The cystine/glutamate antiporter SLC7A11(also commonly known as xCT)functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers.Recent studies reveal...The cystine/glutamate antiporter SLC7A11(also commonly known as xCT)functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers.Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis,a form of regulated cell death induced by excessive lipid peroxidation.However,cancer cells with high expression of SLC7A11(SLC7A11^(high))also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming,leading to glucose-and glutamine-dependency in SLC7A11^(high) cancer cells,which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11^(high) cancer.In this review,we summarize diverse regulatory mechanisms of SLC7A11 in cancer,discuss ferroptosis-dependent and-independent functions of SLC7A11 in promoting tumor development,explore the mechanistic basis of SLC7A11-induced nutrient dependency in cancer cells,and conceptualize therapeutic strategies to target SLC7A11 in cancer treatment.This review will provide the foundation for further understanding SLC7A11 in ferroptosis,nutrient dependency,and tumor biology and for developing novel effective cancer therapies.展开更多
An acute respiratory disease,caused by a novel coronavirus(SARS-CoV-2,previously known as 2019-nCoV),the coronavirus disease 2019(COVID-19)has spread throughout China and received worldwide attention.On 30 January 202...An acute respiratory disease,caused by a novel coronavirus(SARS-CoV-2,previously known as 2019-nCoV),the coronavirus disease 2019(COVID-19)has spread throughout China and received worldwide attention.On 30 January 2020,World Health Organization(WHO)officially declared the COVID-19 epidemic as a public health emergency of international concern.The emergence of SARS-CoV-2,since the severe acute respiratory syndrome coronavirus(SARSCoV)in 2002 and Middle East respiratory syndrome coronavirus(MERS-CoV)in 2012,marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century.As of 1 March 2020,a total of 87,137 confirmed cases globally,79,968 confirmed in China and 7169 outside of China,with 2977 deaths(3.4%)had been reported by WHO.Meanwhile,several independent research groups have identified that SARS-CoV-2 belongs toβ-coronavirus,with highly identical genome to bat coronavirus,pointing to bat as the natural host.The novel coronavirus uses the same receptor,angiotensin-converting enzyme 2(ACE2)as that for SARS-CoV,and mainly spreads through the respiratory tract.Importantly,increasingly evidence showed sustained human-tohuman transmission,along with many exported cases across the globe.The clinical symptoms of COVID-19 patients include fever,cough,fatigue and a small population of patients appeared gastrointestinal infection symptoms.The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes,which may be associated with acute respiratory distress syndrome(ARDS)and cytokine storm.Currently,there are few specific antiviral strategies,but several potent candidates of antivirals and repurposed drugs are under urgent investigation.In this review,we summarized the latest research progress of the epidemiology,pathogenesis,and clinical characteristics of COVID-19,and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.展开更多
Osteoarthritis （OA） is the most common degenerative joint disease and a major cause of pain and disability in adult individuals. The etiology of OA includes joint injury, obesity, aging, and heredity. However, the d...Osteoarthritis （OA） is the most common degenerative joint disease and a major cause of pain and disability in adult individuals. The etiology of OA includes joint injury, obesity, aging, and heredity. However, the detailed molecular mechanisms of OA initiation and progression remain poorly understood and, currently, there are no interventions available to restore degraded cartilage or decelerate disease progression. The diathrodial joint is a complicated organ and its function is to bear weight, perform physical activity and exhibit a joint-specific range of motion during movement. During OA development, the entire joint organ is affected, including articular cartilage, subchondral bone, synovial tissue and meniscus. A full understanding of the pathological mechanism of OA development relies on the discovery of the interplaying mechanisms among different OA symptoms, including articular cartilage degradation, osteophyte formation, subchondral sclerosis and synovial hyperplasia, and the signaling pathway（s） controlling these pathological processes.展开更多
Haplotypic information in diploid organisms provides valuable information on human evolutionary history and plays an important role in identifying a candidate gene in the etiology of complex genetic diseases. However,...Haplotypic information in diploid organisms provides valuable information on human evolutionary history and plays an important role in identifying a candidate gene in the etiology of complex genetic diseases. However, haplotypes of diploid individuals cannot be acquired easily. Molecular haplotyping methods are very costly and have low throughput, and current genotyping and sequenc- ing methods do not provide information on the linkage phase in diploid organisms. The application of statistical methods to infer the haplotype phase in samples of diploid sequences is a very cost-effective approach.展开更多
Cancer cells often upregulate nutrient transporters to fulfill their increased biosynthetic and bioenergetic needs,and to maintain redox homeostasis.One nutrient transporter frequently overexpressed in human cancers i...Cancer cells often upregulate nutrient transporters to fulfill their increased biosynthetic and bioenergetic needs,and to maintain redox homeostasis.One nutrient transporter frequently overexpressed in human cancers is the cystine/glutamate antiporter solute carrier family 7 member 11(SLC7A11;also known as xCT).SLC7A11 promotes cystine uptake and glutathione biosynthesis,resulting in protection from oxidative stress and ferroptotic cell death.Recent studies have unexpectedly revealed that SLC7A11 also plays critical roles in glutamine metabolism and regulates the glucose and glutamine dependency of cancer cells.This review discusses the roles of SLC7A11 in regulating the anti-oxidant response and nutrient dependency of cancer cells,explores our current understanding of SLC7A11 regulation in cancer metabolism,and highlights key open questions for future studies in this emerging research area.A deeper understanding of SLC7A11 in cancer metabolism may identify new therapeutic opportunities to target this important amino acid transporter for cancer treatment.展开更多
The cell-biological program termed the epithelial-to-mesenchymal transition （EMT） plays an important role in both development and cancer progression. Depending on the contextual signals and intracellular gene circui...The cell-biological program termed the epithelial-to-mesenchymal transition （EMT） plays an important role in both development and cancer progression. Depending on the contextual signals and intracellular gene circuits of a particular cell, this program can drive fully epithelial cells to enter into a series of phenotypic states arrayed along the epithelial-mesenehymal phenotypic axis. These cell states display distinctive cellular characteristics, including stemness, invasiveness, drug-resistance and the ability to form metastases at distant organs, and thereby contribute to cancer metastasis and relapse. Currently we still lack a coherent overview of the molecular and biochemical mechanisms inducing cells to enter various states along the epithelial-mesenchymal phenotypic spectrum. An improved understanding of the dynamic and plastic nature of the EMT program has the potential to yield novel therapies targeting this cellular program that may aid in the management of high-grade malignancies.展开更多
The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses.NF-κB induces the expression of various pro-inflammatory g...The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses.NF-κB induces the expression of various pro-inflammatory genes,including those encoding cytokines and chemokines,and also participates in inflammasome regulation.In addition,NF-κB plays a critical role in regulating the survival,activation and differentiation of innate immune cells and inflammatory T cells.Consequently,deregulated NF-κB activation contributes to the pathogenic processes of various inflammatory diseases.In this review,we will discuss the activation and function of NF-κB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-κB inhibition.展开更多
对代谢组学的含义,中心任务,研究方法,样品要求,应用及其发展方向进行了简要综述. 系统生物学概念的诞生标志着研究哲学由“还原论”向“整体论”的变化. 系统生物学的中心任务就是要针对生物系统整体 (无论它是生物细胞,多细胞组织,器...对代谢组学的含义,中心任务,研究方法,样品要求,应用及其发展方向进行了简要综述. 系统生物学概念的诞生标志着研究哲学由“还原论”向“整体论”的变化. 系统生物学的中心任务就是要针对生物系统整体 (无论它是生物细胞,多细胞组织,器官还是生物整体),建立定量,普适,整体和可预测 (QUIP) 的认知. 具体而言,系统生物学研究就是要将给定生物系统的基因,转录,蛋白质和代谢水平所发生的事件,相关性及其对所涉及生物过程的意义进行整体性认识. 从而出现了许多的“组”和“组学”的新概念. 但是现已提出的一百多个“组”和“组学”,可以大体归纳为“基因组”/“基因组学”,“转录组”/“转录组学”,“蛋白质组”/“蛋白质组学”和“代谢组”/“代谢组学”四个方面. 显而易见,DNA,mRNA 以及蛋白质的存在为生物过程的发生提供了物质基础 (但这个过程有可能不发生!),而代谢物质所反映的是已经发生了的生物学事件. 因此代谢组学是对一个生物系统进行全面认识的不可缺少的一部分,是全局系统生物学 (global systems biology) 的重要基础,也是系统生物学的一个重要组成部分. 在现有的英文表述中,代谢组学同时存在两个不同的词汇和概念,即metabonomics 和 metabolomics. 尽管前者多用在动物系统而后者多用于植物和微生物系统,但这些概念的本质从他们的定义中能够得到较细致的了解. Metabonomics 的最初定义是就生物系统对生理和病理刺激以及基因改变的代谢应答的定量测定(“the quantitative measurement of the multi-parametric metabolic response of living systems to pathophysiological stimuli or geneticmodifications”). 我们认为这个定义现在可以更广泛地表述为:代谢组学是关于定量描述生物内源性代谢物质的整体及其对内因和外因变化应答规律的科学 (“Metabonomics is the branch of s展开更多
Background:Gastric cancer mortality decreased substantially over the last decades in most countries worldwide.This study aimed to assess the most recent national trend of gastric cancer mortality and examine the dispa...Background:Gastric cancer mortality decreased substantially over the last decades in most countries worldwide.This study aimed to assess the most recent national trend of gastric cancer mortality and examine the disparity of gastric cancer mortality between rural and urban areas in China.Methods:The crude mortality data of gastric cancer by sex,age group,and area were obtained from China Health Statistical Yearbooks(2003-2015)covering 10%of Chinese population.The age-standardized rates of mortality(ASRM)of gastric cancer in rural and urban areas were estimated using the 2010 Chinese Census population stratified by age,sex,and area.The trend of mortality of gastric cancer was assessed by using Joinpoint analysis.Results:During the 13-year period,the ASRM was reduced from 31.5/100,000 in 2003 to 20.9/100,000 in 2015 in rural areas and from 18.9/100,000 in 2003 to 14.5/100,000 in 2015 in urban areas.In the male population,the annual percent changes of mortality were−2.2%in urban areas(95%confidence interval[CI]−3.8%to−0.6%;P<0.001)and−3.4%in rural areas(95%CI−5.1%to−1.8%;P<0.001).In the female population,the annual percent changes of mortality were−2.7%in urban areas(95%CI−4.2%to−1.2%;P<0.001)and−4.6%in rural areas(95%CI−5.5%to−3.7%;P<0.001).Conclusions:The declining trend of mortality of gastric cancer was presented from 2003 to 2015 in both rural and urban areas in China.The decrease in gastric cancer mortality is greater in rural areas than in urban areas in China.展开更多
Importance:Approximately half of newly-diagnosed hepatocellular carcinoma(HCC)cases in the world occur in China,with hepatitis B virus(HBV)infection being the predominant risk factor.Recently,the guidelines for the ma...Importance:Approximately half of newly-diagnosed hepatocellular carcinoma(HCC)cases in the world occur in China,with hepatitis B virus(HBV)infection being the predominant risk factor.Recently,the guidelines for the management of Chinese HCC patients were updated.Objective:The past decade has witnessed a great improvement in the management of hepatocellular carcinoma(HCC).This study reviews the recommendations in the 2019 Chinese guidelines and makes comparison with the practices from the Western world.Evidence Review:The updated recommendations on the surveillance,diagnosis,and treatment algorithm of HCC in the 2019 Chinese guidelines were summarized,and comparisons among the updated Chinese guidelines,the European Association for the Study of the Liver(EASL)and the American Association for the Study of Liver Diseases(AASLD)guidelines were made.Findings:Besides imaging and pathological diagnoses,novel biomarkers like the seven-micro-RNA panel are advocated for early diagnoses and therapeutic efficacy evaluation in the updated Chinese guidelines.The China liver cancer(CNLC)staging system,proposed in the 2017 guidelines,continues to be the standard model for patient classification,with subsequent modifications and updates being made in treatment allocations.Compared to the Barcelona Clinic Liver Cancer(BCLC)system,the CNLC staging system employs resection,transplantation,and transarterial chemoembolization(TACE)for more progressed HCC.TACE in combination with other regional therapies like ablation or with systemic therapies like sorafenib are also encouraged in select patients in China.The systemic treatments for HCC have evolved considerably since lenvatinib,regorafenib,carbozantinib,ramucirumab and immune checkpoint inhibitors(ICIs)were first prescribed as first-line or second-line agents.Conclusions and Relevances:Novel biomarkers,imaging and operative techniques are recommended in the updated Chinese guideline.More aggressive treatment modalities are suggested for more progressed HBV-related HCC in China.展开更多
Neuroinflammation is associated with neurodegenerative diseases,such as Alzheimer's disease,Parkinson's disease,ancamyotrophic lateral sclerosis.Microglia and astrocytes are key regulators of inflammatory resp...Neuroinflammation is associated with neurodegenerative diseases,such as Alzheimer's disease,Parkinson's disease,ancamyotrophic lateral sclerosis.Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system.The activation of microglia and astrocytes is heterogeneous and traditionally categorized as neurotoxi(M1-phenotype microglia and A1-phenotype astrocytes)or neuroprotective(M2-phenotype microglia and A2-phenotype astrocytes).However,this dichotomized classification may not reflect the various phenotypes of microgliaand astrocytes.The relationship between these activated glial cells is also very complicated,and the phenotypic distribution can change,based on the progression of neurodegenerative diseases.A better understanding of the rolesof microglia and astrocytes in neurodegenerative diseases is essential for developing effective therapies.In this review,we discuss the roles of inflammatory response in neurodegenerative diseases,focusing on the contributions of microglia and astrocytes and their relationship.In addition,we discuss biomarkers to measure neuroinflammation andstudies on therapeutic drugs that can modulate neuroinflammation.展开更多
Rheumatoid arthritis（RA） is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A...Rheumatoid arthritis（RA） is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A better understanding of how the pathological mechanisms drive the deterioration of RA progress in individuals is urgently required in order to develop therapies that will effectively treat patients at each stage of the disease progress. Here we dissect the etiology and pathology at specific stages：（i） triggering,（ii） maturation,（iii） targeting, and（iv） fulminant stage, concomitant with hyperplastic synovium, cartilage damage, bone erosion, and systemic consequences. Modern pharmacologic therapies（including conventional, biological, and novel potential small molecule disease-modifying anti-rheumatic drugs） remain the mainstay of RA treatment and there has been significant progress toward achieving disease remission without joint deformity. Despite this, a significant proportion of RA patients do not effectively respond to the current therapies and thus new drugs are urgently required. This review discusses recent advances of our understanding of RA pathogenesis, disease modifying drugs, and provides perspectives on next generation therapeutics for RA.展开更多
The human liver is usually perceived as a non-immunological organ engaged primarily in metabolic, nutrient storage and detoxification activities. However, we now know that the healthy liver is also a site of complex i...The human liver is usually perceived as a non-immunological organ engaged primarily in metabolic, nutrient storage and detoxification activities. However, we now know that the healthy liver is also a site of complex immunological activity mediated by a diverse immune cell repertoire as well as non-hematopoietic cell populations. In the nondiseased liver, metabolic and tissue remodeling functions require elements of inflammation. This inflammation, in combination with regular exposure to dietary and microbial products, creates the potential for excessive immune activation. In this complex microenvironment, the hepatic immune system tolerates harmless molecules while at the same time remaining alert to possible infectious agents, malignant cells or tissue damage. Upon appropriate immune activation to challenge by pathogens or tissue damage, mechanisms to resolve inflammation are essential to maintain liver homeostasis. Failure to clear ＇dangerous＇ stimuli or regulate appropriately activated immune mechanisms leads to pathological inflammation and disrupted tissue homeostasis characterized by the progressive development of fibrosis, cirrhosis and eventual liver failure. Hepatic inflammatory mechanisms therefore have a spectrum of roles in the healthy adult liver; they are essential to maintain tissue and organ homeostasis and, when dysregulated, are key drivers of the liver pathology associated with chronic infection, autoimmunity and malignancy. In this review, we explore the changing perception of inflammation and inflammatory mediators in normal liver homeostasis and propose targeting of liver-specific immune regulation pathways as a therapeutic approach to treat liver disease.展开更多
Echinococcosis or hydatid disease （HD） is a zoonosis caused by the larval stages of taeniid cestodes belong- ing to the genus Echinococcus. Hepatic echinococcosis is a life-threatening disease, mainly differentiated...Echinococcosis or hydatid disease （HD） is a zoonosis caused by the larval stages of taeniid cestodes belong- ing to the genus Echinococcus. Hepatic echinococcosis is a life-threatening disease, mainly differentiated into alveolar and cystic forms, associated with Echinoc- cus multilocularis （E. multi/ocular/s） and Echinococcus granulosus （E. granulosus） infection, respectively. Cys- tic echinococcosis （CE） has a worldwide distribution, while hepatic alveolar echinococcosis （AE） is endemic in the Northern hemisphere, including North America and several Asian and European countries, like France, Germany and Austria. E. granulosus young cysts are spherical, unilocular vesicles, consisting of an internal germinal layer and an outer acellular layer. Cyst expansion is associated with a host immune reaction and the subsequent development of a fibrous layer, called the per/cyst; old cysts typically present internal septa- tions and daughter cysts. E. multilocularis has a tumor-like, infiltrative behavior, which is responsible for tissue destruction and finally for liver failure. The liver is the main site of HD involvement, for both alveolar and cystic hydatidosis. HD is usually asymptomatic for a long period of time, because cyst growth is commonly slow; the most frequent symptoms are fatigue and abdominal pain. Patients may also present jaundice, hepatomegaly or anaphylaxis, due to cyst leakage or rupture. HD diagnosis is usually accomplished with the combined use of ultrasonography and immunodiagnosis; furthermore, the improvement of surgical techniques, the introduction of minimally invasive treatments [such as puncture, aspiration, injection, re-aspiration （PAIR）] and more effective drugs （such as benzoimidazoles） have deeply changed life expectancy and quality of life of patients with HD. The aim of this article is to provide an up-to-date review of biological, diagnostic, clinical and therapeutic aspects of hepatic echinococcosis.展开更多
Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 （STAT3） in malignant transformation and tumorigenesis. Thus, it is...Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 （STAT3） in malignant transformation and tumorigenesis. Thus, it is now generally accepted that STAT3 is one of the critical players in human cancer formation and represents a valid target for novel anticancer drug design. This review focuses on aberrant STAT3 and its role in promoting tumor cell survival and sup- porting the malignant phenotype. A brief evaluation of the current strategies targeting STAT3 for the development of novel anticancer agents against human tumors harboring constitutively active STAT3 will also be presented.展开更多
Osteonecrosis is a phenomenon involving disruption to the vascular supply to the femoral head, resulting in articular surface collapse and eventual osteoarthritis. Although alcoholism, steroid use, and hip trauma rema...Osteonecrosis is a phenomenon involving disruption to the vascular supply to the femoral head, resulting in articular surface collapse and eventual osteoarthritis. Although alcoholism, steroid use, and hip trauma remain the most common causes, several other etiologies for osteonecrosis have been identified. Basic science research utilizing animal models and stem cell applications continue to further elucidate the pathophysiology of osteonecrosis and promise novel treatment options in the future. Clinical studies evaluating modern joint-sparing procedures have demonstrated significant improvements in outcomes, but hip arthroplasty is still the most common procedure performed in these affected younger adults. Further advances in joint-preserving procedures are required and will be widely studied in the coming decade.展开更多
Hepatic fibrosis is a pathological lesion, characterized by the progressive accumulation of extracellularmatrix （ECM） in the perisinusoidal space and it is a major problem in chronic liver diseases. Phenotypicactiva...Hepatic fibrosis is a pathological lesion, characterized by the progressive accumulation of extracellularmatrix （ECM） in the perisinusoidal space and it is a major problem in chronic liver diseases. Phenotypicactivation of hepatic stellate cells （HSC） plays a central role in the progression of hepatic fibrosis. Retardation of proliferation and clearance of activated HSCs from the injured liver is an appropriate therapeuticstrategy for the resolution and treatment of hepatic fibrosis. Clearance of activated HSCs from the injuredliver by autophagy inhibitors, proapoptotic agents and senescence inducers with the high affinity towardthe activated HSCs may be the novel therapeutic strategy for the treatment of hepatic fibrosis in the nearfuture.展开更多
Non-alcoholic fatty liver disease(NAFLD)has emerged as a public health problem of epidemic proportions worldwide.Accumulating clinical and epidemiological evidence indicates that NAFLD is not only associated with live...Non-alcoholic fatty liver disease(NAFLD)has emerged as a public health problem of epidemic proportions worldwide.Accumulating clinical and epidemiological evidence indicates that NAFLD is not only associated with liver-related morbidity and mortality but also with an increased risk of coronary heart disease(CHD),abnormalities of cardiac function and structure(e.g.,left ventricular dysfunction and hypertrophy,and heart failure),valvular heart disease(e.g.,aortic valve sclerosis)and arrhythmias(e.g.,atrial fibrillation).Experimental evidence suggests that NAFLD itself,especially in its more severe forms,exacerbates systemic/hepatic insulin resistance,causes atherogenic dyslipidemia,and releases a variety of pro-inflammatory,pro-coagulant and pro-fibrogenic mediators that may play important roles in the pathophysiology of cardiac and arrhythmic complications.Collectively,these findings suggest that patients with NAFLD may benefit from more intensive surveillance and early treatment interventions to decrease the risk for CHD and other cardiac/arrhythmic complications.The purpose of this clinical review is to summarize the rapidly expanding body of evidence that supports a strong association between NAFLD and cardiovascular,cardiac and arrhythmic complications,to briefly examine the putative biological mechanisms underlying this association,and to discuss some of the current treatment options that may influence both NAFLD and its related cardiac and arrhythmic complications.展开更多
Acute myocardial infarction(AMI) is the leading cause of death worldwide. Its associated mortality, morbidity and complications have significantly decreased with the development of interventional cardiology and percut...Acute myocardial infarction(AMI) is the leading cause of death worldwide. Its associated mortality, morbidity and complications have significantly decreased with the development of interventional cardiology and percutaneous coronary angioplasty(PCA) treatment, which quick-ly and effectively restore the blood flow to the area previously subjected to ischemia. Paradoxi-cally, the restoration of blood flow to the ischemic zone leads to a massive production of reactive oxygen species(ROS) which generate rapid and severe damage to biomolecules, generating a phenomenon called myocardial reperfusion injury(MRI). In the clinical setting, MRI is associated with multiple complications such as lethal reperfusion, no-reflow, myocardial stunning, and reperfusion arrhythmias. Despite significant advances in the understanding of the mechanisms accounting for the myocardial ischemia reperfusion injury, it remains an unsolved problem. Although promising results have been obtained in experimental studies(mainly in animal models), these benefits have not been translated into clinical settings. Thus, clinical trials have failed to find benefits from any therapy to prevent MRI. There is major evidence with respect to the contribution of oxidative stress to MRI in cardiovascular diseases. The lack- of consistency between basic studies and clinical trials is not solely based on the diversity inherent in epidemiology but is also a result of the methodological weak-nesses of some studies. It is quite possible that pharmacological issues, such as doses, active ingredients, bioavailability, routes of administration, co-therapies, startup time of the drug intervention,and its continuity may also have some responsibility for the lack- of consistency between different studies. Furthermore, the administration of high ascorbate doses prior to reperfusion appears to be a safe and rational therapy against the development of oxidative damage associated with myocardial reperfusion. In addition, the association with N-acetylcysteine(a glutathione do展开更多
基金The research in authors'lab has been supported by The University of Texas MD Anderson Cancer Center,KC180131 from Department of Defense Kidney Cancer Research Program,R01CA181196,R01CA190370,R01CA244144 from the National Institutes of Health(to BG)CPRIT Research Training Grant(RP170067)Dr.John J.Kopchick Research Award from The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences(to PK).
文摘The cystine/glutamate antiporter SLC7A11(also commonly known as xCT)functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers.Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis,a form of regulated cell death induced by excessive lipid peroxidation.However,cancer cells with high expression of SLC7A11(SLC7A11^(high))also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming,leading to glucose-and glutamine-dependency in SLC7A11^(high) cancer cells,which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11^(high) cancer.In this review,we summarize diverse regulatory mechanisms of SLC7A11 in cancer,discuss ferroptosis-dependent and-independent functions of SLC7A11 in promoting tumor development,explore the mechanistic basis of SLC7A11-induced nutrient dependency in cancer cells,and conceptualize therapeutic strategies to target SLC7A11 in cancer treatment.This review will provide the foundation for further understanding SLC7A11 in ferroptosis,nutrient dependency,and tumor biology and for developing novel effective cancer therapies.
基金by the National Natural Science Foundation of China(81870019)Guangdong Provincial Natural Science Foundation(2018A030313554)+2 种基金National Key R&D Program of China(2018YFC0910601)the National Medical Research Council,Singapore(NMRC/CIRG/1458/2016)a recipient of fellowship support from European Allergy and Clinical Immunology(EAACI)Research Fellowship 2019。
文摘An acute respiratory disease,caused by a novel coronavirus(SARS-CoV-2,previously known as 2019-nCoV),the coronavirus disease 2019(COVID-19)has spread throughout China and received worldwide attention.On 30 January 2020,World Health Organization(WHO)officially declared the COVID-19 epidemic as a public health emergency of international concern.The emergence of SARS-CoV-2,since the severe acute respiratory syndrome coronavirus(SARSCoV)in 2002 and Middle East respiratory syndrome coronavirus(MERS-CoV)in 2012,marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century.As of 1 March 2020,a total of 87,137 confirmed cases globally,79,968 confirmed in China and 7169 outside of China,with 2977 deaths(3.4%)had been reported by WHO.Meanwhile,several independent research groups have identified that SARS-CoV-2 belongs toβ-coronavirus,with highly identical genome to bat coronavirus,pointing to bat as the natural host.The novel coronavirus uses the same receptor,angiotensin-converting enzyme 2(ACE2)as that for SARS-CoV,and mainly spreads through the respiratory tract.Importantly,increasingly evidence showed sustained human-tohuman transmission,along with many exported cases across the globe.The clinical symptoms of COVID-19 patients include fever,cough,fatigue and a small population of patients appeared gastrointestinal infection symptoms.The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes,which may be associated with acute respiratory distress syndrome(ARDS)and cytokine storm.Currently,there are few specific antiviral strategies,but several potent candidates of antivirals and repurposed drugs are under urgent investigation.In this review,we summarized the latest research progress of the epidemiology,pathogenesis,and clinical characteristics of COVID-19,and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.
基金supported by NIH grants AR055915 and AR054465 to DC
文摘Osteoarthritis （OA） is the most common degenerative joint disease and a major cause of pain and disability in adult individuals. The etiology of OA includes joint injury, obesity, aging, and heredity. However, the detailed molecular mechanisms of OA initiation and progression remain poorly understood and, currently, there are no interventions available to restore degraded cartilage or decelerate disease progression. The diathrodial joint is a complicated organ and its function is to bear weight, perform physical activity and exhibit a joint-specific range of motion during movement. During OA development, the entire joint organ is affected, including articular cartilage, subchondral bone, synovial tissue and meniscus. A full understanding of the pathological mechanism of OA development relies on the discovery of the interplaying mechanisms among different OA symptoms, including articular cartilage degradation, osteophyte formation, subchondral sclerosis and synovial hyperplasia, and the signaling pathway（s） controlling these pathological processes.
文摘Haplotypic information in diploid organisms provides valuable information on human evolutionary history and plays an important role in identifying a candidate gene in the etiology of complex genetic diseases. However, haplotypes of diploid individuals cannot be acquired easily. Molecular haplotyping methods are very costly and have low throughput, and current genotyping and sequenc- ing methods do not provide information on the linkage phase in diploid organisms. The application of statistical methods to infer the haplotype phase in samples of diploid sequences is a very cost-effective approach.
基金supported by the Andrew Sabin Family Fellow Award and Institutional Research Grant from the University of Texas MD Anderson Cancer Center,Grants from National Institutes of Health(CA181196 and CA190370)Anna Fuller Fund,and Ellison Medical Foundation(AG-NS-0973-13).
文摘Cancer cells often upregulate nutrient transporters to fulfill their increased biosynthetic and bioenergetic needs,and to maintain redox homeostasis.One nutrient transporter frequently overexpressed in human cancers is the cystine/glutamate antiporter solute carrier family 7 member 11(SLC7A11;also known as xCT).SLC7A11 promotes cystine uptake and glutathione biosynthesis,resulting in protection from oxidative stress and ferroptotic cell death.Recent studies have unexpectedly revealed that SLC7A11 also plays critical roles in glutamine metabolism and regulates the glucose and glutamine dependency of cancer cells.This review discusses the roles of SLC7A11 in regulating the anti-oxidant response and nutrient dependency of cancer cells,explores our current understanding of SLC7A11 regulation in cancer metabolism,and highlights key open questions for future studies in this emerging research area.A deeper understanding of SLC7A11 in cancer metabolism may identify new therapeutic opportunities to target this important amino acid transporter for cancer treatment.
文摘The cell-biological program termed the epithelial-to-mesenchymal transition （EMT） plays an important role in both development and cancer progression. Depending on the contextual signals and intracellular gene circuits of a particular cell, this program can drive fully epithelial cells to enter into a series of phenotypic states arrayed along the epithelial-mesenehymal phenotypic axis. These cell states display distinctive cellular characteristics, including stemness, invasiveness, drug-resistance and the ability to form metastases at distant organs, and thereby contribute to cancer metastasis and relapse. Currently we still lack a coherent overview of the molecular and biochemical mechanisms inducing cells to enter various states along the epithelial-mesenchymal phenotypic spectrum. An improved understanding of the dynamic and plastic nature of the EMT program has the potential to yield novel therapies targeting this cellular program that may aid in the management of high-grade malignancies.
基金laboratory is supported by grants from the US National Institutes of Health(AI057555,AI064639,AI104519 and GM84459)Cancer Prevention and Research Institute of Texas(RP150235 and RP140244).
文摘The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses.NF-κB induces the expression of various pro-inflammatory genes,including those encoding cytokines and chemokines,and also participates in inflammasome regulation.In addition,NF-κB plays a critical role in regulating the survival,activation and differentiation of innate immune cells and inflammatory T cells.Consequently,deregulated NF-κB activation contributes to the pathogenic processes of various inflammatory diseases.In this review,we will discuss the activation and function of NF-κB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-κB inhibition.
文摘对代谢组学的含义,中心任务,研究方法,样品要求,应用及其发展方向进行了简要综述. 系统生物学概念的诞生标志着研究哲学由“还原论”向“整体论”的变化. 系统生物学的中心任务就是要针对生物系统整体 (无论它是生物细胞,多细胞组织,器官还是生物整体),建立定量,普适,整体和可预测 (QUIP) 的认知. 具体而言,系统生物学研究就是要将给定生物系统的基因,转录,蛋白质和代谢水平所发生的事件,相关性及其对所涉及生物过程的意义进行整体性认识. 从而出现了许多的“组”和“组学”的新概念. 但是现已提出的一百多个“组”和“组学”,可以大体归纳为“基因组”/“基因组学”,“转录组”/“转录组学”,“蛋白质组”/“蛋白质组学”和“代谢组”/“代谢组学”四个方面. 显而易见,DNA,mRNA 以及蛋白质的存在为生物过程的发生提供了物质基础 (但这个过程有可能不发生!),而代谢物质所反映的是已经发生了的生物学事件. 因此代谢组学是对一个生物系统进行全面认识的不可缺少的一部分,是全局系统生物学 (global systems biology) 的重要基础,也是系统生物学的一个重要组成部分. 在现有的英文表述中,代谢组学同时存在两个不同的词汇和概念,即metabonomics 和 metabolomics. 尽管前者多用在动物系统而后者多用于植物和微生物系统,但这些概念的本质从他们的定义中能够得到较细致的了解. Metabonomics 的最初定义是就生物系统对生理和病理刺激以及基因改变的代谢应答的定量测定(“the quantitative measurement of the multi-parametric metabolic response of living systems to pathophysiological stimuli or geneticmodifications”). 我们认为这个定义现在可以更广泛地表述为:代谢组学是关于定量描述生物内源性代谢物质的整体及其对内因和外因变化应答规律的科学 (“Metabonomics is the branch of s
基金This work was supported in part by National Natural Science Foundation of China (Grant 31870983).
文摘Background:Gastric cancer mortality decreased substantially over the last decades in most countries worldwide.This study aimed to assess the most recent national trend of gastric cancer mortality and examine the disparity of gastric cancer mortality between rural and urban areas in China.Methods:The crude mortality data of gastric cancer by sex,age group,and area were obtained from China Health Statistical Yearbooks(2003-2015)covering 10%of Chinese population.The age-standardized rates of mortality(ASRM)of gastric cancer in rural and urban areas were estimated using the 2010 Chinese Census population stratified by age,sex,and area.The trend of mortality of gastric cancer was assessed by using Joinpoint analysis.Results:During the 13-year period,the ASRM was reduced from 31.5/100,000 in 2003 to 20.9/100,000 in 2015 in rural areas and from 18.9/100,000 in 2003 to 14.5/100,000 in 2015 in urban areas.In the male population,the annual percent changes of mortality were−2.2%in urban areas(95%confidence interval[CI]−3.8%to−0.6%;P<0.001)and−3.4%in rural areas(95%CI−5.1%to−1.8%;P<0.001).In the female population,the annual percent changes of mortality were−2.7%in urban areas(95%CI−4.2%to−1.2%;P<0.001)and−4.6%in rural areas(95%CI−5.5%to−3.7%;P<0.001).Conclusions:The declining trend of mortality of gastric cancer was presented from 2003 to 2015 in both rural and urban areas in China.The decrease in gastric cancer mortality is greater in rural areas than in urban areas in China.
基金This work was supported by the National Natural Science Foundation of China(no.91859105,no.8196112802)the Basic Research Project from the Technology Commission of Shanghai Municipality(no.17JC1402200)the Shanghai Municipal Key Clinical Specialty.
文摘Importance:Approximately half of newly-diagnosed hepatocellular carcinoma(HCC)cases in the world occur in China,with hepatitis B virus(HBV)infection being the predominant risk factor.Recently,the guidelines for the management of Chinese HCC patients were updated.Objective:The past decade has witnessed a great improvement in the management of hepatocellular carcinoma(HCC).This study reviews the recommendations in the 2019 Chinese guidelines and makes comparison with the practices from the Western world.Evidence Review:The updated recommendations on the surveillance,diagnosis,and treatment algorithm of HCC in the 2019 Chinese guidelines were summarized,and comparisons among the updated Chinese guidelines,the European Association for the Study of the Liver(EASL)and the American Association for the Study of Liver Diseases(AASLD)guidelines were made.Findings:Besides imaging and pathological diagnoses,novel biomarkers like the seven-micro-RNA panel are advocated for early diagnoses and therapeutic efficacy evaluation in the updated Chinese guidelines.The China liver cancer(CNLC)staging system,proposed in the 2017 guidelines,continues to be the standard model for patient classification,with subsequent modifications and updates being made in treatment allocations.Compared to the Barcelona Clinic Liver Cancer(BCLC)system,the CNLC staging system employs resection,transplantation,and transarterial chemoembolization(TACE)for more progressed HCC.TACE in combination with other regional therapies like ablation or with systemic therapies like sorafenib are also encouraged in select patients in China.The systemic treatments for HCC have evolved considerably since lenvatinib,regorafenib,carbozantinib,ramucirumab and immune checkpoint inhibitors(ICIs)were first prescribed as first-line or second-line agents.Conclusions and Relevances:Novel biomarkers,imaging and operative techniques are recommended in the updated Chinese guideline.More aggressive treatment modalities are suggested for more progressed HBV-related HCC in China.
基金supported by the Basic Science Research Program of the National Research Foundation of Korea,which was funded by the Ministry of Science,ICT,and Future Planning(2018R1A2A2A15023219)a grant of the Korea Health Technology R&D Projea through the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,Republic of Korea(HI20C0253)the Medical Research Centre(2017R1A5A2015395).
文摘Neuroinflammation is associated with neurodegenerative diseases,such as Alzheimer's disease,Parkinson's disease,ancamyotrophic lateral sclerosis.Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system.The activation of microglia and astrocytes is heterogeneous and traditionally categorized as neurotoxi(M1-phenotype microglia and A1-phenotype astrocytes)or neuroprotective(M2-phenotype microglia and A2-phenotype astrocytes).However,this dichotomized classification may not reflect the various phenotypes of microgliaand astrocytes.The relationship between these activated glial cells is also very complicated,and the phenotypic distribution can change,based on the progression of neurodegenerative diseases.A better understanding of the rolesof microglia and astrocytes in neurodegenerative diseases is essential for developing effective therapies.In this review,we discuss the roles of inflammatory response in neurodegenerative diseases,focusing on the contributions of microglia and astrocytes and their relationship.In addition,we discuss biomarkers to measure neuroinflammation andstudies on therapeutic drugs that can modulate neuroinflammation.
基金supported in part by the Australian National Health and Medical Research Council (NHMRC, No. 1107828)Arthritis foundation of Australiathe University of Western Australia Research Collaboration Awards
文摘Rheumatoid arthritis（RA） is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A better understanding of how the pathological mechanisms drive the deterioration of RA progress in individuals is urgently required in order to develop therapies that will effectively treat patients at each stage of the disease progress. Here we dissect the etiology and pathology at specific stages：（i） triggering,（ii） maturation,（iii） targeting, and（iv） fulminant stage, concomitant with hyperplastic synovium, cartilage damage, bone erosion, and systemic consequences. Modern pharmacologic therapies（including conventional, biological, and novel potential small molecule disease-modifying anti-rheumatic drugs） remain the mainstay of RA treatment and there has been significant progress toward achieving disease remission without joint deformity. Despite this, a significant proportion of RA patients do not effectively respond to the current therapies and thus new drugs are urgently required. This review discusses recent advances of our understanding of RA pathogenesis, disease modifying drugs, and provides perspectives on next generation therapeutics for RA.
基金We acknowledge funding from Science Foundation Ireland （grant # 12/IA/1667） and the Health Research Board （grant # HRA-POR-2013- 424）. In addition, we gratefully acknowledge the on-going research contributions from the Liver Transplant Unit at St. Vincent＇s University Hospital.
文摘The human liver is usually perceived as a non-immunological organ engaged primarily in metabolic, nutrient storage and detoxification activities. However, we now know that the healthy liver is also a site of complex immunological activity mediated by a diverse immune cell repertoire as well as non-hematopoietic cell populations. In the nondiseased liver, metabolic and tissue remodeling functions require elements of inflammation. This inflammation, in combination with regular exposure to dietary and microbial products, creates the potential for excessive immune activation. In this complex microenvironment, the hepatic immune system tolerates harmless molecules while at the same time remaining alert to possible infectious agents, malignant cells or tissue damage. Upon appropriate immune activation to challenge by pathogens or tissue damage, mechanisms to resolve inflammation are essential to maintain liver homeostasis. Failure to clear ＇dangerous＇ stimuli or regulate appropriately activated immune mechanisms leads to pathological inflammation and disrupted tissue homeostasis characterized by the progressive development of fibrosis, cirrhosis and eventual liver failure. Hepatic inflammatory mechanisms therefore have a spectrum of roles in the healthy adult liver; they are essential to maintain tissue and organ homeostasis and, when dysregulated, are key drivers of the liver pathology associated with chronic infection, autoimmunity and malignancy. In this review, we explore the changing perception of inflammation and inflammatory mediators in normal liver homeostasis and propose targeting of liver-specific immune regulation pathways as a therapeutic approach to treat liver disease.
文摘Echinococcosis or hydatid disease （HD） is a zoonosis caused by the larval stages of taeniid cestodes belong- ing to the genus Echinococcus. Hepatic echinococcosis is a life-threatening disease, mainly differentiated into alveolar and cystic forms, associated with Echinoc- cus multilocularis （E. multi/ocular/s） and Echinococcus granulosus （E. granulosus） infection, respectively. Cys- tic echinococcosis （CE） has a worldwide distribution, while hepatic alveolar echinococcosis （AE） is endemic in the Northern hemisphere, including North America and several Asian and European countries, like France, Germany and Austria. E. granulosus young cysts are spherical, unilocular vesicles, consisting of an internal germinal layer and an outer acellular layer. Cyst expansion is associated with a host immune reaction and the subsequent development of a fibrous layer, called the per/cyst; old cysts typically present internal septa- tions and daughter cysts. E. multilocularis has a tumor-like, infiltrative behavior, which is responsible for tissue destruction and finally for liver failure. The liver is the main site of HD involvement, for both alveolar and cystic hydatidosis. HD is usually asymptomatic for a long period of time, because cyst growth is commonly slow; the most frequent symptoms are fatigue and abdominal pain. Patients may also present jaundice, hepatomegaly or anaphylaxis, due to cyst leakage or rupture. HD diagnosis is usually accomplished with the combined use of ultrasonography and immunodiagnosis; furthermore, the improvement of surgical techniques, the introduction of minimally invasive treatments [such as puncture, aspiration, injection, re-aspiration （PAIR）] and more effective drugs （such as benzoimidazoles） have deeply changed life expectancy and quality of life of patients with HD. The aim of this article is to provide an up-to-date review of biological, diagnostic, clinical and therapeutic aspects of hepatic echinococcosis.
文摘Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 （STAT3） in malignant transformation and tumorigenesis. Thus, it is now generally accepted that STAT3 is one of the critical players in human cancer formation and represents a valid target for novel anticancer drug design. This review focuses on aberrant STAT3 and its role in promoting tumor cell survival and sup- porting the malignant phenotype. A brief evaluation of the current strategies targeting STAT3 for the development of novel anticancer agents against human tumors harboring constitutively active STAT3 will also be presented.
文摘Osteonecrosis is a phenomenon involving disruption to the vascular supply to the femoral head, resulting in articular surface collapse and eventual osteoarthritis. Although alcoholism, steroid use, and hip trauma remain the most common causes, several other etiologies for osteonecrosis have been identified. Basic science research utilizing animal models and stem cell applications continue to further elucidate the pathophysiology of osteonecrosis and promise novel treatment options in the future. Clinical studies evaluating modern joint-sparing procedures have demonstrated significant improvements in outcomes, but hip arthroplasty is still the most common procedure performed in these affected younger adults. Further advances in joint-preserving procedures are required and will be widely studied in the coming decade.
文摘Hepatic fibrosis is a pathological lesion, characterized by the progressive accumulation of extracellularmatrix （ECM） in the perisinusoidal space and it is a major problem in chronic liver diseases. Phenotypicactivation of hepatic stellate cells （HSC） plays a central role in the progression of hepatic fibrosis. Retardation of proliferation and clearance of activated HSCs from the injured liver is an appropriate therapeuticstrategy for the resolution and treatment of hepatic fibrosis. Clearance of activated HSCs from the injuredliver by autophagy inhibitors, proapoptotic agents and senescence inducers with the high affinity towardthe activated HSCs may be the novel therapeutic strategy for the treatment of hepatic fibrosis in the nearfuture.
基金Supported by(in part)the Southampton National Institute for Health Research Biomedical Research Centre(Byrne CD)grants from the School of Medicine of the Verona University(Targher GT)
文摘Non-alcoholic fatty liver disease(NAFLD)has emerged as a public health problem of epidemic proportions worldwide.Accumulating clinical and epidemiological evidence indicates that NAFLD is not only associated with liver-related morbidity and mortality but also with an increased risk of coronary heart disease(CHD),abnormalities of cardiac function and structure(e.g.,left ventricular dysfunction and hypertrophy,and heart failure),valvular heart disease(e.g.,aortic valve sclerosis)and arrhythmias(e.g.,atrial fibrillation).Experimental evidence suggests that NAFLD itself,especially in its more severe forms,exacerbates systemic/hepatic insulin resistance,causes atherogenic dyslipidemia,and releases a variety of pro-inflammatory,pro-coagulant and pro-fibrogenic mediators that may play important roles in the pathophysiology of cardiac and arrhythmic complications.Collectively,these findings suggest that patients with NAFLD may benefit from more intensive surveillance and early treatment interventions to decrease the risk for CHD and other cardiac/arrhythmic complications.The purpose of this clinical review is to summarize the rapidly expanding body of evidence that supports a strong association between NAFLD and cardiovascular,cardiac and arrhythmic complications,to briefly examine the putative biological mechanisms underlying this association,and to discuss some of the current treatment options that may influence both NAFLD and its related cardiac and arrhythmic complications.
文摘Acute myocardial infarction(AMI) is the leading cause of death worldwide. Its associated mortality, morbidity and complications have significantly decreased with the development of interventional cardiology and percutaneous coronary angioplasty(PCA) treatment, which quick-ly and effectively restore the blood flow to the area previously subjected to ischemia. Paradoxi-cally, the restoration of blood flow to the ischemic zone leads to a massive production of reactive oxygen species(ROS) which generate rapid and severe damage to biomolecules, generating a phenomenon called myocardial reperfusion injury(MRI). In the clinical setting, MRI is associated with multiple complications such as lethal reperfusion, no-reflow, myocardial stunning, and reperfusion arrhythmias. Despite significant advances in the understanding of the mechanisms accounting for the myocardial ischemia reperfusion injury, it remains an unsolved problem. Although promising results have been obtained in experimental studies(mainly in animal models), these benefits have not been translated into clinical settings. Thus, clinical trials have failed to find benefits from any therapy to prevent MRI. There is major evidence with respect to the contribution of oxidative stress to MRI in cardiovascular diseases. The lack- of consistency between basic studies and clinical trials is not solely based on the diversity inherent in epidemiology but is also a result of the methodological weak-nesses of some studies. It is quite possible that pharmacological issues, such as doses, active ingredients, bioavailability, routes of administration, co-therapies, startup time of the drug intervention,and its continuity may also have some responsibility for the lack- of consistency between different studies. Furthermore, the administration of high ascorbate doses prior to reperfusion appears to be a safe and rational therapy against the development of oxidative damage associated with myocardial reperfusion. In addition, the association with N-acetylcysteine(a glutathione do
