Background:Liqi Huoxue dripping pill(LQHXDP),a traditional Chinese drug for coronary heart disease,has a protective effect on the heart of rats with myocardial ischemia-reperfusion injury(MIRI)in previous studies;howe...Background:Liqi Huoxue dripping pill(LQHXDP),a traditional Chinese drug for coronary heart disease,has a protective effect on the heart of rats with myocardial ischemia-reperfusion injury(MIRI)in previous studies;however,its mechanism of action remains unclear.The purpose of this study was to investigate the protective mechanism of LQHXDP on MIRI in rats and its relationship with the PI3K/Akt signaling pathway.Methods:In this study,Sprague-Dawley rats were pre-infused with LQHXDP(175 mg/kg/d)for 10 days.PI3K inhibitor LY294002(0.3 mg/kg)was intravenously injected 15 minutes before ischemia.The rat model of MIRI was established by ligating the left anterior descending coronary artery.Subsequently,cardiac hemodynamics,serum myocardial injury markers,inflammatory factors,myocardial infarct size,antioxidant indexes,myocardial histopathology,and phosphorylation levels of key proteins of PI3K/Akt signaling pathway were assessed in rats.Results:LQHXDP was found to improve cardiac hemodynamic indexes,reduce serum creatine kinase MB isoenzyme activity and cardiac troponin and heart-type fatty acid binding protein levels,lower serum interleukin-1 beta,interleukin-6 and tumour necrosis factorαlevels,reduce the myocardial infarct size and enhance the antioxidant capacity of myocardial tissue in MIRI rats.Pathological analysis revealed that LQHXDP attenuated the extent of myocardial injury and protected mitochondria from damage in MIRI rats.Immunoblot analysis revealed that LQHXDP increased the expression levels of p-Akt and p-GSK-3βin MIRI rat cardiomyocytes.PI3K inhibitor LY294002 could impair these effects of LQHXDP.Conclusion:LQHXDP attenuated myocardial injury,attenuated oxidative stress injury and reduced inflammatory response in MIRI rats,and its protective effects were mediated by activating of PI3K/Akt/GSK-3βsignaling pathway.展开更多
Objective:Physical exercise,a common non-drug intervention,is an important strategy in cancer treatment,including hepatocellular carcinoma(HCC).However,the mechanism remains largely unknown.Due to the importance of hy...Objective:Physical exercise,a common non-drug intervention,is an important strategy in cancer treatment,including hepatocellular carcinoma(HCC).However,the mechanism remains largely unknown.Due to the importance of hypoxia and cancer stemness in the development of HCC,the present study investigated whether the anti-HCC effect of physical exercise is related to its suppression on hypoxia and cancer stemness.Methods:A physical exercise intervention of swimming(30 min/d,5 d/week,for 4 weeks)was administered to BALB/c nude mice bearing subcutaneous human HCC tumor.The anti-HCC effect of swimming was assessed in vivo by tumor weight monitoring,hematoxylin and eosin(HE)staining,and immunohistochemistry(IHC)detection of proliferating cell nuclear antigen(PCNA)and Ki67.The expression of stemness transcription factors,including Nanog homeobox(NANOG),octamer-binding transcription factor 4(OCT-4),v-Myc avian myelocytomatosis viral oncogene homolog(C-MYC)and hypoxia-inducible factor-1a(HIF-1a),was detected using real-time reverse transcription polymerase chain reaction.A hypoxia probe was used to explore the intratumoral hypoxia status.Western blot was used to detect the expression of HIF-1a and proteins related to protein kinase B(Akt)/glycogen synthase kinase-3β(GSK-3β)/β-catenin signaling pathway.The IHC analysis of platelet endothelial cell adhesion molecule-1(CD31),and the immunofluorescence co-location of CD31 and desmin were used to analyze tumor blood perfusion.SMMC-7721 cells were treated with nude mice serum.The inhibition effect on cancer stemness in vitro was detected using suspension sphere experiments and the expression of stemness transcription factors.The hypoxia status was inferred by measuring the protein and mRNA levels of HIF-1a.Further,the expression of proteins related to Akt/GSK-3β/β-catenin signaling pathway was detected.Results:Swimming significantly reduced the body weight and tumor weight in nude mice bearing HCC tumor.HE staining and IHC results showed a lower necrotic area ratio as well as fewer PCNA or Ki67 positive cells in mice receiving the swimming intervention.Swimming potently alleviated the intratumoral hypoxia,attenuated the cancer stemness,and inhibited the Akt/GSK-3β/β-catenin signaling pathway.Additionally,the desmin+/CD31+ratio,rather than the number of CD31+vessels,was significantly increased in swimming-treated mice.In vitro experiments showed that treating cells with the serum from the swimming intervention mice significantly reduced the formation of SMMC-7721 cell suspension sphere,as well as the m RNA expression level of stemness transcription factors.Consistent with the in vivo results,HIF-1a and Akt/GSK-3β/β-catenin signaling pathway were also inhibited in cells treated with serum from swimming group.Conclusion:Swimming alleviated hypoxia and attenuated cancer stemness in HCC,through suppression of the Akt/GSK-3β/β-catenin signaling pathway.The alleviation of intratumoral hypoxia was related to the increase in blood perfusion in the tumor.展开更多
Dihydromyricetin(DHM),as a bioactive flavanonol compound,is mainly found in“Tengcha”(Ampelopsis grossedentata)cultivated in south of China.This study aimed to investigate the anti-hyperglycemic and antidyslipidemic ...Dihydromyricetin(DHM),as a bioactive flavanonol compound,is mainly found in“Tengcha”(Ampelopsis grossedentata)cultivated in south of China.This study aimed to investigate the anti-hyperglycemic and antidyslipidemic activities of DHM using type 2 diabetes mellitus(T2D)rats,which was induced by feeding with high fat and fructose diet for 42 days and intraperitoneal administration of streptozocin.Forty-eight freshlyweaned rats were randomly assigned into the negative control(Blank),low dose(100 mg/kg),medium dose(200 mg/kg),high dose(400 mg/kg),and positive(40 mg/kg,met)groups.Fasting blood glucose and body weight were measured at weekly interval.Oral glucose tolerance tests were performed on days 42.The results revealed that DHM possessed significant antihyperglycaemic and antihyperinsulinemic effects.Moreover,after the DHM treatment,p-Akt and p-AMPK expression was upregulated,and glycogen synthase kinase-3β(GSK-3β)expression was downregulated,indicating that the potential anti-diabetic mechanism of DHM might be due to the regulation of the AMPK/Akt/GSK-3βsignaling pathway.展开更多
Ventricular hypertrophy is a powerful and independent predictor of cardiovascular morbid events. The vascular properties of low-dose acetyl salicylic acid （aspirin） provide cardiovascular benefits through the irreve...Ventricular hypertrophy is a powerful and independent predictor of cardiovascular morbid events. The vascular properties of low-dose acetyl salicylic acid （aspirin） provide cardiovascular benefits through the irreversible inhibition of platelet cyclooxygenase 1; however, the possible anti-hypertrophic properties and potential mechanism of aspirin have not been investigated in detail. In this study, healthy wild-type male mice were randomly divided into three groups and subjected to transverse aortic constriction （TAC） or sham operation. The TAC-operated mice were treated with the human equivalent of low-dose aspirin （10 mg·kg^-1· d^-1）; the remaining mice received an equal amount of phosphate buffered saline with 0.65% ethanol, which was used as a vehicle. A cardiomyocyte hypertrophy model induced by angiotensin II （10 nmol· L^-1） was treated with the human equivalent of low （10 or 100μmol·L^-1） and high （1000μmol·L^-1） aspirin concentrations in plasma. Changes in the cardiac structure and function were assessed through echocardiography and transmission electron microscopy. Gene expression was determined through RT-PCR and western blot analysis. Results indicated that aspirin treatment abrogated the increased thickness of the left ventricular anterior and posterior walls, the swelling of mitochondria, and the increased surface area in in vivo and in vitro hypertrophy models. Aspirin also normalized the upregulated hypertrophic biomarkers, p-myosin heavy chain （IS-MHC）, atrial natriuretic peptide （ANP）, and b-type natriuretic peptide （BNP）. Aspirin efficiently reversed the upregulation of β-catenin and P-Akt expression and the TAC- or ANG II-induced downregulation of GSK-3~. Therefore, low-dose aspirin possesses significant anti-hypertrophic properties at clinically relevant concentrations for anti-thrombotic therapy. The downregulation of β-catenin and Akt may be the underlying signaling mechanism of the effects of aspirin.展开更多
Colorectal cancer(CRC)represents the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide.The modern concept of cancer biology indicates that cancer is formed of a small populati...Colorectal cancer(CRC)represents the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide.The modern concept of cancer biology indicates that cancer is formed of a small population of cells called cancer stem cells(CSCs),which present both pluripotency and self-renewal properties.These cells are considered responsible for the progression of the disease,recurrence and tumor resistance.Interestingly,some cell signaling pathways participate in CRC survival,proliferation,and selfrenewal properties,and most of them are dysregulated in CSCs,including the Wingless(Wnt)/β-catenin,Notch,Hedgehog,nuclear factor kappa B(NF-κB),Janus kinase/signal transducer and activator of transcription(JAK/STAT),peroxisome proliferator-activated receptor(PPAR),phosphatidyl-inositol-3-kinase/Akt/mechanistic target of rapamycin(PI3K/Akt/mTOR),and transforming growth factor-β(TGF-β)/Smad pathways.In this review,we summarize the strategies for eradicating CRC stem cells by modulating these dysregulated pathways,which will contribute to the study of potential therapeutic schemes,combining conventional drugs with CSC-targeting drugs,and allowing better cure rates in anti-CRC therapy.展开更多
This study investigated the specific mechanism of knockdown of neuropeptide Y(NPY) in reducing obesity-induced insulin resistance in the white adipose tissue. Adeno-associated virus(AAV)-mediated RNAi was utilized to ...This study investigated the specific mechanism of knockdown of neuropeptide Y(NPY) in reducing obesity-induced insulin resistance in the white adipose tissue. Adeno-associated virus(AAV)-mediated RNAi was utilized to downregulate NPY expression in rats fed either regular chow or high fat diet. By investigating the differences in rat body weight and food intake, we assessed the effect of knockdown of NPY expression on insulin sensitivity and β-cell proliferation. Glucose consumption and 2-[3 H]DG uptake in 3 T3-L1 adipocytes were assessed to determine the molecular mechanisms. The results showed that knockdown of NPY expression in the dorsomedial hypothalamus(DMH) reduced obesity-induced insulin resistance, increased glucose consumption, and decreased 2-[3 H]DG uptake in 3 T3-L1 adipocytes via the PI3 K/Akt/GSK-3β signaling pathways and the NPY Y5 receptor.展开更多
基金supported by National Natural Science Foundation of China(Grant No.81860873 and 81960864)the Scientific and Technological Projects of Guizhou Province(Qian Kehe Jichu(2016)1401)High-level Talents Project of Guizhou Province(GUTCM(ZQ2018005)).
文摘Background:Liqi Huoxue dripping pill(LQHXDP),a traditional Chinese drug for coronary heart disease,has a protective effect on the heart of rats with myocardial ischemia-reperfusion injury(MIRI)in previous studies;however,its mechanism of action remains unclear.The purpose of this study was to investigate the protective mechanism of LQHXDP on MIRI in rats and its relationship with the PI3K/Akt signaling pathway.Methods:In this study,Sprague-Dawley rats were pre-infused with LQHXDP(175 mg/kg/d)for 10 days.PI3K inhibitor LY294002(0.3 mg/kg)was intravenously injected 15 minutes before ischemia.The rat model of MIRI was established by ligating the left anterior descending coronary artery.Subsequently,cardiac hemodynamics,serum myocardial injury markers,inflammatory factors,myocardial infarct size,antioxidant indexes,myocardial histopathology,and phosphorylation levels of key proteins of PI3K/Akt signaling pathway were assessed in rats.Results:LQHXDP was found to improve cardiac hemodynamic indexes,reduce serum creatine kinase MB isoenzyme activity and cardiac troponin and heart-type fatty acid binding protein levels,lower serum interleukin-1 beta,interleukin-6 and tumour necrosis factorαlevels,reduce the myocardial infarct size and enhance the antioxidant capacity of myocardial tissue in MIRI rats.Pathological analysis revealed that LQHXDP attenuated the extent of myocardial injury and protected mitochondria from damage in MIRI rats.Immunoblot analysis revealed that LQHXDP increased the expression levels of p-Akt and p-GSK-3βin MIRI rat cardiomyocytes.PI3K inhibitor LY294002 could impair these effects of LQHXDP.Conclusion:LQHXDP attenuated myocardial injury,attenuated oxidative stress injury and reduced inflammatory response in MIRI rats,and its protective effects were mediated by activating of PI3K/Akt/GSK-3βsignaling pathway.
基金supported by the National Natural Science Foundation of China(No.82104977)Youth Start-up Foundation of Changhai Hospital(No.2019QNB05)。
文摘Objective:Physical exercise,a common non-drug intervention,is an important strategy in cancer treatment,including hepatocellular carcinoma(HCC).However,the mechanism remains largely unknown.Due to the importance of hypoxia and cancer stemness in the development of HCC,the present study investigated whether the anti-HCC effect of physical exercise is related to its suppression on hypoxia and cancer stemness.Methods:A physical exercise intervention of swimming(30 min/d,5 d/week,for 4 weeks)was administered to BALB/c nude mice bearing subcutaneous human HCC tumor.The anti-HCC effect of swimming was assessed in vivo by tumor weight monitoring,hematoxylin and eosin(HE)staining,and immunohistochemistry(IHC)detection of proliferating cell nuclear antigen(PCNA)and Ki67.The expression of stemness transcription factors,including Nanog homeobox(NANOG),octamer-binding transcription factor 4(OCT-4),v-Myc avian myelocytomatosis viral oncogene homolog(C-MYC)and hypoxia-inducible factor-1a(HIF-1a),was detected using real-time reverse transcription polymerase chain reaction.A hypoxia probe was used to explore the intratumoral hypoxia status.Western blot was used to detect the expression of HIF-1a and proteins related to protein kinase B(Akt)/glycogen synthase kinase-3β(GSK-3β)/β-catenin signaling pathway.The IHC analysis of platelet endothelial cell adhesion molecule-1(CD31),and the immunofluorescence co-location of CD31 and desmin were used to analyze tumor blood perfusion.SMMC-7721 cells were treated with nude mice serum.The inhibition effect on cancer stemness in vitro was detected using suspension sphere experiments and the expression of stemness transcription factors.The hypoxia status was inferred by measuring the protein and mRNA levels of HIF-1a.Further,the expression of proteins related to Akt/GSK-3β/β-catenin signaling pathway was detected.Results:Swimming significantly reduced the body weight and tumor weight in nude mice bearing HCC tumor.HE staining and IHC results showed a lower necrotic area ratio as well as fewer PCNA or Ki67 positive cells in mice receiving the swimming intervention.Swimming potently alleviated the intratumoral hypoxia,attenuated the cancer stemness,and inhibited the Akt/GSK-3β/β-catenin signaling pathway.Additionally,the desmin+/CD31+ratio,rather than the number of CD31+vessels,was significantly increased in swimming-treated mice.In vitro experiments showed that treating cells with the serum from the swimming intervention mice significantly reduced the formation of SMMC-7721 cell suspension sphere,as well as the m RNA expression level of stemness transcription factors.Consistent with the in vivo results,HIF-1a and Akt/GSK-3β/β-catenin signaling pathway were also inhibited in cells treated with serum from swimming group.Conclusion:Swimming alleviated hypoxia and attenuated cancer stemness in HCC,through suppression of the Akt/GSK-3β/β-catenin signaling pathway.The alleviation of intratumoral hypoxia was related to the increase in blood perfusion in the tumor.
基金the National Natural Science Foundation of China(NSFC,Grant No.31801459,31701520)Science and Technology General Projects of Fujian Province(2019J01393)Educational research project for young and middleaged teachers in Fujian Province(JT180116).
文摘Dihydromyricetin(DHM),as a bioactive flavanonol compound,is mainly found in“Tengcha”(Ampelopsis grossedentata)cultivated in south of China.This study aimed to investigate the anti-hyperglycemic and antidyslipidemic activities of DHM using type 2 diabetes mellitus(T2D)rats,which was induced by feeding with high fat and fructose diet for 42 days and intraperitoneal administration of streptozocin.Forty-eight freshlyweaned rats were randomly assigned into the negative control(Blank),low dose(100 mg/kg),medium dose(200 mg/kg),high dose(400 mg/kg),and positive(40 mg/kg,met)groups.Fasting blood glucose and body weight were measured at weekly interval.Oral glucose tolerance tests were performed on days 42.The results revealed that DHM possessed significant antihyperglycaemic and antihyperinsulinemic effects.Moreover,after the DHM treatment,p-Akt and p-AMPK expression was upregulated,and glycogen synthase kinase-3β(GSK-3β)expression was downregulated,indicating that the potential anti-diabetic mechanism of DHM might be due to the regulation of the AMPK/Akt/GSK-3βsignaling pathway.
基金Acknowledgements This work was supported by the Funds for Creative Research Groups （No. 81421063） and the Major Program of the National Natural Science Foundation of China （Nos. 81130088, 81230081, and 31450OO9）.
文摘Ventricular hypertrophy is a powerful and independent predictor of cardiovascular morbid events. The vascular properties of low-dose acetyl salicylic acid （aspirin） provide cardiovascular benefits through the irreversible inhibition of platelet cyclooxygenase 1; however, the possible anti-hypertrophic properties and potential mechanism of aspirin have not been investigated in detail. In this study, healthy wild-type male mice were randomly divided into three groups and subjected to transverse aortic constriction （TAC） or sham operation. The TAC-operated mice were treated with the human equivalent of low-dose aspirin （10 mg·kg^-1· d^-1）; the remaining mice received an equal amount of phosphate buffered saline with 0.65% ethanol, which was used as a vehicle. A cardiomyocyte hypertrophy model induced by angiotensin II （10 nmol· L^-1） was treated with the human equivalent of low （10 or 100μmol·L^-1） and high （1000μmol·L^-1） aspirin concentrations in plasma. Changes in the cardiac structure and function were assessed through echocardiography and transmission electron microscopy. Gene expression was determined through RT-PCR and western blot analysis. Results indicated that aspirin treatment abrogated the increased thickness of the left ventricular anterior and posterior walls, the swelling of mitochondria, and the increased surface area in in vivo and in vitro hypertrophy models. Aspirin also normalized the upregulated hypertrophic biomarkers, p-myosin heavy chain （IS-MHC）, atrial natriuretic peptide （ANP）, and b-type natriuretic peptide （BNP）. Aspirin efficiently reversed the upregulation of β-catenin and P-Akt expression and the TAC- or ANG II-induced downregulation of GSK-3~. Therefore, low-dose aspirin possesses significant anti-hypertrophic properties at clinically relevant concentrations for anti-thrombotic therapy. The downregulation of β-catenin and Akt may be the underlying signaling mechanism of the effects of aspirin.
基金Coordenação de Aperfeiçoamento de Pessoal de Nível Superior(CAPES,Brazil)Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq,Brazil)。
文摘Colorectal cancer(CRC)represents the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide.The modern concept of cancer biology indicates that cancer is formed of a small population of cells called cancer stem cells(CSCs),which present both pluripotency and self-renewal properties.These cells are considered responsible for the progression of the disease,recurrence and tumor resistance.Interestingly,some cell signaling pathways participate in CRC survival,proliferation,and selfrenewal properties,and most of them are dysregulated in CSCs,including the Wingless(Wnt)/β-catenin,Notch,Hedgehog,nuclear factor kappa B(NF-κB),Janus kinase/signal transducer and activator of transcription(JAK/STAT),peroxisome proliferator-activated receptor(PPAR),phosphatidyl-inositol-3-kinase/Akt/mechanistic target of rapamycin(PI3K/Akt/mTOR),and transforming growth factor-β(TGF-β)/Smad pathways.In this review,we summarize the strategies for eradicating CRC stem cells by modulating these dysregulated pathways,which will contribute to the study of potential therapeutic schemes,combining conventional drugs with CSC-targeting drugs,and allowing better cure rates in anti-CRC therapy.
基金Supported by the Zhengzhou Science and Technology Innovation Team Project(131PCXTD631)
文摘This study investigated the specific mechanism of knockdown of neuropeptide Y(NPY) in reducing obesity-induced insulin resistance in the white adipose tissue. Adeno-associated virus(AAV)-mediated RNAi was utilized to downregulate NPY expression in rats fed either regular chow or high fat diet. By investigating the differences in rat body weight and food intake, we assessed the effect of knockdown of NPY expression on insulin sensitivity and β-cell proliferation. Glucose consumption and 2-[3 H]DG uptake in 3 T3-L1 adipocytes were assessed to determine the molecular mechanisms. The results showed that knockdown of NPY expression in the dorsomedial hypothalamus(DMH) reduced obesity-induced insulin resistance, increased glucose consumption, and decreased 2-[3 H]DG uptake in 3 T3-L1 adipocytes via the PI3 K/Akt/GSK-3β signaling pathways and the NPY Y5 receptor.
