Pub Date : 2025-01-07DOI: 10.1016/j.mce.2025.112457
Rajesh Chaudhary , Tahra K. Suhan , Chao Wu , Afnan Alzamrooni , Nageswara Madamanchi , Ahmed Abdel-Latif
Preclinical heart failure studies rely heavily on mouse models despite their higher metabolic and heart rates compared to humans. This study examines how mouse strain (C57BL/6J vs. C57BL/6N) and housing temperature (23 °C vs. 30 °C) affect a well-established two-hit HFpEF model using high-fat diet with L-NAME treatment in male C57BL/6 mouse. Metabolic parameters and cardiac function were assessed at baseline, week 5, and week 15. Thermoneutral housing (30 °C) reduced early diastolic dysfunction in the J strain and altered metabolic profiles in both strains, decreasing energy expenditure and fat oxidation. The J strain specifically showed reduced respiratory exchange ratio and glucose oxidation at 30 °C. While physical activity remained constant across groups, both strains exhibited increased cardiac fibrosis and inflammatory gene expression under HFD + L-NAME, independent of housing temperature. These findings reveal strain-specific physiological adaptations to housing temperature, emphasizing the need to consider environmental conditions in heart failure research carefully.
临床前心力衰竭研究严重依赖于小鼠模型，尽管它们的代谢和心率比人类高。本研究考察了小鼠品系（C57BL/6J vs. C57BL/6N）和饲养温度（23°C vs. 30°C）对C57BL/6雄性小鼠高脂饮食加L-NAME治疗的两击HFpEF模型的影响。在基线、第5周和第15周评估代谢参数和心功能。热中性环境（30°C）减少了J菌株的早期舒张功能障碍，并改变了两种菌株的代谢谱，减少了能量消耗和脂肪氧化。在30°C时，J菌株的呼吸交换率和葡萄糖氧化率明显降低。虽然各组之间的身体活动保持不变，但在HFD+L-NAME下，两种菌株的心脏纤维化和炎症基因表达均有所增加，与住房温度无关。这些发现揭示了菌株对环境温度的特定生理适应，强调了在心力衰竭研究中仔细考虑环境条件的必要性。
{"title":"Housing temperature influences metabolic phenotype of heart failure with preserved ejection fraction in J vs N strain C57BL/6 mice","authors":"Rajesh Chaudhary , Tahra K. Suhan , Chao Wu , Afnan Alzamrooni , Nageswara Madamanchi , Ahmed Abdel-Latif","doi":"10.1016/j.mce.2025.112457","DOIUrl":"10.1016/j.mce.2025.112457","url":null,"abstract":"<div><div>Preclinical heart failure studies rely heavily on mouse models despite their higher metabolic and heart rates compared to humans. This study examines how mouse strain (C57BL/6J vs. C57BL/6N) and housing temperature (23 °C vs. 30 °C) affect a well-established two-hit HFpEF model using high-fat diet with L-NAME treatment in male C57BL/6 mouse. Metabolic parameters and cardiac function were assessed at baseline, week 5, and week 15. Thermoneutral housing (30 °C) reduced early diastolic dysfunction in the J strain and altered metabolic profiles in both strains, decreasing energy expenditure and fat oxidation. The J strain specifically showed reduced respiratory exchange ratio and glucose oxidation at 30 °C. While physical activity remained constant across groups, both strains exhibited increased cardiac fibrosis and inflammatory gene expression under HFD + L-NAME, independent of housing temperature. These findings reveal strain-specific physiological adaptations to housing temperature, emphasizing the need to consider environmental conditions in heart failure research carefully.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"598 ","pages":"Article 112457"},"PeriodicalIF":3.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951786","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 : 2025-01-07DOI: 10.1016/j.mce.2025.112458
Firman P. Idris , Jocelyn van den Bergen , Gorjana Robevska , Lucas G.A. Ferreira , Karen R. Ferreira , Marina M.L. Kizys , Magnus R. Dias da Silva , Hennie T. Bruggenwirth , Yolande van Bever , Andrew H. Sinclair , Katie L. Ayers
In mammals, male sexual development is initiated by the expression of the Sex-determining-Region-Y (SRY) gene. SRY contains a highly conserved high mobility group (HMG) box essential for DNA binding and activity. Variants in SRY cause Differences of Sex Development (DSD), accounting for 10–15% of 46, XY gonadal dysgenesis cases. Here, we present the functional analysis of five SRY coding variants identified in patients with 46, XY DSD. Four variants (p.Asp58Glu, p.Arg75Lys, p.Met85Thr, and p.Arg86Ter) are located within the HMG box and one variant (p.Tyr198Cysfs∗18) located in the C-terminal domain. We functionally characterise the impact of these variants in vitro, investigating SRY localisation and transactivational activity using SOX9 regulatory elements that are responsive to SRY. We find that three variants (p.Met85Thr, p.Arg86Ter, and p.Tyr198Cysfs∗18) have reduced or abolished transactivational activity suggesting these are pathogenic, with the p.Arg86Ter variant undetectable in our assays and the p.Met85Thr variant exhibiting reduced nuclear localisation. The pathogenic mechanisms underlying reduced activity of the novel elongated p.Tyr198Cysfs∗18 variant is however unclear, although this variant also affected localisation. In contrast, two additional variants (p.Asp58Glu and p.Arg75Lys) had no discernible effects on nuclear localisation or transactivational activity despite in silico analysis predicting impaired DNA binding. Taken together, our data establish the likely pathogenicity of these SRY variants and improve diagnostic certainty for the patients in which they were identified.
{"title":"Functional analysis of SRY variants in individuals with 46,XY differences of sex development","authors":"Firman P. Idris , Jocelyn van den Bergen , Gorjana Robevska , Lucas G.A. Ferreira , Karen R. Ferreira , Marina M.L. Kizys , Magnus R. Dias da Silva , Hennie T. Bruggenwirth , Yolande van Bever , Andrew H. Sinclair , Katie L. Ayers","doi":"10.1016/j.mce.2025.112458","DOIUrl":"10.1016/j.mce.2025.112458","url":null,"abstract":"<div><div>In mammals, male sexual development is initiated by the expression of the <em>Sex-determining-Region-Y</em> (<em>SRY</em>) gene. <em>SRY</em> contains a highly conserved high mobility group (HMG) box essential for DNA binding and activity. Variants in <em>SRY</em> cause Differences of Sex Development (DSD), accounting for 10–15% of 46, XY gonadal dysgenesis cases. Here, we present the functional analysis of five <em>SRY</em> coding variants identified in patients with 46, XY DSD. Four variants (p.Asp58Glu, p.Arg75Lys, p.Met85Thr, and p.Arg86Ter) are located within the HMG box and one variant (p.Tyr198Cysfs∗18) located in the C-terminal domain. We functionally characterise the impact of these variants <em>in vitro</em>, investigating SRY localisation and transactivational activity using <em>SOX9</em> regulatory elements that are responsive to SRY. We find that three variants (p.Met85Thr, p.Arg86Ter, and p.Tyr198Cysfs∗18) have reduced or abolished transactivational activity suggesting these are pathogenic, with the p.Arg86Ter variant undetectable in our assays and the p.Met85Thr variant exhibiting reduced nuclear localisation. The pathogenic mechanisms underlying reduced activity of the novel elongated p.Tyr198Cysfs∗18 variant is however unclear, although this variant also affected localisation. In contrast, two additional variants (p.Asp58Glu and p.Arg75Lys) had no discernible effects on nuclear localisation or transactivational activity despite <em>in silico</em> analysis predicting impaired DNA binding. Taken together, our data establish the likely pathogenicity of these <em>SRY</em> variants and improve diagnostic certainty for the patients in which they were identified.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"598 ","pages":"Article 112458"},"PeriodicalIF":3.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951785","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}
Liver fibrosis is potentially a reversible form of liver disease that evolved from the early stage of liver scarring as a consequence of chronic liver injuries. Recurrent injuries in the liver without any appropriate medication cause the injuries to get intense and deeper, which gradually leads to the progression of irreversible cirrhosis or carcinoma. Unfortunately, there are no approved treatment strategies for reversing hepatic fibrosis, making it one of the significant risk factors for developing advanced liver disorders and liver disease-associated mortality. Consequently, the interpretation of the fundamental mechanisms, etiology, and pathogenesis is crucial for identifying the potential therapeutic target as well as evaluating novel anti-fibrotic therapy. However, despite innumerable research, the functional mechanism and disease characteristics are still obscure. To accelerate the understanding of underlying disease pathophysiology, molecular pathways and disease progression mechanism, it is crucial to mimic human liver disease through the formation of precise disease models. Although various in vitro and in vivo liver fibrotic models have emerged and developed already, a perfect clinical model replicating human liver diseases is yet to be established, which is one of the major challenges in discovering proper therapeutics. This review paper will shed light on pathophysiology, signaling pathways, preclinical models of liver fibrosis, and their limitations.
{"title":"A guide to pathophysiology, signaling pathways, and preclinical models of liver fibrosis","authors":"Mehonaz Sultana, Md Asrarul Islam, Rhema Khairnar, Sunil Kumar","doi":"10.1016/j.mce.2024.112448","DOIUrl":"10.1016/j.mce.2024.112448","url":null,"abstract":"<div><div>Liver fibrosis is potentially a reversible form of liver disease that evolved from the early stage of liver scarring as a consequence of chronic liver injuries. Recurrent injuries in the liver without any appropriate medication cause the injuries to get intense and deeper, which gradually leads to the progression of irreversible cirrhosis or carcinoma. Unfortunately, there are no approved treatment strategies for reversing hepatic fibrosis, making it one of the significant risk factors for developing advanced liver disorders and liver disease-associated mortality. Consequently, the interpretation of the fundamental mechanisms, etiology, and pathogenesis is crucial for identifying the potential therapeutic target as well as evaluating novel anti-fibrotic therapy. However, despite innumerable research, the functional mechanism and disease characteristics are still obscure. To accelerate the understanding of underlying disease pathophysiology, molecular pathways and disease progression mechanism, it is crucial to mimic human liver disease through the formation of precise disease models. Although various <em>in vitro</em> and <em>in vivo</em> liver fibrotic models have emerged and developed already, a perfect clinical model replicating human liver diseases is yet to be established, which is one of the major challenges in discovering proper therapeutics. This review paper will shed light on pathophysiology, signaling pathways, preclinical models of liver fibrosis, and their limitations.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"598 ","pages":"Article 112448"},"PeriodicalIF":3.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927612","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 : 2024-12-24DOI: 10.1016/j.mce.2024.112444
Damáris Barcelos Cunha Azeredo , Denilson de Sousa Anselmo , Ana Clara Falcão Veríssimo , Luana Lopes de Souza , Patricia Cristina Lisboa , Paula Soares , Ana Paula Santos-Silva , Jones Bernardes Graceli , Denise Pires de Carvalho , D'Angelo Magliano , Leandro Miranda-Alves
Methylparaben (MP) belongs to the paraben class and is widely used as a preservative in personal care products, medicines, and some foods. MP acts as an endocrine disrupting chemical (EDC) on the hypothalamic-pituitary-thyroid (HPT) axis. However, the effects of MP have not yet been completely elucidated, as published results are scarce and controversial. The objective of this work was to evaluate the effects of subacute exposure to MP on the HPT axis of male rats. To achieve this, in this study the animals were divided into four experimental groups: control, MP3, MP30 and MP300 (3, 30 and 300 μg/kg/day, respectively). The rats were gavage for 14 days and sacrificed at the end of MP treatment. Our findings demonstrated that MP can promote important changes in thyroid morphology, including a decrease in follicular area, colloid area, epithelial area, and epithelial height, affecting the homeostasis of the HPT axis, and affecting the expression of genes related to hormonal biosynthesis. Furthermore, changes in interstitial collagen deposition were also demonstrated. Finally, we conclude that exposure to MP can be harmful to health, as it is involved in the dysregulation of the thyroid gland, affecting its morphophysiology, suggesting that even doses considered safe by current legislation can be dangerous and should be reconsidered.
{"title":"Endocrine-disrupting chemical, methylparaben, in environmentally relevant exposure promotes hazardous effects on the hypothalamus-pituitary-thyroid axis","authors":"Damáris Barcelos Cunha Azeredo , Denilson de Sousa Anselmo , Ana Clara Falcão Veríssimo , Luana Lopes de Souza , Patricia Cristina Lisboa , Paula Soares , Ana Paula Santos-Silva , Jones Bernardes Graceli , Denise Pires de Carvalho , D'Angelo Magliano , Leandro Miranda-Alves","doi":"10.1016/j.mce.2024.112444","DOIUrl":"10.1016/j.mce.2024.112444","url":null,"abstract":"<div><div>Methylparaben (MP) belongs to the paraben class and is widely used as a preservative in personal care products, medicines, and some foods. MP acts as an endocrine disrupting chemical (EDC) on the hypothalamic-pituitary-thyroid (HPT) axis. However, the effects of MP have not yet been completely elucidated, as published results are scarce and controversial. The objective of this work was to evaluate the effects of subacute exposure to MP on the HPT axis of male rats. To achieve this, in this study the animals were divided into four experimental groups: control, MP3, MP30 and MP300 (3, 30 and 300 μg/kg/day, respectively). The rats were gavage for 14 days and sacrificed at the end of MP treatment. Our findings demonstrated that MP can promote important changes in thyroid morphology, including a decrease in follicular area, colloid area, epithelial area, and epithelial height, affecting the homeostasis of the HPT axis, and affecting the expression of genes related to hormonal biosynthesis. Furthermore, changes in interstitial collagen deposition were also demonstrated. Finally, we conclude that exposure to MP can be harmful to health, as it is involved in the dysregulation of the thyroid gland, affecting its morphophysiology, suggesting that even doses considered safe by current legislation can be dangerous and should be reconsidered.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"598 ","pages":"Article 112444"},"PeriodicalIF":3.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896075","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 : 2024-11-26DOI: 10.1016/j.mce.2024.112430
Gabriel Fernandes Teixeira , Juliana Mentzinger , Juliana Arruda de Souza Monnerat , Larissa Lírio Velasco , Bianca Bittencourt Lucchetti , Luiza Rocha , Livia Alves de Oliveira , Renata Frauches Medeiros , Antonio Claudio Lucas da Nóbrega , Helena Naly Miguens Rocha , Natália Galito Rocha
Stress is considered an independent risk factor for the development of cardiometabolic disorders, especially when it occurs during pregnancy, and it may play an important role in stress-induced fetal programming on the protein-folding homeostasis in hepatic endoplasmic reticulum. The study aimed to determine the effects of prenatal stress on the unfolded protein responses in the liver of male and female offspring of Wistar rats. Pregnant Wistar rats at 90 days old were divided into control and stress groups. The unpredictable stress protocol was performed from the 14th to the 21st day of pregnancy. The offspring of each group were divided into four groups according to sex and intervention. After the lactation period, the dams were anesthetized and euthanized for blood collection to determine plasma corticosterone levels. At 90 days old, the offspring were anesthetized and euthanized for liver tissue collection to measure protein expression of the endoplasmic reticulum stress. Dams submitted to prenatal stress showed an increase in corticosterone levels when compared to the control group. In the male offspring, prenatal stress induced lower body mass at birth and at 90 days compared to control, while females presented lower body mass only at birth. Prenatal stress reduced eIF2α expression in males, while increased p-eIF2α expression similarly in both sexes. Furthermore, only males had a greater p-eIF2α/eIF2α ratio and androgen receptor expression when compared to its respective control group and females. Prenatal stress induced a hepatic programming in the reticulum endoplasmic responses only in males at 90 days old by increasing androgen receptor, eIF2α phosphorylation and activity, while in females stress during pregnancy reduced cHDL and had little impact on hepatic unfolded protein response.
{"title":"Stress in pregnancy alters hepatic unfolded protein responses in male adult offspring","authors":"Gabriel Fernandes Teixeira , Juliana Mentzinger , Juliana Arruda de Souza Monnerat , Larissa Lírio Velasco , Bianca Bittencourt Lucchetti , Luiza Rocha , Livia Alves de Oliveira , Renata Frauches Medeiros , Antonio Claudio Lucas da Nóbrega , Helena Naly Miguens Rocha , Natália Galito Rocha","doi":"10.1016/j.mce.2024.112430","DOIUrl":"10.1016/j.mce.2024.112430","url":null,"abstract":"<div><div>Stress is considered an independent risk factor for the development of cardiometabolic disorders, especially when it occurs during pregnancy, and it may play an important role in stress-induced fetal programming on the protein-folding homeostasis in hepatic endoplasmic reticulum. The study aimed to determine the effects of prenatal stress on the unfolded protein responses in the liver of male and female offspring of Wistar rats. Pregnant Wistar rats at 90 days old were divided into control and stress groups. The unpredictable stress protocol was performed from the 14th to the 21st day of pregnancy. The offspring of each group were divided into four groups according to sex and intervention. After the lactation period, the dams were anesthetized and euthanized for blood collection to determine plasma corticosterone levels. At 90 days old, the offspring were anesthetized and euthanized for liver tissue collection to measure protein expression of the endoplasmic reticulum stress. Dams submitted to prenatal stress showed an increase in corticosterone levels when compared to the control group. In the male offspring, prenatal stress induced lower body mass at birth and at 90 days compared to control, while females presented lower body mass only at birth. Prenatal stress reduced eIF2α expression in males, while increased p-eIF2α expression similarly in both sexes. Furthermore, only males had a greater p-eIF2α/eIF2α ratio and androgen receptor expression when compared to its respective control group and females. Prenatal stress induced a hepatic programming in the reticulum endoplasmic responses only in males at 90 days old by increasing androgen receptor, eIF2α phosphorylation and activity, while in females stress during pregnancy reduced cHDL and had little impact on hepatic unfolded protein response.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"596 ","pages":"Article 112430"},"PeriodicalIF":3.8,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142746424","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.2024.112419
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}
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