mRNA is associated with increased phosphorylation of the KH-type splicing regulatory protein","authors":"Gang-Qing Yao, Meiling Zhu, Karl Insogna","doi":"10.1016/j.mce.2024.112412","DOIUrl":"10.1016/j.mce.2024.112412","url":null,"abstract":"<div><div>Parathyroid hormone (PTH) receptor agonists promote bone formation but also increase osteoclastogenesis, in part by increasing expression of the receptor activator of nuclear factor kappa-Β ligand (RANKL). In addition to activation of transcription, regulation of mRNA stability is another important molecular mechanism controlling mRNA abundance. PTH treatment for 6 h resulted in a 7.4-fold elevation in RANKL mRNA expression in UAMS-32P cells, despite prior inhibition of cellular transcription by thiophosphoryl (TPL). RANKL mRNA, like other TNF family members, contains AU-Rich Elements (AREs) in the 3’ UTR. AU-Rich Element Binding Proteins (ABPs including KSRP, TTP, AUF1 and HuR) bind to AREs and regulate mRNA stability. There was significantly more KSRP bound to RANKL mRNA than any of the other ABPs. PTH did not increase the amount of ABPs bound to the RANKL transcript. However, the level of cellular phosphorylated KSRP was significantly increased in UAMS-32P cells pre-treated with TPL followed by PTH exposure, compared to cells treated with vehicle following TPL. The extent of phosphorylation of cellular AUF1, HuR, and TTP did not increase with PTH treatment. There were no significant changes in the cellular content of total Pin1 and phospho-Pin1 protein with PTH treatment. We conclude that increases in cellular phospho-KSRP following PTH treatment, together with fact that the total amount of the KSRP bound to the RANKL mRNA did not change with PTH-treatment, may indicate that phospho-KSRP plays some role in stabilizing the RANKL transcript.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"595 ","pages":"Article 112412"},"PeriodicalIF":3.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623965","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}
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