Specificity protein(Sp)transcription factors(TFs)Sp1,Sp3 and Sp4,and the orphan nuclear receptor 4A1(NR4A1)are highly expressed in pancreatic tumors and Sp1 is a negative prognostic factor for pancreatic cancer patien...Specificity protein(Sp)transcription factors(TFs)Sp1,Sp3 and Sp4,and the orphan nuclear receptor 4A1(NR4A1)are highly expressed in pancreatic tumors and Sp1 is a negative prognostic factor for pancreatic cancer patient survival.Results of knockdown and overexpression of Sp1,Sp3 and Sp4 in pancreatic and other cancer lines show that these TFs are individually pro-oncogenic factors and loss of one Sp TF is not compensated by other members.NR4A1 is also a prooncogenic factor and both NR4A1 and Sp TFs exhibit similar functions in pancreatic cancer cells and regulate cell growth,survival,migration and invasion.There is also evidence that Sp TFs and NR4A1 regulate some of the same genes including survivin,epidermal growth factor receptor,PAX3-FOXO1,α5-andα6-integrins,β1-,β3-andβ4-integrins;this is due to NR4A1 acting as a cofactor and mediating NR4A1/Sp1/4-regulated gene expression through GC-rich gene promoter sites.Several studies show that drugs targeting Sp downregulation or NR4A1 antagonists are highly effective inhibitors of Sp/NR4A1-regulated pathways and genes in pancreatic and other cancer cells,and the triterpenoid celastrol is a novel dual-acting agent that targets both Sp TFs and NR4A1.展开更多
Major depressive disorder(MDD)is highly prevalent and is a significant cause of mortality and morbidity worldwide.Currently,conventional pharmacological treatments for MDD produce temporary remission in<50%of patie...Major depressive disorder(MDD)is highly prevalent and is a significant cause of mortality and morbidity worldwide.Currently,conventional pharmacological treatments for MDD produce temporary remission in<50%of patients;therefore,there is an urgent need for a wider spectrum of novel antidepressants to target newly discovered underlying disease mechanisms.Accumulated evidence has shown that immune inflammation,particularly inflammasome activity,plays an important role in the pathophysiology of MDD.In this review,we summarize the evidence on nuclear receptors(NRs),such as glucocorticoid receptor,mineralocorticoid receptor,estrogen receptor,aryl hydrocarbon receptor,and peroxisome proliferator-activated receptor,in modulating the inflammasome activity and depression-associated behaviors.This review provides evidence from an endocrine perspective to understand the role of activated NRs in the pathophysiology of MDD,and to provide insight for the discovery of antidepressants with novel mechanisms for this devastating disorder.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is a devastating disease with a median overall survival time of5 mo and the five years survival less than 5%,a rate essentially unchanged over the course of the years.A well defin...Pancreatic ductal adenocarcinoma(PDAC)is a devastating disease with a median overall survival time of5 mo and the five years survival less than 5%,a rate essentially unchanged over the course of the years.A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease.However,due to the its subtle nature and concurring events PDAC cure remains elusive.Nuclear receptors(NR)are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism,to growth and development.Given the nature of their ligands,NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases.There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages;nonetheless many aspects of their role are not fully understood.The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors,retinoic acid receptors,retinoid X receptor,androgen receptor,estrogen receptors and the orphan NR Nur,chicken ovalbumin upstream promoter transcription factorⅡand the liver receptor homologue-1 receptor to PDAC development,connections that could lead to the identification of novel therapies for this disease.展开更多
Objective To explore Effects of marine collagen peptides (MCPs) on markers of metablic nuclear receptors, i.e peroxisome proliferator-activated receptor (PPARs), liver X receptor (LXRs) and farnesoid X receptor (FXRs)...Objective To explore Effects of marine collagen peptides (MCPs) on markers of metablic nuclear receptors, i.e peroxisome proliferator-activated receptor (PPARs), liver X receptor (LXRs) and farnesoid X receptor (FXRs) in type 2 diabetic patients with/without hypertension. Method Study population consisted of 200 type 2 diabetic patients with/without hypertension and 50 healthy subjects, all of whom were randomly assigned to MCPs-treated diabetics (n=50), placebo-treated diabetics (n=50), MCPs-treated diabetics with hypertension (n=50), placebo-treated diabetics with hypertension (n=50), and healthy controls (n=50). MCPs or placebo (water-soluble starch) were given daily before breakfast and bedtime over three months. Levels of free fatty acid, cytochrome P450, leptin, resistin, adiponectin, bradykinin, NO, and Prostacyclin were determined before intervention, and 1.5 months, and 3 months after intervention. Hypoglycemia and the endpoint events during the study were recorded and compared among the study groups. Result At the end of the study period, MCPs-treated patients showed marked improvement compared with patients receiving placebo. The protection exerted by MCPs seemed more profound in diabetics than in diabetics with hypertension. In particular, after MCPs intervention, levels of free fatty acid, hs-CRP, resistin, Prostacyclin decreased significantly in diabetics and tended to decrease in diabetic and hypertensive patients whereas levels of cytochrome P450, leptin, NO tended to decrease in diabetics with/without hypertension. Meanwhile, levels of adiponectin and bradykinin rose markedly in diabetics following MCPs administration. Conclusion MCPs could offer protection against diabetes and hypertension by affecting levels of molecules involved in diabetic and hypertensive pathogenesis. Regulation on metabolic nuclear receptors by MCPs may be the possible underlying mechanism for its observed effects in the study. Further study into its action may shed light on development of new drugs based on bioactive peptides from marine sources.展开更多
AIM:To investigate the expression of P450 enzyme genes by using end-stage liver disease samples and trimmed normal Chinese donor livers.METHODS:The end-stage liver disease samples[n=93,including hepatocellular carcino...AIM:To investigate the expression of P450 enzyme genes by using end-stage liver disease samples and trimmed normal Chinese donor livers.METHODS:The end-stage liver disease samples[n=93,including hepatocellular carcinoma(HCC),peri-HCC tissue,hepatitis B virus cirrhosis,alcoholic cirrhosis,and severe cirrhosis]and trimmed normal Chinese donor livers(n=35)from The Institute of Organ Transplantation in Beijing,China.Total RNA was extracted,purified,and subjected to real-time RT-PCR analysis.RESULTS:For cytochrome P450 enzymes 1(CYP1)family,the expression of CYP1A2 was decreased 90%in HCC,80%in alcoholic cirrhosis,and 65%in severe cirrhosis.For CYP2 family,the expression of CAR was decreased 50%in HCC,but increased 50%in peri-HCC tissues.Similar decreases(about 50%)of CYP2B6,CYP2C9,CYP2C19,CYP2D6 and CYP2E1 were observed in HCC,as compared to peri-HCC tissues and normal livers.CYP2C19 were decreased in all end-stage liver diseases and CYP2E1 also decreased in alcoholic cirrhosis and severe cirrhosis.For CYP3 family,the expression of PXR was decreased 60%in HCC,together with decreases in CYP3A4,CYP3A5,and CYP3A7.In contrast,the expression of CYP3A7 was slightly increased in HBV cirrhosis.The expression of CYP4A11 was decreased85%in HCC,7%in alcoholic cirrhosis and severe liver cirrhosis,along with decreases in PPARα.The 93 endstage livers had much higher inter-individual variations in gene expression than 35 normal livers.CONCLUSION:The expression of CYP enzyme genes and corresponding nuclear receptors was generally decreased in end-stage liver diseases,and significant differences in gene expression were evident between peri-HCC and HCC.展开更多
The canalicular membrane represents the excretory pole of hepatocytes.Bile is an important route of elimination of potentially toxic endo-and xenobiotics(including drugs and toxins),mediated by the major canalicular t...The canalicular membrane represents the excretory pole of hepatocytes.Bile is an important route of elimination of potentially toxic endo-and xenobiotics(including drugs and toxins),mediated by the major canalicular transporters:multidrug resistance protein 1(MDR1, ABCB1),also known as P-glycoprotein,multidrug resistance-associated protein 2(MRP2,ABCC2),and the breast cancer resistance protein(BCRP,ABCG2).Their activities depend on regulation of expression and proper localization at the canalicular membrane,as regulated by transcriptional and post-transcriptional events,respectively.At transcriptional level,specific nuclear receptors(NR)s modulated by ligands,co-activators and co-repressors,mediate the physiological requirements of these transporters.This complex system is also responsible for alterations occurring in specific liver pathologies.We briefly describe the major ClassⅡNRs, pregnane X receptor(PXR)and constitutive androstane receptor(CAR),and their role in regulating expression of multidrug resistance proteins.Several therapeutic agents regulate the expression of relevant drug transporters through activation/inactivation of these NRs.We provide some representative examples of the action of therapeutic agents modulating liver drug transporters, which in addition,involve CAR or PXR as mediators.展开更多
·Fungal keratitis(FK) is a worldwide visual impairment disease. This infectious fungus initiates the primary innate immune response and, later the adaptive immune response. The inflammatory process is related to ...·Fungal keratitis(FK) is a worldwide visual impairment disease. This infectious fungus initiates the primary innate immune response and, later the adaptive immune response. The inflammatory process is related to a variety of immune cells, including macrophages, helper T cells, neutrophils, dendritic cells, and Treg cells, and is associated with proinflammatory, chemotactic and regulatory cytokines. All-trans retinoic acids(ATRA)have diverse immunomodulatory actions in a number of inflammatory and autoimmune conditions. These retinoids regulate the transcriptional levels of target genes through the activation of nuclear receptors.Retinoic acid receptor α(RAR α), retinoic acid receptor γ(RAR γ), and retinoid X receptor α(RXR α) are expressed in the cornea and immune cells. This paper summarizes new findings regarding ATRA in immune and inflammatory diseases and analyzes the perspective application of ATRA in FK.展开更多
The recapitulation of primary tumour heterogenity and the existence of a minor sub-population of cancer cells,capable of initiating tumour growth in xenografts on serial passages, led to the hypothesis that cancer ste...The recapitulation of primary tumour heterogenity and the existence of a minor sub-population of cancer cells,capable of initiating tumour growth in xenografts on serial passages, led to the hypothesis that cancer stem cells(CSCs) exist. CSCs are present in many tumours, among which is breast cancer. Breast CSCs(BCSCs) are likely to sustain the growth of the primary tumour mass, as wellas to be responsible for disease relapse and metastatic spreading. Consequently, BCSCs represent the most significant target for new drugs in breast cancer therapy. Both the hypoxic condition in BCSCs biology and proinflammatory cytokine network has gained increasing importance in the recent past. Breast stromal cells are crucial components of the tumours milieu and are a major source of inflammatory mediators. Recently, the antiinflammatory role of some nuclear receptors ligands has emerged in several diseases, including breast cancer. Therefore, the use of nuclear receptors ligands may be a valid strategy to inhibit BCSCs viability and consequently breast cancer growth and disease relapse.展开更多
Colorectal cancer(CRC) is one of the most common human cancers and the cause of about 700000 deaths per year worldwide. Deregulation of the WNT/β-catenin pathway is a key event in CRC initiation. This pathway interac...Colorectal cancer(CRC) is one of the most common human cancers and the cause of about 700000 deaths per year worldwide. Deregulation of the WNT/β-catenin pathway is a key event in CRC initiation. This pathway interacts with other nuclear signaling pathways, including members of the nuclear receptor superfamily and their transcription coregulators. In this review, we provide an overview of the literature dealing with the main coactivators(NCo A-1 to 3, NCo A-6, PGC1-α, p300, CREBBP and MED1) and corepressors(N-Co R1 and 2, NRIP1 and MTA1) of nuclear receptors and summarize their links with the WNT/β-catenin signaling cascade, their expression in CRC and their role in intestinal physiopathology.展开更多
The etiology of most cases of idiopathic bile acid malabsorption (IBAM) is unknown. In this study, a Swedish family with bile acid malabsorption in three consecutive generations was screened for mutations in the ileal...The etiology of most cases of idiopathic bile acid malabsorption (IBAM) is unknown. In this study, a Swedish family with bile acid malabsorption in three consecutive generations was screened for mutations in the ileal apical sodium-bile acid cotransporter gene (ASBT; gene symbol, SLC10A2) and in the genes for several of the nuclear receptors known to be important for ASBT expression: the farnesoid X receptor (FXR) and peroxisome proliferator activated receptor alpha (PPARa). The patients presented with a clinical history of idiopathic chronic watery diarrhea, which was responsive to cholestyramine treatment and consistent with IBAM. Bile acid absorption was determined using 75Se-homocholic acid taurine (SeHCAT); bile acid synthesis was estimated by measuring the plasma levels of 7a-hydroxy-4-cholesten-3-one (C4). The ASBT, FXR, and PPARa genes in the affected and unaffected family members were analyzed using single stranded conformation polymorphism (SSCP), denaturing HPLC, and direct sequencing. No ASBT mutations were identified and the ASBT gene did not segregate withthe bile acid malabsorption phenotype. Similarly, no mutations or polymorphisms were identified in the FXR or PPARa genes associated with the bile acid malabsorption phenotype. These studies indicate that the intestinal bile acid malabsorption in these patients cannot be attributed to defects in ASBT. In the absence of apparent ileal disease, alternative explanations such as accelerated transit through the small intestine may be responsible for the IBAM.展开更多
Objective: To explore the possible biological function of human nuclear receptor hLRH-1 in tumorigenesis and progress of colon cancer. Methods: Plasmids pcDNA3-hLRH-1 were introduced into SW480 cells via lipofectamine...Objective: To explore the possible biological function of human nuclear receptor hLRH-1 in tumorigenesis and progress of colon cancer. Methods: Plasmids pcDNA3-hLRH-1 were introduced into SW480 cells via lipofectamine. The expression of mRNA and protein of exogenous hLRH-1 were detected by RT-PCR and western blotting, respectively. MTT assay was carried out to survey the proliferation of SW480 cells with overexpression of hLRH-1. Meanwhile, the expression of proliferation-related genes cyclin E1 and cyclin D1, and apoptosis-related genes PTEN and Rb1, were analyzed by real- time RT-PCR. Results: The proliferation of SW480 cells was promoted under the condition of overexpression of hLRH-1. The expression of cyclin E1 was up-regulated significantly, while that of PTEN and Rb1 were down-regulated in SW480 cells with overexpressed hLRH-1. Conclusion: The expression of exogenous hLRH-1 in SW480 cells induced the proliferation resulting form up-regulation of cyclin E1, as well as participated in the regulation of apoptosis via influencing the expression of PTEN and Rb1.展开更多
Objective:To explore the expression of nuclear receptor corepressor (NCoR) in androgen independence prostate cancer (AIPC) and its clinical significance. Methods:The expression of NCoR and androgen receptor (AR) in pr...Objective:To explore the expression of nuclear receptor corepressor (NCoR) in androgen independence prostate cancer (AIPC) and its clinical significance. Methods:The expression of NCoR and androgen receptor (AR) in prostatic tissues, from 15 cases with AIPC, 20 cases with androgen dependence prostate cancer (ADPC) and 20 cases with benign prostatic hyperplasia (BPH), was detected by immunohistochemistry respectively. Results:The expression of NCoR was observed mainly in the nucleus and slightly in the nucleus. The positive cell percentage of NCoR in AIPC was significantly lower than that in ADPC and BPH (P<0.01). The NCoR expression was significantly lower in low differentiation prostate cancer (Pca) than that in high differentiation Pca (P<0.05). The rate of NCoR expression was significantly higher in low stage Pca than that in high stage Pca (P<0.05). AR, expressing in the nucleus, was found to be negative in one case of AIPC, while was strongly expressed in other cases of AIPC, and all cases of ADPC and BPH. Conclusion: The transition to AIPC of Pca may be correlated with the decrease of NCoR protein.展开更多
Nuclear receptors such as pregnane X receptor (PXR) and constitutive androstane receptor (CAR) regulate the transcription of transporter and cytochrome P450 (CYP). The diurnal variation was observed in some transporte...Nuclear receptors such as pregnane X receptor (PXR) and constitutive androstane receptor (CAR) regulate the transcription of transporter and cytochrome P450 (CYP). The diurnal variation was observed in some transporters regulated by nuclear receptors. We investigated whether diurnal variation in PXR and CAR exists in mice. We also examined the effect of food intake on the diurnal rhythm of hepatic PXR and CAR using fed and fasted mice. In liver and small intestine of fed mice, the mRNA levels of PXR and CAR were unchanged between 7:00 AM and 7:00 PM. In contrast to fed mice, fasting mice partly exhibited the diurnal variation in PXR, not in CAR. The mRNA levels of PXR at 7:00 AM were significantly higher than that those at 7:00 PM in liver of fasting mice. These results indicated the different effects of fasting in mice on diurnal variation of PXR in each tissue.展开更多
Transcriptional coactivators regulate the rate of gene expression in the nucleus.Nuclear receptor coactivator 6(NCOA6),a coactivator,has been implicated in embryonic development,metabolism,and cancer pathogenesis,but ...Transcriptional coactivators regulate the rate of gene expression in the nucleus.Nuclear receptor coactivator 6(NCOA6),a coactivator,has been implicated in embryonic development,metabolism,and cancer pathogenesis,but its role in innate immunity and inflammatory diseases remains unclear.Here,we demonstrated that NCOA6 was expressed in monocytes and macrophages and that its level was increased under proinflammatory conditions.Unexpectedly,nuclear NCOA6 was found to translocate to the cytoplasm in activated monocytes and then become incorporated into the inflammasome with NLRP3 and ASC,forming cytoplasmic specks.Mechanistically,NCOA6 associated with the ATP hydrolysis motifs in the NACHT domain of NLRP3,promoting the oligomerization of NLRP3 and ASC and thereby instigating the production of IL-1βand active caspase-1.Of note,Ncoa6 deficiency markedly inhibited NLRP3 hyperactivation caused by the Nlrp3^(R258W) gain-of-function mutation in macrophages.Genetic ablation of Ncoa6 substantially attenuated the severity of two NLRP3-dependent diseases,folic-induced acute tubular necrosis and crystal-induced arthritis,in mice.Consistent with these findings,NCOA6 was highly expressed in macrophages derived from gout patients,and NCOA6-positive macrophages were significantly enriched in gout macrophages according to the transcriptome profiling results.Conclusively,NCOA6 is a critical regulator of NLRP3 inflammasome activation and is therefore a promising target for NLRP3-dependent diseases,including gout.展开更多
Background:In many cancer types,aryl hydrocarbon receptor nuclear translocator 2(ARNT2)has been found to be associated with tumor cell proliferation and prognosis.However,the role of ARNT2 in clear cell renal cell car...Background:In many cancer types,aryl hydrocarbon receptor nuclear translocator 2(ARNT2)has been found to be associated with tumor cell proliferation and prognosis.However,the role of ARNT2 in clear cell renal cell carcinoma(ccRCC)has not been completely elucidated.In this study,the potential role of ARNT2 in ccRCC development was characterized.Methods:A pan-cancer dataset(TCGA-TARGET-GTEx)was accessed from UCSC Xena Data Browser.ARNT2 expression in normal and tumor samples was compared.Univariate Cox regression was performed to evaluate the prognostic value of ARNT2.Single sample gene set enrichment analysis(ssGSEA)was used to estimate the enrichment of functional pathways and gene signatures.CIBERSORT and ESTIMATE methods evaluated the immune infiltration.The ARNT2 expression was determined in ccRCC tissue and cell lines using RT-qPCR and Western blot.Results:ARNT2 expression was significantly dysregulated in 23 out of 30 cancer types.Pan-cancer data revealed a strong correlation between ARNT2 expression and immune modulators,immune cell infiltration,and genomic alternations.In ccRCC patients,the low-ARNT2 expression group had higher immune infiltration,CD8 T cells,and programmed cell death ligand 1 expression,as well as higher enrichment score of immunotherapeutic predictors than those in the high-ARNT2 expression group.Low-ARNT2 expression group was more responsive to immunotherapy.Moreover,low ARNT2 expression was observed in ccRCC tissue and cell lines.Conclusions:Dysregulated ARNT2 expression is involved in cancer development and the modulation of the immune microenvironment.ARNT2 can be potentially used as a prognostic indicator and an immunotherapeutic indicator for ccRCC.展开更多
Pharmacological activation of the xenobiotic-sensing nuclear receptors pregnane X receptor(PXR) and constitutive androstane receptor(CAR) is well-known to increase drug metabolism and reduce inflammation. Little is kn...Pharmacological activation of the xenobiotic-sensing nuclear receptors pregnane X receptor(PXR) and constitutive androstane receptor(CAR) is well-known to increase drug metabolism and reduce inflammation. Little is known regarding their physiological functions on the gut microbiome. In this study, we discovered bivalent hormetic functions of PXR/CAR modulating the richness of the gut microbiome using genetically engineered mice. The absence of PXR or CAR increased microbial richness, and absence of both receptors synergistically increased microbial richness. PXR and CAR deficiency increased the pro-inflammatory bacteria Helicobacteraceae and Helicobacter. Deficiency in both PXR and CAR increased the relative abundance of Lactobacillus, which has bile salt hydrolase activity, corresponding to decreased primary taurine-conjugated bile acids(BAs) in feces, which may lead to higher internal burden of taurine and unconjugated BAs, both of which are linked to inflammation, oxidative stress, and cytotoxicity. The basal effect of PXR/CAR on the gut microbiome was distinct from pharmacological and toxicological activation of these receptors. Common PXR/CAR-targeted bacteria were identified, the majority of which were suppressed by these receptors. h PXR-TG mice had a distinct microbial profile as compared to wild-type mice. This study is the first to unveil the basal functions of PXR and CAR on the gut microbiome.展开更多
Developmental diapause is a widespread strategy for animals to survive seasonal starvation and environmental harshness.Diapaused animals often ration body fat to generate a basal level of energy for enduring survival....Developmental diapause is a widespread strategy for animals to survive seasonal starvation and environmental harshness.Diapaused animals often ration body fat to generate a basal level of energy for enduring survival.How diapause and fat rationing are coupled,however,is poorly understood.The nematode Caenorhabditis elegans excretes pheromones to the environment to induce a diapause form called dauer larva.Through saturated forward genetic screens and CRISPR knockout,we found that dauer pheromones feed back to repress the transcription of ACOX-3,MAOC-1,DHS-28,DAF-22(peroxisomalβ-oxidation enzymes dually involved in pheromone synthesis and fat burning),ALH-4(aldehyde dehydrogenase for pheromone synthesis),PRX-10 and PRX-11(peroxisome assembly and proliferation factors).Dysfunction of these pheromone enzymes and factors relieves the repression.Surprisingly,transcription is repressed not by pheromones excreted but by pheromones endogenous to each animal.The endogenous pheromones regulate the nuclear translocation of HNF4αfamily nuclear receptor NHR-79 and its co-receptor NHR-49,and,repress transcription through the two receptors.The feedback repression maintains pheromone homeostasis,increases fat storage,decreases fat burning,and prolongs dauer lifespan.Thus,the exocrine dauer pheromones possess an unexpected endocrine function to mediate a peroxisome-nucleus crosstalk,coupling dauer diapause to fat rationing.展开更多
Estrogen-related receptor gamma(ERRg)is one of three members of the ERR family and remains an orphan,as there are no known natural ligands.ERRg is an inducible transcription factor,and its ligandindependent transcript...Estrogen-related receptor gamma(ERRg)is one of three members of the ERR family and remains an orphan,as there are no known natural ligands.ERRg is an inducible transcription factor,and its ligandindependent transcriptional activity is regulated by co-regulator interactions and post-transcriptional modifications.Recent findings from animal models show that ERRg,as a downstream mediator of multiple extracellular signals,plays a key role in coordinating endocrine and metabolic signals,resulting in changes in glucose,alcohol,lipid,and iron metabolism in the liver.Therefore,dysregulation of this receptor contributes to the pathogenesis of metabolic diseases such as hyperglycemia,insulin resistance,and alcoholic liver injury.Interestingly,ERRg is also involved in responses to bacterial infection.These findings establish the importance of ERRg in the endocrine and metabolic control of liver metabolism,and suggest that ERRg may be a promising therapeutic target for metabolic diseases of the liver.展开更多
Associate Prof.Grace Liejun Guo is a tenured faculty in the Department of Pharmacology and Toxicology in the School of Pharmacy at the Rutgers University in New Jersey,USA.Dr.Guo graduated from the West China Universi...Associate Prof.Grace Liejun Guo is a tenured faculty in the Department of Pharmacology and Toxicology in the School of Pharmacy at the Rutgers University in New Jersey,USA.Dr.Guo graduated from the West China University of Medical Sciences in 1993.In 1997,Dr.Guo obtained a MS degree展开更多
Non-alcoholic fatty liver disease(NAFLD)has become the leading cause of chronic liver disease in adults and children worldwide.The symptoms of NAFLD range from simple steatosis and non-alcoholic stea-tohepatitis(NASH)...Non-alcoholic fatty liver disease(NAFLD)has become the leading cause of chronic liver disease in adults and children worldwide.The symptoms of NAFLD range from simple steatosis and non-alcoholic stea-tohepatitis(NASH)to hepatic fibrosis or cirrhosis,even ultimately develops to hepatocellular carcinoma.Nuclear receptors(NRs)are a superfamily of ligand-activated transcription factors,most of which are ligand-activated that control cellular homeostasis in the liver and other tissues.A growing number of studies demonstrated the important role of NRs in NAFLD.In this review,the current findings on the role of NRs in NAFLD are summarized and future perspectives to target NRs for NAFLD are discussed.展开更多
基金Supported by Houston Methodist Cancer Center Innovation Award。
文摘Specificity protein(Sp)transcription factors(TFs)Sp1,Sp3 and Sp4,and the orphan nuclear receptor 4A1(NR4A1)are highly expressed in pancreatic tumors and Sp1 is a negative prognostic factor for pancreatic cancer patient survival.Results of knockdown and overexpression of Sp1,Sp3 and Sp4 in pancreatic and other cancer lines show that these TFs are individually pro-oncogenic factors and loss of one Sp TF is not compensated by other members.NR4A1 is also a prooncogenic factor and both NR4A1 and Sp TFs exhibit similar functions in pancreatic cancer cells and regulate cell growth,survival,migration and invasion.There is also evidence that Sp TFs and NR4A1 regulate some of the same genes including survivin,epidermal growth factor receptor,PAX3-FOXO1,α5-andα6-integrins,β1-,β3-andβ4-integrins;this is due to NR4A1 acting as a cofactor and mediating NR4A1/Sp1/4-regulated gene expression through GC-rich gene promoter sites.Several studies show that drugs targeting Sp downregulation or NR4A1 antagonists are highly effective inhibitors of Sp/NR4A1-regulated pathways and genes in pancreatic and other cancer cells,and the triterpenoid celastrol is a novel dual-acting agent that targets both Sp TFs and NR4A1.
基金the National Natural Science Foundation of China,No.31650005.
文摘Major depressive disorder(MDD)is highly prevalent and is a significant cause of mortality and morbidity worldwide.Currently,conventional pharmacological treatments for MDD produce temporary remission in<50%of patients;therefore,there is an urgent need for a wider spectrum of novel antidepressants to target newly discovered underlying disease mechanisms.Accumulated evidence has shown that immune inflammation,particularly inflammasome activity,plays an important role in the pathophysiology of MDD.In this review,we summarize the evidence on nuclear receptors(NRs),such as glucocorticoid receptor,mineralocorticoid receptor,estrogen receptor,aryl hydrocarbon receptor,and peroxisome proliferator-activated receptor,in modulating the inflammasome activity and depression-associated behaviors.This review provides evidence from an endocrine perspective to understand the role of activated NRs in the pathophysiology of MDD,and to provide insight for the discovery of antidepressants with novel mechanisms for this devastating disorder.
基金Supported by Fondo per gli Investimenti della Ricerca di Base(FIRB)(RBAP10MY35_002)by Ente Cassa di Risparmio di Firenzeby FiorGen ONLUS to Galli A
文摘Pancreatic ductal adenocarcinoma(PDAC)is a devastating disease with a median overall survival time of5 mo and the five years survival less than 5%,a rate essentially unchanged over the course of the years.A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease.However,due to the its subtle nature and concurring events PDAC cure remains elusive.Nuclear receptors(NR)are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism,to growth and development.Given the nature of their ligands,NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases.There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages;nonetheless many aspects of their role are not fully understood.The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors,retinoic acid receptors,retinoid X receptor,androgen receptor,estrogen receptors and the orphan NR Nur,chicken ovalbumin upstream promoter transcription factorⅡand the liver receptor homologue-1 receptor to PDAC development,connections that could lead to the identification of novel therapies for this disease.
基金grants from the National Key Technology R&D Program (No. 2006BAD27B01)Chinese Center for Disease Control and Prevention Dalone Foundation of Dietary Nutrition (No. DIC-200710)a grant from Shenzhen Bureau of Science Technology & Information (No. 200802002)
文摘Objective To explore Effects of marine collagen peptides (MCPs) on markers of metablic nuclear receptors, i.e peroxisome proliferator-activated receptor (PPARs), liver X receptor (LXRs) and farnesoid X receptor (FXRs) in type 2 diabetic patients with/without hypertension. Method Study population consisted of 200 type 2 diabetic patients with/without hypertension and 50 healthy subjects, all of whom were randomly assigned to MCPs-treated diabetics (n=50), placebo-treated diabetics (n=50), MCPs-treated diabetics with hypertension (n=50), placebo-treated diabetics with hypertension (n=50), and healthy controls (n=50). MCPs or placebo (water-soluble starch) were given daily before breakfast and bedtime over three months. Levels of free fatty acid, cytochrome P450, leptin, resistin, adiponectin, bradykinin, NO, and Prostacyclin were determined before intervention, and 1.5 months, and 3 months after intervention. Hypoglycemia and the endpoint events during the study were recorded and compared among the study groups. Result At the end of the study period, MCPs-treated patients showed marked improvement compared with patients receiving placebo. The protection exerted by MCPs seemed more profound in diabetics than in diabetics with hypertension. In particular, after MCPs intervention, levels of free fatty acid, hs-CRP, resistin, Prostacyclin decreased significantly in diabetics and tended to decrease in diabetic and hypertensive patients whereas levels of cytochrome P450, leptin, NO tended to decrease in diabetics with/without hypertension. Meanwhile, levels of adiponectin and bradykinin rose markedly in diabetics following MCPs administration. Conclusion MCPs could offer protection against diabetes and hypertension by affecting levels of molecules involved in diabetic and hypertensive pathogenesis. Regulation on metabolic nuclear receptors by MCPs may be the possible underlying mechanism for its observed effects in the study. Further study into its action may shed light on development of new drugs based on bioactive peptides from marine sources.
基金Supported by Grants from the Chinese 863 project,No.2012AA022409Guizhou Science and Technology Foundation,No.2009-70019
文摘AIM:To investigate the expression of P450 enzyme genes by using end-stage liver disease samples and trimmed normal Chinese donor livers.METHODS:The end-stage liver disease samples[n=93,including hepatocellular carcinoma(HCC),peri-HCC tissue,hepatitis B virus cirrhosis,alcoholic cirrhosis,and severe cirrhosis]and trimmed normal Chinese donor livers(n=35)from The Institute of Organ Transplantation in Beijing,China.Total RNA was extracted,purified,and subjected to real-time RT-PCR analysis.RESULTS:For cytochrome P450 enzymes 1(CYP1)family,the expression of CYP1A2 was decreased 90%in HCC,80%in alcoholic cirrhosis,and 65%in severe cirrhosis.For CYP2 family,the expression of CAR was decreased 50%in HCC,but increased 50%in peri-HCC tissues.Similar decreases(about 50%)of CYP2B6,CYP2C9,CYP2C19,CYP2D6 and CYP2E1 were observed in HCC,as compared to peri-HCC tissues and normal livers.CYP2C19 were decreased in all end-stage liver diseases and CYP2E1 also decreased in alcoholic cirrhosis and severe cirrhosis.For CYP3 family,the expression of PXR was decreased 60%in HCC,together with decreases in CYP3A4,CYP3A5,and CYP3A7.In contrast,the expression of CYP3A7 was slightly increased in HBV cirrhosis.The expression of CYP4A11 was decreased85%in HCC,7%in alcoholic cirrhosis and severe liver cirrhosis,along with decreases in PPARα.The 93 endstage livers had much higher inter-individual variations in gene expression than 35 normal livers.CONCLUSION:The expression of CYP enzyme genes and corresponding nuclear receptors was generally decreased in end-stage liver diseases,and significant differences in gene expression were evident between peri-HCC and HCC.
基金Grants from Agencia Nacional de Promoción Científicay Tecnológica (PICT N° 05-26306)Consejo Nacional de Investigaciones Científicasy Técnicas (PIP N° 6442)Universidad Nacional de Rosario,Argentina
文摘The canalicular membrane represents the excretory pole of hepatocytes.Bile is an important route of elimination of potentially toxic endo-and xenobiotics(including drugs and toxins),mediated by the major canalicular transporters:multidrug resistance protein 1(MDR1, ABCB1),also known as P-glycoprotein,multidrug resistance-associated protein 2(MRP2,ABCC2),and the breast cancer resistance protein(BCRP,ABCG2).Their activities depend on regulation of expression and proper localization at the canalicular membrane,as regulated by transcriptional and post-transcriptional events,respectively.At transcriptional level,specific nuclear receptors(NR)s modulated by ligands,co-activators and co-repressors,mediate the physiological requirements of these transporters.This complex system is also responsible for alterations occurring in specific liver pathologies.We briefly describe the major ClassⅡNRs, pregnane X receptor(PXR)and constitutive androstane receptor(CAR),and their role in regulating expression of multidrug resistance proteins.Several therapeutic agents regulate the expression of relevant drug transporters through activation/inactivation of these NRs.We provide some representative examples of the action of therapeutic agents modulating liver drug transporters, which in addition,involve CAR or PXR as mediators.
基金Supported by National Natural Science Foundation of China(No.81300727)Jilin University Basic Scientific Research Operating Expenses Fund(Research Fund of the Bethune B Plan of Jilin University,2012No.2012230)
文摘·Fungal keratitis(FK) is a worldwide visual impairment disease. This infectious fungus initiates the primary innate immune response and, later the adaptive immune response. The inflammatory process is related to a variety of immune cells, including macrophages, helper T cells, neutrophils, dendritic cells, and Treg cells, and is associated with proinflammatory, chemotactic and regulatory cytokines. All-trans retinoic acids(ATRA)have diverse immunomodulatory actions in a number of inflammatory and autoimmune conditions. These retinoids regulate the transcriptional levels of target genes through the activation of nuclear receptors.Retinoic acid receptor α(RAR α), retinoic acid receptor γ(RAR γ), and retinoid X receptor α(RXR α) are expressed in the cornea and immune cells. This paper summarizes new findings regarding ATRA in immune and inflammatory diseases and analyzes the perspective application of ATRA in FK.
文摘The recapitulation of primary tumour heterogenity and the existence of a minor sub-population of cancer cells,capable of initiating tumour growth in xenografts on serial passages, led to the hypothesis that cancer stem cells(CSCs) exist. CSCs are present in many tumours, among which is breast cancer. Breast CSCs(BCSCs) are likely to sustain the growth of the primary tumour mass, as wellas to be responsible for disease relapse and metastatic spreading. Consequently, BCSCs represent the most significant target for new drugs in breast cancer therapy. Both the hypoxic condition in BCSCs biology and proinflammatory cytokine network has gained increasing importance in the recent past. Breast stromal cells are crucial components of the tumours milieu and are a major source of inflammatory mediators. Recently, the antiinflammatory role of some nuclear receptors ligands has emerged in several diseases, including breast cancer. Therefore, the use of nuclear receptors ligands may be a valid strategy to inhibit BCSCs viability and consequently breast cancer growth and disease relapse.
基金Supported by SIRIC and the PHC-UTIQUE program,No.16G 0805PHC-UTIQUE program,No.16G 0805+1 种基金Tunisian government(Bourse d’alternance)INSERM,Universitéde Montpellier,INCa,SIRIC Montpellier,the Institut régional du Cancer de Montpellier
文摘Colorectal cancer(CRC) is one of the most common human cancers and the cause of about 700000 deaths per year worldwide. Deregulation of the WNT/β-catenin pathway is a key event in CRC initiation. This pathway interacts with other nuclear signaling pathways, including members of the nuclear receptor superfamily and their transcription coregulators. In this review, we provide an overview of the literature dealing with the main coactivators(NCo A-1 to 3, NCo A-6, PGC1-α, p300, CREBBP and MED1) and corepressors(N-Co R1 and 2, NRIP1 and MTA1) of nuclear receptors and summarize their links with the WNT/β-catenin signaling cascade, their expression in CRC and their role in intestinal physiopathology.
基金Supported by grants from the Swedish Research Council, the Karolinska Institutet and the Swedish Society of Medicine (to CE) and National Institutes of Health grants DK-47987 (to PAD)
文摘The etiology of most cases of idiopathic bile acid malabsorption (IBAM) is unknown. In this study, a Swedish family with bile acid malabsorption in three consecutive generations was screened for mutations in the ileal apical sodium-bile acid cotransporter gene (ASBT; gene symbol, SLC10A2) and in the genes for several of the nuclear receptors known to be important for ASBT expression: the farnesoid X receptor (FXR) and peroxisome proliferator activated receptor alpha (PPARa). The patients presented with a clinical history of idiopathic chronic watery diarrhea, which was responsive to cholestyramine treatment and consistent with IBAM. Bile acid absorption was determined using 75Se-homocholic acid taurine (SeHCAT); bile acid synthesis was estimated by measuring the plasma levels of 7a-hydroxy-4-cholesten-3-one (C4). The ASBT, FXR, and PPARa genes in the affected and unaffected family members were analyzed using single stranded conformation polymorphism (SSCP), denaturing HPLC, and direct sequencing. No ASBT mutations were identified and the ASBT gene did not segregate withthe bile acid malabsorption phenotype. Similarly, no mutations or polymorphisms were identified in the FXR or PPARa genes associated with the bile acid malabsorption phenotype. These studies indicate that the intestinal bile acid malabsorption in these patients cannot be attributed to defects in ASBT. In the absence of apparent ileal disease, alternative explanations such as accelerated transit through the small intestine may be responsible for the IBAM.
基金the Young Scientific and Technical Innovation Foundation of Fujian Province (No. 2004J067)Foundation of Fuzhou General Hospital (No. 200638)
文摘Objective: To explore the possible biological function of human nuclear receptor hLRH-1 in tumorigenesis and progress of colon cancer. Methods: Plasmids pcDNA3-hLRH-1 were introduced into SW480 cells via lipofectamine. The expression of mRNA and protein of exogenous hLRH-1 were detected by RT-PCR and western blotting, respectively. MTT assay was carried out to survey the proliferation of SW480 cells with overexpression of hLRH-1. Meanwhile, the expression of proliferation-related genes cyclin E1 and cyclin D1, and apoptosis-related genes PTEN and Rb1, were analyzed by real- time RT-PCR. Results: The proliferation of SW480 cells was promoted under the condition of overexpression of hLRH-1. The expression of cyclin E1 was up-regulated significantly, while that of PTEN and Rb1 were down-regulated in SW480 cells with overexpressed hLRH-1. Conclusion: The expression of exogenous hLRH-1 in SW480 cells induced the proliferation resulting form up-regulation of cyclin E1, as well as participated in the regulation of apoptosis via influencing the expression of PTEN and Rb1.
文摘Objective:To explore the expression of nuclear receptor corepressor (NCoR) in androgen independence prostate cancer (AIPC) and its clinical significance. Methods:The expression of NCoR and androgen receptor (AR) in prostatic tissues, from 15 cases with AIPC, 20 cases with androgen dependence prostate cancer (ADPC) and 20 cases with benign prostatic hyperplasia (BPH), was detected by immunohistochemistry respectively. Results:The expression of NCoR was observed mainly in the nucleus and slightly in the nucleus. The positive cell percentage of NCoR in AIPC was significantly lower than that in ADPC and BPH (P<0.01). The NCoR expression was significantly lower in low differentiation prostate cancer (Pca) than that in high differentiation Pca (P<0.05). The rate of NCoR expression was significantly higher in low stage Pca than that in high stage Pca (P<0.05). AR, expressing in the nucleus, was found to be negative in one case of AIPC, while was strongly expressed in other cases of AIPC, and all cases of ADPC and BPH. Conclusion: The transition to AIPC of Pca may be correlated with the decrease of NCoR protein.
文摘Nuclear receptors such as pregnane X receptor (PXR) and constitutive androstane receptor (CAR) regulate the transcription of transporter and cytochrome P450 (CYP). The diurnal variation was observed in some transporters regulated by nuclear receptors. We investigated whether diurnal variation in PXR and CAR exists in mice. We also examined the effect of food intake on the diurnal rhythm of hepatic PXR and CAR using fed and fasted mice. In liver and small intestine of fed mice, the mRNA levels of PXR and CAR were unchanged between 7:00 AM and 7:00 PM. In contrast to fed mice, fasting mice partly exhibited the diurnal variation in PXR, not in CAR. The mRNA levels of PXR at 7:00 AM were significantly higher than that those at 7:00 PM in liver of fasting mice. These results indicated the different effects of fasting in mice on diurnal variation of PXR in each tissue.
基金supported by grants from the National Research Foundation of Korea(NRF)funded by the Ministry of Science and ICT(2015R1A3A2032927 and 2021R1A2C1008130).
文摘Transcriptional coactivators regulate the rate of gene expression in the nucleus.Nuclear receptor coactivator 6(NCOA6),a coactivator,has been implicated in embryonic development,metabolism,and cancer pathogenesis,but its role in innate immunity and inflammatory diseases remains unclear.Here,we demonstrated that NCOA6 was expressed in monocytes and macrophages and that its level was increased under proinflammatory conditions.Unexpectedly,nuclear NCOA6 was found to translocate to the cytoplasm in activated monocytes and then become incorporated into the inflammasome with NLRP3 and ASC,forming cytoplasmic specks.Mechanistically,NCOA6 associated with the ATP hydrolysis motifs in the NACHT domain of NLRP3,promoting the oligomerization of NLRP3 and ASC and thereby instigating the production of IL-1βand active caspase-1.Of note,Ncoa6 deficiency markedly inhibited NLRP3 hyperactivation caused by the Nlrp3^(R258W) gain-of-function mutation in macrophages.Genetic ablation of Ncoa6 substantially attenuated the severity of two NLRP3-dependent diseases,folic-induced acute tubular necrosis and crystal-induced arthritis,in mice.Consistent with these findings,NCOA6 was highly expressed in macrophages derived from gout patients,and NCOA6-positive macrophages were significantly enriched in gout macrophages according to the transcriptome profiling results.Conclusively,NCOA6 is a critical regulator of NLRP3 inflammasome activation and is therefore a promising target for NLRP3-dependent diseases,including gout.
基金funded by the Shenzhen Longhua District Medical and Health Institutions Research Fund(Project No.2022102).
文摘Background:In many cancer types,aryl hydrocarbon receptor nuclear translocator 2(ARNT2)has been found to be associated with tumor cell proliferation and prognosis.However,the role of ARNT2 in clear cell renal cell carcinoma(ccRCC)has not been completely elucidated.In this study,the potential role of ARNT2 in ccRCC development was characterized.Methods:A pan-cancer dataset(TCGA-TARGET-GTEx)was accessed from UCSC Xena Data Browser.ARNT2 expression in normal and tumor samples was compared.Univariate Cox regression was performed to evaluate the prognostic value of ARNT2.Single sample gene set enrichment analysis(ssGSEA)was used to estimate the enrichment of functional pathways and gene signatures.CIBERSORT and ESTIMATE methods evaluated the immune infiltration.The ARNT2 expression was determined in ccRCC tissue and cell lines using RT-qPCR and Western blot.Results:ARNT2 expression was significantly dysregulated in 23 out of 30 cancer types.Pan-cancer data revealed a strong correlation between ARNT2 expression and immune modulators,immune cell infiltration,and genomic alternations.In ccRCC patients,the low-ARNT2 expression group had higher immune infiltration,CD8 T cells,and programmed cell death ligand 1 expression,as well as higher enrichment score of immunotherapeutic predictors than those in the high-ARNT2 expression group.Low-ARNT2 expression group was more responsive to immunotherapy.Moreover,low ARNT2 expression was observed in ccRCC tissue and cell lines.Conclusions:Dysregulated ARNT2 expression is involved in cancer development and the modulation of the immune microenvironment.ARNT2 can be potentially used as a prognostic indicator and an immunotherapeutic indicator for ccRCC.
基金supported by National Institutes of Health(NIH,USA)grant ES025708,ES030197,GM111381,ES031098the University of Washington Center for Exposures,Diseases,Genomics,and Environment,USA[P30 ES0007033]+2 种基金the Murphy Endowment,USAThe Peer Reviewed Medical Research Program-Investigator Initiated Research Award under Award No.W81XWH-17-1-0479NIH grants(CA 222469,USA)。
文摘Pharmacological activation of the xenobiotic-sensing nuclear receptors pregnane X receptor(PXR) and constitutive androstane receptor(CAR) is well-known to increase drug metabolism and reduce inflammation. Little is known regarding their physiological functions on the gut microbiome. In this study, we discovered bivalent hormetic functions of PXR/CAR modulating the richness of the gut microbiome using genetically engineered mice. The absence of PXR or CAR increased microbial richness, and absence of both receptors synergistically increased microbial richness. PXR and CAR deficiency increased the pro-inflammatory bacteria Helicobacteraceae and Helicobacter. Deficiency in both PXR and CAR increased the relative abundance of Lactobacillus, which has bile salt hydrolase activity, corresponding to decreased primary taurine-conjugated bile acids(BAs) in feces, which may lead to higher internal burden of taurine and unconjugated BAs, both of which are linked to inflammation, oxidative stress, and cytotoxicity. The basal effect of PXR/CAR on the gut microbiome was distinct from pharmacological and toxicological activation of these receptors. Common PXR/CAR-targeted bacteria were identified, the majority of which were suppressed by these receptors. h PXR-TG mice had a distinct microbial profile as compared to wild-type mice. This study is the first to unveil the basal functions of PXR and CAR on the gut microbiome.
基金supported by the National Natural Science Foundation of China(91857106 and 31770865)by the CGC,which is funded by NIH Office of Research Infrastructure Programs(P40 OD010440)of USAby the Mitani Lab through the National Bio-Resource Project of the MEXT of Japan。
文摘Developmental diapause is a widespread strategy for animals to survive seasonal starvation and environmental harshness.Diapaused animals often ration body fat to generate a basal level of energy for enduring survival.How diapause and fat rationing are coupled,however,is poorly understood.The nematode Caenorhabditis elegans excretes pheromones to the environment to induce a diapause form called dauer larva.Through saturated forward genetic screens and CRISPR knockout,we found that dauer pheromones feed back to repress the transcription of ACOX-3,MAOC-1,DHS-28,DAF-22(peroxisomalβ-oxidation enzymes dually involved in pheromone synthesis and fat burning),ALH-4(aldehyde dehydrogenase for pheromone synthesis),PRX-10 and PRX-11(peroxisome assembly and proliferation factors).Dysfunction of these pheromone enzymes and factors relieves the repression.Surprisingly,transcription is repressed not by pheromones excreted but by pheromones endogenous to each animal.The endogenous pheromones regulate the nuclear translocation of HNF4αfamily nuclear receptor NHR-79 and its co-receptor NHR-49,and,repress transcription through the two receptors.The feedback repression maintains pheromone homeostasis,increases fat storage,decreases fat burning,and prolongs dauer lifespan.Thus,the exocrine dauer pheromones possess an unexpected endocrine function to mediate a peroxisome-nucleus crosstalk,coupling dauer diapause to fat rationing.
基金This work was supported by National Creative Research Initiatives Grant(No.20110018305 to H.-S.Choi and National Research Foundation(NRF)No.2018R1D1A1B07043953 to D.-K.Kim)the NRF funded by the Korean government(Ministry of Science,ICT&Future Planning and Ministry of Education)also carried out with the support of“Cooperative Research Program for Agriculture Science and Technology Development(No.PJ01280701 to D.-K.Kim)”Rural Development Administration,Republic of Korea.
文摘Estrogen-related receptor gamma(ERRg)is one of three members of the ERR family and remains an orphan,as there are no known natural ligands.ERRg is an inducible transcription factor,and its ligandindependent transcriptional activity is regulated by co-regulator interactions and post-transcriptional modifications.Recent findings from animal models show that ERRg,as a downstream mediator of multiple extracellular signals,plays a key role in coordinating endocrine and metabolic signals,resulting in changes in glucose,alcohol,lipid,and iron metabolism in the liver.Therefore,dysregulation of this receptor contributes to the pathogenesis of metabolic diseases such as hyperglycemia,insulin resistance,and alcoholic liver injury.Interestingly,ERRg is also involved in responses to bacterial infection.These findings establish the importance of ERRg in the endocrine and metabolic control of liver metabolism,and suggest that ERRg may be a promising therapeutic target for metabolic diseases of the liver.
文摘Associate Prof.Grace Liejun Guo is a tenured faculty in the Department of Pharmacology and Toxicology in the School of Pharmacy at the Rutgers University in New Jersey,USA.Dr.Guo graduated from the West China University of Medical Sciences in 1993.In 1997,Dr.Guo obtained a MS degree
基金The work was supported by the Natural Science Foundation of China(81973392,81320108027)the National Key Research and Development Program of China(2017YFE0109900)+2 种基金the Natural Science Foundation of Guangdong Province(2017A030310330,2017A030311018)China Postdoctoral Science Foundation(2019TQ0398)the Fundamental Research Funds for the Central Universities(19ykyjs34).
文摘Non-alcoholic fatty liver disease(NAFLD)has become the leading cause of chronic liver disease in adults and children worldwide.The symptoms of NAFLD range from simple steatosis and non-alcoholic stea-tohepatitis(NASH)to hepatic fibrosis or cirrhosis,even ultimately develops to hepatocellular carcinoma.Nuclear receptors(NRs)are a superfamily of ligand-activated transcription factors,most of which are ligand-activated that control cellular homeostasis in the liver and other tissues.A growing number of studies demonstrated the important role of NRs in NAFLD.In this review,the current findings on the role of NRs in NAFLD are summarized and future perspectives to target NRs for NAFLD are discussed.
