BACKGROUND Fibrosis is a critical event in the progression of pediatric nonalcoholic fatty liver disease(NAFLD).AIM To develop less invasive models based on machine learning(ML)to predict significant fibrosis in Chine...BACKGROUND Fibrosis is a critical event in the progression of pediatric nonalcoholic fatty liver disease(NAFLD).AIM To develop less invasive models based on machine learning(ML)to predict significant fibrosis in Chinese NAFLD children.METHODS In this cross-sectional study,222 and 101 NAFLD children with available liver biopsy data were included in the development of screening models for tertiary hospitals and community health centers,respectively.Predictive factors were selected using least absolute shrinkage and selection operator regression and stepwise logistic regression analyses.Logistic regression(LR)and other ML models were applied to construct the prediction models.RESULTS Simplified indicators of the ATS and BIU indices were constructed for tertiary hospitals and community health centers,respectively.When models based on the ATS and BIU parameter combinations were constructed,the random forest(RF)model demonstrated higher screening accuracy compared to the LR model(0.80 and 0.79 for the RF model and 0.72 and 0.77 for the LR model,respectively).Using cutoff values of 90%for sensitivity and 90%for specificity,the RF models could effectively identify and exclude NAFLD children with significant fibrosis in the internal validation set(with positive predictive values and negative prediction values exceeding 0.80),which could prevent liver biopsy in 60%and 71.4%of NAFLD children,respectively.CONCLUSION This study developed new models for predicting significant fibrosis in NAFLD children in tertiary hospitals and community health centers,which can serve as preliminary screening tools to detect the risk population in a timely manner.展开更多
Natural products are the important sources in cardiovascular drug development.In this study,twenty-nine buthutin derivatives were designed,synthesized,and evaluated for their NHE-1 inhibition and protective effects on...Natural products are the important sources in cardiovascular drug development.In this study,twenty-nine buthutin derivatives were designed,synthesized,and evaluated for their NHE-1 inhibition and protective effects on cardiomyo-cyte injury.The structure of the newly synthesized compounds had been confirmed by 1H-NMR,13C-NMR,and HR-ESI-MS spectra.Among all target compounds at 1μM,compounds 9d,9f,9k,9m,and 9n,with a protection ratio exceeding 30%,exerted stronger protective effects on H9c2 cardiomyocyte than positive control dexrazoxane and buthutin A.Meanwhile,compounds 9k,9m,and 9o showed the significant NHE-1 inhibitory activities on H9c2 cardiomyocyte,all with a dpHi/min value less than 0.23.What is more,compounds 9k,9m,9o and buthutin A all exhibited the specificity on NHE-1 inhibition.Molecular modelling studies suggested the ability of compounds 9m and 9o to establish interactions with three hydrogen bonds to Asp267 and Glu346 of NHE-1,but also the ability with much lower CDOCKER energies than positive control cariporide and buthutin A.The structure-activity relationship(SAR)studies suggested that the presences of amide group,four-carbon linker,and para hydroxyl benzene ring were advantageous pharmacophores for above two pharmacological actions.This research would open new avenues for developing amide-guanidine-based cardioprotective agents.展开更多
Objective:Osteoarthritis(OA)is a degenerative joint disorder characterized by the gradual degradation of joint cartilage and local inflammation.This study aimed to investigate the anti-OA effect of scutellarein(SCU),a...Objective:Osteoarthritis(OA)is a degenerative joint disorder characterized by the gradual degradation of joint cartilage and local inflammation.This study aimed to investigate the anti-OA effect of scutellarein(SCU),a single-unit flavonoid compound obtained from Scutellaria barbata D.Don,in rats.Methods:The extracted rat chondrocytes were treated with SCU and IL-1β.The chondrocytes were divided into control group,IL-1βgroup,IL-1β+SCU 50µmol/L group,and IL-1β+SCU 100µmol/L group.Morphology of rat chondrocytes was observed by toluidine blue and safranin O staining.CCK-8 method was used to detect the cytotoxicity of SCU.ELISA,qRT-PCR,Western blotting,immunofluorescence,SAβ-gal staining,flow cytometry,and bioinformatics analysis were applied to evaluate the effect of SCU on rat chondrocytes under IL-1βintervention.Additionally,anterior cruciate ligament transection(ACL-T)was used to establish a rat OA model.Histological changes were detected by safranin O/fast green,hematoxylin-eosin(HE)staining,and immunohistochemistry.Results:SCU protected cartilage and exhibited anti-inflammatory effects via multiple mechanisms.Specifically,it could enhance the synthesis of extracellular matrix in cartilage cells and inhibit its degradation.In addition,SCU partially inhibited the nuclear factor kappa-B/mitogen-activated protein kinase(NF-κB/MAPK)pathway,thereby reducing inflammatory cytokine production in the joint cartilage.Furthermore,SCU significantly reduced IL-1β-induced apoptosis and senescence in rat chondrocytes,further highlighting its potential role in OA treatment.In vivo experiments revealed that SCU(at a dose of 50 mg/kg)administered for 2 months could significantly delay the progression of cartilage damage,which was reflected in a lower Osteoarthritis Research Society International(OARSI)score,and reduced expression of matrix metalloproteinase 13(MMP13)in cartilage.Conclusion:SCU is effective in the therapeutic management of OA and could serve as a potential candidate for future clinical drug therapy for OA.展开更多
基金Supported by National Natural Science Foundation of China,No.82272433Fujian Provincial Key Laboratory of Hepatic Drug Research,No.2022-YF-0050+1 种基金the Major Science and Technology Projects for Health of Zhejiang Province,No.WKJ-ZJ-2216the Cyrus Tang Foundation for Young Scholar,No.2022(2022-B126).
文摘BACKGROUND Fibrosis is a critical event in the progression of pediatric nonalcoholic fatty liver disease(NAFLD).AIM To develop less invasive models based on machine learning(ML)to predict significant fibrosis in Chinese NAFLD children.METHODS In this cross-sectional study,222 and 101 NAFLD children with available liver biopsy data were included in the development of screening models for tertiary hospitals and community health centers,respectively.Predictive factors were selected using least absolute shrinkage and selection operator regression and stepwise logistic regression analyses.Logistic regression(LR)and other ML models were applied to construct the prediction models.RESULTS Simplified indicators of the ATS and BIU indices were constructed for tertiary hospitals and community health centers,respectively.When models based on the ATS and BIU parameter combinations were constructed,the random forest(RF)model demonstrated higher screening accuracy compared to the LR model(0.80 and 0.79 for the RF model and 0.72 and 0.77 for the LR model,respectively).Using cutoff values of 90%for sensitivity and 90%for specificity,the RF models could effectively identify and exclude NAFLD children with significant fibrosis in the internal validation set(with positive predictive values and negative prediction values exceeding 0.80),which could prevent liver biopsy in 60%and 71.4%of NAFLD children,respectively.CONCLUSION This study developed new models for predicting significant fibrosis in NAFLD children in tertiary hospitals and community health centers,which can serve as preliminary screening tools to detect the risk population in a timely manner.
基金supported by the National Natural Science Foundation of China(NSFC)Youth Project(No.82204397).
文摘Natural products are the important sources in cardiovascular drug development.In this study,twenty-nine buthutin derivatives were designed,synthesized,and evaluated for their NHE-1 inhibition and protective effects on cardiomyo-cyte injury.The structure of the newly synthesized compounds had been confirmed by 1H-NMR,13C-NMR,and HR-ESI-MS spectra.Among all target compounds at 1μM,compounds 9d,9f,9k,9m,and 9n,with a protection ratio exceeding 30%,exerted stronger protective effects on H9c2 cardiomyocyte than positive control dexrazoxane and buthutin A.Meanwhile,compounds 9k,9m,and 9o showed the significant NHE-1 inhibitory activities on H9c2 cardiomyocyte,all with a dpHi/min value less than 0.23.What is more,compounds 9k,9m,9o and buthutin A all exhibited the specificity on NHE-1 inhibition.Molecular modelling studies suggested the ability of compounds 9m and 9o to establish interactions with three hydrogen bonds to Asp267 and Glu346 of NHE-1,but also the ability with much lower CDOCKER energies than positive control cariporide and buthutin A.The structure-activity relationship(SAR)studies suggested that the presences of amide group,four-carbon linker,and para hydroxyl benzene ring were advantageous pharmacophores for above two pharmacological actions.This research would open new avenues for developing amide-guanidine-based cardioprotective agents.
基金financially sponsored by the National Natural Science Foundation of China(No.51537004).
文摘Objective:Osteoarthritis(OA)is a degenerative joint disorder characterized by the gradual degradation of joint cartilage and local inflammation.This study aimed to investigate the anti-OA effect of scutellarein(SCU),a single-unit flavonoid compound obtained from Scutellaria barbata D.Don,in rats.Methods:The extracted rat chondrocytes were treated with SCU and IL-1β.The chondrocytes were divided into control group,IL-1βgroup,IL-1β+SCU 50µmol/L group,and IL-1β+SCU 100µmol/L group.Morphology of rat chondrocytes was observed by toluidine blue and safranin O staining.CCK-8 method was used to detect the cytotoxicity of SCU.ELISA,qRT-PCR,Western blotting,immunofluorescence,SAβ-gal staining,flow cytometry,and bioinformatics analysis were applied to evaluate the effect of SCU on rat chondrocytes under IL-1βintervention.Additionally,anterior cruciate ligament transection(ACL-T)was used to establish a rat OA model.Histological changes were detected by safranin O/fast green,hematoxylin-eosin(HE)staining,and immunohistochemistry.Results:SCU protected cartilage and exhibited anti-inflammatory effects via multiple mechanisms.Specifically,it could enhance the synthesis of extracellular matrix in cartilage cells and inhibit its degradation.In addition,SCU partially inhibited the nuclear factor kappa-B/mitogen-activated protein kinase(NF-κB/MAPK)pathway,thereby reducing inflammatory cytokine production in the joint cartilage.Furthermore,SCU significantly reduced IL-1β-induced apoptosis and senescence in rat chondrocytes,further highlighting its potential role in OA treatment.In vivo experiments revealed that SCU(at a dose of 50 mg/kg)administered for 2 months could significantly delay the progression of cartilage damage,which was reflected in a lower Osteoarthritis Research Society International(OARSI)score,and reduced expression of matrix metalloproteinase 13(MMP13)in cartilage.Conclusion:SCU is effective in the therapeutic management of OA and could serve as a potential candidate for future clinical drug therapy for OA.
