Objective: The aim of this work was to evaluate anti-tumor effects of mDRA-6 plus nimesulide on a human hepatocellular cancer cell line, SMMC-7721, and study the main mechanisms. Methods: The DR5 receptor of SMMC-7721...Objective: The aim of this work was to evaluate anti-tumor effects of mDRA-6 plus nimesulide on a human hepatocellular cancer cell line, SMMC-7721, and study the main mechanisms. Methods: The DR5 receptor of SMMC-7721 cells was detected by flow cytometry (FCM). For further experimental application, SMMC-7721 cells were treated with proper dose of mDRA-6, nimesulide, or mDRA-6 plus 200 μmol/L nimesulide; untreated SMMC-7721 cells were comparably set as control. Cytotoxicity was tested by MTT assay; cell morphology was examined using Hoechst 33258 staining; and apoptosis was determined by FCM. Results: The positive rate of DR5 on SMMC-7721 was 95.0%. Either mDRA-6 or nimesulide alone induces SMMC-7721 cell death in a dose-dependent manner. Treatment of 1,600 ng/mL mDRA-6 for 12h led to a cell-death rate of 35.0%, while an increased cell-death rate (91.1%) was found under the same condition of mDRA-6 treatment supple- mented with 200 μmol/L nimesulide. Hoechst 33258 and Annexin V/PI staining confirmed apoptosis as the main cause of this anti-tumor response. Conclusion: Both mDRA-6 and nimesulide can induce apoptosis of SMMC-7721 cells, and they have synergistic anti-tumor activities against SMMC-7721.展开更多
Building self-assembly nanostructures is an important way to overcome the limitations of paclitaxel in tumor therapy.However,this strategy is also faced with challenges,such as difficulties in efficient release and th...Building self-assembly nanostructures is an important way to overcome the limitations of paclitaxel in tumor therapy.However,this strategy is also faced with challenges,such as difficulties in efficient release and the potential for drug resistance.Herein,we developed a near-infrared light-activatable melanized paclitaxel self-assembly nanoparticles for synergistic anti-tumor therapy.In this strategy,paclitaxel dimer prodrugs were synthesized and paclitaxel nanoparticles were obtained through self-assembly.Finally,the paclitaxel dimer nanoparticles were capped with polydopamine(PDA,melanoidin)and human serum albumin(HSA).The disulfide bonds in paclitaxel dimeric prodrug specifically respond to high concentrations of glutathione(GSH)and reactive oxygen species(ROS)in tumor cells.PDA enhances the biocompatibility of the drug molecules and imparts near-infrared photothermal conversion capability to the nano-self-assemblies.Both the in vitro and in vivo experiments demonstrated that this paclitaxel nanoprodrug exhibited enhanced tumor therapeutic efficacy under near-infrared light irradiation.展开更多
Objective: To explore the specific pharmacological molecular mechanisms of Laoke Formula(LK)on treating advanced non-small cell lung cancer(NSCLC) based on clinical application, network pharmacology and experimental v...Objective: To explore the specific pharmacological molecular mechanisms of Laoke Formula(LK)on treating advanced non-small cell lung cancer(NSCLC) based on clinical application, network pharmacology and experimental validation. Methods: Kaplan-Meier method and Cox regression analysis were used to evaluate the survival benefit of Chinese medicine(CM) treatment in 296 patients with NSCLC in Tianjin Medical University Cancer Institute and Hospital from January 2011 to December 2015. The compounds of LK were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and the corresponding targets were performed from Swiss Target Prediction. NSCLC-related targets were obtained from Therapeutic Target Database and Comparative Toxicogenomics Database. Key compounds and targets were identified from the compound-target-disease network and protein-protein interaction(PPI) network analysis, respectively. Kyoto Encyclopedia of Genes and Genomes(KEGG) and Gene Ontology(GO) enrichment analysis were used to predict the potential signaling pathways involved in the treatment of advanced NSCLC with LK. The binding affinities between key ingredients and targets were further verified using molecular docking. Finally, A549 cell proliferation and migration assay were used to evaluate the antitumor activity of LK. Western blot was used to further verify the expression of key target proteins related to the predicted pathways. Results: Kaplan-Meier survival analysis showed that the overall survival of the CM group was longer than that of the non-CM group(36 months vs.26 months), and COX regression analysis showed that LK treatment was an independent favorable prognostic factor(P=0.027). Next, 97 components and 86 potential targets were included in the network pharmacology, KEGG and GO analyses, and the results indicated that LK was associated with proliferation and apoptosis. Moreover,molecular docking revealed a good binding affinity between the key ingredients and targets. In vitro, A549 cell proliferation and migration assay showed that the biological inhibition effect was more obvious with the increase of LK concentration(P<0.05). And decreased expressions of nuclear factor κB1(NF-κB1), epidermal growth factor receptor(EGFR) and AKT serine/threonine kinase 1(AKT1) and increased expression of p53(P<0.05)indicated the inhibitory effect of LK on NSCLC by Western blot. Conclusion: LK inhibits NSCLC by inhibiting EGFR/phosphoinositide 3-kinase(PI3K)/AKT signaling pathway, NFκB signaling pathway and inducing apoptosis, which provides evidence for the therapeutic mechanism of LK to increase overall survival in NSCLC patients.展开更多
Direct administration of drugs and genes to the lungs by pulmonary delivery offers a potential effective therapy for lung cancers.In this study,combined doxorubicin（DOX） and Bcl2 siRNA was employed for cancer therap...Direct administration of drugs and genes to the lungs by pulmonary delivery offers a potential effective therapy for lung cancers.In this study,combined doxorubicin（DOX） and Bcl2 siRNA was employed for cancer therapy using polyethylenimine（PEI） as the carrier of Bcl2 siRNA.Most of the DOX and siRNA possessed high cellular uptake efficiency in B16F10 cells,which was proved by FCM and CLSM analysis.Real-time PCR showed that PEI/Bcl2 siRNA exhibited high gene silencing efficiency with 70%Bcl2 mRNA being knocked down.The combination of DOX and siRNA could enhance the cell proliferation inhibition and the cell apoptosis against B16F10 cells compared to free DOX or PEI/Bcl2 siRNA.Furthermore,the biodistribution of DOX and siRNA via pulmonary administration was studied in mice with B16F10 metastatic lung cancer.The results showed that most of the DOX and siRNA were accumulated in lungs and lasted at least for 3 days,which suggested that combined DOX and siRNA by pulmonary administration may have high anti-tumor effects for metastatic lung cancer treatment in vivo.展开更多
Chronic heart failure(CHF)is a severe public health problem with increasing morbidity and mortality,any treatment targeting a single session is insufficient to tackle this.CHF is characterized by reduced cardiac outpu...Chronic heart failure(CHF)is a severe public health problem with increasing morbidity and mortality,any treatment targeting a single session is insufficient to tackle this.CHF is characterized by reduced cardiac output resulting from neurohumoral dysregulation and cardiac remodeling,which might be related to oxidative stress,inflammation,endoplasmic reticulum stress,apoptosis,autophagy,mitochondrial function,and angiogenesis.These molecular mechanisms interact with each other through crosstalk.Historically,Chinese medicinal herbs have been widely applied in the treatment of CHF,and therapeutic effects of Chinese medicinal herbs and their ingredients have been scientifically confirmed over the past decades.Traditional Chinese medicine(TCM)with multiple components can confront the different pathogenesis of CHF through multiple targets.This review analyzes commonly used TCM patent drugs and TCM decoctions that are applicable to different stages of CHF based on clinical trials.Diverse bioactive ingredients in Chinese medicinal herbs have been found to treat CHF via multiple molecular mechanisms.This review comprehensively covers the key works on the effects and underlying mechanisms of TCM,herbal ingredients and synergistic effects of constituent compatibility in treating CHF,providing additional ideas to address this threat.展开更多
Prodrug self-delivery carriers with targeting that specifically responded to tumor microenvironments have good potential to improve the application dilemma of approved clinical therapeutic drugs(systemic distribution ...Prodrug self-delivery carriers with targeting that specifically responded to tumor microenvironments have good potential to improve the application dilemma of approved clinical therapeutic drugs(systemic distribution and side effects).It's noted the conversion of gemcitabine(GEM)to inactive ingredients under the action of cytidine deaminase(CDA)during metabolism in vivo limits its clinical effect.A high level of reactive oxygen species(ROS)results in a high level of oxidative stress in tumor cells,which changes the expression of CDA and optimizes the metabolism of GEM in vivo and overcome drug resistance.In this study,the ROS responsive and ROS self-supplied prodrug of artemisia(ART)-thioacetal bond(TK)-GEM was synthesized and self-vectors based on ART-TK-GEM(TK@FA NPs)was prepared by using nano precipitation.ROS responsive characteristics ensure specific release of prodrugs in tumor cells with high level of ROS thereby reducing side effects on normal cells and tissues.The endogenous ROS and newly generated ROS by ART can reduce the expression of CDA and optimizes the metabolism of GEM,and the accumulated ROS can also induce apoptosis of tumor cells,realizing synergistic anti-tumor effect of chemical drugs and traditional Chinese medicines.This paper proposes a simple method by using clinically approved drugs to improve the insufficient effect of existing chemotherapy and overcome resistance,which has potential to appropriately shorten the drug development cycle and accelerate the clinical investigation of drugs.展开更多
基金Supported by a grant from the National Nature Sciences Foundation of China (No. 30571697).
文摘Objective: The aim of this work was to evaluate anti-tumor effects of mDRA-6 plus nimesulide on a human hepatocellular cancer cell line, SMMC-7721, and study the main mechanisms. Methods: The DR5 receptor of SMMC-7721 cells was detected by flow cytometry (FCM). For further experimental application, SMMC-7721 cells were treated with proper dose of mDRA-6, nimesulide, or mDRA-6 plus 200 μmol/L nimesulide; untreated SMMC-7721 cells were comparably set as control. Cytotoxicity was tested by MTT assay; cell morphology was examined using Hoechst 33258 staining; and apoptosis was determined by FCM. Results: The positive rate of DR5 on SMMC-7721 was 95.0%. Either mDRA-6 or nimesulide alone induces SMMC-7721 cell death in a dose-dependent manner. Treatment of 1,600 ng/mL mDRA-6 for 12h led to a cell-death rate of 35.0%, while an increased cell-death rate (91.1%) was found under the same condition of mDRA-6 treatment supple- mented with 200 μmol/L nimesulide. Hoechst 33258 and Annexin V/PI staining confirmed apoptosis as the main cause of this anti-tumor response. Conclusion: Both mDRA-6 and nimesulide can induce apoptosis of SMMC-7721 cells, and they have synergistic anti-tumor activities against SMMC-7721.
基金financially supported by National Natural Science Foundation of China(NSFC)(22007083)Zhejiang Provincial Innovation Center of Advanced Textile Technology and the Fundamental Research Funds of Shaoxing Keqiao Research Institute of Zhejiang Sci-Tech University(KYY2022004C)the Fundamental Research Funds of Shengzhou Innovation Research Institute of Zhejiang SciTech University(SYY2023B000004)
文摘Building self-assembly nanostructures is an important way to overcome the limitations of paclitaxel in tumor therapy.However,this strategy is also faced with challenges,such as difficulties in efficient release and the potential for drug resistance.Herein,we developed a near-infrared light-activatable melanized paclitaxel self-assembly nanoparticles for synergistic anti-tumor therapy.In this strategy,paclitaxel dimer prodrugs were synthesized and paclitaxel nanoparticles were obtained through self-assembly.Finally,the paclitaxel dimer nanoparticles were capped with polydopamine(PDA,melanoidin)and human serum albumin(HSA).The disulfide bonds in paclitaxel dimeric prodrug specifically respond to high concentrations of glutathione(GSH)and reactive oxygen species(ROS)in tumor cells.PDA enhances the biocompatibility of the drug molecules and imparts near-infrared photothermal conversion capability to the nano-self-assemblies.Both the in vitro and in vivo experiments demonstrated that this paclitaxel nanoprodrug exhibited enhanced tumor therapeutic efficacy under near-infrared light irradiation.
基金Supported by National Natural Science Foundation of China(Nos.82174103 and 81473441)。
文摘Objective: To explore the specific pharmacological molecular mechanisms of Laoke Formula(LK)on treating advanced non-small cell lung cancer(NSCLC) based on clinical application, network pharmacology and experimental validation. Methods: Kaplan-Meier method and Cox regression analysis were used to evaluate the survival benefit of Chinese medicine(CM) treatment in 296 patients with NSCLC in Tianjin Medical University Cancer Institute and Hospital from January 2011 to December 2015. The compounds of LK were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and the corresponding targets were performed from Swiss Target Prediction. NSCLC-related targets were obtained from Therapeutic Target Database and Comparative Toxicogenomics Database. Key compounds and targets were identified from the compound-target-disease network and protein-protein interaction(PPI) network analysis, respectively. Kyoto Encyclopedia of Genes and Genomes(KEGG) and Gene Ontology(GO) enrichment analysis were used to predict the potential signaling pathways involved in the treatment of advanced NSCLC with LK. The binding affinities between key ingredients and targets were further verified using molecular docking. Finally, A549 cell proliferation and migration assay were used to evaluate the antitumor activity of LK. Western blot was used to further verify the expression of key target proteins related to the predicted pathways. Results: Kaplan-Meier survival analysis showed that the overall survival of the CM group was longer than that of the non-CM group(36 months vs.26 months), and COX regression analysis showed that LK treatment was an independent favorable prognostic factor(P=0.027). Next, 97 components and 86 potential targets were included in the network pharmacology, KEGG and GO analyses, and the results indicated that LK was associated with proliferation and apoptosis. Moreover,molecular docking revealed a good binding affinity between the key ingredients and targets. In vitro, A549 cell proliferation and migration assay showed that the biological inhibition effect was more obvious with the increase of LK concentration(P<0.05). And decreased expressions of nuclear factor κB1(NF-κB1), epidermal growth factor receptor(EGFR) and AKT serine/threonine kinase 1(AKT1) and increased expression of p53(P<0.05)indicated the inhibitory effect of LK on NSCLC by Western blot. Conclusion: LK inhibits NSCLC by inhibiting EGFR/phosphoinositide 3-kinase(PI3K)/AKT signaling pathway, NFκB signaling pathway and inducing apoptosis, which provides evidence for the therapeutic mechanism of LK to increase overall survival in NSCLC patients.
基金the National Natural Science Foundationof China(Nos.51503200,21474104,5123300451520105004 and 51390484)Jilin Province Science and Technology Development Program(No.20160204032GX)the National Program for Support of Top-notch Young Professionals for financial support
文摘Direct administration of drugs and genes to the lungs by pulmonary delivery offers a potential effective therapy for lung cancers.In this study,combined doxorubicin（DOX） and Bcl2 siRNA was employed for cancer therapy using polyethylenimine（PEI） as the carrier of Bcl2 siRNA.Most of the DOX and siRNA possessed high cellular uptake efficiency in B16F10 cells,which was proved by FCM and CLSM analysis.Real-time PCR showed that PEI/Bcl2 siRNA exhibited high gene silencing efficiency with 70%Bcl2 mRNA being knocked down.The combination of DOX and siRNA could enhance the cell proliferation inhibition and the cell apoptosis against B16F10 cells compared to free DOX or PEI/Bcl2 siRNA.Furthermore,the biodistribution of DOX and siRNA via pulmonary administration was studied in mice with B16F10 metastatic lung cancer.The results showed that most of the DOX and siRNA were accumulated in lungs and lasted at least for 3 days,which suggested that combined DOX and siRNA by pulmonary administration may have high anti-tumor effects for metastatic lung cancer treatment in vivo.
基金the National Key Research&Development Program of China(Grant Nos.2017YFC1700400,2017YFC1700403)National Natural Science Foundation of China(NNSFC+1 种基金Grant Nos.82073978,81725024,and 82104441)Beijing Natural Science Foundation(Grant No.JQ18026,China)。
文摘Chronic heart failure(CHF)is a severe public health problem with increasing morbidity and mortality,any treatment targeting a single session is insufficient to tackle this.CHF is characterized by reduced cardiac output resulting from neurohumoral dysregulation and cardiac remodeling,which might be related to oxidative stress,inflammation,endoplasmic reticulum stress,apoptosis,autophagy,mitochondrial function,and angiogenesis.These molecular mechanisms interact with each other through crosstalk.Historically,Chinese medicinal herbs have been widely applied in the treatment of CHF,and therapeutic effects of Chinese medicinal herbs and their ingredients have been scientifically confirmed over the past decades.Traditional Chinese medicine(TCM)with multiple components can confront the different pathogenesis of CHF through multiple targets.This review analyzes commonly used TCM patent drugs and TCM decoctions that are applicable to different stages of CHF based on clinical trials.Diverse bioactive ingredients in Chinese medicinal herbs have been found to treat CHF via multiple molecular mechanisms.This review comprehensively covers the key works on the effects and underlying mechanisms of TCM,herbal ingredients and synergistic effects of constituent compatibility in treating CHF,providing additional ideas to address this threat.
基金financial support from Guangdong Nature Resource Center(GDNRC,No.(2020)037)Natural Science Foundation of Guangdong Province(Nos.22019A1515011498,2019A1515011619)。
文摘Prodrug self-delivery carriers with targeting that specifically responded to tumor microenvironments have good potential to improve the application dilemma of approved clinical therapeutic drugs(systemic distribution and side effects).It's noted the conversion of gemcitabine(GEM)to inactive ingredients under the action of cytidine deaminase(CDA)during metabolism in vivo limits its clinical effect.A high level of reactive oxygen species(ROS)results in a high level of oxidative stress in tumor cells,which changes the expression of CDA and optimizes the metabolism of GEM in vivo and overcome drug resistance.In this study,the ROS responsive and ROS self-supplied prodrug of artemisia(ART)-thioacetal bond(TK)-GEM was synthesized and self-vectors based on ART-TK-GEM(TK@FA NPs)was prepared by using nano precipitation.ROS responsive characteristics ensure specific release of prodrugs in tumor cells with high level of ROS thereby reducing side effects on normal cells and tissues.The endogenous ROS and newly generated ROS by ART can reduce the expression of CDA and optimizes the metabolism of GEM,and the accumulated ROS can also induce apoptosis of tumor cells,realizing synergistic anti-tumor effect of chemical drugs and traditional Chinese medicines.This paper proposes a simple method by using clinically approved drugs to improve the insufficient effect of existing chemotherapy and overcome resistance,which has potential to appropriately shorten the drug development cycle and accelerate the clinical investigation of drugs.
