BACKGROUND Thalidomide is an effective treatment for refractory Crohn’s disease(CD).However,thalidomide-induced peripheral neuropathy(TiPN),which has a large individual variation,is a major cause of treatment failure...BACKGROUND Thalidomide is an effective treatment for refractory Crohn’s disease(CD).However,thalidomide-induced peripheral neuropathy(TiPN),which has a large individual variation,is a major cause of treatment failure.TiPN is rarely predictable and recognized,especially in CD.It is necessary to develop a risk model to predict TiPN occurrence.AIM To develop and compare a predictive model of TiPN using machine learning based on comprehensive clinical and genetic variables.METHODS A retrospective cohort of 164 CD patients from January 2016 to June 2022 was used to establish the model.The National Cancer Institute Common Toxicity Criteria Sensory Scale(version 4.0)was used to assess TiPN.With 18 clinical features and 150 genetic variables,five predictive models were established and evaluated by the confusion matrix receiver operating characteristic curve(AUROC),area under the precision-recall curve(AUPRC),specificity,sensitivity(recall rate),precision,accuracy,and F1 score.RESULTS The top-ranking five risk variables associated with TiPN were interleukin-12 rs1353248[P=0.0004,odds ratio(OR):8.983,95%confidence interval(CI):2.497-30.90],dose(mg/d,P=0.002),brainderived neurotrophic factor(BDNF)rs2030324(P=0.001,OR:3.164,95%CI:1.561-6.434),BDNF rs6265(P=0.001,OR:3.150,95%CI:1.546-6.073)and BDNF rs11030104(P=0.001,OR:3.091,95%CI:1.525-5.960).In the training set,gradient boosting decision tree(GBDT),extremely random trees(ET),random forest,logistic regression and extreme gradient boosting(XGBoost)obtained AUROC values>0.90 and AUPRC>0.87.Among these models,XGBoost and GBDT obtained the first two highest AUROC(0.90 and 1),AUPRC(0.98 and 1),accuracy(0.96 and 0.98),precision(0.90 and 0.95),F1 score(0.95 and 0.98),specificity(0.94 and 0.97),and sensitivity(1).In the validation set,XGBoost algorithm exhibited the best predictive performance with the highest specificity(0.857),accuracy(0.818),AUPRC(0.86)and AUROC(0.89).ET and GBDT obtained the highest sensitivity(1)and F1 score(0.8).Overall,compared with other state-of-the-art classifiers such as ET,GBDT and RF,XGBoost algorithm not only showed a more stable performance,but also yielded higher ROC-AUC and PRC-AUC scores,demonstrating its high accuracy in prediction of TiPN occurrence.CONCLUSION The powerful XGBoost algorithm accurately predicts TiPN using 18 clinical features and 14 genetic variables.With the ability to identify high-risk patients using single nucleotide polymorphisms,it offers a feasible option for improving thalidomide efficacy in CD patients.展开更多
Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases(CVDs),the world’s primary cause of death.Ginkgo biloba,a we...Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases(CVDs),the world’s primary cause of death.Ginkgo biloba,a well-known traditional Chinese medicine with notable cardiovascular actions,has been used as a cardio-and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries.Preclinical studies have shown that ginkgolide B,a bioactive component in Ginkgo biloba,can ameliorate atherosclerosis in cultured vascular cells and disease models.Of clinical relevance,several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases,such as ischemia stroke.Here,we present a comprehensive review of the pharmacological activities,pharmacokinetic characteristics,and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy.We highlight new molecular targets of ginkgolide B,including nicotinamide adenine dinucleotide phosphate oxidases(NADPH oxidase),lectin-like oxidized LDL receptor-1(LOX-1),sirtuin 1(SIRT1),platelet-activating factor(PAF),proprotein convertase subtilisin/kexin type 9(PCSK9)and others.Finally,we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis.展开更多
Lipotoxicity, caused by intracellular lipid accumulation, accelerates the degenerative process of cellular senescence, which has implications in cancer development and therapy. Previously, carnitine palmitoyltransfera...Lipotoxicity, caused by intracellular lipid accumulation, accelerates the degenerative process of cellular senescence, which has implications in cancer development and therapy. Previously, carnitine palmitoyltransferase 1C(CPT1C), a mitochondrial enzyme that catalyzes carnitinylation of fatty acids, was found to be a critical regulator of cancer cell senescence. However, whether loss of CPT1C could induce senescence as a result of lipotoxicity remains unknown. An LC/MS-based lipidomic analysis of PANC-1,MDA-MB-231, HCT-116 and A549 cancer cells was conducted after siRNA depletion of CPT1C. Cellular lipotoxicity was further confirmed by lipotoxicity assays. Significant changes were found in the lipidome of CPT1C-depleted cells, including major alterations in fatty acid, diacylglycerol, triacylglycerol, oxidative lipids, cardiolipin, phosphatidylglycerol, phosphatidylcholine/phosphatidylethanolamine ratio and sphingomyelin. This was coincident with changes in expressions of mRNAs involved in lipogenesis.Histological and biochemical analyses revealed higher lipid accumulation and increased malondialdehyde and reactive oxygen species, signatures of lipid peroxidation and oxidative stress. Reduction of ATP synthesis, loss of mitochondrial transmembrane potential and down-regulation of expression of mitochondriogenesis gene m RNAs indicated mitochondrial dysfunction induced by lipotoxicity, which could further result in cellular senescence. Taken together, this study demonstrated CPT1C plays a critical role in the regulation of cancer cell lipotoxicity and cell senescence, suggesting that inhibition of CPT1C may serve as a new therapeutic strategy through induction of tumor lipotoxicity and senescence.展开更多
Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has spread worldwide.Effective treatments against COVID-19 remain urgently in need although vaccination signific...Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has spread worldwide.Effective treatments against COVID-19 remain urgently in need although vaccination significantly reduces the incidence,hospitalization,and mortality.At present,antiviral drugs including Nirmatrelvir/Ritonavir(Paxlovid^(TM)),Remdesivir,and Molnupiravir have been authorized to treat COVID-19 and become more globally available.On the other hand,traditional Chinese medicine(TCM)has been used for the treatment of epidemic diseases for a long history.Currently,various TCM formulae against COVID-19 such as Qingfei Paidu decoction,Xuanfei Baidu granule,Huashi Baidu granule,Jinhua Qinggan granule,Lianhua Qingwen capsule,and Xuebijing injection have been widely used in clinical practice in China,which may cause potential herb-drug interactions(HDIs)in patients under treatment with antiviral drugs and affect the efficacy and safety of medicines.However,information on potential HDIs between the above anti-COVID-19 drugs and TCM formulae is lacking,and thus this work seeks to summarize and highlight potential HDIs between antiviral drugs and TCM formulae against COVID-19,and especially pharmacokinetic HDIs mediated by metabolizing enzymes and/or transporters.These well-characterized HDIs could provide useful information on clinical concomitant medicine use to maximize clinical outcomes and minimize adverse and toxic effects.展开更多
Neurotrophic receptor kinase(NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors,and tropomyosin receptor kinase(TRK) has been considered as an attractive therapeutic target for...Neurotrophic receptor kinase(NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors,and tropomyosin receptor kinase(TRK) has been considered as an attractive therapeutic target for "pan-cancer" harboring these fusions.Currently,two generations TRK inhibitors have been developed.The representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target mutations.However,xDFG(TRKAG667C/A/S,homologous TRKCG696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib,and overcoming these resistances represents a major unmet clinical need.In this review,we summarize the acquired resistance mechanism of the first-and second-generation TRK inhibitors,and firstly put forward the emerging selective type Ⅱ TRK inhibitors to overcome xDFG mutations mediated resistance.Additionally,we concluded our perspectives on new challenges and future directions in this field.展开更多
Cholestasis is caused by the obstacle of bile formation or secretion and can develop into severe liver diseases. We previously reported the ethanol extract of Schisandra sphenanthera(Wuzhi tablet, WZ) can significantl...Cholestasis is caused by the obstacle of bile formation or secretion and can develop into severe liver diseases. We previously reported the ethanol extract of Schisandra sphenanthera(Wuzhi tablet, WZ) can significantly protect against lithocholic acid(LCA)-induced intrahepatic cholestasis in mice, partially due to the activation of PXR pathway and promotion of liver regeneration.However, the effect of WZ on the bile acids profile and gut microbiome in cholestastic mice remain unknown. In this study, the effect of WZ against LCA-induced liver injury was evaluated and its effect on the bile acids metabolome and gut microbiome profiles in cholestastic mice was further investigated. Targeted metabolomics analysis was performed to examine the change of bile acids in the serum, liver, intestine and feces. The change of intestinal flora were detected by the genomics method. Targeted metabolomics analysis revealed that WZ enhanced the excretion of bile acids from serum and liver to intestine and feces. Genomics analysis of gut microbiome showed that WZ can reverse LCA-induced gut microbiome disorder to the normal level. In conclusion, WZ protects against LCAinduced cholestastic liver injury by reversing abnormal bile acids profiles and alteration of gut microbiome.展开更多
Bioassay-guided fractionation of an ethanolic extract of Ochrosia borbonica led to the isolation of two known pyridocarbazole alkaloids,ellipticine(1)and 9-methoxyellipticine(2),and six known monoterpenoid indole alka...Bioassay-guided fractionation of an ethanolic extract of Ochrosia borbonica led to the isolation of two known pyridocarbazole alkaloids,ellipticine(1)and 9-methoxyellipticine(2),and six known monoterpenoid indole alkaloids(3-8).Lipid-lowering assay in 3 T3-L1 cell model revealed that 1 and 2 could significantly inhibit the lipid droplet formation(EC50(28)0.41 and 0.92μmol·L^–1,respectively)and lower triglyceride levels by 50%-60%at the concentration of 1μmol·L^–1,being more potent than the positive drug luteolin(EC50(28)2.63μmol·L–^1).A mechanistic study indicated that 1 and 2 could intercalate into supercoiled DNA,which consequently inhibited the mitotic clonal expansion of 3 T3-L1 cells at the early differentiation phase,leading to the retardance of following adipogenesis and lipogenesis.These findings suggest that 1 and 2 may serve as promising leads for further d evelopment of anti-obesity drugs.展开更多
Ganoderma triterpenoids(GTs),a class of major active constituents of Ganoderma fungi,possess diverse structures and remarkable activities.In the present study,nine new GTs,namely applanoids A—I(1—9),were isolated fr...Ganoderma triterpenoids(GTs),a class of major active constituents of Ganoderma fungi,possess diverse structures and remarkable activities.In the present study,nine new GTs,namely applanoids A—I(1—9),were isolated from the medicinal fungus of Ganoderma applanatum.Their structures including absolute configurations were established by comprehensive spectroscopic analyses and ECD calculation.Applanoids A—E(1—5)represent the first example of GTs with 6/6/5/6/5 pentacyclic system and the formation of the ether ring between C-15 and C-20 involves Michael addition reaction.Furthermore,compounds 1—8 were evaluated for their human pregnane X receptor(hPXR)agonistic activity using dual-luciferase reporter gene assay,and the results showed that compounds 1,2 and 4 can dose-dependently activate hPXR.This investigation further illustrated the structural diversity of GTs and provided new insights for searching PXR agonists from GTs.展开更多
Anemarrhena asphodeloides is an immensely popular medicinal herb in China,which contains an abundant of mangiferin.As an important bioactive xanthone C-glycoside,mangiferin possesses a variety of pharmacological activ...Anemarrhena asphodeloides is an immensely popular medicinal herb in China,which contains an abundant of mangiferin.As an important bioactive xanthone C-glycoside,mangiferin possesses a variety of pharmacological activities and is derived from the cyclization reaction of a benzophenone C-glycoside(maclurin).Biosyntheti-cally,C-glycosyltransferases are critical for the formation of benzophenone C-glycosides.However,the benzo-phenone C-glycosyltransferases from Anemarrhena asphodeloides have not been discovered.Herein,a promiscuous C-glycosyltransferase(AaCGT)was identified from Anemarrhena asphodeloides.It was able to catalyze efficiently mono-C-glycosylation of benzophenone,together with di-C-glycosylation of dihydrochalcone.It also exhibited the weak O-glycosylation or potent S-glycosylation capacities toward 12 other types of flavonoid scaffolds and a simple aromatic compound with–SH group.Homology modeling and mutagenesis experiments revealed that the glycosylation reaction of AaCGT was initiated by the conserved residue H23 as the catalytic base.Three critical residues H356,W359 and D380 were involved in the recognition of sugar donor through hydrogen-bonding interactions.In particular,the double mutant of F94W/L378M led to an unexpected enzy-matic conversion of mono-C-to di-C-glycosylation.This study highlights the important value of AaCGT as a potential biocatalyst for efficiently synthesizing high-value C-glycosides.展开更多
The clinical utilization of doxorubicin(Dox)in various malignancies is restrained by its major adverse effect:irreversible cardiomyopathy.Extensive studies have been done to explore the prevention of Dox cardiomyopath...The clinical utilization of doxorubicin(Dox)in various malignancies is restrained by its major adverse effect:irreversible cardiomyopathy.Extensive studies have been done to explore the prevention of Dox cardiomyopathy.Currently,ferroptosis has been shown to participate in the incidence and development of Dox cardiomyopathy.Sorting Nexin 3(SNX3),the retromer-associated cargo binding protein with important physiological functions,was identified as a potent therapeutic target for cardiac hypertrophy in our previous study.However,few study has shown whether SNX3 plays a critical role in Dox-induced cardiomyopathy.In this study,a decreased level of SNX3 in Dox-induced cardiomyopathy was observed.Cardiac-specific Snx3 knockout(Snx3-cKO)significantly alleviated cardiomyopathy by downregulating Dox-induced ferroptosis significantly.SNX3 was further demonstrated to exacerbate Dox-induced cardiomyopathy via induction of ferroptosis in vivo and in vitro,and cardiac-specific Snx3 transgenic(Snx3-cTg)mice were more susceptible to Dox-induced feroptosis and cardiomyopathy.Mechanistically,SNX3 facilitated the recycling of transferrin 1 receptor(TFRC)via direct interaction,disrupting iron homeostasis,increasing the accumulation of iron,triggering ferroptosis,and eventually exacerbating Dox-induced cardiomyopathy.Overall,these findings established a direct SNX3-TFRC-ferroptosis positive regulatory axis in Dox-induced cardiomyopathy and suggested that targeting SNX3 provided a new effective therapeutic strategy for Dox-induced cardiomyopathy through TFRCdependentferroptosis.展开更多
The ribosome is a cellular system responsible for translating the nucleotide code of mRNA into proteins.In human cells,this complex consists of four distinct ribosomal RNAs(rRNAs):The 28S,18S,5.8S,and 5S rRNAs,along w...The ribosome is a cellular system responsible for translating the nucleotide code of mRNA into proteins.In human cells,this complex consists of four distinct ribosomal RNAs(rRNAs):The 28S,18S,5.8S,and 5S rRNAs,along with 80 ribosomal proteins.Polymerase Ⅰ is responsible for synthesizing the 28S,18S,and 5.8S rRNAs,while polymerase Ⅲ is responsible for synthesizing the 5S rRNA[1].展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection can cause acute respiratory distress syndrome,hypercoagulability,hypertension,and multiorgan dysfunction.Effective antivirals with safe clinical pro...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection can cause acute respiratory distress syndrome,hypercoagulability,hypertension,and multiorgan dysfunction.Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis.In an analysis of a randomly collected cohort of 124 patients with COVID-19,we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity.By virtual screening of a U.S.FDA approved drug library,we identified an anticoagulation agent dipyridamole(DIP)in silico,which suppressed SARS-CoV-2 replication in vitro.In a proof-of-concept trial involving 31 patients with COVID-19,DIP supplementation was associated with significantly decreased concentrations of D-dimers(P<0.05),increased lymphocyte and platelet recovery in the circulation,and markedly improved clinical outcomes in comparison to the control patients.In particular,all 8 of the DIP-treated severely ill patients showed remarkable improvement:7 patients(87.5%)achieved clinical cure and were discharged from the hospitals while the remaining 1 patient(12.5%)was in clinical remission.展开更多
The constitutive androstane receptor(CAR, NR3 I1) belongs to nuclear receptor superfamily.It was reported that CAR agonist TCPOBOP induces hepatomegaly but the underlying mechanism remains largely unknown. Yes-associa...The constitutive androstane receptor(CAR, NR3 I1) belongs to nuclear receptor superfamily.It was reported that CAR agonist TCPOBOP induces hepatomegaly but the underlying mechanism remains largely unknown. Yes-associated protein(YAP) is a potent regulator of organ size. The aim of this study is to explore the role of YAP in CAR activation-induced hepatomegaly and liver regeneration.TCPOBOP-induced CAR activation on hepatomegaly and liver regeneration was evaluated in wildtype(WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy(PHx) mice. The results demonstrate that TCPOBOP can increase the liver-to-body weight ratio in wild-type mice and PHx mice.Hepatocytes enlargement around central vein(CV) area was observed, meanwhile hepatocytesproliferation was promoted as evidenced by the increased number of KI67+cells around portal vein(PV)area. The protein levels of YAP and its downstream targets were upregulated in TCPOBOP-treated mice and YAP translocation can be induced by CAR activation. Co-immunoprecipitation results suggested a potential proteineprotein interaction of CAR and YAP. However, CAR activation-induced hepatomegaly can still be observed in liver-specific YAP-deficient(Yape/e) mice. In summary, CAR activation promotes hepatomegaly and liver regeneration partially by inducing YAP translocation and interaction with YAP signaling pathway, which provides new insights to further understand the physiological functions of CAR.展开更多
Sirtuins(SIRTs)are nicotinamide adenine dinucleotide(NAD^+)-dependent histone deacetylases with diverse physiological functions.A variety of small molecules have been developed to interrogate the physiological functio...Sirtuins(SIRTs)are nicotinamide adenine dinucleotide(NAD^+)-dependent histone deacetylases with diverse physiological functions.A variety of small molecules have been developed to interrogate the physiological function of SIRTs.Therefore,it is desirable to establish efficient and convenient assays to screen SIRTs modulators.In this study,we designed a series of fluorescent nonapeptide probes derived from substrates of SIRTI-SIRT3.Fluorescence increment of these probes is based on SIRT-mediated removal of the acyl side chain with fluorophore,which makes this system free of lysine-recognizing protease.Comparing the reaction of these fluorescent nonapeptide substrates with SIRT1-SIRT3 and SIRT6,it was confirmed that this assessment system was the most suitable for SIRT2activity detection.Thus,SIRT2 was used to modify substrates by truncating the amino acids or lysine side chain of nonapeptide.Finally,two specific and efficient fluorescent probes for SIRT2,ne-D9 and ne-K4a,were developed.Evaluation of the results revealed that ne-K4a based assay was more suitable for modulators screening in vitro,while the other specific substrate ne-D9 was stable in cell lysate and could detect the activity of SIRT2 in the same.In summary,this study presents a novel strategy for detecting SIRT2 activity in vitro and in cell lysate.展开更多
Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance.However,their interplays are poorly understood.We report here that elevated TIGAR(TP53-induced glycolysis and apoptosis regu...Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance.However,their interplays are poorly understood.We report here that elevated TIGAR(TP53-induced glycolysis and apoptosis regulator),an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2(nuclear receptor binding SET domain protein 2),is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark.Mechanistically,TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2,H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new(NSD2)and established(NQO1/2,PRDX1 and GSTM4)targets of NRF2,independent of its enzymatic activity.Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis.In addition,nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival.These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.展开更多
The bromodomain and extraterminal(BET)family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy.BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin,facilitating the phosphor...The bromodomain and extraterminal(BET)family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy.BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin,facilitating the phosphorylation of RNA polymerases II(Pol II)and leading to transcription elongation.The present study identified a novel post-translational modification of BRD4:poly(ADPribosyl)ation(PARylation),that was mediated by poly(ADP-ribose)polymerase-1(PARP1)in cardiac hypertrophy.BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol(ISO),whereas overexpression of BRD4 promoted cardiac hypertrophy,confirming the critical role of BRD4 in pathological cardiac hypertrophy.PARP1 was activated in ISOinduced cardiac hypertrophy and facilitated the development of cardiac hypertrophy.BRD4 was involved in the prohypertrophic effect of PARP1,as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses,and that BRD4 overexpression suppressed the antihypertrophic effect of PARP1 inhibitors.Interactions of BRD4 and PARP1 were observed by coimmunoprecipitation and immunofluorescence.PARylation of BRD4 induced by PARP1 was investigated by PARylation assays.In response to hypertrophic stimuli like ISO,PARylation level of BRD4 was elevated,along with enhanced interactions between BRD4 and PARP1.By investigating the PARylation of truncation mutants of BRD4,the C-terminal domain(CTD)was identified as the PARylation modification sites of BRD4.PARylation of BRD4 facilitated its binding to the transcription start sites(TSS)of hypertrophic genes,resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes.The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.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
Liver is the central hub regulating energy metabolism during feeding-fasting transition.Evidence suggests that fasting and refeeding induce dynamic changes in liver size,but the underlying mechanisms remain unclear.Ye...Liver is the central hub regulating energy metabolism during feeding-fasting transition.Evidence suggests that fasting and refeeding induce dynamic changes in liver size,but the underlying mechanisms remain unclear.Yes-associated protein(YAP)is a key regulator of organ size.This study aims to explore the role of YAP in fasting-and refeeding-induced changes in liver size.Here,fasting significantly reduced liver size,which was recovered to the normal level after refeeding.Moreover,hepatocyte size was decreased and hepatocyte proliferation was inhibited after fasting.Conversely,refeeding promoted hepatocyte enlargement and proliferation compared to fasted state.Mechanistically,fasting or refeeding regulated the expression of YAP and its downstream targets,as well as the proliferation-related protein cyclin D1(CCND1).Furthermore,fasting significantly reduced the liver size in AAV-control mice,which was mitigated in AAV Yap(5SA)mice.Yap overexpression also prevented the effect of fasting on hepatocyte size and proliferation.Besides,the recovery of liver size after refeeding was delayed in AAV Yap shRNA mice.Yap knockdown attenuated refeeding-induced hepatocyte enlargement and proliferation.In summary,this study demonstrated that YAP plays an important role in dynamic changes of liver size during fasting-refeeding transition,which provides new evidence for YAP in regulating liver size under energy stress.展开更多
As an effective anticancer drug, the clinical limitation of doxorubicin(Dox) is the time-and dose-dependent cardiotoxicity. Yes-associated protein 1(YAP1) interacts with transcription factor TEA domain 1(TEAD1) and pl...As an effective anticancer drug, the clinical limitation of doxorubicin(Dox) is the time-and dose-dependent cardiotoxicity. Yes-associated protein 1(YAP1) interacts with transcription factor TEA domain 1(TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced in vivo and in vitro cardiotoxic model. Ectopic expression of Yap1 significantly blocked Dox-induced cardiomyocytes apoptosis in TEAD1 dependent manner. Isorhapontigenin(Isor) is a new derivative of stilbene and responsible for a wide range of biological processes. Here, we found that Isor effectively relieved Doxinduced cardiomyocytes apoptosis in a dose-dependent manner in vitro. Administration with Isor(30 mg/kg/day, intraperitoneally, 3 weeks) significantly protected against Dox-induced cardiotoxicity in mice. Interestingly, Isor increased Dox-caused repression in YAP1 and the expression of its target genes in vivo and in vitro. Knockout or inhibition of Yap1 blocked the protective effects of Isor on Dox-induced cardiotoxicity. In conclusion, YAP1 may be a novel target for Dox-induced cardiotoxicity and Isor might be a new compound to fight against Dox-induced cardiotoxicity by increasing YAP1 expression.展开更多
Prostate cancer(PCa)patients who progress to metastatic castration-resistant PCa(mCRPC)mostly have poor outcomes due to the lack of effective therapies.Our recent study established the orphan nuclear receptor RORγas ...Prostate cancer(PCa)patients who progress to metastatic castration-resistant PCa(mCRPC)mostly have poor outcomes due to the lack of effective therapies.Our recent study established the orphan nuclear receptor RORγas a novel therapeutic target for CRPC.Here,we reveal that elaiophylin(Elai),an antibiotic from Actinomycete streptomyces,is a novel RORy antagonist and showed potent antitumor activity against CRPC in vitro and in vivo.We demonstrated that Elai selectively binded to RORy protein and potently blocked RORγtranscriptional regulation activities.Structure-activity relationship studies showed that Elai occupied the binding pocket with several key interactions.Furthermore,Elai markedly reduced the recruitment of RORγto its genomic DNA response element(RORE),suppressed the expression of RORγtarget genes AR and AR variants,and significantly inhibited PCa cell growth.Importantly,Elai strongly suppressed tumor growth in both cell line based and patient-derived PCa xenograft models.Taken together,these results suggest that Elai is novel therapeutic RORγinhibitor that can be used as a drug candidate for the treatment of human CRPC.展开更多
基金National Natural Science Foundation of China,No.81973398,No.81730103,No.81573507 and No.82020108031The National Key Research and Development Program,No.2017YFC0909300 and No.2016YFC0905001+5 种基金Guangdong Provincial Key Laboratory of Construction Foundation,No.2017B030314030 and No.2020B1212060034Science and Technology Program of Guangzhou,No.201607020031National Engineering and Technology Research Center for New Drug Druggability Evaluation(Seed Program of Guangdong Province),No.2017B090903004The 111 Project,No.B16047China Postdoctoral Science Foundation,No.2019M66324,No.2020M683140 and No.2020M683139Natural Science Foundation of Guangdong Province,No.2022A1515012549 and No.2023A1515012667.
文摘BACKGROUND Thalidomide is an effective treatment for refractory Crohn’s disease(CD).However,thalidomide-induced peripheral neuropathy(TiPN),which has a large individual variation,is a major cause of treatment failure.TiPN is rarely predictable and recognized,especially in CD.It is necessary to develop a risk model to predict TiPN occurrence.AIM To develop and compare a predictive model of TiPN using machine learning based on comprehensive clinical and genetic variables.METHODS A retrospective cohort of 164 CD patients from January 2016 to June 2022 was used to establish the model.The National Cancer Institute Common Toxicity Criteria Sensory Scale(version 4.0)was used to assess TiPN.With 18 clinical features and 150 genetic variables,five predictive models were established and evaluated by the confusion matrix receiver operating characteristic curve(AUROC),area under the precision-recall curve(AUPRC),specificity,sensitivity(recall rate),precision,accuracy,and F1 score.RESULTS The top-ranking five risk variables associated with TiPN were interleukin-12 rs1353248[P=0.0004,odds ratio(OR):8.983,95%confidence interval(CI):2.497-30.90],dose(mg/d,P=0.002),brainderived neurotrophic factor(BDNF)rs2030324(P=0.001,OR:3.164,95%CI:1.561-6.434),BDNF rs6265(P=0.001,OR:3.150,95%CI:1.546-6.073)and BDNF rs11030104(P=0.001,OR:3.091,95%CI:1.525-5.960).In the training set,gradient boosting decision tree(GBDT),extremely random trees(ET),random forest,logistic regression and extreme gradient boosting(XGBoost)obtained AUROC values>0.90 and AUPRC>0.87.Among these models,XGBoost and GBDT obtained the first two highest AUROC(0.90 and 1),AUPRC(0.98 and 1),accuracy(0.96 and 0.98),precision(0.90 and 0.95),F1 score(0.95 and 0.98),specificity(0.94 and 0.97),and sensitivity(1).In the validation set,XGBoost algorithm exhibited the best predictive performance with the highest specificity(0.857),accuracy(0.818),AUPRC(0.86)and AUROC(0.89).ET and GBDT obtained the highest sensitivity(1)and F1 score(0.8).Overall,compared with other state-of-the-art classifiers such as ET,GBDT and RF,XGBoost algorithm not only showed a more stable performance,but also yielded higher ROC-AUC and PRC-AUC scores,demonstrating its high accuracy in prediction of TiPN occurrence.CONCLUSION The powerful XGBoost algorithm accurately predicts TiPN using 18 clinical features and 14 genetic variables.With the ability to identify high-risk patients using single nucleotide polymorphisms,it offers a feasible option for improving thalidomide efficacy in CD patients.
基金This work is supported by National Natural Science Foundation of China(82270500,81870324,82203304,82070464,U1401225,U21A20419)National Mega-Project for Innovative Drugs(2019ZX09735002)+1 种基金Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y036,2017BT01Y093,China)National Engineering and Technology Research Center for New drug Druggability Evaluation(Seed Program of Guangdong Province,2017B090903004,China).
文摘Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases(CVDs),the world’s primary cause of death.Ginkgo biloba,a well-known traditional Chinese medicine with notable cardiovascular actions,has been used as a cardio-and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries.Preclinical studies have shown that ginkgolide B,a bioactive component in Ginkgo biloba,can ameliorate atherosclerosis in cultured vascular cells and disease models.Of clinical relevance,several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases,such as ischemia stroke.Here,we present a comprehensive review of the pharmacological activities,pharmacokinetic characteristics,and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy.We highlight new molecular targets of ginkgolide B,including nicotinamide adenine dinucleotide phosphate oxidases(NADPH oxidase),lectin-like oxidized LDL receptor-1(LOX-1),sirtuin 1(SIRT1),platelet-activating factor(PAF),proprotein convertase subtilisin/kexin type 9(PCSK9)and others.Finally,we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis.
基金supported by the National Key Research and Development Program of China (Grant No. 2017YFE0109900)the National Natural Science Foundation of China (Grant Nos. 82025034 and 81973392)+5 种基金the Shenzhen Science and Technology Program (Grant No. KQTD20190929174023858)the Natural Science Foundation of Guangdong (Grant No. 2017A030311018)the 111 project (Grant No. B16047)the Key Laboratory Foundation of Guangdong Province (Grant No. 2017B030314030)the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (Grant No. 2017BT01Y093)the National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, Grant No. 2017B090903004)。
文摘Lipotoxicity, caused by intracellular lipid accumulation, accelerates the degenerative process of cellular senescence, which has implications in cancer development and therapy. Previously, carnitine palmitoyltransferase 1C(CPT1C), a mitochondrial enzyme that catalyzes carnitinylation of fatty acids, was found to be a critical regulator of cancer cell senescence. However, whether loss of CPT1C could induce senescence as a result of lipotoxicity remains unknown. An LC/MS-based lipidomic analysis of PANC-1,MDA-MB-231, HCT-116 and A549 cancer cells was conducted after siRNA depletion of CPT1C. Cellular lipotoxicity was further confirmed by lipotoxicity assays. Significant changes were found in the lipidome of CPT1C-depleted cells, including major alterations in fatty acid, diacylglycerol, triacylglycerol, oxidative lipids, cardiolipin, phosphatidylglycerol, phosphatidylcholine/phosphatidylethanolamine ratio and sphingomyelin. This was coincident with changes in expressions of mRNAs involved in lipogenesis.Histological and biochemical analyses revealed higher lipid accumulation and increased malondialdehyde and reactive oxygen species, signatures of lipid peroxidation and oxidative stress. Reduction of ATP synthesis, loss of mitochondrial transmembrane potential and down-regulation of expression of mitochondriogenesis gene m RNAs indicated mitochondrial dysfunction induced by lipotoxicity, which could further result in cellular senescence. Taken together, this study demonstrated CPT1C plays a critical role in the regulation of cancer cell lipotoxicity and cell senescence, suggesting that inhibition of CPT1C may serve as a new therapeutic strategy through induction of tumor lipotoxicity and senescence.
基金supported by the National Natural Science Foundation of China(grants 82025034 and 81973392 to Huichang Bi.And grants 82274193 and 82074110 to Ling Ye)the Open Project of State Key Laboratory of Natural Medicines(grant SKLNMKF202209 to Ling Ye,China)+2 种基金the Shenzhen Science and Technology Program(No.KQTD20190929174023858 to Huichang Bi,China)Guangdong Basic and Applied Basic Research Foundation(2023A1515012859 to Shicheng Fan,China)Guangdong Medical Research Foundation(A2023109 to Shicheng Fan,China)。
文摘Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has spread worldwide.Effective treatments against COVID-19 remain urgently in need although vaccination significantly reduces the incidence,hospitalization,and mortality.At present,antiviral drugs including Nirmatrelvir/Ritonavir(Paxlovid^(TM)),Remdesivir,and Molnupiravir have been authorized to treat COVID-19 and become more globally available.On the other hand,traditional Chinese medicine(TCM)has been used for the treatment of epidemic diseases for a long history.Currently,various TCM formulae against COVID-19 such as Qingfei Paidu decoction,Xuanfei Baidu granule,Huashi Baidu granule,Jinhua Qinggan granule,Lianhua Qingwen capsule,and Xuebijing injection have been widely used in clinical practice in China,which may cause potential herb-drug interactions(HDIs)in patients under treatment with antiviral drugs and affect the efficacy and safety of medicines.However,information on potential HDIs between the above anti-COVID-19 drugs and TCM formulae is lacking,and thus this work seeks to summarize and highlight potential HDIs between antiviral drugs and TCM formulae against COVID-19,and especially pharmacokinetic HDIs mediated by metabolizing enzymes and/or transporters.These well-characterized HDIs could provide useful information on clinical concomitant medicine use to maximize clinical outcomes and minimize adverse and toxic effects.
基金financial support from the National Natural Science Foundation of China (82273763)the Natural Science Foundation of Guangdong Province (2022A-1515011939, China)+2 种基金the Opening Project of State Key Laboratory of Respiratory Disease (SKLRD-OP-202313, China)the Opening Project of Guangdong Provincial Key Laboratory of New Drug Design and Evaluation (2020B1212060034, China)Wang Kuancheng Young Scholar of Jinan University
文摘Neurotrophic receptor kinase(NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors,and tropomyosin receptor kinase(TRK) has been considered as an attractive therapeutic target for "pan-cancer" harboring these fusions.Currently,two generations TRK inhibitors have been developed.The representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target mutations.However,xDFG(TRKAG667C/A/S,homologous TRKCG696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib,and overcoming these resistances represents a major unmet clinical need.In this review,we summarize the acquired resistance mechanism of the first-and second-generation TRK inhibitors,and firstly put forward the emerging selective type Ⅱ TRK inhibitors to overcome xDFG mutations mediated resistance.Additionally,we concluded our perspectives on new challenges and future directions in this field.
基金supported by the Natural Science Foundation of China(Nos.81973392,81573489)the National Key Research and Development Program(No.2017YFE 0109900)+4 种基金the Natural Science Foundation of Guangdong(No.2017A030311018)the 111 project(No.B16047)the Key Laboratory Foundation of Guangdong Province(No.2017B030314030)the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(No.2017BT01Y093)the National Engineering and Technology Research Center for New drug Druggability Evaluation(Seed Program of Guangdong Province,No.2017B090903004)。
文摘Cholestasis is caused by the obstacle of bile formation or secretion and can develop into severe liver diseases. We previously reported the ethanol extract of Schisandra sphenanthera(Wuzhi tablet, WZ) can significantly protect against lithocholic acid(LCA)-induced intrahepatic cholestasis in mice, partially due to the activation of PXR pathway and promotion of liver regeneration.However, the effect of WZ on the bile acids profile and gut microbiome in cholestastic mice remain unknown. In this study, the effect of WZ against LCA-induced liver injury was evaluated and its effect on the bile acids metabolome and gut microbiome profiles in cholestastic mice was further investigated. Targeted metabolomics analysis was performed to examine the change of bile acids in the serum, liver, intestine and feces. The change of intestinal flora were detected by the genomics method. Targeted metabolomics analysis revealed that WZ enhanced the excretion of bile acids from serum and liver to intestine and feces. Genomics analysis of gut microbiome showed that WZ can reverse LCA-induced gut microbiome disorder to the normal level. In conclusion, WZ protects against LCAinduced cholestastic liver injury by reversing abnormal bile acids profiles and alteration of gut microbiome.
基金supported by the National Natural Science Foundation of China(Nos.81573302,81722042,and 81703336)the Guangdong Natural Science Funds for Distinguished Young Scholar(No.2014A0303 06047)+2 种基金the Science and Technology Planning Project of Guangdong Province,China(No.2015A020211007)the Fundamental Research Funds for the Central Universities(No.17ykzd12)the Guangdong Provincial Key Laboratory of Construction Foundation(No.2017B030314030)
文摘Bioassay-guided fractionation of an ethanolic extract of Ochrosia borbonica led to the isolation of two known pyridocarbazole alkaloids,ellipticine(1)and 9-methoxyellipticine(2),and six known monoterpenoid indole alkaloids(3-8).Lipid-lowering assay in 3 T3-L1 cell model revealed that 1 and 2 could significantly inhibit the lipid droplet formation(EC50(28)0.41 and 0.92μmol·L^–1,respectively)and lower triglyceride levels by 50%-60%at the concentration of 1μmol·L^–1,being more potent than the positive drug luteolin(EC50(28)2.63μmol·L–^1).A mechanistic study indicated that 1 and 2 could intercalate into supercoiled DNA,which consequently inhibited the mitotic clonal expansion of 3 T3-L1 cells at the early differentiation phase,leading to the retardance of following adipogenesis and lipogenesis.These findings suggest that 1 and 2 may serve as promising leads for further d evelopment of anti-obesity drugs.
基金supported by the Basic Research Project of Yunnan Province(202001AT070070)the Youth Innovation Promotion Association of CAS(2019383)+1 种基金the Natural Science Foundation of China(Nos.82025034,81973392,81973195 and 82104020)the Shenzhen Science and Technology Program(No.KQTD20190929174023858).
文摘Ganoderma triterpenoids(GTs),a class of major active constituents of Ganoderma fungi,possess diverse structures and remarkable activities.In the present study,nine new GTs,namely applanoids A—I(1—9),were isolated from the medicinal fungus of Ganoderma applanatum.Their structures including absolute configurations were established by comprehensive spectroscopic analyses and ECD calculation.Applanoids A—E(1—5)represent the first example of GTs with 6/6/5/6/5 pentacyclic system and the formation of the ether ring between C-15 and C-20 involves Michael addition reaction.Furthermore,compounds 1—8 were evaluated for their human pregnane X receptor(hPXR)agonistic activity using dual-luciferase reporter gene assay,and the results showed that compounds 1,2 and 4 can dose-dependently activate hPXR.This investigation further illustrated the structural diversity of GTs and provided new insights for searching PXR agonists from GTs.
基金the National Natural Science Foundation of China No.81874333the Guangdong Foundation for Basic and Applied Basic Research No.2020A1515010926.
文摘Anemarrhena asphodeloides is an immensely popular medicinal herb in China,which contains an abundant of mangiferin.As an important bioactive xanthone C-glycoside,mangiferin possesses a variety of pharmacological activities and is derived from the cyclization reaction of a benzophenone C-glycoside(maclurin).Biosyntheti-cally,C-glycosyltransferases are critical for the formation of benzophenone C-glycosides.However,the benzo-phenone C-glycosyltransferases from Anemarrhena asphodeloides have not been discovered.Herein,a promiscuous C-glycosyltransferase(AaCGT)was identified from Anemarrhena asphodeloides.It was able to catalyze efficiently mono-C-glycosylation of benzophenone,together with di-C-glycosylation of dihydrochalcone.It also exhibited the weak O-glycosylation or potent S-glycosylation capacities toward 12 other types of flavonoid scaffolds and a simple aromatic compound with–SH group.Homology modeling and mutagenesis experiments revealed that the glycosylation reaction of AaCGT was initiated by the conserved residue H23 as the catalytic base.Three critical residues H356,W359 and D380 were involved in the recognition of sugar donor through hydrogen-bonding interactions.In particular,the double mutant of F94W/L378M led to an unexpected enzy-matic conversion of mono-C-to di-C-glycosylation.This study highlights the important value of AaCGT as a potential biocatalyst for efficiently synthesizing high-value C-glycosides.
基金supported by the National Natural Science Foundation of China(82173808,U21A20419,82270500)Natural Science Foundation of Guangdong Province(2021B1515020100,China)+3 种基金Guangzhou Basic and Applied Basic Research Project(202206080007,China)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093,China)Guangdong Provincial Key Laboratory of Construction Foundation(2017B030314030,China)Academic promotion program of Shandong First Medical University(2019LJ003,China).
文摘The clinical utilization of doxorubicin(Dox)in various malignancies is restrained by its major adverse effect:irreversible cardiomyopathy.Extensive studies have been done to explore the prevention of Dox cardiomyopathy.Currently,ferroptosis has been shown to participate in the incidence and development of Dox cardiomyopathy.Sorting Nexin 3(SNX3),the retromer-associated cargo binding protein with important physiological functions,was identified as a potent therapeutic target for cardiac hypertrophy in our previous study.However,few study has shown whether SNX3 plays a critical role in Dox-induced cardiomyopathy.In this study,a decreased level of SNX3 in Dox-induced cardiomyopathy was observed.Cardiac-specific Snx3 knockout(Snx3-cKO)significantly alleviated cardiomyopathy by downregulating Dox-induced ferroptosis significantly.SNX3 was further demonstrated to exacerbate Dox-induced cardiomyopathy via induction of ferroptosis in vivo and in vitro,and cardiac-specific Snx3 transgenic(Snx3-cTg)mice were more susceptible to Dox-induced feroptosis and cardiomyopathy.Mechanistically,SNX3 facilitated the recycling of transferrin 1 receptor(TFRC)via direct interaction,disrupting iron homeostasis,increasing the accumulation of iron,triggering ferroptosis,and eventually exacerbating Dox-induced cardiomyopathy.Overall,these findings established a direct SNX3-TFRC-ferroptosis positive regulatory axis in Dox-induced cardiomyopathy and suggested that targeting SNX3 provided a new effective therapeutic strategy for Dox-induced cardiomyopathy through TFRCdependentferroptosis.
基金supported by the National Key Research and Development Program of China(2022YFC2601800)the Key-Area Research and Development Program of Guangdong Province(2023B1111020007)+6 种基金the National Natural Science Foundation of China(32161143017,82173833,81973343,and 82272658)the Guangdong Basic and Applied Basic Research Foundation(2023B1515040006)the Open Program of Shenzhen Bay Laboratory(SZBL202009051006)the Guangdong Provincial Key Laboratory of Construction Foundation(2023B1212060022)the Sichuan Science and Technology Program(2022JDRC0042 and 2022NSFSC0776)the Joint Research Foundation of Chengdu Medical College and the Seventh People’s Hospital(2022LHTD-02,2021LHJYPJ-08,and 2022488)the Shenzhen Bay Scholars Program。
文摘The ribosome is a cellular system responsible for translating the nucleotide code of mRNA into proteins.In human cells,this complex consists of four distinct ribosomal RNAs(rRNAs):The 28S,18S,5.8S,and 5S rRNAs,along with 80 ribosomal proteins.Polymerase Ⅰ is responsible for synthesizing the 28S,18S,and 5.8S rRNAs,while polymerase Ⅲ is responsible for synthesizing the 5S rRNA[1].
基金National Key R&D Program of China(2017YFB0202600 and 2020YFC0841400)National Natural Science Foundation of China(91742109,8152204,31770978,81773674,and 21877134)+8 种基金National Health&Medical Research of Australia(1080321,1143976 and 1150425)Science Foundation of Guangzhou City(201904020023,China)Guangdong Province Higher Vocational Colleges and Schools Pearl River Scholar Funded Scheme(2016 and 2019,China)Guangdong Provincial Key Laboratory of Construction Foundation(2017B030314030,China)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093,China)Zhejiang University special scientific research fund for COVID-19 prevention and control(China)National Health&Medical Research of Australia(1080321,1143976,and 1150425)Taikang Insurance Group Co.,Ltd.Beijing Taikang Yicai Foundation(Beijing,China)
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection can cause acute respiratory distress syndrome,hypercoagulability,hypertension,and multiorgan dysfunction.Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis.In an analysis of a randomly collected cohort of 124 patients with COVID-19,we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity.By virtual screening of a U.S.FDA approved drug library,we identified an anticoagulation agent dipyridamole(DIP)in silico,which suppressed SARS-CoV-2 replication in vitro.In a proof-of-concept trial involving 31 patients with COVID-19,DIP supplementation was associated with significantly decreased concentrations of D-dimers(P<0.05),increased lymphocyte and platelet recovery in the circulation,and markedly improved clinical outcomes in comparison to the control patients.In particular,all 8 of the DIP-treated severely ill patients showed remarkable improvement:7 patients(87.5%)achieved clinical cure and were discharged from the hospitals while the remaining 1 patient(12.5%)was in clinical remission.
基金supported by the Natural Science Foundation of China (Grant numbers:82025034 and 81973392)the National Key Research and Development Program (Grant number:2017YFE0109900, China)+5 种基金the Shenzhen Science and Technology Program (Grant number:KQTD20190929174023858, China)the Natural Science Foundation of Guangdong (Grant number:2017A030311018, China)the 111 project (Grant number:B16047, China)the Key Laboratory Foundation of Guangdong Province (Grant number:2017B030314030, China)the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (Grant number:2017BT01Y093, China)the National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, Grant number:2017B090903004, China)。
文摘The constitutive androstane receptor(CAR, NR3 I1) belongs to nuclear receptor superfamily.It was reported that CAR agonist TCPOBOP induces hepatomegaly but the underlying mechanism remains largely unknown. Yes-associated protein(YAP) is a potent regulator of organ size. The aim of this study is to explore the role of YAP in CAR activation-induced hepatomegaly and liver regeneration.TCPOBOP-induced CAR activation on hepatomegaly and liver regeneration was evaluated in wildtype(WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy(PHx) mice. The results demonstrate that TCPOBOP can increase the liver-to-body weight ratio in wild-type mice and PHx mice.Hepatocytes enlargement around central vein(CV) area was observed, meanwhile hepatocytesproliferation was promoted as evidenced by the increased number of KI67+cells around portal vein(PV)area. The protein levels of YAP and its downstream targets were upregulated in TCPOBOP-treated mice and YAP translocation can be induced by CAR activation. Co-immunoprecipitation results suggested a potential proteineprotein interaction of CAR and YAP. However, CAR activation-induced hepatomegaly can still be observed in liver-specific YAP-deficient(Yape/e) mice. In summary, CAR activation promotes hepatomegaly and liver regeneration partially by inducing YAP translocation and interaction with YAP signaling pathway, which provides new insights to further understand the physiological functions of CAR.
基金supported in part by the National Natural Science Foundation of China(31671437)the Natural Science Foundation of Guangdong Province,China(2016A030313335)+1 种基金the Guangdong Provincial Key Laboratory of Construction Foundation,China(2017B030314030)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program,China(2017BT01Y093).
文摘Sirtuins(SIRTs)are nicotinamide adenine dinucleotide(NAD^+)-dependent histone deacetylases with diverse physiological functions.A variety of small molecules have been developed to interrogate the physiological function of SIRTs.Therefore,it is desirable to establish efficient and convenient assays to screen SIRTs modulators.In this study,we designed a series of fluorescent nonapeptide probes derived from substrates of SIRTI-SIRT3.Fluorescence increment of these probes is based on SIRT-mediated removal of the acyl side chain with fluorophore,which makes this system free of lysine-recognizing protease.Comparing the reaction of these fluorescent nonapeptide substrates with SIRT1-SIRT3 and SIRT6,it was confirmed that this assessment system was the most suitable for SIRT2activity detection.Thus,SIRT2 was used to modify substrates by truncating the amino acids or lysine side chain of nonapeptide.Finally,two specific and efficient fluorescent probes for SIRT2,ne-D9 and ne-K4a,were developed.Evaluation of the results revealed that ne-K4a based assay was more suitable for modulators screening in vitro,while the other specific substrate ne-D9 was stable in cell lysate and could detect the activity of SIRT2 in the same.In summary,this study presents a novel strategy for detecting SIRT2 activity in vitro and in cell lysate.
基金This work was supported by the National Natural Science Foundation of China(81872891)the Guangdong Natural Science Funds for Distinguished Young Scholar(No.2019B151502016,China)+4 种基金Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093,China)National Engineering and Technology Research Center for New drug Druggability Evaluation(Seed Program of Guangdong Province,2017B090903004,China)the Fundamental Research Funds for the Central Universities(No.19ykzd23,China)The Manitoba Breast Tumor Bank,a member of the Canadian Tissue Repository Network,was funded in part by the Cancer Care Manitoba Foundation(CCMF,Canada)previously the Canadian Institutes of Health Research(CIHR,PRG80155,Canada).
文摘Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance.However,their interplays are poorly understood.We report here that elevated TIGAR(TP53-induced glycolysis and apoptosis regulator),an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2(nuclear receptor binding SET domain protein 2),is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark.Mechanistically,TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2,H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new(NSD2)and established(NQO1/2,PRDX1 and GSTM4)targets of NRF2,independent of its enzymatic activity.Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis.In addition,nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival.These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.
基金supported by grants from the National Natural Science Foundation of China(81872860,81673433,and 81973318)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093,China)+6 种基金National Major Special Projects for the Creation and Manufacture of New Drugs(2019ZX09301104,China)Special Program for Applied Science and Technology of Guangdong Province(2015B020232009,China)National Engineering and Technology Research Center for New drug Druggability Evaluation(Seed Program of Guangdong Province,2017B090903004,China)Guangdong Basic and Applied Basic Research Foundation(2019A1515011256,China)Guangzhou Science and Technology Program Project(201604020121 and 201804010227,China)Yang Fan Project of Guangdong Province(Grant No.2014YT02S044,China)Guangdong Provincial Key Laboratory of Construction Foundation(No.2017B030314030,China)。
文摘The bromodomain and extraterminal(BET)family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy.BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin,facilitating the phosphorylation of RNA polymerases II(Pol II)and leading to transcription elongation.The present study identified a novel post-translational modification of BRD4:poly(ADPribosyl)ation(PARylation),that was mediated by poly(ADP-ribose)polymerase-1(PARP1)in cardiac hypertrophy.BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol(ISO),whereas overexpression of BRD4 promoted cardiac hypertrophy,confirming the critical role of BRD4 in pathological cardiac hypertrophy.PARP1 was activated in ISOinduced cardiac hypertrophy and facilitated the development of cardiac hypertrophy.BRD4 was involved in the prohypertrophic effect of PARP1,as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses,and that BRD4 overexpression suppressed the antihypertrophic effect of PARP1 inhibitors.Interactions of BRD4 and PARP1 were observed by coimmunoprecipitation and immunofluorescence.PARylation of BRD4 induced by PARP1 was investigated by PARylation assays.In response to hypertrophic stimuli like ISO,PARylation level of BRD4 was elevated,along with enhanced interactions between BRD4 and PARP1.By investigating the PARylation of truncation mutants of BRD4,the C-terminal domain(CTD)was identified as the PARylation modification sites of BRD4.PARylation of BRD4 facilitated its binding to the transcription start sites(TSS)of hypertrophic genes,resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes.The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.
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.
基金supported by the National Key R&D Program of China(2022YFA1104900)the Natural Science Foundation of China(Grant number:82025034,81973392)+3 种基金the Shenzhen Science and Technology Program(KQTD20190929174023858,China)the 111 project(Grant number:B16047,China)the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(Grant number:2017BT01Y093,China)the National Engineering and Technology Research Center for New drug Druggability Evaluation(Seed Program of Guangdong Province,Grant number:2017B090903004,China)。
文摘Liver is the central hub regulating energy metabolism during feeding-fasting transition.Evidence suggests that fasting and refeeding induce dynamic changes in liver size,but the underlying mechanisms remain unclear.Yes-associated protein(YAP)is a key regulator of organ size.This study aims to explore the role of YAP in fasting-and refeeding-induced changes in liver size.Here,fasting significantly reduced liver size,which was recovered to the normal level after refeeding.Moreover,hepatocyte size was decreased and hepatocyte proliferation was inhibited after fasting.Conversely,refeeding promoted hepatocyte enlargement and proliferation compared to fasted state.Mechanistically,fasting or refeeding regulated the expression of YAP and its downstream targets,as well as the proliferation-related protein cyclin D1(CCND1).Furthermore,fasting significantly reduced the liver size in AAV-control mice,which was mitigated in AAV Yap(5SA)mice.Yap overexpression also prevented the effect of fasting on hepatocyte size and proliferation.Besides,the recovery of liver size after refeeding was delayed in AAV Yap shRNA mice.Yap knockdown attenuated refeeding-induced hepatocyte enlargement and proliferation.In summary,this study demonstrated that YAP plays an important role in dynamic changes of liver size during fasting-refeeding transition,which provides new evidence for YAP in regulating liver size under energy stress.
基金supported by grants from the National Natural Science Foundation of China (81872860, 81803521, 81673433)National Major Special Projects for the Creation and Manufacture of New Drugs (2019ZX09301104, China)+5 种基金Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093, China)National Engineering and Technology Research Center for New drug Druggability Evaluation(Seed Program of Guangdong Province, 2017B090903004,China)Natural Science Foundation of Guangdong Province(2019A1515010273, China)Foundation from Guangdong Traditional Medicine Bureau (20191060, China)Fundamental Research Funds for the Central Universities (19ykpy131, China)Research and Industrialization team of Taxus chinensis var.mairel (2014YT02S044, China)。
文摘As an effective anticancer drug, the clinical limitation of doxorubicin(Dox) is the time-and dose-dependent cardiotoxicity. Yes-associated protein 1(YAP1) interacts with transcription factor TEA domain 1(TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced in vivo and in vitro cardiotoxic model. Ectopic expression of Yap1 significantly blocked Dox-induced cardiomyocytes apoptosis in TEAD1 dependent manner. Isorhapontigenin(Isor) is a new derivative of stilbene and responsible for a wide range of biological processes. Here, we found that Isor effectively relieved Doxinduced cardiomyocytes apoptosis in a dose-dependent manner in vitro. Administration with Isor(30 mg/kg/day, intraperitoneally, 3 weeks) significantly protected against Dox-induced cardiotoxicity in mice. Interestingly, Isor increased Dox-caused repression in YAP1 and the expression of its target genes in vivo and in vitro. Knockout or inhibition of Yap1 blocked the protective effects of Isor on Dox-induced cardiotoxicity. In conclusion, YAP1 may be a novel target for Dox-induced cardiotoxicity and Isor might be a new compound to fight against Dox-induced cardiotoxicity by increasing YAP1 expression.
基金supported by the National Natural Science Foundation of China(81872891,81572925,81774339 and 41776169)the Guangdong Natural Science Funds for Distinguished Young Scholar(No.2019B151502016,China)+5 种基金the Science and Technology Planning Project of Guangdong Province(No.2017A050506042,China)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093,China)National Major Special Projects for the Creation and Manufacture of New Drugs(2019ZX09301104,China)National Engineering and Technology Research Center for New drug Druggability Evaluation(Seed Program of Guangdong Province,2017B090903004,China)the Fundamental Research Funds for the Central Universities(No.19ykzd23,China)Pearl River S&T Nova Program of Guangzhou(No.201710010136,China)
文摘Prostate cancer(PCa)patients who progress to metastatic castration-resistant PCa(mCRPC)mostly have poor outcomes due to the lack of effective therapies.Our recent study established the orphan nuclear receptor RORγas a novel therapeutic target for CRPC.Here,we reveal that elaiophylin(Elai),an antibiotic from Actinomycete streptomyces,is a novel RORy antagonist and showed potent antitumor activity against CRPC in vitro and in vivo.We demonstrated that Elai selectively binded to RORy protein and potently blocked RORγtranscriptional regulation activities.Structure-activity relationship studies showed that Elai occupied the binding pocket with several key interactions.Furthermore,Elai markedly reduced the recruitment of RORγto its genomic DNA response element(RORE),suppressed the expression of RORγtarget genes AR and AR variants,and significantly inhibited PCa cell growth.Importantly,Elai strongly suppressed tumor growth in both cell line based and patient-derived PCa xenograft models.Taken together,these results suggest that Elai is novel therapeutic RORγinhibitor that can be used as a drug candidate for the treatment of human CRPC.
