加强生物医学大数据建设应用,推动健康中国战略实施

我国政府始终将人民的权益放在优先发展的地位,不断努力提高人民健康水平,主要健康指标总体上优于中高收入国家平均水平[1].2017年,“健康中国”被写入党的十九大报告,健康中国上升为国家战略[2].2019年印发的《关于实施健康中国行动的意见》(https://www.gov.cn/zhengce/content/2019-07/15/content_5409492.htm)和《健康中国行动(2019~2030年)》(https://www.gov.cn/xinwen/2019-07/15/content_5409694.htm)明确了健康中国战略的总体目标,部署了重点方向和任务.

Idebenone alleviates doxorubicin-induced cardiotoxicity by stabilizing FSP1 to inhibit ferroptosis

Doxorubicin(DOX)-mediated cardiotoxicity can exacerbate mortality in oncology patients,but related pharmacotherapeutic measures are relatively limited.Ferroptosis was recently identified as a major mechanism of DOX-induced cardiotoxicity.Idebenone,a novel ferroptosis inhibitor,is a well-described clinical drug widely used.However,its role and pathological mechanism in DOX-induced cardiotoxicity are still unclear.In this study,we demonstrated the effects of idebenone on DOX-induced cardiotoxicity and elucidated its underlying mechanism.A single intraperitoneal injection of DOX(15 mg/kg)was administrated to establish DOX-induced cardiotoxicity.The results showed that idebenone significantly attenuated DOX-induced cardiac dysfunction due to its ability to regulate acute DOX-induced Fe^(2+)and ROS overload,which resulted in ferroptosis.CESTA and BLI further revealed that idebenone's anti-ferroptosis effect was mediated by FSP1.Interestingly,idebenone increased FSP1 protein levels but did not affect Fsp1 mRNA levels in the presence of DOX.Idebenone could form stable hydrogen bonds with FSP1 protein at K355,which may influence its association with ubiquitin.The results confirmed that idebenone stabilized FSP1 protein levels by inhibiting its ubiquitination degradation.In conclusion,this study demonstrates idebenone attenuated DOX-induced cardiotoxicity by inhibiting ferroptosis via regulation of FSP1,making it a potential clinical drug for patients receiving DOX treatment.

Metabolic landscape in cardiac aging:insights into molecular biology and therapeutic implications

Cardiac aging is evident by a reduction in function which subsequently contributes to heart failure.The metabolic microenvironment has been identified as a hallmark of malignancy,but recent studies have shed light on its role in cardiovascular diseases(CVDs).Various metabolic pathways in cardiomyocytes and noncardiomyocytes determine cellular senescence in the aging heart.Metabolic alteration is a common process throughout cardiac degeneration.Importantly,the involvement of cellular senescence in cardiac injuries,including heart failure and myocardial ischemia and infarction,has been reported.However,metabolic complexity among human aging hearts hinders the development of strategies that targets metabolic susceptibility.Advances over the past decade have linked cellular senescence and function with their metabolic reprogramming pathway in cardiac aging,including autophagy,oxidative stress,epigenetic modifications,chronic inflammation,and myocyte systolic phenotype regulation.In addition,metabolic status is involved in crucial aspects of myocardial biology,from fibrosis to hypertrophy and chronic inflammation.However,further elucidation of the metabolism involvement in cardiac degeneration is still needed.Thus,deciphering the mechanisms underlying how metabolic reprogramming impacts cardiac aging is thought to contribute to the novel interventions to protect or even restore cardiac function in aging hearts.Here,we summarize emerging concepts about metabolic landscapes of cardiac aging,with specific focuses on why metabolic profile alters during cardiac degeneration and how we could utilize the current knowledge to improve the management of cardiac aging.

Matrine attenuates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway

Oxidative stress and cardiomyocyte apoptosis are involved in the pathogenesis of doxorubicin(DOX)-induced cardiotoxicity. Matrine is well-known for its powerful anti-oxidant and anti-apoptotic capacities. Our present study aimed to investigate the effect of matrine on DOX-induced cardiotoxicity and try to unearth the underlying mechanisms. Mice were exposed with DOX to generate DOX-induced cardiotoxicity or normal saline as control. H9 C2 cells were used to verify the effect of matrine in vitro.DOX injection triggered increased generation of reactive oxygen species(ROS) and excessive cardiomyocyte apoptosis, which were significantly mitigated by matrine. Mechanistically, we found that matrine ameliorated DOX-induced uncoupling protein 2(UCP2) downregulation, and UCP2 inhibition bygenipin could blunt the protective effect of matrine on DOX-induced oxidative stress and cardiomyocyte apoptosis. Besides, 50-AMP-activated protein kinase α2(Ampkα2) deficiency inhibited matrine-mediated UCP2 preservation and abolished the beneficial effect of matrine in mice. Besides, we observed that matrine incubation alleviated DOX-induced H9 C2 cells apoptosis and oxidative stress level via activating AMPKα/UCP2, which were blunted by either AMPKα or UCP2 inhibition with genetic or pharmacological methods. Matrine attenuated oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway, and it might be a promising therapeutic agent for the treatment of DOX-induced cardiotoxicity.

Cardiac fibroblast heat shock protein 47 aggravates cardiac fibrosis post myocardial ischemia-reperfusion injury by encouraging ubiquitin specific peptidase 10 dependent Smad4 deubiquitination

Despite complications were significantly reduced due to the popularity of percutaneous coronary intervention(PCI) in clinical trials, reperfusion injury and chronic cardiac remodeling significantly contribute to poor prognosis and rehabilitation in AMI patients. We revealed the effects of HSP47 on myocardial ischemia-reperfusion injury(IRI) and shed light on the underlying molecular mechanism.We generated adult mice with lentivirus-mediated or miRNA(mi1/133TS)-aided cardiac fibroblastselective HSP47 overexpression. Myocardial IRI was induced by 45-min occlusion of the left anterior descending(LAD) artery followed by 24 h reperfusion in mice, while ischemia-mediated cardiac remodeling was induced by four weeks of reperfusion. Also, the role of HSP47 in fibrogenesis was evaluated in cardiac fibroblasts following hypoxia-reoxygenation(HR). Extensive HSP47 was observed in murine infarcted hearts, human ischemic hearts, and cardiac fibroblasts and accelerated oxidative stress and apoptosis after myocardial IRI. Cardiac fibroblast-selective HSP47 overexpression exacerbated cardiac dysfunction caused by chronic myocardial IRI and presented deteriorative fibrosis and cell proliferation.HSP47 upregulation in cardiac fibroblasts promoted TGFβ1-Smad4 pathway activation and Smad4 deubiquitination by recruiting ubiquitin-specific peptidase 10(USP10) in fibroblasts. However, cardiac fibroblast specific USP10 deficiency abolished HSP47-mediated fibrogenesis in hearts. Moreover, blockage of HSP47 with Col003 disturbed fibrogenesis in fibroblasts following HR. Altogether, cardiac fibroblast HSP47 aggravates fibrosis post-myocardial IRI by enhancing USP10-dependent Smad4 deubiquitination,which provided a potential strategy for myocardial IRI and cardiac remodeling.