OBJECTIVE Our previous studies demonstrated that various ingredients from the traditional Chinese medicine(TCM)for promoting blood circulation and removing blood stasis,as exemplified by cryptotanshinone and salvianol...OBJECTIVE Our previous studies demonstrated that various ingredients from the traditional Chinese medicine(TCM)for promoting blood circulation and removing blood stasis,as exemplified by cryptotanshinone and salvianolic acid B,exerted striking effects on modulating angiogenesis and vascular permeability,which suggests that they may be effective in treating vascular leak-driven diseases(e.g.tumor,cerebral cavernous malformation and diabetic retinopathy).However,the lack of reliable and advanced technologies and models sets up difficult hurdles for better understanding the role of TCM for promoting blood circulation and removing blood stasis.To this end,this study is to outline numerous cutting-edge platforms that can be utilized for exploring the function of TCM for promoting blood circulation and removing blood stasis in vascular leak-driven diseases.METHODS Two-photon laser scanning fluorescence microscopy was used to observe the interactions between neutrophils and blood vessels in a real-time manner.Dynamic flow system was employed to mimic the in vivo behaviors of neutrophils.RIP1-Tag5 spontaneous pancreatic cancer model was used to study the function of tumor blood vessels.CCM2ECKO(deletion of CCM2 in endothelial cells)mice were employed to establish the cerebral cavernous malformation(CCM)animal model.Micro-computed tomography(micro-CT)was utilized to assess the CCM lesion.Müller cell-knockout mouse model was used to study the progression of diabetic retinopathy.Vascular permeability in this model was assessed by fluorescein angiography.RESULTS The interactions between neutrophils and endothelial cells involve a series of complicated processes,including rolling,adhesion,intraluminal crawling and transmigration,which were all monitored in vivo by two-photon laser scanning fluorescence microscopy in a real-time manner.Dynamic flow system was capable of recapitulating the biological behaviors of neutrophils in vitro.Tumor vascular function in particular vascular perfusion could be assessed in the RIP1-Tag5 spontaneous pancreatic cancer model.In terms of CCM studies,specific deletion of CCM2 in endothelial cells resulted in the initiation of CCM lesion.The size and number of CCM lesions could be visualized and quantified by micro-CT.Furthermore,the Müller cell-knockout mouse model was able to precisely reflect the clinical symptoms of diabetic retinopathy.Vascular leak could be monitored at different time points using fluorescein angiography.CONCLUSION An array of high technologies and animal models can be used in investigating the occurrence and progression of multiple vascular leak-driven diseases.The pre-clinical and clinical studies of TCM for promoting blood circulation and removing blood stasis provide fundamental support for the application of the above-mentioned platforms,with the purpose of uncovering the scientific basis of TCM for promoting blood circulation and removing blood stasis.展开更多
Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy.Cannabidiol(CBD)is a non-psychoactive natural active ingredient from the cannabis plant that has...Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy.Cannabidiol(CBD)is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects,including neuroprotective,antiemetic,anti-inflammatory,and antineoplastic activities.This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing(scRNA-seq)and single-cell ATAC sequencing(scATAC-seq)technologies.Here,we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment(TME).Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity.Furthermore,CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages,thereby preventing tumor progression.Mechanistically,CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways.We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes.Furthermore,CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1(PD-1)immunotherapy in xenografted mice.Taken together,we provide new insights into the anti-tumor effects of CBD.展开更多
Chinese medicine(CM)diagnosis intellectualization is one of the hotspots in the research of CM modernization.The traditional CM intelligent diagnosis models transform the CM diagnosis issues into classification issues...Chinese medicine(CM)diagnosis intellectualization is one of the hotspots in the research of CM modernization.The traditional CM intelligent diagnosis models transform the CM diagnosis issues into classification issues,however,it is difficult to solve the problems such as excessive or similar categories.With the development of natural language processing techniques,text generation technique has become increasingly mature.In this study,we aimed to establish the CM diagnosis generation model by transforming the CM diagnosis issues into text generation issues.The semantic context characteristic learning capacity was enhanced referring to Bidirectional Long Short-Term Memory(BILSTM)with Transformer as the backbone network.Meanwhile,the CM diagnosis generation model Knowledge Graph Enhanced Transformer(KGET)was established by introducing the knowledge in medical field to enhance the inferential capability.The KGET model was established based on 566 CM case texts,and was compared with the classic text generation models including Long Short-Term Memory sequence-to-sequence(LSTM-seq2seq),Bidirectional and Auto-Regression Transformer(BART),and Chinese Pre-trained Unbalanced Transformer(CPT),so as to analyze the model manifestations.Finally,the ablation experiments were performed to explore the influence of the optimized part on the KGET model.The results of Bilingual Evaluation Understudy(BLEU),Recall-Oriented Understudy for Gisting Evaluation 1(ROUGE1),ROUGE2 and Edit distance of KGET model were 45.85,73.93,54.59 and 7.12,respectively in this study.Compared with LSTM-seq2seq,BART and CPT models,the KGET model was higher in BLEU,ROUGE1 and ROUGE2 by 6.00–17.09,1.65–9.39 and 0.51–17.62,respectively,and lower in Edit distance by 0.47–3.21.The ablation experiment results revealed that introduction of BILSTM model and prior knowledge could significantly increase the model performance.Additionally,the manual assessment indicated that the CM diagnosis results of the KGET model used in this study were highly consistent with the practical diagnosis results.In conclusion,text generation technology can be effectively applied to CM diagnostic modeling.It can effectively avoid the problem of poor diagnostic performance caused by excessive and similar categories in traditional CM diagnostic classification models.CM diagnostic text generation technology has broad application prospects in the future.展开更多
Opioid abuse can suppress the lymphatic system function,and produce severe immunosuppression that poses a significant risk of opportunistic infections such as methicillinresistant Staphylococcus aureus(MRSA)pneumonia....Opioid abuse can suppress the lymphatic system function,and produce severe immunosuppression that poses a significant risk of opportunistic infections such as methicillinresistant Staphylococcus aureus(MRSA)pneumonia.^(1,2)Gypenosides(Gps)are the most important immunomodulator components in the Chinese herbal medicine Gynostemma pentaphyllum.展开更多
Objective:In this study,we screened for therapeutic targets of the Xian-Lian-Jie-Du decoction(XLJDD)for colorectal cancer(CRC)and explored the underlying mechanisms using network pharmacology techniques.Methods:Genes ...Objective:In this study,we screened for therapeutic targets of the Xian-Lian-Jie-Du decoction(XLJDD)for colorectal cancer(CRC)and explored the underlying mechanisms using network pharmacology techniques.Methods:Genes associated with CRC were collected from the Gene Cards database.The names of the active compounds of XLJDD were used as keywords in the“chemical name”in the Traditional Chinese Medicine Systems Pharmacology(TCMSP)database to search the targets.The protein-protein interaction(PPI)network was constructed using Cytoscape 3.8.1.Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were performed to identify key target proteins.Results:A total of 234 XLJDD-related targets and 250 cross-targets between XLJDD and CRC were collected based on the TCMSP and HIT 2.0 databases.A PPI network constructed based on the STRING database revealed interactions for all 250 proteins.The network results revealed TP53,MYC,CCND1,AKT1,CASP3,and STAT3 as core potential targets.KEGG pathway analysis of the 250 potential XLJDD targets for CRC in the Metascape database was performed using RStudio software.The top 12 gene ratio aggregated analysis results were visualized in bubble charts.The interleukin(IL)-17 signaling pathway had the highest correlation with the tumor necrosis factor(TNF)signaling pathway.Conclusions:XLJDD may be effective in ameliorating CRC by controlling inflammatory factors related to the IL-17 and TNF pathways and targeting proto-oncogenes and tumor suppressor genes,including MYC,CCND1,CTNNB1,and TP53.展开更多
Accumulative evidences have underpinned the nature candidates from Chinese medicine(CM), particularly CM served as blood activating and stasis resolving(BASR, Huoxue Huayu in Chinese) by targeting tumor-associated ang...Accumulative evidences have underpinned the nature candidates from Chinese medicine(CM), particularly CM served as blood activating and stasis resolving(BASR, Huoxue Huayu in Chinese) by targeting tumor-associated angiogenesis. However, recent experiment research on the therapeutic angiogenesis by BASR-CM attracts wide attention and discussion. This opinion review focused on the underlying link between two indications and anticipated that(1) BASR-CM might emphasize on a balanced multi-cytokines network interaction;(2) BASR-CM might address on the nature of diseases prior to differently affecting physiological and pathological angiogenesis;(3) BASR-CM might mainly act on perivascular cells, either promotes arteriogenesis by increasing arteriogenic factors in ischemic diseases, or simultaneously keep a quiescent vasculature to impede angiogenesis in tumor context.展开更多
Background and Aims:Oxaliplatin is widely used in can-cer chemotherapy with adverse effects such as liver toxicity.Magnesium isoglycyrrhizinate(MgIG)has hepatoprotective effects,but the underlying mechanism remains el...Background and Aims:Oxaliplatin is widely used in can-cer chemotherapy with adverse effects such as liver toxicity.Magnesium isoglycyrrhizinate(MgIG)has hepatoprotective effects,but the underlying mechanism remains elusive.The study’s aim was to investigate the mechanism underlying the hepatoprotective effects of MgIG against oxaliplatin-induced liver injury.Methods:A xenografted colorectal cancer mouse model was established with MC38 cells.Mice were given ox-aliplatin(6 mg/kg/week)for 5 weeks to mimic oxaliplatin-induced liver injury in vivo.LX-2 human hepatic stellate cell s(HSCs)were employed for in vitro studies.Serological tests,hematoxylin and eosin staining,oil red O staining and trans-mission electron microscopy were used for histopathological examinations.Real-time PCR,western blotting,immuno-fluorescence and immunohistochemical staining were used to determine Cx43 mRNA or protein levels.Flow cytometry was used to assay reactive oxygen species(ROS)and mito-chondrial membrane.Short hairpin RNA targeting Cx43 was lentivirally transduced in LX-2 cells.Ultra-high performance liquid chromatography-tandem mass spectrometry was used to determine MgIG and metabolite concentration.Results:MgIG(40 mg/kg/day)treatment significantly reduced se-rum aspartate transaminase(AST)and alanine transami-nase(ALT)levels in the mouse model,and alleviated liver pathological changes,including necrosis,sinusoidal expan-sion,mitochondrial damage,and fibrosis.MgIG reduced the abnormal expression of Cx43 in the mitochondria and nuclei of HSCs.MgIG inhibited the activation of HSCs via reducing ROS generation,mitochondrial dysfunction,and N-cadherin transcription.MgIG’s inhibition of HSCs activation was abol-ished after knockdown of Cx43 in LX-2 cells.Conclusions:Cx43 mediated MgIG’s hepatoprotective effects against ox-aliplatin-induced toxicity.展开更多
OBJECTIVE: To assess the efficacy and safety of Aidi injection plus transarterial chemoembolization(TACE) in patients with primary hepatic carcinoma.METHODS: A comprehensive research of seven electronic databases was ...OBJECTIVE: To assess the efficacy and safety of Aidi injection plus transarterial chemoembolization(TACE) in patients with primary hepatic carcinoma.METHODS: A comprehensive research of seven electronic databases was performed for comparative studies evaluating Aidi injection combined with TACE for primary hepatic carcinoma until September 2016. Two authors independently extracted data and assessed the methodological quality of the included trials using the Cochrane risk of bias tool from the Cochrane Handbook version 5.1.0. Data was synthesized by using Rev Man 5.3 software.RESULTS: Forty-nine studies involving 3435 patients met the inclusion criteria, most of which were low methodological quality. Compared with TACE alone, Aidi injection plus TACE can significantly improve the efficiency rate [RR = 1.33, 95% CI(1.24, 1.43), P < 0.000 01], clinical beneficial rate[RR = 1.25, 95% CI(1.17, 1.33), P < 0.000 01], survival rate [6 months, RR = 1.19, 95% CI(1.09, 1.29), P <0.0001], 12 months, [RR = 1.37, 95% CI(1.24, 1.52),P < 0.000 01], 18 months, [RR = 2.00, 95% CI(1.26,3.20), P < 0.004], 24 months, [RR = 1.44, 95% CI(1.22, 1.70), P < 0.0001], 36 months, [RR = 1.50, 95%CI(1.07, 2.11), P = 0.02 < 0.05], quality of life [RR =1.84, 95% CI(1.64, 2.05), P < 0.000 01] and immune function [CD3+, MD = 11.12, 95% CI(7.93, 14.30),P < 0.000 01], CD4 +, [MD = 10.37, 95% CI(7.29,13.45), P < 0.000 01], CD4+/CD8+, [MD = 0.30, 95%CI(0.07, 0.53), P = 0.01 < 0.05], NK, [MD = 7.49, 95%CI(6.64, 8.34), P < 0.000 01]. A significant improvement was also found in improvement of symptoms[RR = 1.64, 95%CI(1.38, 1.94), P < 0.000 01], leukopenia [RR = 0.60, 95% CI(0.54, 0.66), P < 0.000 01],thrombocytopenia [RR = 0.46, 95% CI(0.34, 0.61),P < 0.000 01], nausea and vomiting incidence [RR =0.66, 95% CI(0.54, 0.81), P < 0.0001), liver damage rate [RR = 0.57, 95% CI(0.42, 0.77), P = 0.0003 <0.05), and kidney damage rate [RR = 0.18, 95% CI(0.05, 0.68), P = 0.01 < 0.05].CONCLUSION: The results suggested that Aidi injection plus TACE significantly improve the clinical effect of TACE, and reduce the incidence of adverse events. However, rigorous multicenter trials with larger size are warranted to further confirm the findings.展开更多
A lasting imbalance between fatty acid synthesis and consumption leads to non-alcoholic fatty liver disease(NAFLD),coupled with hepatitis and insulin resistance.Yet the details of the underlying mechanisms are not ful...A lasting imbalance between fatty acid synthesis and consumption leads to non-alcoholic fatty liver disease(NAFLD),coupled with hepatitis and insulin resistance.Yet the details of the underlying mechanisms are not fully understood.Here,we unraveled that the expression of the transcription factor Zbtb18 is markedly decreased in the livers of both patients and murine models of NAFLD.Hepatic Zbtb18 knockout promoted NAFLD features like impaired energy expenditure and fatty acid oxidation(FAO),and induced insulin resistance.Conversely,hepatic Zbtb18 overexpression alleviated hepato-steatosis,insulin resistance,and hyperglycemia in mice fed on a high-fat diet(HFD)or in diabetic mice.Notably,in vitro and in vivo mechanistic studies revealed that Zbtb18 transcriptional activation of Farnesoid X receptor(FXR)mediated FAO and Clathrin Heavy Chain(CLTC)protein hinders NLRP3 inflammasome activity.This key mechanism by which hepatocyte’s Zbtb18 expression alleviates NAFLD and consequent liver fibrosis was further verified by FXR’s deletion and forced expression in mice and cultured mouse primary hepatocytes(MPHs).Moreover,CLTC deletion significantly abrogated the hepatic Zbtb18 overexpression-driven inhibition of NLRP3 inflammasome activity in macrophages.Altogether,Zbtb18 transcriptionally activates the FXR-mediated FAO and CLTC expression,which inhibits NLRP3 inflammasome’s activity alleviating inflammatory stress and insulin resistance,representing an attractive remedy for hepatic steatosis and fibrosis.展开更多
Chemoresistance remains a major obstacle to successful treatment of triple negative breast cancer(TNBC).Identification of druggable vulnerabilities is an important aim for TNBC therapy.Here,we report that SERCA2 expre...Chemoresistance remains a major obstacle to successful treatment of triple negative breast cancer(TNBC).Identification of druggable vulnerabilities is an important aim for TNBC therapy.Here,we report that SERCA2 expression correlates with TNBC progression in human patients,which promotes TNBC cell proliferation,migration and chemoresistance.Mechanistically,SERCA2 interacts with LC3B via LIR motif,facilitating WIPI2-independent autophagosome formation to induce autophagy.Autophagy-mediated SERCA2 degradation induces SERCA2 transactivation through a Ca^(2+)/CaMKK/CREB-1 feedback.Moreover,we found that SERCA2-targeting small molecule RL71 enhances SERCA2-LC3B interaction and induces excessive autophagic cell death.The increase in SERCA2 expression predisposes TNBC cells to RL71-induced autophagic cell death in vitro and in vivo.This study elucidates a mechanism by which TNBC cells maintain their high autophagy activity to induce chemoresistance,and suggests increased SERCA2 expression as a druggable vulnerability for TNBC.展开更多
文摘OBJECTIVE Our previous studies demonstrated that various ingredients from the traditional Chinese medicine(TCM)for promoting blood circulation and removing blood stasis,as exemplified by cryptotanshinone and salvianolic acid B,exerted striking effects on modulating angiogenesis and vascular permeability,which suggests that they may be effective in treating vascular leak-driven diseases(e.g.tumor,cerebral cavernous malformation and diabetic retinopathy).However,the lack of reliable and advanced technologies and models sets up difficult hurdles for better understanding the role of TCM for promoting blood circulation and removing blood stasis.To this end,this study is to outline numerous cutting-edge platforms that can be utilized for exploring the function of TCM for promoting blood circulation and removing blood stasis in vascular leak-driven diseases.METHODS Two-photon laser scanning fluorescence microscopy was used to observe the interactions between neutrophils and blood vessels in a real-time manner.Dynamic flow system was employed to mimic the in vivo behaviors of neutrophils.RIP1-Tag5 spontaneous pancreatic cancer model was used to study the function of tumor blood vessels.CCM2ECKO(deletion of CCM2 in endothelial cells)mice were employed to establish the cerebral cavernous malformation(CCM)animal model.Micro-computed tomography(micro-CT)was utilized to assess the CCM lesion.Müller cell-knockout mouse model was used to study the progression of diabetic retinopathy.Vascular permeability in this model was assessed by fluorescein angiography.RESULTS The interactions between neutrophils and endothelial cells involve a series of complicated processes,including rolling,adhesion,intraluminal crawling and transmigration,which were all monitored in vivo by two-photon laser scanning fluorescence microscopy in a real-time manner.Dynamic flow system was capable of recapitulating the biological behaviors of neutrophils in vitro.Tumor vascular function in particular vascular perfusion could be assessed in the RIP1-Tag5 spontaneous pancreatic cancer model.In terms of CCM studies,specific deletion of CCM2 in endothelial cells resulted in the initiation of CCM lesion.The size and number of CCM lesions could be visualized and quantified by micro-CT.Furthermore,the Müller cell-knockout mouse model was able to precisely reflect the clinical symptoms of diabetic retinopathy.Vascular leak could be monitored at different time points using fluorescein angiography.CONCLUSION An array of high technologies and animal models can be used in investigating the occurrence and progression of multiple vascular leak-driven diseases.The pre-clinical and clinical studies of TCM for promoting blood circulation and removing blood stasis provide fundamental support for the application of the above-mentioned platforms,with the purpose of uncovering the scientific basis of TCM for promoting blood circulation and removing blood stasis.
基金supported by the National Key Research and Development Plan,China(Grant No.:2022YFC3500202)the Natural Science Foundation of China(Grant Nos.:82172558,and 82205024)+4 种基金the Scientific and Technological Innovation Action Plan of Natural Science Foundation Project of Shanghai,China(Grant No.:22ZR1447400)the Scientific and Technological Innovation Action Plan,China(Grant No.:22ZR1447400)the Fundamental Research Funds for the Central Universities,China(Grant Nos.:020814380179,020814380174)the Distinguished Young Scholars of Nanjing,China(Grant No.:JQX20008)the School of Life Science(NJU)-Sipimo Joint Funds and Mountain Climbing Talents Project of Nanjing University,China(Grant No.:2015018).
文摘Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy.Cannabidiol(CBD)is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects,including neuroprotective,antiemetic,anti-inflammatory,and antineoplastic activities.This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing(scRNA-seq)and single-cell ATAC sequencing(scATAC-seq)technologies.Here,we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment(TME).Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity.Furthermore,CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages,thereby preventing tumor progression.Mechanistically,CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways.We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes.Furthermore,CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1(PD-1)immunotherapy in xenografted mice.Taken together,we provide new insights into the anti-tumor effects of CBD.
基金Supported by the National Natural Science Foundation of China(No.82174276 and 82074580)the Key Research and Development Program of Jiangsu Province(No.BE2022712)+2 种基金China Postdoctoral Foundation(No.2021M701674)Postdoctoral Research Program of Jiangsu Province(No.2021K457C)Qinglan Project of Jiangsu Universities 2021。
文摘Chinese medicine(CM)diagnosis intellectualization is one of the hotspots in the research of CM modernization.The traditional CM intelligent diagnosis models transform the CM diagnosis issues into classification issues,however,it is difficult to solve the problems such as excessive or similar categories.With the development of natural language processing techniques,text generation technique has become increasingly mature.In this study,we aimed to establish the CM diagnosis generation model by transforming the CM diagnosis issues into text generation issues.The semantic context characteristic learning capacity was enhanced referring to Bidirectional Long Short-Term Memory(BILSTM)with Transformer as the backbone network.Meanwhile,the CM diagnosis generation model Knowledge Graph Enhanced Transformer(KGET)was established by introducing the knowledge in medical field to enhance the inferential capability.The KGET model was established based on 566 CM case texts,and was compared with the classic text generation models including Long Short-Term Memory sequence-to-sequence(LSTM-seq2seq),Bidirectional and Auto-Regression Transformer(BART),and Chinese Pre-trained Unbalanced Transformer(CPT),so as to analyze the model manifestations.Finally,the ablation experiments were performed to explore the influence of the optimized part on the KGET model.The results of Bilingual Evaluation Understudy(BLEU),Recall-Oriented Understudy for Gisting Evaluation 1(ROUGE1),ROUGE2 and Edit distance of KGET model were 45.85,73.93,54.59 and 7.12,respectively in this study.Compared with LSTM-seq2seq,BART and CPT models,the KGET model was higher in BLEU,ROUGE1 and ROUGE2 by 6.00–17.09,1.65–9.39 and 0.51–17.62,respectively,and lower in Edit distance by 0.47–3.21.The ablation experiment results revealed that introduction of BILSTM model and prior knowledge could significantly increase the model performance.Additionally,the manual assessment indicated that the CM diagnosis results of the KGET model used in this study were highly consistent with the practical diagnosis results.In conclusion,text generation technology can be effectively applied to CM diagnostic modeling.It can effectively avoid the problem of poor diagnostic performance caused by excessive and similar categories in traditional CM diagnostic classification models.CM diagnostic text generation technology has broad application prospects in the future.
基金supported by the National Natural Science Foundation of China(No.82174498,82174141)the National Administration of Traditional Chinese Medicine Youth Qihuang Scholars Support Project,the Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine(China)(No.2020YLXK013)the Postgraduate Research&Practice Innovation Program of Jiangsu Province,China(No.KYCX21_1796).
文摘Opioid abuse can suppress the lymphatic system function,and produce severe immunosuppression that poses a significant risk of opportunistic infections such as methicillinresistant Staphylococcus aureus(MRSA)pneumonia.^(1,2)Gypenosides(Gps)are the most important immunomodulator components in the Chinese herbal medicine Gynostemma pentaphyllum.
基金supported by the National Key R&D Program of China(2022YFC3500200,2022YFC3500202)the Key Research Project of TCM in Zhejiang Province(2022ZZ007)+3 种基金Innovation Team and Talents Cultivation Program of National Administration of TCM(ZYYCXTD-C-202208)National Science Foundation of China(81930117)National Science Foundation of Zhejiang Province(LGF22H040016)Clinical Research and Application Project of Zhejiang Health Science and Technology Plan(2022KY125)。
文摘Objective:In this study,we screened for therapeutic targets of the Xian-Lian-Jie-Du decoction(XLJDD)for colorectal cancer(CRC)and explored the underlying mechanisms using network pharmacology techniques.Methods:Genes associated with CRC were collected from the Gene Cards database.The names of the active compounds of XLJDD were used as keywords in the“chemical name”in the Traditional Chinese Medicine Systems Pharmacology(TCMSP)database to search the targets.The protein-protein interaction(PPI)network was constructed using Cytoscape 3.8.1.Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were performed to identify key target proteins.Results:A total of 234 XLJDD-related targets and 250 cross-targets between XLJDD and CRC were collected based on the TCMSP and HIT 2.0 databases.A PPI network constructed based on the STRING database revealed interactions for all 250 proteins.The network results revealed TP53,MYC,CCND1,AKT1,CASP3,and STAT3 as core potential targets.KEGG pathway analysis of the 250 potential XLJDD targets for CRC in the Metascape database was performed using RStudio software.The top 12 gene ratio aggregated analysis results were visualized in bubble charts.The interleukin(IL)-17 signaling pathway had the highest correlation with the tumor necrosis factor(TNF)signaling pathway.Conclusions:XLJDD may be effective in ameliorating CRC by controlling inflammatory factors related to the IL-17 and TNF pathways and targeting proto-oncogenes and tumor suppressor genes,including MYC,CCND1,CTNNB1,and TP53.
基金Supported by the National Natural Science Foundation of China(Nos.81173174,81403260 and 81573859)China Post-doctoral Science Foundation(No.2014M551639)+4 种基金Natural Science Foundation of Jiangsu Province(No.BK2012854)Postdoctoral Funding in Jiangsu Province(No.1401138C)2013 Program for Excellent Scientific and Technological Innovation Team of Jiangsu Higher Education(No.PPZY2015A070)the Priority Academic Program Development of Jiangsu Higher Education InstitutionsJiangsu College Graduate Research and Innovation Projects(No.CXZZ13_0627)
文摘Accumulative evidences have underpinned the nature candidates from Chinese medicine(CM), particularly CM served as blood activating and stasis resolving(BASR, Huoxue Huayu in Chinese) by targeting tumor-associated angiogenesis. However, recent experiment research on the therapeutic angiogenesis by BASR-CM attracts wide attention and discussion. This opinion review focused on the underlying link between two indications and anticipated that(1) BASR-CM might emphasize on a balanced multi-cytokines network interaction;(2) BASR-CM might address on the nature of diseases prior to differently affecting physiological and pathological angiogenesis;(3) BASR-CM might mainly act on perivascular cells, either promotes arteriogenesis by increasing arteriogenic factors in ischemic diseases, or simultaneously keep a quiescent vasculature to impede angiogenesis in tumor context.
基金the Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica(No.JKLPSE201501)the Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine(No.2020YLXK20)the Science and Technology Development Foundation of Nanjing Medical University(No.NMUB2019186).
文摘Background and Aims:Oxaliplatin is widely used in can-cer chemotherapy with adverse effects such as liver toxicity.Magnesium isoglycyrrhizinate(MgIG)has hepatoprotective effects,but the underlying mechanism remains elusive.The study’s aim was to investigate the mechanism underlying the hepatoprotective effects of MgIG against oxaliplatin-induced liver injury.Methods:A xenografted colorectal cancer mouse model was established with MC38 cells.Mice were given ox-aliplatin(6 mg/kg/week)for 5 weeks to mimic oxaliplatin-induced liver injury in vivo.LX-2 human hepatic stellate cell s(HSCs)were employed for in vitro studies.Serological tests,hematoxylin and eosin staining,oil red O staining and trans-mission electron microscopy were used for histopathological examinations.Real-time PCR,western blotting,immuno-fluorescence and immunohistochemical staining were used to determine Cx43 mRNA or protein levels.Flow cytometry was used to assay reactive oxygen species(ROS)and mito-chondrial membrane.Short hairpin RNA targeting Cx43 was lentivirally transduced in LX-2 cells.Ultra-high performance liquid chromatography-tandem mass spectrometry was used to determine MgIG and metabolite concentration.Results:MgIG(40 mg/kg/day)treatment significantly reduced se-rum aspartate transaminase(AST)and alanine transami-nase(ALT)levels in the mouse model,and alleviated liver pathological changes,including necrosis,sinusoidal expan-sion,mitochondrial damage,and fibrosis.MgIG reduced the abnormal expression of Cx43 in the mitochondria and nuclei of HSCs.MgIG inhibited the activation of HSCs via reducing ROS generation,mitochondrial dysfunction,and N-cadherin transcription.MgIG’s inhibition of HSCs activation was abol-ished after knockdown of Cx43 in LX-2 cells.Conclusions:Cx43 mediated MgIG’s hepatoprotective effects against ox-aliplatin-induced toxicity.
基金Supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)SJZZ15_0119
文摘OBJECTIVE: To assess the efficacy and safety of Aidi injection plus transarterial chemoembolization(TACE) in patients with primary hepatic carcinoma.METHODS: A comprehensive research of seven electronic databases was performed for comparative studies evaluating Aidi injection combined with TACE for primary hepatic carcinoma until September 2016. Two authors independently extracted data and assessed the methodological quality of the included trials using the Cochrane risk of bias tool from the Cochrane Handbook version 5.1.0. Data was synthesized by using Rev Man 5.3 software.RESULTS: Forty-nine studies involving 3435 patients met the inclusion criteria, most of which were low methodological quality. Compared with TACE alone, Aidi injection plus TACE can significantly improve the efficiency rate [RR = 1.33, 95% CI(1.24, 1.43), P < 0.000 01], clinical beneficial rate[RR = 1.25, 95% CI(1.17, 1.33), P < 0.000 01], survival rate [6 months, RR = 1.19, 95% CI(1.09, 1.29), P <0.0001], 12 months, [RR = 1.37, 95% CI(1.24, 1.52),P < 0.000 01], 18 months, [RR = 2.00, 95% CI(1.26,3.20), P < 0.004], 24 months, [RR = 1.44, 95% CI(1.22, 1.70), P < 0.0001], 36 months, [RR = 1.50, 95%CI(1.07, 2.11), P = 0.02 < 0.05], quality of life [RR =1.84, 95% CI(1.64, 2.05), P < 0.000 01] and immune function [CD3+, MD = 11.12, 95% CI(7.93, 14.30),P < 0.000 01], CD4 +, [MD = 10.37, 95% CI(7.29,13.45), P < 0.000 01], CD4+/CD8+, [MD = 0.30, 95%CI(0.07, 0.53), P = 0.01 < 0.05], NK, [MD = 7.49, 95%CI(6.64, 8.34), P < 0.000 01]. A significant improvement was also found in improvement of symptoms[RR = 1.64, 95%CI(1.38, 1.94), P < 0.000 01], leukopenia [RR = 0.60, 95% CI(0.54, 0.66), P < 0.000 01],thrombocytopenia [RR = 0.46, 95% CI(0.34, 0.61),P < 0.000 01], nausea and vomiting incidence [RR =0.66, 95% CI(0.54, 0.81), P < 0.0001), liver damage rate [RR = 0.57, 95% CI(0.42, 0.77), P = 0.0003 <0.05), and kidney damage rate [RR = 0.18, 95% CI(0.05, 0.68), P = 0.01 < 0.05].CONCLUSION: The results suggested that Aidi injection plus TACE significantly improve the clinical effect of TACE, and reduce the incidence of adverse events. However, rigorous multicenter trials with larger size are warranted to further confirm the findings.
基金supported by National Natural Science Foundation of China(82370872,82070891,82160891,82174319,82370235)National Natural Science Foundation of Guangdong(2023A1515012618)+5 种基金Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-C-202208)Key projects of Guangdong Provincial Department of Education(2021ZDZX2010)Basic and Applied Basic Research Project of Guangzhou(202201011501,202201010134,202201011240)the Natural Science Foundation of Jiangsu Province(BK20211055)the Jiangsu Qing Lan Project,China Postdoctoral Science Foundation(2022M710120)Guangdong Provincial Key Laboratory of TCM Pathogenesis and Prescriptions of Heart and Spleen Diseases(2022B1212010012).
文摘A lasting imbalance between fatty acid synthesis and consumption leads to non-alcoholic fatty liver disease(NAFLD),coupled with hepatitis and insulin resistance.Yet the details of the underlying mechanisms are not fully understood.Here,we unraveled that the expression of the transcription factor Zbtb18 is markedly decreased in the livers of both patients and murine models of NAFLD.Hepatic Zbtb18 knockout promoted NAFLD features like impaired energy expenditure and fatty acid oxidation(FAO),and induced insulin resistance.Conversely,hepatic Zbtb18 overexpression alleviated hepato-steatosis,insulin resistance,and hyperglycemia in mice fed on a high-fat diet(HFD)or in diabetic mice.Notably,in vitro and in vivo mechanistic studies revealed that Zbtb18 transcriptional activation of Farnesoid X receptor(FXR)mediated FAO and Clathrin Heavy Chain(CLTC)protein hinders NLRP3 inflammasome activity.This key mechanism by which hepatocyte’s Zbtb18 expression alleviates NAFLD and consequent liver fibrosis was further verified by FXR’s deletion and forced expression in mice and cultured mouse primary hepatocytes(MPHs).Moreover,CLTC deletion significantly abrogated the hepatic Zbtb18 overexpression-driven inhibition of NLRP3 inflammasome activity in macrophages.Altogether,Zbtb18 transcriptionally activates the FXR-mediated FAO and CLTC expression,which inhibits NLRP3 inflammasome’s activity alleviating inflammatory stress and insulin resistance,representing an attractive remedy for hepatic steatosis and fibrosis.
基金This study was funded by National Natural Science Foundation of China(Nos.21937005 and 81974504)Natural Science Foundation of Jiangsu Province(No.BK 20191251,China)+1 种基金the Fundamental Research Funds for the Central Universities(China)National Key R&D·Program of China(No.2017YFA0506000).
文摘Chemoresistance remains a major obstacle to successful treatment of triple negative breast cancer(TNBC).Identification of druggable vulnerabilities is an important aim for TNBC therapy.Here,we report that SERCA2 expression correlates with TNBC progression in human patients,which promotes TNBC cell proliferation,migration and chemoresistance.Mechanistically,SERCA2 interacts with LC3B via LIR motif,facilitating WIPI2-independent autophagosome formation to induce autophagy.Autophagy-mediated SERCA2 degradation induces SERCA2 transactivation through a Ca^(2+)/CaMKK/CREB-1 feedback.Moreover,we found that SERCA2-targeting small molecule RL71 enhances SERCA2-LC3B interaction and induces excessive autophagic cell death.The increase in SERCA2 expression predisposes TNBC cells to RL71-induced autophagic cell death in vitro and in vivo.This study elucidates a mechanism by which TNBC cells maintain their high autophagy activity to induce chemoresistance,and suggests increased SERCA2 expression as a druggable vulnerability for TNBC.
