People living with human immunodeficiency virus (HIV) (PLWH) on antiretroviral treatment (ART) have an increased risk of atherosclerotic cardiovascular disease (CVD) and metabolic syndrome (combinations of adiposity, insulin resistance, hypertension, and dyslipidemia). Together, CVD and metabolic syndrome constitute the cardiometabolic syndrome. Traditional CVD risk factors and high-density lipoproteins (HDL) alterations seem to contribute to the elevated CVD risk. Cumulative evidence suggests that assessing HDL function instead of HDL cholesterol levels (HDL-C) may be a better way to assess cardiometabolic risk. In HIV infection, HIV-1, ART, and the altered function of organs like the liver, gastrointestinal tract, and immune system affect the proteome, lipidome, and metabolism of HDL, ultimately leading to its dysfunction. However, the impact of altered HDL functions on PLWH remains unclear and whether HDL dysfunction reflects and/or contributes to cardiometabolic syndrome in HIV infection (bidirectional cross talk regarding how HDL function impacts the cardiometabolic syndrome and vice versa). Large cohorts of PLWH with variable CVD risk using independent assays of HDL function are needed to elucidate the bidirectional crosstalk between HDL functions and cardiometabolic syndrome. Developing novel treatments to improve HDL function in PLWH may have multiple beneficial results, reducing chronic inflammation and cardiometabolic risk in PLWH. This review aims to summarize the scientific evidence related to the role of HDL functions in HIV and how therapeutic targeting of HDL dysfunction may contribute to reduced cardiometabolic risk in PLWH.
{"title":"HDL dysfunction: a role in the pathogenesis of cardiometabolic syndrome in chronic HIV infection?","authors":"Konstantinos Markakis , Leila Fotooh Abadi , Arnaud Kombe Kombe , Martinos Christodoulides , Theodoros Kelesidis","doi":"10.1016/j.metabol.2025.156432","DOIUrl":"10.1016/j.metabol.2025.156432","url":null,"abstract":"<div><div>People living with human immunodeficiency virus (HIV) (PLWH) on antiretroviral treatment (ART) have an increased risk of atherosclerotic cardiovascular disease (CVD) and metabolic syndrome (combinations of adiposity, insulin resistance, hypertension, and dyslipidemia). Together, CVD and metabolic syndrome constitute the cardiometabolic syndrome. Traditional CVD risk factors and high-density lipoproteins (HDL) alterations seem to contribute to the elevated CVD risk. Cumulative evidence suggests that assessing HDL function instead of HDL cholesterol levels (HDL-C) may be a better way to assess cardiometabolic risk. In HIV infection, HIV-1, ART, and the altered function of organs like the liver, gastrointestinal tract, and immune system affect the proteome, lipidome, and metabolism of HDL, ultimately leading to its dysfunction. However, the impact of altered HDL functions on PLWH remains unclear and whether HDL dysfunction reflects and/or contributes to cardiometabolic syndrome in HIV infection (bidirectional cross talk regarding how HDL function impacts the cardiometabolic syndrome and <em>vice versa</em>). Large cohorts of PLWH with variable CVD risk using independent assays of HDL function are needed to elucidate the bidirectional crosstalk between HDL functions and cardiometabolic syndrome. Developing novel treatments to improve HDL function in PLWH may have multiple beneficial results, reducing chronic inflammation and cardiometabolic risk in PLWH. This review aims to summarize the scientific evidence related to the role of HDL functions in HIV and how therapeutic targeting of HDL dysfunction may contribute to reduced cardiometabolic risk in PLWH.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156432"},"PeriodicalIF":11.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-12DOI: 10.1016/j.metabol.2025.156436
Junpeng Long , Shasha Liu , Yaning Shi , Chanjuan Zhang , Li Qin , Qidi Ai
The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neural homeostasis and function. Neurodegenerative diseases—including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)—are characterized by progressive neuronal dysfunction and myelin degeneration. These conditions predominantly affect aging populations and represent a growing global health challenge. While aging remains the primary risk factor, compelling evidence now underscores the involvement of dysregulated lipid metabolism in their pathogenesis. However, the precise mechanisms linking dynamic lipid metabolic alterations to disease progression remain incompletely elucidated. This review systematically examines the multifaceted contributions of lipid metabolism to neurodegenerative processes and critically assesses emerging therapeutic strategies that target lipid pathways for the treatment of neurodegenerative disorders.
{"title":"Targeting lipid metabolism in neurodegenerative diseases: From experimental to clinical","authors":"Junpeng Long , Shasha Liu , Yaning Shi , Chanjuan Zhang , Li Qin , Qidi Ai","doi":"10.1016/j.metabol.2025.156436","DOIUrl":"10.1016/j.metabol.2025.156436","url":null,"abstract":"<div><div>The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neural homeostasis and function. Neurodegenerative diseases—including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)—are characterized by progressive neuronal dysfunction and myelin degeneration. These conditions predominantly affect aging populations and represent a growing global health challenge. While aging remains the primary risk factor, compelling evidence now underscores the involvement of dysregulated lipid metabolism in their pathogenesis. However, the precise mechanisms linking dynamic lipid metabolic alterations to disease progression remain incompletely elucidated. This review systematically examines the multifaceted contributions of lipid metabolism to neurodegenerative processes and critically assesses emerging therapeutic strategies that target lipid pathways for the treatment of neurodegenerative disorders.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156436"},"PeriodicalIF":11.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-10DOI: 10.1016/j.metabol.2025.156435
Xing Ming , Jialin Tan , Miaomiao Yuan , Xiaoqin Ma , Feiye Zhou , Shushu Wang , Qianqian Lyu , Wenzhi Xue , Tingting Bo , Yunxia Liu , Xuejiao Zhang , Fuhua Yan , Jie Hong , Jie Zheng , Guang Ning , Weiqing Wang , Jiqiu Wang , Haipeng Sun , Libin Zhou , Xiao Wang
The role of hypothalamic branched-chain amino acid (BCAA) catabolism in the maintenance of energy homeostasis remains elusive. By using Mendelian randomization, we found that genetically predicted branched-chain keto acid dehydrogenase E1α subunit (BCKDHA) expression in the hypothalamus was negatively associated with fat mass. Hypothalamic deletion of BCKDHA (Bckdhaf/f;RIP-Cre) leads to increased fat mass, reduced energy expenditure, and blunted browning of white adipose tissue in mice, with decreases of thyrotropin-releasing hormone (TRH) expression in the paraventricular nucleus (PVN) and hypothalamic-pituitary-thyroid (HPT) axis activity. Mice with adeno-associated virus-mediated deletion of BCKDHA in the PVNTRH neurons displays a similar metabolic phenotype to Bckdhaf/f;RIP-Cre mice. TRH supplementation ameliorates the abnormal phenotypes of Bckdhaf/f;RIP-Cre mice. Defective BCAA catabolism in the hypothalamus results in hypoacetylation of histone H3 lysine 27 (H3K27) due to decreased acetyl-CoA content, reducing its binding to the Trh promoter. Our study highlights the crucial role of hypothalamic BCAA catabolism in maintaining energy homeostasis through HPT axis.
{"title":"BCAA catabolism in TRH neurons of paraventricular nucleus regulates energy expenditure","authors":"Xing Ming , Jialin Tan , Miaomiao Yuan , Xiaoqin Ma , Feiye Zhou , Shushu Wang , Qianqian Lyu , Wenzhi Xue , Tingting Bo , Yunxia Liu , Xuejiao Zhang , Fuhua Yan , Jie Hong , Jie Zheng , Guang Ning , Weiqing Wang , Jiqiu Wang , Haipeng Sun , Libin Zhou , Xiao Wang","doi":"10.1016/j.metabol.2025.156435","DOIUrl":"10.1016/j.metabol.2025.156435","url":null,"abstract":"<div><div>The role of hypothalamic branched-chain amino acid (BCAA) catabolism in the maintenance of energy homeostasis remains elusive. By using Mendelian randomization, we found that genetically predicted branched-chain keto acid dehydrogenase E1α subunit (BCKDHA) expression in the hypothalamus was negatively associated with fat mass. Hypothalamic deletion of BCKDHA (<em>Bckdha</em><sup>f/f;RIP-Cre</sup>) leads to increased fat mass, reduced energy expenditure, and blunted browning of white adipose tissue in mice, with decreases of thyrotropin-releasing hormone (TRH) expression in the paraventricular nucleus (PVN) and hypothalamic-pituitary-thyroid (HPT) axis activity. Mice with adeno-associated virus-mediated deletion of BCKDHA in the PVN<sup>TRH</sup> neurons displays a similar metabolic phenotype to <em>Bckdha</em><sup>f/f;RIP-Cre</sup> mice. TRH supplementation ameliorates the abnormal phenotypes of <em>Bckdha</em><sup>f/f;RIP-Cre</sup> mice. Defective BCAA catabolism in the hypothalamus results in hypoacetylation of histone H3 lysine 27 (H3K27) due to decreased acetyl-CoA content, reducing its binding to the <em>Trh</em> promoter. Our study highlights the crucial role of hypothalamic BCAA catabolism in maintaining energy homeostasis through HPT axis.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156435"},"PeriodicalIF":11.9,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145505679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-09DOI: 10.1016/j.metabol.2025.156434
Eleonore Fröhlich , Richard Wahl
Calcitonin (CT) is a hormone produced by C cells in the thyroid gland. Its primary function is to regulate bone turnover. However, it is believed to be of little importance to human physiology because its absence following thyroidectomy has no dramatic effects. It was used in the treatment of osteoporosis but has now largely been replaced by bisphosphonates and monoclonal antibodies. However, some studies suggest that CT may have additional functions, such as those related to bone structure, osteoprotection, and pain management. This review summarizes CT synthesis and function and discusses its role and that of its precursor, procalcitonin, as biomarkers. Procalcitonin detection has advantages over some established markers in sepsis management and due to its greater stability, it is also an alternative to CT for managing medullary thyroid carcinoma. Recent research has raised the possibility that procalcitonin could serve as a direct molecular target for treating sepsis. Potential roles of various regulatory peptides released by C cells that may contribute to paracrine fine-tuning of thyroid hormone secretion by follicular thyrocytes are considered. Health-care providers should inform patients that despite optimal thyroxine replacement therapy, subtle symptoms may still occur due to the absence of C cells.
{"title":"Calcitonin and procalcitonin: Revisiting the overlooked role of C cells","authors":"Eleonore Fröhlich , Richard Wahl","doi":"10.1016/j.metabol.2025.156434","DOIUrl":"10.1016/j.metabol.2025.156434","url":null,"abstract":"<div><div>Calcitonin (CT) is a hormone produced by C cells in the thyroid gland. Its primary function is to regulate bone turnover. However, it is believed to be of little importance to human physiology because its absence following thyroidectomy has no dramatic effects. It was used in the treatment of osteoporosis but has now largely been replaced by bisphosphonates and monoclonal antibodies. However, some studies suggest that CT may have additional functions, such as those related to bone structure, osteoprotection, and pain management. This review summarizes CT synthesis and function and discusses its role and that of its precursor, procalcitonin, as biomarkers. Procalcitonin detection has advantages over some established markers in sepsis management and due to its greater stability, it is also an alternative to CT for managing medullary thyroid carcinoma. Recent research has raised the possibility that procalcitonin could serve as a direct molecular target for treating sepsis. Potential roles of various regulatory peptides released by C cells that may contribute to paracrine fine-tuning of thyroid hormone secretion by follicular thyrocytes are considered. Health-care providers should inform patients that despite optimal thyroxine replacement therapy, subtle symptoms may still occur due to the absence of C cells.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156434"},"PeriodicalIF":11.9,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145493273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-08DOI: 10.1016/j.metabol.2025.156433
Ju Zhang , Xiangfeng Guan , Mowei Kong , Meng Xia , Yang Yu , Chunxiang Zhang
Background
Cardiovascular disease (CVD) and chronic kidney disease (CKD) frequently coexist, with obesity and type 2 diabetes (T2D) being major contributors to adverse outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and tirzepatide have shown cardiorenal benefits beyond glycemic control, but their efficacy across metabolic phenotypes remains unclear.
Methods
This review was prospectively registered in PROSPERO (CRD420251088042). PubMed, Embase, Web of Science, and Cochrane Library were searched (January 2015–July 2025) for RCTs comparing GLP-1RAs or tirzepatide with placebo in patients with cardiovascular or renal disease. Subgroup analyses were performed according to T2D and obesity status.
Results
A total of 18 RCTs (n = 97,800) involving eight GLP-1RAs and tirzepatide were included, primarily enrolling patients with established cardiovascular or renal disease. GLP-1RAs significantly reduced the risk of the primary composite outcome (RR 0.88, 95 % CI 0.84–0.91, P < 0.001). GLP-1RAs and tirzepatide also significantly reduced the risk of death from any cause (RR 0.88, 95 % CI 0.84–0.92, P < 0.001), and death from cardiovascular causes (RR 0.88, 95 % CI 0.83–0.93, P < 0.001). Although the overall effect of GLP-1RAs on hospitalization for heart failure was not statistically significant (RR 0.92, 95 % CI 0.78–1.08), a potential benefit was observed in obese patients (P for interaction = 0.02), warranting further investigation. GLP-1RAs showed favorable overall safety profile, with a lower incidence of serious adverse events (RR 0.93, 95 % CI 0.89–0.99, P = 0.01) and cardiac adverse events (RR 0.90, 95 % CI 0.85–0.96, P < 0.01) compared with placebo.
Conclusion
In patients with cardiovascular or renal disease, GLP-1RAs and tirzepatide provide consistent cardiovascular and renal protection, with a possible benefit in reducing hospitalization for heart failure among individuals with obesity.
背景：心血管疾病（CVD）和慢性肾脏疾病（CKD）经常共存，肥胖和2型糖尿病（T2D）是导致不良结局的主要因素。胰高血糖素样肽-1受体激动剂（GLP-1RAs）和替西肽已显示出除血糖控制外的心脏肾脏益处，但它们在代谢表型中的功效尚不清楚。方法：本综述在PROSPERO （CRD420251088042）前瞻性注册。检索PubMed， Embase， Web of Science和Cochrane Library（2015年1月- 2025年7月），比较GLP-1RAs或替西肽与安慰剂在心血管或肾脏疾病患者中的作用。根据T2D和肥胖状况进行亚组分析。结果：共纳入18项随机对照试验（n = 97,800），涉及8个GLP-1RAs和替西帕肽，主要纳入已确诊的心血管或肾脏疾病患者。GLP-1RAs显著降低了主要复合结局的风险（RR 0.88, 95 % CI 0.84-0.91, P ）结论：在心血管或肾脏疾病患者中，GLP-1RAs和替西肽提供一致的心血管和肾脏保护，可能有利于减少肥胖患者因心力衰竭住院治疗。
{"title":"GLP-1RAs and tirzepatide may reduce heart failure risk in obese but not in non-obese patients with cardiovascular or renal disease: A systematic review and meta-analysis","authors":"Ju Zhang , Xiangfeng Guan , Mowei Kong , Meng Xia , Yang Yu , Chunxiang Zhang","doi":"10.1016/j.metabol.2025.156433","DOIUrl":"10.1016/j.metabol.2025.156433","url":null,"abstract":"<div><h3>Background</h3><div>Cardiovascular disease (CVD) and chronic kidney disease (CKD) frequently coexist, with obesity and type 2 diabetes (T2D) being major contributors to adverse outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and tirzepatide have shown cardiorenal benefits beyond glycemic control, but their efficacy across metabolic phenotypes remains unclear.</div></div><div><h3>Methods</h3><div>This review was prospectively registered in PROSPERO (CRD420251088042). PubMed, Embase, Web of Science, and Cochrane Library were searched (January 2015–July 2025) for RCTs comparing GLP-1RAs or tirzepatide with placebo in patients with cardiovascular or renal disease. Subgroup analyses were performed according to T2D and obesity status.</div></div><div><h3>Results</h3><div>A total of 18 RCTs (<em>n</em> = 97,800) involving eight GLP-1RAs and tirzepatide were included, primarily enrolling patients with established cardiovascular or renal disease. GLP-1RAs significantly reduced the risk of the primary composite outcome (RR 0.88, 95 % CI 0.84–0.91, <em>P</em> < 0.001). GLP-1RAs and tirzepatide also significantly reduced the risk of death from any cause (RR 0.88, 95 % CI 0.84–0.92, <em>P</em> < 0.001), and death from cardiovascular causes (RR 0.88, 95 % CI 0.83–0.93, P < 0.001). Although the overall effect of GLP-1RAs on hospitalization for heart failure was not statistically significant (RR 0.92, 95 % CI 0.78–1.08), a potential benefit was observed in obese patients (P for interaction = 0.02), warranting further investigation. GLP-1RAs showed favorable overall safety profile, with a lower incidence of serious adverse events (RR 0.93, 95 % CI 0.89–0.99, <em>P</em> = 0.01) and cardiac adverse events (RR 0.90, 95 % CI 0.85–0.96, <em>P</em> < 0.01) compared with placebo.</div></div><div><h3>Conclusion</h3><div>In patients with cardiovascular or renal disease, GLP-1RAs and tirzepatide provide consistent cardiovascular and renal protection, with a possible benefit in reducing hospitalization for heart failure among individuals with obesity.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156433"},"PeriodicalIF":11.9,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-06DOI: 10.1016/j.metabol.2025.156429
Daosheng Ai , Baoshan Qiu , Xing-jun Chen , Fengzhi Li , Di Yao , Huijie Mi , Jun-Liszt Li , Bing Zhou , Jian Zuo , Yilong Wang , Woo-ping Ge , Wenzhi Sun
Acute ischemic stroke (AIS) is one of the leading causes of mortality and disability globally. Despite its complex pathological mechanisms, effective neuroprotective strategies are still lacking in clinical practice. Microglia and their metabolic processes play a pivotal role in the pathogenesis of AIS, yet the impact and underlying mechanisms of microglial fructose metabolism remain unclear. In this study, we identified Slc2a5 (also known as Glut5), a crucial regulator of fructose metabolism in microglia, as a key factor contributing to the early progression of AIS. Conditional deletion of Slc2a5 in microglia significantly alleviated brain injury in a mouse model of AIS. Single-cell transcriptomic (scRNA-seq) analysis demonstrated that the deletion of Slc2a5 promoted the differentiation of microglia into stroke-associated subpopulations with neuroprotective properties. Moreover, in vitro experiments indicated that this microglial differentiation process was primarily mediated by the activity of pyruvate kinase M2 (PKM2). Collectively, our findings unveil a novel microglial Slc2a5-mediated fructose metabolism pathway that exacerbates brain injury after AIS. This study provides evidence for SLC2A5 as a promising therapeutic target for the clinical treatment of AIS by offering insights into its critical role in microglial metabolism and neuroprotection.
{"title":"Inhibition of microglial Slc2a5 attenuates ischemic brain injury","authors":"Daosheng Ai , Baoshan Qiu , Xing-jun Chen , Fengzhi Li , Di Yao , Huijie Mi , Jun-Liszt Li , Bing Zhou , Jian Zuo , Yilong Wang , Woo-ping Ge , Wenzhi Sun","doi":"10.1016/j.metabol.2025.156429","DOIUrl":"10.1016/j.metabol.2025.156429","url":null,"abstract":"<div><div>Acute ischemic stroke (AIS) is one of the leading causes of mortality and disability globally. Despite its complex pathological mechanisms, effective neuroprotective strategies are still lacking in clinical practice. Microglia and their metabolic processes play a pivotal role in the pathogenesis of AIS, yet the impact and underlying mechanisms of microglial fructose metabolism remain unclear. In this study, we identified <em>Slc2a5</em> (also known as <em>Glut5</em>), a crucial regulator of fructose metabolism in microglia, as a key factor contributing to the early progression of AIS. Conditional deletion of <em>Slc2a5</em> in microglia significantly alleviated brain injury in a mouse model of AIS. Single-cell transcriptomic (scRNA-seq) analysis demonstrated that the deletion of <em>Slc2a5</em> promoted the differentiation of microglia into stroke-associated subpopulations with neuroprotective properties. Moreover, in vitro experiments indicated that this microglial differentiation process was primarily mediated by the activity of pyruvate kinase M2 (PKM2). Collectively, our findings unveil a novel microglial <em>Slc2a5</em>-mediated fructose metabolism pathway that exacerbates brain injury after AIS. This study provides evidence for SLC2A5 as a promising therapeutic target for the clinical treatment of AIS by offering insights into its critical role in microglial metabolism and neuroprotection.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156429"},"PeriodicalIF":11.9,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-05DOI: 10.1016/j.metabol.2025.156428
Ting Gong , Danru Wang , Yawei Jin , Liming Chen , Nan Qiu , Wenyan Qiu , Na Zheng , Yang Lv , Suling Ding , Jie Yuan , Jian Wu , Ling Lin , Chunjie Yang , Miyesaier Abudureyimu , Xiang Wang , Gulinazi Yesitayi , Lei Xu , Peng Zhang , Wei Hu , Gang Zhao , Shijun Wang
Background
Lipid peroxidation and iron overload-mediated cardiac ferroptosis play a critical role in myocardial ischemic injury and remodeling. Sphingosine kinase 2 (Sphk2) is implicated in lipid metabolism and cell survival, yet its role in myocardial infarction (MI) remains elusive. Given the critical function of ferroptosis in ischemic injury, we investigated whether Sphk2 protects the heart by regulating this novel cell death pathway.
Methods
Sphk2 expression was assessed in human failing hearts and a murine MI model. Sphk2−/− mice and AAV9-mediated cardiac-specific Sphk2 overexpression were used to assess cardiac function by echocardiography, remodeling by Masson's trichrome staining and molecular events.
Results
Sphk2 was significantly downregulated in human and murine failing hearts. Sphk2−/− mice exhibited exacerbated cardiac dysfunction, fibrosis and ferroptosis post-MI. Inhibition of CD36 signaling attenuated lipid uptake and ischemia-induced ferroptosis in Sphk2−/− mice, whereas pharmacological activation of TFEB restored autophagosome-lysosome function and further suppressed ferroptosis. Mechanistically, Sphk2 deficiency impaired the interaction with and stability of HSP90, leading to suppressed TFEB nuclear translocation, lysosomal biogenesis, and autophagic clearance of lipid peroxides. This exacerbated ferroptosis and ischemic injury via lipid-ROS accumulation and oxidative stress. Crucially, cardiac-specific overexpression of Sphk2 in knockout mice restored HSP90-TFEB signaling, ameliorated ferroptosis, and fully rescued cardiac function and remodeling after MI.
Conclusion
Our study unveils a novel role of Sphk2 in stabilizing HSP90 to activate TFEB-dependent lysosomal function, thereby mitigating lipid peroxidation and ferroptosis following ischemic injury. Our findings establish a direct causal link between Sphk2 deficiency and ischemic heart failure, which highlights the therapeutic potential of Sphk2 restoration in treating ischemic heart disease.
{"title":"Sphk2 suppresses ferroptosis in ischemic hearts by promoting HSP90AA1-mediated TFEB nuclear translocation, lysosome biogenesis and lysosome-autophagy pathway-dependent lipid-ROS clearance","authors":"Ting Gong , Danru Wang , Yawei Jin , Liming Chen , Nan Qiu , Wenyan Qiu , Na Zheng , Yang Lv , Suling Ding , Jie Yuan , Jian Wu , Ling Lin , Chunjie Yang , Miyesaier Abudureyimu , Xiang Wang , Gulinazi Yesitayi , Lei Xu , Peng Zhang , Wei Hu , Gang Zhao , Shijun Wang","doi":"10.1016/j.metabol.2025.156428","DOIUrl":"10.1016/j.metabol.2025.156428","url":null,"abstract":"<div><h3>Background</h3><div>Lipid peroxidation and iron overload-mediated cardiac ferroptosis play a critical role in myocardial ischemic injury and remodeling. Sphingosine kinase 2 (Sphk2) is implicated in lipid metabolism and cell survival, yet its role in myocardial infarction (MI) remains elusive. Given the critical function of ferroptosis in ischemic injury, we investigated whether Sphk2 protects the heart by regulating this novel cell death pathway.</div></div><div><h3>Methods</h3><div>Sphk2 expression was assessed in human failing hearts and a murine MI model. Sphk2<sup>−/−</sup> mice and AAV9-mediated cardiac-specific Sphk2 overexpression were used to assess cardiac function by echocardiography, remodeling by Masson's trichrome staining and molecular events.</div></div><div><h3>Results</h3><div>Sphk2 was significantly downregulated in human and murine failing hearts. Sphk2<sup>−/−</sup> mice exhibited exacerbated cardiac dysfunction, fibrosis and ferroptosis post-MI. Inhibition of CD36 signaling attenuated lipid uptake and ischemia-induced ferroptosis in Sphk2<sup>−/−</sup> mice, whereas pharmacological activation of TFEB restored autophagosome-lysosome function and further suppressed ferroptosis. Mechanistically, Sphk2 deficiency impaired the interaction with and stability of HSP90, leading to suppressed TFEB nuclear translocation, lysosomal biogenesis, and autophagic clearance of lipid peroxides. This exacerbated ferroptosis and ischemic injury via lipid-ROS accumulation and oxidative stress. Crucially, cardiac-specific overexpression of Sphk2 in knockout mice restored HSP90-TFEB signaling, ameliorated ferroptosis, and fully rescued cardiac function and remodeling after MI.</div></div><div><h3>Conclusion</h3><div>Our study unveils a novel role of Sphk2 in stabilizing HSP90 to activate TFEB-dependent lysosomal function, thereby mitigating lipid peroxidation and ferroptosis following ischemic injury. Our findings establish a direct causal link between Sphk2 deficiency and ischemic heart failure, which highlights the therapeutic potential of Sphk2 restoration in treating ischemic heart disease.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156428"},"PeriodicalIF":11.9,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-05DOI: 10.1016/j.metabol.2025.156431
Eun-Seon Yoo , Jieun Yu , Moonsun Sa , C. Justin Lee , Jong-Woo Sohn
<div><h3>Objectives</h3><div>The serotonin 2C receptor (<em>Htr2c</em>) is one of the plausible targets for the development of appetite suppressants. Previous studies have demonstrated the complexity of neuronal circuitry underlying the appetite-suppressing effects of <em>Htr2c</em> stimulation. To develop a safe and effective anti-obesity medication targeting <em>Htr2c</em>, we need to better understand how <em>Htr2c</em> agonists suppress appetite. In this study, we focused on the effects of <em>Htr2c</em> agonists on corticotropin-releasing hormone (CRH) neurons to identify the contribution of humoral components to the suppression of fasting-induced food intake.</div></div><div><h3>Methods</h3><div>We used the <em>Crh</em>-ires-cre mice to fluorescently label CRH neurons for whole-cell patch-clamp recordings (<em>Crh</em>-ires-cre::tdTomato mice) and to delete <em>Htr2c</em> selectively in CRH neurons by breeding with <em>Htr2c</em><sup>flox/Y</sup> mice (<em>Crh</em>-ires-cre::<em>Htr2c</em><sup>flox/Y</sup> mice). We also injected <em>Htr2c</em>-targeting short hairpin RNA (shRNA) into the paraventricular nucleus of the hypothalamus (PVH) of <em>Crh</em>-ires-cre mice to knock down <em>Htr2c</em> selectively in CRH neurons within the PVH (CRH<sup>PVH</sup> neurons). Using these model mice, we tested the effects of WAY161503, a selective <em>Htr2c</em> agonist, on CRH neuronal activity <em>ex vivo</em> as well as fasting-induced food intake and plasma corticosterone (CORT) levels <em>in vivo</em>.</div></div><div><h3>Results</h3><div>WAY161503 inhibited the activity of CRH<sup>PVH</sup> neurons. The appetite-suppressing effects of WAY161503 were significantly attenuated when <em>Htr2c</em> was deleted selectively in CRH<sup>PVH</sup> neurons. On the other hand, WAY161503 promoted the reduction of plasma CORT levels during fasting-induced refeeding <em>via Htr2c</em> expressed by CRH<sup>PVH</sup> neurons. Importantly, when mice were pretreated with RU486, a glucocorticoid receptor antagonist that blocks CORT action, WAY161503 suppressed food intake whether CRH<sup>PVH</sup> neurons expressed functional <em>Htr2c</em> or not. Finally, we characterized the expression of single-minded 1 (<em>Sim1</em>) messenger RNA (mRNA), <em>Crh</em> mRNA, and <em>Htr2c</em> mRNA in PVH neurons, which may help to explain the effects of <em>Htr2c</em> stimulation on fasting-induced refeeding.</div></div><div><h3>Conclusions</h3><div>Our results demonstrate that <em>Htr2c</em> expression in the CRH<sup>PVH</sup> neurons is necessary for the appetite-suppressing effects of WAY161503 during fasting-induced refeeding. Importantly, we found that WAY161503 suppresses the hypothalamic-pituitary-adrenal (HPA) axis and promotes the reduction of plasma CORT levels, thereby enabling the appetite-suppressing effects of <em>Htr2c</em> stimulation during fasting-induced refeeding. To our knowledge, this study is the first to highlight the necessity of coordination between n
{"title":"Serotonin 2C receptors inhibit hypothalamic CRH neurons to suppress appetite","authors":"Eun-Seon Yoo , Jieun Yu , Moonsun Sa , C. Justin Lee , Jong-Woo Sohn","doi":"10.1016/j.metabol.2025.156431","DOIUrl":"10.1016/j.metabol.2025.156431","url":null,"abstract":"<div><h3>Objectives</h3><div>The serotonin 2C receptor (<em>Htr2c</em>) is one of the plausible targets for the development of appetite suppressants. Previous studies have demonstrated the complexity of neuronal circuitry underlying the appetite-suppressing effects of <em>Htr2c</em> stimulation. To develop a safe and effective anti-obesity medication targeting <em>Htr2c</em>, we need to better understand how <em>Htr2c</em> agonists suppress appetite. In this study, we focused on the effects of <em>Htr2c</em> agonists on corticotropin-releasing hormone (CRH) neurons to identify the contribution of humoral components to the suppression of fasting-induced food intake.</div></div><div><h3>Methods</h3><div>We used the <em>Crh</em>-ires-cre mice to fluorescently label CRH neurons for whole-cell patch-clamp recordings (<em>Crh</em>-ires-cre::tdTomato mice) and to delete <em>Htr2c</em> selectively in CRH neurons by breeding with <em>Htr2c</em><sup>flox/Y</sup> mice (<em>Crh</em>-ires-cre::<em>Htr2c</em><sup>flox/Y</sup> mice). We also injected <em>Htr2c</em>-targeting short hairpin RNA (shRNA) into the paraventricular nucleus of the hypothalamus (PVH) of <em>Crh</em>-ires-cre mice to knock down <em>Htr2c</em> selectively in CRH neurons within the PVH (CRH<sup>PVH</sup> neurons). Using these model mice, we tested the effects of WAY161503, a selective <em>Htr2c</em> agonist, on CRH neuronal activity <em>ex vivo</em> as well as fasting-induced food intake and plasma corticosterone (CORT) levels <em>in vivo</em>.</div></div><div><h3>Results</h3><div>WAY161503 inhibited the activity of CRH<sup>PVH</sup> neurons. The appetite-suppressing effects of WAY161503 were significantly attenuated when <em>Htr2c</em> was deleted selectively in CRH<sup>PVH</sup> neurons. On the other hand, WAY161503 promoted the reduction of plasma CORT levels during fasting-induced refeeding <em>via Htr2c</em> expressed by CRH<sup>PVH</sup> neurons. Importantly, when mice were pretreated with RU486, a glucocorticoid receptor antagonist that blocks CORT action, WAY161503 suppressed food intake whether CRH<sup>PVH</sup> neurons expressed functional <em>Htr2c</em> or not. Finally, we characterized the expression of single-minded 1 (<em>Sim1</em>) messenger RNA (mRNA), <em>Crh</em> mRNA, and <em>Htr2c</em> mRNA in PVH neurons, which may help to explain the effects of <em>Htr2c</em> stimulation on fasting-induced refeeding.</div></div><div><h3>Conclusions</h3><div>Our results demonstrate that <em>Htr2c</em> expression in the CRH<sup>PVH</sup> neurons is necessary for the appetite-suppressing effects of WAY161503 during fasting-induced refeeding. Importantly, we found that WAY161503 suppresses the hypothalamic-pituitary-adrenal (HPA) axis and promotes the reduction of plasma CORT levels, thereby enabling the appetite-suppressing effects of <em>Htr2c</em> stimulation during fasting-induced refeeding. To our knowledge, this study is the first to highlight the necessity of coordination between n","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156431"},"PeriodicalIF":11.9,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-04DOI: 10.1016/j.metabol.2025.156426
Yuting Ma , Sunye Feng , Yujie Jiang , Jingting Jiang , Ronghui Liu , Yuxin Ma , Xinglei Yin , Huimin Bian , Ruigong Zhu
Background
Atherosclerosis, a leading cause of cardiovascular morbidity and mortality, is driven by endothelial dysfunction. While metabolic reprogramming toward glycolysis in endothelial cells exacerbates disease progression, the role of lactate-derived lactylation in atherogenesis remains poorly understood.
Methods
We performed RNA-seq on aortic tissues from atherosclerotic mice to identify differentially expressed genes, along with Seahorse XF metabolic flux analysis. Endothelium-specific solute carrier family 22 member 6 (Slc22a6) knockout and AAV-delivered acyl-CoA synthetase short-chain family member 1 (Acss1) knockdown mice were established on an ApoEKO background. Integrated multi-omics (RNA-seq, CUT&Tag, metabolomics) elucidated downstream regulatory networks, and in vivo pharmacological inhibition validated key pathways.
Results
Our study reveals a marked elevation of histone H3 Lysine 9 Lactylation (H3K9la) relative to acetylation in atherosclerotic aortic tissue, potentially via SLC22A6-mediated glycolytic enhancement and lactate uptake. Additionally, endothelial-specific knockout of Slc22a6 attenuates H3K9la-driven endothelial dysfunction and atherosclerosis. Integrated RNA-seq and CUT&Tag analyses identify that upregulated ACSS1 and E1A binding protein p300 (EP300) drive H3K9la, which transcriptionally activates stearoyl-CoA desaturase 1 (SCD1), thereby exacerbating endothelial dysfunction. Pharmacological inhibition of H3K9la or SCD1 alleviates endothelial dysfunction and atherosclerosis in vitro and in vivo. We further establish the clinical relevance of lactate, SLC22A6, and ACSS1 in atherosclerosis.
Conclusions
Our findings unveil a metabolism-epigenetics-transcription regulatory axis in endothelial pathophysiology, thus providing novel therapeutic strategies for atherosclerosis by targeting the SLC22A6-dependent ACSS1-H3K9la-SCD1 pathway.
{"title":"SLC22A6-dependent lactylation of H3K9 aggravates endothelial dysfunction and atherosclerosis","authors":"Yuting Ma , Sunye Feng , Yujie Jiang , Jingting Jiang , Ronghui Liu , Yuxin Ma , Xinglei Yin , Huimin Bian , Ruigong Zhu","doi":"10.1016/j.metabol.2025.156426","DOIUrl":"10.1016/j.metabol.2025.156426","url":null,"abstract":"<div><h3>Background</h3><div>Atherosclerosis, a leading cause of cardiovascular morbidity and mortality, is driven by endothelial dysfunction. While metabolic reprogramming toward glycolysis in endothelial cells exacerbates disease progression, the role of lactate-derived lactylation in atherogenesis remains poorly understood.</div></div><div><h3>Methods</h3><div>We performed RNA-seq on aortic tissues from atherosclerotic mice to identify differentially expressed genes, along with Seahorse XF metabolic flux analysis. Endothelium-specific solute carrier family 22 member 6 (Slc22a6) knockout and AAV-delivered acyl-CoA synthetase short-chain family member 1 (Acss1) knockdown mice were established on an ApoE<sup>KO</sup> background. Integrated multi-omics (RNA-seq, CUT&Tag, metabolomics) elucidated downstream regulatory networks, and in vivo pharmacological inhibition validated key pathways.</div></div><div><h3>Results</h3><div>Our study reveals a marked elevation of histone H3 Lysine 9 Lactylation (H3K9la) relative to acetylation in atherosclerotic aortic tissue, potentially via SLC22A6-mediated glycolytic enhancement and lactate uptake. Additionally, endothelial-specific knockout of Slc22a6 attenuates H3K9la-driven endothelial dysfunction and atherosclerosis. Integrated RNA-seq and CUT&Tag analyses identify that upregulated ACSS1 and E1A binding protein p300 (EP300) drive H3K9la, which transcriptionally activates stearoyl-CoA desaturase 1 (SCD1), thereby exacerbating endothelial dysfunction. Pharmacological inhibition of H3K9la or SCD1 alleviates endothelial dysfunction and atherosclerosis in vitro and in vivo. We further establish the clinical relevance of lactate, SLC22A6, and ACSS1 in atherosclerosis.</div></div><div><h3>Conclusions</h3><div>Our findings unveil a metabolism-epigenetics-transcription regulatory axis in endothelial pathophysiology, thus providing novel therapeutic strategies for atherosclerosis by targeting the SLC22A6-dependent ACSS1-H3K9la-SCD1 pathway.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156426"},"PeriodicalIF":11.9,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-03DOI: 10.1016/j.metabol.2025.156430
Yiying Wang , Arvid Sandforth , Reiner Jumprtz-von Schwartzenberg , Marlene Ganslmeier , Yurong Cheng , Leontine Sandforth , Sarah Katzenstein , Jürgen Machann , Fritz Schick , Konstantinos Kantartzis , Hubert Preissl , Andreas Fritsche , Norbert Stefan , Michael Bergman , Andreas L. Birkenfeld
Background
High 1-h-post-load plasma glucose (1 h-PG) is an early diabetes risk marker. We hypothesized that isolated high 1 h-PG represents an intermediate state between normal glucose regulation (NGR) and impaired glucose regulation (IGR) and is amendable to greater lifestyle intervention (LI) benefit.
Methods
In the Tübingen Lifestyle Intervention Program, 317 people with either NGR, IGR or isolated high 1 h-PG without IGR underwent LI for 9 months to achieve ≥5 % weight loss.
Results
Before LI initiation, insulin sensitivity and β-cell function declined progressively from NGR (n = 106) to high 1 h-PG (n = 96) and to IGR (n = 115). Visceral adipose tissue (VAT) volume and liver fat content increased from NGT to high 1 h-PG and to IGR. LI improved insulin sensitivity and ß-cell function in the high 1 h-PG group to levels observed in NGR together with a marked reduction in hepatic fat content. Compared to the IGR group, T2D risk was reduced by 80 % (37–96 %, p = 0.005) in the high 1 h-PG group during a 12-year follow-up period. The odds of remission to complete normoglycemia were doubled in the high 1 h-PG group compared to the IGR group (2.18 [1.13–4.28], p = 0.021).
Conclusion
High 1 h-PG indicates an intermediate metabolic state with pathophysiological changes more severe than in NGR but milder than in IGR. In people with high 1 h-PG, LI significantly improved insulin sensitivity and β-cell function and reduced ectopic lipid deposition and the risk of developing T2D compared to IGR. These findings highlight the value of 1 h-PG as a clinically useful biomarker, providing a critical window for early intervention to reverse core metabolic defects driving prediabetes and T2D.
{"title":"Lifestyle intervention is more effective in high 1-hour post-load glucose than in prediabetes for restoring β-cell function, reducing ectopic fat, and preventing type 2 diabetes","authors":"Yiying Wang , Arvid Sandforth , Reiner Jumprtz-von Schwartzenberg , Marlene Ganslmeier , Yurong Cheng , Leontine Sandforth , Sarah Katzenstein , Jürgen Machann , Fritz Schick , Konstantinos Kantartzis , Hubert Preissl , Andreas Fritsche , Norbert Stefan , Michael Bergman , Andreas L. Birkenfeld","doi":"10.1016/j.metabol.2025.156430","DOIUrl":"10.1016/j.metabol.2025.156430","url":null,"abstract":"<div><h3>Background</h3><div>High 1-h-post-load plasma glucose (1 h-PG) is an early diabetes risk marker. We hypothesized that isolated high 1 h-PG represents an intermediate state between normal glucose regulation (NGR) and impaired glucose regulation (IGR) and is amendable to greater lifestyle intervention (LI) benefit.</div></div><div><h3>Methods</h3><div>In the Tübingen Lifestyle Intervention Program, 317 people with either NGR, IGR or isolated high 1 h-PG without IGR underwent LI for 9 months to achieve ≥5 % weight loss.</div></div><div><h3>Results</h3><div>Before LI initiation, insulin sensitivity and β-cell function declined progressively from NGR (<em>n</em> = 106) to high 1 h-PG (<em>n</em> = 96) and to IGR (<em>n</em> = 115). Visceral adipose tissue (VAT) volume and liver fat content increased from NGT to high 1 h-PG and to IGR. LI improved insulin sensitivity and ß-cell function in the high 1 h-PG group to levels observed in NGR together with a marked reduction in hepatic fat content. Compared to the IGR group, T2D risk was reduced by 80 % (37–96 %, <em>p</em> = 0.005) in the high 1 h-PG group during a 12-year follow-up period. The odds of remission to complete normoglycemia were doubled in the high 1 h-PG group compared to the IGR group (2.18 [1.13–4.28], <em>p</em> = 0.021).</div></div><div><h3>Conclusion</h3><div>High 1 h-PG indicates an intermediate metabolic state with pathophysiological changes more severe than in NGR but milder than in IGR. In people with high 1 h-PG, LI significantly improved insulin sensitivity and β-cell function and reduced ectopic lipid deposition and the risk of developing T2D compared to IGR. These findings highlight the value of 1 h-PG as a clinically useful biomarker, providing a critical window for early intervention to reverse core metabolic defects driving prediabetes and T2D.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156430"},"PeriodicalIF":11.9,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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