Clinical Science (London, England : 1979)最新文献_第8页

Maternal high-fat diet induces long-term obesity with sex-dependent metabolic programming of adipocyte differentiation, hypertrophy and dysfunction in the offspring. 母体高脂肪饮食诱导后代的脂肪细胞分化、肥大和功能障碍的性别依赖性代谢程序的长期肥胖。

IF 6

Clinical Science (London, England : 1979) Pub Date : 2020-04-17 DOI: 10.1042/CS20191229

Thorsten Litzenburger, Eva-Kristina Huber, Katharina Dinger, Rebecca Wilke, Christina Vohlen, Jaco Selle, Mazlum Kadah, Thorsten Persigehl, Carola Heneweer, Jörg Dötsch, Miguel A Alejandre Alcazar

{"title":"Maternal high-fat diet induces long-term obesity with sex-dependent metabolic programming of adipocyte differentiation, hypertrophy and dysfunction in the offspring.","authors":"Thorsten Litzenburger, Eva-Kristina Huber, Katharina Dinger, Rebecca Wilke, Christina Vohlen, Jaco Selle, Mazlum Kadah, Thorsten Persigehl, Carola Heneweer, Jörg Dötsch, Miguel A Alejandre Alcazar","doi":"10.1042/CS20191229","DOIUrl":"https://doi.org/10.1042/CS20191229","url":null,"abstract":"Maternal obesity determines obesity and metabolic diseases in the offspring. The white adipose tissue (WAT) orchestrates metabolic pathways, and its dysfunction contributes to metabolic disorders in a sex-dependent manner. Here, we tested if sex differences influence the molecular mechanisms of metabolic programming of WAT in offspring of obese dams. To this end, maternal obesity was induced with high-fat diet (HFD) and the offspring were studied at an early phase [postnatal day 21 (P21)], a late phase (P70) and finally P120. In the early phase we found a sex-independent increase in WAT in offspring of obese dams using magnetic resonance imaging (MRI), which was more pronounced in females than males. While the adipocyte size increased in both sexes, the distribution of WAT differed in males and females. As mechanistic hints, we identified an inflammatory response in females and a senescence-associated reduction in the preadipocyte factor DLK in males. In the late phase, the obese body composition persisted in both sexes, with a partial reversal in females. Moreover, female offspring recovered completely from both the adipocyte hypertrophy and the inflammatory response. These findings were linked to a dysregulation of lipolytic, adipogenic and stemness-related markers as well as AMPKα and Akt signaling. Finally, the sex-dependent metabolic programming persisted with sex-specific differences in adipocyte size until P120. In conclusion, we do not only provide new insights into the molecular mechanisms of sex-dependent metabolic programming of WAT dysfunction, but also highlight the sex-dependent development of low- and high-grade pathogenic obesity.","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"921-939"},"PeriodicalIF":6.0,"publicationDate":"2020-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37795355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 31

Targeting mitochondria to protect the heart: a matter of balance? 靶向线粒体保护心脏：平衡问题？

Clinical Science (London, England : 1979) Pub Date : 2020-04-17 DOI: 10.1042/CS20200236

Fouad A Zouein, George W Booz

{"title":"Targeting mitochondria to protect the heart: a matter of balance?","authors":"Fouad A Zouein, George W Booz","doi":"10.1042/CS20200236","DOIUrl":"10.1042/CS20200236","url":null,"abstract":"Mitochondria are dynamic, undergoing both fission and fusion. Evidence indicates that a balance between these two processes is necessary to maintain a healthy state. With ischemia/reperfusion (I/R) of the heart, fission is enhanced and is associated with mitochondrial swelling, depolarization, and production of reactive oxygen species (ROS), as well as apoptosis. Blocking fission is effective in reducing I/R-induced tissue damage and contractile dysfunction. In a groundbreaking study appearing in Clinical Science, Maneechote et al. assessed whether correcting the imbalance in mitochondrial dynamics with I/R by enhancing fusion would also be protective. Using a rat model, they investigated the efficacy of pharmacological intervention with mitochondrial fusion promoter-M1 (M1) given before ischemia, during ischemia, or at the onset of reperfusion. With pretreatment being the most effective, they found that M1 attenuated the incidence of arrhythmias, reduced infarct size, preserved cardiac function, and decreased mortality. M1 reduced I/R-induced increases in cytosolic cytochrome c, cleaved caspase 3, and apoptosis. All M1 groups exhibited modestly attenuated I/R-induced mitochondrial ROS levels and swelling, and preserved mitochondrial membrane potential. M1 also prevented a decrease in complex V levels with I/R. However, exactly how M1 stimulates mitochondrial fusion is unclear and other nonfusion-related actions of this phenylhydrazone compound should be considered, such as anti-oxidant actions, preconditioning signaling, or effects on putative mitochondrial connexin 43.","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"885-888"},"PeriodicalIF":0.0,"publicationDate":"2020-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37832587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tumoral PD-1hiCD8+ T cells are partially exhausted and predict favorable outcome in triple-negative breast cancer. 肿瘤PD-1hiCD8+ T细胞部分衰竭，预测三阴性乳腺癌的有利结局。

IF 6

Clinical Science (London, England : 1979) Pub Date : 2020-04-17 DOI: 10.1042/CS20191261

Liang Guo, Chunmei Cao, Shyamal Goswami, Xiaoyan Huang, Linxiaoxi Ma, Yicheng Guo, Benlong Yang, Teng Li, Yayun Chi, Xiaoming Zhang, Jiong Wu

{"title":"Tumoral PD-1hiCD8+ T cells are partially exhausted and predict favorable outcome in triple-negative breast cancer.","authors":"Liang Guo, Chunmei Cao, Shyamal Goswami, Xiaoyan Huang, Linxiaoxi Ma, Yicheng Guo, Benlong Yang, Teng Li, Yayun Chi, Xiaoming Zhang, Jiong Wu","doi":"10.1042/CS20191261","DOIUrl":"https://doi.org/10.1042/CS20191261","url":null,"abstract":"Tumor-infiltrating PD-1hi dysfunctional CD8+ T cells have been identified in several tumors but largely unexplored in breast cancer (BC). Here we aimed to extensively explore PD-1hiCD8+ T cells in BC, focusing on the triple-negative BC (TNBC) subtype. Flow cytometry was used to study the phenotypes and functions of CD8+ T-cell subsets in peripheral blood and surgical specimens from treatment-naive BC patients. RNA-seq expression data generated to dissect the molecular features of tumoral PD-1neg, PD-1lo and PD-1hi CD8+ T cells. Further, the associations between tumoral PD-1hi CD8+ T cells and the clinicopathological features of 503 BC patients were explored. Finally, multiplexed immunohistochemistry (mIHC) was performed to evaluate in situ PD-1hiCD8+ T cells on the tissue microarrays (TMAs, n=328) for prognostic assessment and stratification of TNBC patients. PD-1hiCD8+ T cells found readily detectable in tumor tissues but rarely in peripheral blood. These cells shared the phenotypic and molecular features with exhausted and tissue-resident memory T cells (TRM) with a skewed TCR repertoire involvement. Interestingly, PD-1hiCD8+ T cells are in the state of exhaustion characterized by higher T-BET and reduced EOMES expression. PD-1hiCD8+ T cells found preferentially enriched within solid tumors, but predominant stromal infiltration of PD-1hiCD8+ T subset was associated with improved survival in TNBC patients. Taken together, tumoral PD-1hiCD8+ T-cell subpopulation in BC is partially exhausted, and their abundance signifies 'hot' immune status with favorable outcomes. Reinvigorating this population may provide further therapeutic opportunities in TNBC patients.","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"711-726"},"PeriodicalIF":6.0,"publicationDate":"2020-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37764147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 15

DsbA-L deficiency exacerbates mitochondrial dysfunction of tubular cells in diabetic kidney disease. DsbA-L缺乏加重糖尿病肾病小管细胞线粒体功能障碍。

IF 6

Clinical Science (London, England : 1979) Pub Date : 2020-04-17 DOI: 10.1042/CS20200005

Peng Gao, Ming Yang, Xianghui Chen, Shan Xiong, Jiahao Liu, Lin Sun

{"title":"DsbA-L deficiency exacerbates mitochondrial dysfunction of tubular cells in diabetic kidney disease.","authors":"Peng Gao, Ming Yang, Xianghui Chen, Shan Xiong, Jiahao Liu, Lin Sun","doi":"10.1042/CS20200005","DOIUrl":"https://doi.org/10.1042/CS20200005","url":null,"abstract":"Excessive mitochondrial fission has been identified as the central pathogenesis of diabetic kidney disease (DKD), but the precise mechanisms remain unclear. Disulfide-bond A oxidoreductase-like protein (DsbA-L) is highly expressed in mitochondria in tubular cells of the kidney, but its pathophysiological role in DKD is unknown. Our bioinformatics analysis showed that tubular DsbA-L mRNA levels were positively associated with eGFR but negatively associated with Scr and 24h-proteinuria in CKD patients. Furthermore, the genes that were coexpressed with DsbA-L were mainly enriched in mitochondria and were involved in oxidative phosphorylation. In vivo, knockout of DsbA-L exacerbated diabetic mice tubular cell mitochondrial fragmentation, oxidative stress and renal damage. In vitro, we found that DsbA-L was localized in the mitochondria of HK-2 cells. High glucose (HG, 30 mM) treatment decreased DsbA-L expression followed by increased mitochondrial ROS (mtROS) generation and mitochondrial fragmentation. In addition, DsbA-L knockdown exacerbated these abnormalities, but this effect was reversed by overexpression of DsbA-L. Mechanistically, under HG conditions, knockdown DsbA-L expression accentuated JNK phosphorylation in HK-2 cells. Furthermore, administration of a JNK inhibitor (SP600125) or the mtROS scavenger MitoQ significantly attenuated JNK activation and subsequent mitochondrial fragmentation in DsbA-L-knockdown HK-2 cells. Additionally, the down-regulation of DsbA-L also amplified the gene and protein expression of mitochondrial fission factor (MFF) via the JNK pathway, enhancing its ability to recruit DRP1 to mitochondria. Taken together, these results link DsbA-L to alterations in mitochondrial dynamics during tubular injury in the pathogenesis of DKD and unveil a novel mechanism by which DsbA-L modifies mtROS/JNK/MFF-related mitochondrial fission.","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"677-694"},"PeriodicalIF":6.0,"publicationDate":"2020-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37734011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 20

Alamandine attenuates hepatic fibrosis by regulating autophagy induced by NOX4-dependent ROS. almanmanine通过调节nox4依赖性ROS诱导的自噬来减轻肝纤维化。

IF 6

Clinical Science (London, England : 1979) Pub Date : 2020-04-17 DOI: 10.1042/CS20191235

Yun Huang, Yang Li, Anni Lou, Guo Zhen Wang, Ye Hu, Yijie Zhang, Weichang Huang, Jun Wang, Yue Li, Xintao Zhu, Tingting Chen, Jiayi Lin, Ying Meng, Xu Li

{"title":"Alamandine attenuates hepatic fibrosis by regulating autophagy induced by NOX4-dependent ROS.","authors":"Yun Huang, Yang Li, Anni Lou, Guo Zhen Wang, Ye Hu, Yijie Zhang, Weichang Huang, Jun Wang, Yue Li, Xintao Zhu, Tingting Chen, Jiayi Lin, Ying Meng, Xu Li","doi":"10.1042/CS20191235","DOIUrl":"https://doi.org/10.1042/CS20191235","url":null,"abstract":"Angiotensin II (Ang II) has been reported to aggravate hepatic fibrosis by inducing NADPH oxidase (NOX)-dependent oxidative stress. Alamandine (ALA) protects against fibrosis by counteracting Ang II via the MAS-related G-protein coupled (MrgD) receptor, though the effects of alamandine on hepatic fibrosis remain unknown. Autophagy activated by reactive oxygen species (ROS) is a novel mechanism of hepatic fibrosis. However, whether autophagy is involved in the regulation of Ang II-induced hepatic fibrosis still requires investigation. We explored the effect of alamandine on hepatic fibrosis via regulation of autophagy by redox balance modulation. In vivo, alamandine reduced CCl4-induced hepatic fibrosis, hydrogen peroxide (H2O2) content, protein levels of NOX4 and autophagy impairment. In vitro, Ang II treatment elevated NOX4 protein expression and ROS production along with up-regulation of the angiotensin converting enzyme (ACE)/Ang II/Ang II type 1 receptor (AT1R) axis. These changes resulted in the accumulation of impaired autophagosomes in hepatic stellate cells (HSCs). Treatment with NOX4 inhibitor VAS2870, ROS scavenger N-acetylcysteine (NAC), and NOX4 small interfering RNA (siRNA) inhibited Ang II-induced autophagy and collagen synthesis. Alamandine shifted the balance of renin-angiotensin system (RAS) toward the angiotensin converting enzyme 2 (ACE2)/alamandine/MrgD axis, and inhibited both Ang II-induced ROS and autophagy activation, leading to attenuation of HSCs migration or collagen synthesis. In summary, alamandine attenuated liver fibrosis by regulating autophagy induced by NOX4-dependent ROS.","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"853-869"},"PeriodicalIF":6.0,"publicationDate":"2020-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37783666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 22

Effects of corticosteroids on COPD lung macrophage phenotype and function. 皮质类固醇对COPD肺巨噬细胞表型和功能的影响。

IF 6

Clinical Science (London, England : 1979) Pub Date : 2020-04-17 DOI: 10.1042/CS20191202

Andrew Higham, Tom Scott, Jian Li, Rosemary Gaskell, Aisha Baba Dikwa, Rajesh Shah, M Angeles Montero-Fernandez, Simon Lea, Dave Singh

{"title":"Effects of corticosteroids on COPD lung macrophage phenotype and function.","authors":"Andrew Higham, Tom Scott, Jian Li, Rosemary Gaskell, Aisha Baba Dikwa, Rajesh Shah, M Angeles Montero-Fernandez, Simon Lea, Dave Singh","doi":"10.1042/CS20191202","DOIUrl":"https://doi.org/10.1042/CS20191202","url":null,"abstract":"The numbers of macrophages are increased in the lungs of chronic obstructive pulmonary disease (COPD) patients. COPD lung macrophages have reduced ability to phagocytose microbes and efferocytose apoptotic cells. Inhaled corticosteroids (ICSs) are widely used anti-inflammatory drugs in COPD; however, their role beyond suppression of cytokine release has not been explored in COPD macrophages. We have examined the effects of corticosteroids on COPD lung macrophage phenotype and function. Lung macrophages from controls and COPD patients were treated with corticosteroids; effects on gene and protein expression of CD163, CD164, CD206, MERTK, CD64, CD80 and CD86 were studied. We also examined the effect of corticosteroids on the function of CD163, MERTK and cluster of differentiation 64 (CD64). Corticosteroid increased CD163, CD164, CD206 and MERTK expression and reduced CD64, CD80 and CD86 expression. We also observed an increase in the uptake of the haemoglobin-haptoglobin complex (CD163) from 59 up to 81% and an increase in efferocytosis of apoptotic neutrophils (MERTK) from 15 up to 28% following corticosteroid treatment. We observed no effect on bacterial phagocytosis. Corticosteroids alter the phenotype and function of COPD lung macrophages. Our findings suggest mechanisms by which corticosteroids exert therapeutic benefit in COPD, reducing iron available for bacterial growth and enhancing efferocytosis.","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"751-763"},"PeriodicalIF":6.0,"publicationDate":"2020-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37784497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 18

Targeting perivascular and epicardial adipose tissue inflammation: therapeutic opportunities for cardiovascular disease. 针对血管周围和心外膜脂肪组织炎症:心血管疾病的治疗机会。

IF 6

Clinical Science (London, England : 1979) Pub Date : 2020-04-17 DOI: 10.1042/CS20190227

Rim Rafeh, Anissa Viveiros, Gavin Y Oudit, Ahmed F El-Yazbi

{"title":"Targeting perivascular and epicardial adipose tissue inflammation: therapeutic opportunities for cardiovascular disease.","authors":"Rim Rafeh, Anissa Viveiros, Gavin Y Oudit, Ahmed F El-Yazbi","doi":"10.1042/CS20190227","DOIUrl":"https://doi.org/10.1042/CS20190227","url":null,"abstract":"Major shifts in human lifestyle and dietary habits toward sedentary behavior and refined food intake triggered steep increase in the incidence of metabolic disorders including obesity and Type 2 diabetes. Patients with metabolic disease are at a high risk of cardiovascular complications ranging from microvascular dysfunction to cardiometabolic syndromes including heart failure. Despite significant advances in the standards of care for obese and diabetic patients, current therapeutic approaches are not always successful in averting the accompanying cardiovascular deterioration. There is a strong relationship between adipose inflammation seen in metabolic disorders and detrimental changes in cardiovascular structure and function. The particular importance of epicardial and perivascular adipose pools emerged as main modulators of the physiology or pathology of heart and blood vessels. Here, we review the peculiarities of these two fat depots in terms of their origin, function, and pathological changes during metabolic deterioration. We highlight the rationale for pharmacological targeting of the perivascular and epicardial adipose tissue or associated signaling pathways as potential disease modifying approaches in cardiometabolic syndromes.","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"827-851"},"PeriodicalIF":6.0,"publicationDate":"2020-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37817690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 37

(Letter to the Editor) Response to: protective role of peroxiredoxin-4 in heart failure. (致编辑的信)对:过氧化物还毒素-4在心力衰竭中的保护作用的回应。

IF 6

Clinical Science (London, England : 1979) Pub Date : 2020-01-17 DOI: 10.1042/CS20191184

Natalia López-Andrés

引用次数: 0

Inflammation both increases and causes resistance to FGF23 in normal and uremic rats. 在正常和尿毒症大鼠中，炎症既增加又引起对FGF23的抵抗。

IF 6

Clinical Science (London, England : 1979) Pub Date : 2020-01-17 DOI: 10.1042/CS20190779

Maria E Rodríguez-Ortiz, Juan M Díaz-Tocados, Juan R Muñoz-Castañeda, Carmen Herencia, Carmen Pineda, Julio M Martínez-Moreno, Addy Montes de Oca, Rodrigo López-Baltanás, Juan Alcalá-Díaz, Alberto Ortiz, Escolástico Aguilera-Tejero, Arnold Felsenfeld, Mariano Rodríguez, Yolanda Almadén

{"title":"Inflammation both increases and causes resistance to FGF23 in normal and uremic rats.","authors":"Maria E Rodríguez-Ortiz, Juan M Díaz-Tocados, Juan R Muñoz-Castañeda, Carmen Herencia, Carmen Pineda, Julio M Martínez-Moreno, Addy Montes de Oca, Rodrigo López-Baltanás, Juan Alcalá-Díaz, Alberto Ortiz, Escolástico Aguilera-Tejero, Arnold Felsenfeld, Mariano Rodríguez, Yolanda Almadén","doi":"10.1042/CS20190779","DOIUrl":"https://doi.org/10.1042/CS20190779","url":null,"abstract":"Fibroblast growth factor 23 (FGF23) increases phosphorus excretion and decreases calcitriol (1,25(OH)2D) levels. FGF23 increases from early stages of renal failure. We evaluated whether strict control of phosphorus intake in renal failure prevents the increase in FGF23 and to what extent inflammation impairs regulation of FGF23. The study was performed in 5/6 nephrectomized (Nx) Wistar rats fed diets containing 0.2-1.2% phosphorus for 3 or 15 days. FGF23 levels significantly increased in all Nx groups in the short-term (3-day) experiment. However, at 15 days, FGF23 increased in all Nx rats except in those fed 0.2% phosphorus. In a second experiment, Nx rats fed low phosphorus diets (0.2 and 0.4%) for 15 days received daily intraperitoneal lipopolysaccharide (LPS) injections to induce inflammation. In these rats, FGF23 increased despite the low phosphorus diets. Thus, higher FGF23 levels were needed to maintain phosphaturia and normal serum phosphorus values. Renal Klotho expression was preserved in Nx rats on a 0.2% phosphorus diet, reduced on a 0.4% phosphorus diet, and markedly reduced in Nx rats receiving LPS. In ex vivo experiments, high phosphorus and LPS increased nuclear β-catenin and p65-NFκB and decreased Klotho. Inhibition of inflammation and Wnt signaling activation resulted in decreased FGF23 levels and increased renal Klotho. In conclusion, strict control of phosphorus intake prevented the increase in FGF23 in renal failure, whereas inflammation independently increased FGF23 values. Decreased Klotho may explain the renal resistance to FGF23 in inflammation. These effects are likely mediated by the activation of NFkB and Wnt/β-catenin signaling.","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"15-32"},"PeriodicalIF":6.0,"publicationDate":"2020-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37477125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 15

Down-regulation of placental Cdc42 and Rac1 links mTORC2 inhibition to decreased trophoblast amino acid transport in human intrauterine growth restriction. 胎盘Cdc42和Rac1的下调将mTORC2抑制与人类宫内生长受限中滋养细胞氨基酸运输减少联系起来。

IF 6

Clinical Science (London, England : 1979) Pub Date : 2020-01-17 DOI: 10.1042/CS20190794

Thomas Jansson, Marisol Castillo-Castrejon, Madhulika B Gupta, Theresa L Powell, Fredrick J Rosario

{"title":"Down-regulation of placental Cdc42 and Rac1 links mTORC2 inhibition to decreased trophoblast amino acid transport in human intrauterine growth restriction.","authors":"Thomas Jansson, Marisol Castillo-Castrejon, Madhulika B Gupta, Theresa L Powell, Fredrick J Rosario","doi":"10.1042/CS20190794","DOIUrl":"https://doi.org/10.1042/CS20190794","url":null,"abstract":"Intrauterine growth restriction (IUGR) increases the risk for perinatal complications and metabolic and cardiovascular disease later in life. The syncytiotrophoblast (ST) is the transporting epithelium of the human placenta, and decreased expression of amino acid transporter isoforms in the ST plasma membranes is believed to contribute to IUGR. Placental mechanistic target of rapamycin Complex 2 (mTORC2) signaling is inhibited in IUGR and regulates the trafficking of key amino acid transporter (AAT) isoforms to the ST plasma membrane; however, the molecular mechanisms are unknown. Cdc42 and Rac1 are Rho-GTPases that regulate actin-binding proteins, thereby modulating the structure and dynamics of the actin cytoskeleton. We hypothesized that inhibition of mTORC2 decreases AAT expression in the plasma membrane and amino acid uptake in primary human trophoblast (PHT) cells mediated by down-regulation of Cdc42 and Rac1. mTORC2, but not mTORC1, inhibition decreased the Cdc42 and Rac1 expression. Silencing of Cdc42 and Rac1 inhibited the activity of the System L and A transporters and markedly decreased the trafficking of LAT1 (System L isoform) and SNAT2 (System A isoform) to the plasma membrane. mTORC2 inhibition by silencing of rictor failed to decrease AAT following activation of Cdc42/Rac1. Placental Cdc42 and Rac1 protein expression was down-regulated in human IUGR and was positively correlated with placental mTORC2 signaling. In conclusion, mTORC2 regulates AAT trafficking in PHT cells by modulating Cdc42 and Rac1. Placental mTORC2 inhibition in human IUGR may contribute to decreased placental amino acid transfer and reduced fetal growth mediated by down-regulation of Cdc42 and Rac1.","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"53-70"},"PeriodicalIF":6.0,"publicationDate":"2020-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8812325/pdf/nihms-1772089.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37447294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 11