Type 2 diabetes mellitus(T2DM)is a complex metabolic disease threatening human health.We investigated the effects of Tegillarca granosa polysaccharide(TGP)and determined its potential mechanisms in a mouse model of T2...Type 2 diabetes mellitus(T2DM)is a complex metabolic disease threatening human health.We investigated the effects of Tegillarca granosa polysaccharide(TGP)and determined its potential mechanisms in a mouse model of T2DM established through a high-fat diet and streptozotocin.TGP(5.1×10^(3) Da)was composed of mannose,glucosamine,rhamnose,glucuronic acid,galactosamine,glucose,galactose,xylose,and fucose.It could significantly alleviate weight loss,reduce fasting blood glucose levels,reverse dyslipidemia,reduce liver damage from oxidative stress,and improve insulin sensitivity.RT-PCR and Western blotting indicated that TGP could activate the phosphatidylinositol-3-kinase/protein kinase B signaling pathway to regulate disorders in glucolipid metabolism and improve insulin resistance.TGP increased the abundance of Allobaculum,Akkermansia,and Bifidobacterium,restored the microbiota abundance in the intestinal tracts of mice with T2DM,and promoted short-chain fatty acid production.This study provides new insights into the antidiabetic effects of TGP and highlights its potential as a natural hypoglycemic nutraceutical.展开更多
Objective:To investigate the mechanism of JAK2/STAT3/SOCS1 signaling pathway in electroacupuncture of different acupoints on acute colitis rats.Methods:36 SPF SD rats were randomly divided into 6 groups,with 6 rats in...Objective:To investigate the mechanism of JAK2/STAT3/SOCS1 signaling pathway in electroacupuncture of different acupoints on acute colitis rats.Methods:36 SPF SD rats were randomly divided into 6 groups,with 6 rats in each group.The rat model of acute colitis was prepared by enema with glacial acetic acid solution.After the model was established,electroacupuncture was given to each acupoint group,with density wave,frequency 2Hz-50 Hz,intensity 2 mA,muscle tremor as the degree 20 min/time,1 time/day,for 3 consecutive days.Observe the general condition of rats;the pathological changes of colonic mucosa in rats were observed by HE method.The contents of serum interleukin-4(IL-4)and interleukin-8(IL-8)were detected by ELISA.Western blot and RT-PCR were used to detect the expression of JAK2,STAT3,SOCS1 protein and mRNA in rat colon tissue.Results:In contrast to the normal group,the overall condition of the model group was worse,the colonic mucosa was severely damaged,even necrotic,and the ulcer surface was obvious.The content of IL-4 in serum was obviously reduced,and the content of IL-8 was obviously go up(P<0.01).The protein content of JAK2,STAT3 and the expression of JAK2,STAT3 mRNA in colon tissue of rats were obviously go up,while the protein content of SOCS1 and the expression of SOCS1 mRNA were obviously reduced(P<0.01).In contrast to the model group,the general condition of rats in each acupoint group was significantly improved,the damage and necrosis of colonic mucosa and ulcer surface were obviously alleviated,the content of IL-4 in serum was obviously go up,and the content of IL-8 was significantly decreased(P<0.01).The protein content of JAK2,STAT3 and the expression of JAK2,STAT3 mRNA in colon tissue of rats were obviously reduced,while the protein content of SOCS1 and the expression of SOCS1 mRNA were obviously go up(P<0.05,P<0.01).Comparison of different acupoint groups,the colonic mucosal injury in the Zusanli group was significantly reduced,the content of serum IL-4 was significantly increased,and the content of IL-8 was significantly decreased(P<0.05,P<0.01).The protein content and mRNA expression of JAK2 and STAT3 in colon tissue were significantly down-regulated,while the protein content and mRNA expression of SOCS1 were significantly go up(P<0.05,P<0.01).Conclusion:Electroacupuncture at each acupoint can improve the damage of colonic mucosa and reduce the inflammatory response.The therapeutic effect of Zusanli(ST36)is better than that of Tianshu(ST25),Dachangshu(BL25)and Shangjuxu(ST37).The mechanism may be related to the regulation of JAK2/STAT3/SOCS1 signaling pathway related proteins and inflammatory cytokines IL-4 and IL-8.展开更多
Background:Oleanolic acid(OA),a pentacyclic triterpenoid exhibiting specific anti-cancer properties and highly effective antioxidant activity,was isolated from traditional Chinese medicinal herbs.Conversely,the OA that...Background:Oleanolic acid(OA),a pentacyclic triterpenoid exhibiting specific anti-cancer properties and highly effective antioxidant activity,was isolated from traditional Chinese medicinal herbs.Conversely,the OA that impacts colon cancer(CC)cells and its underlying mechanisms remain poorly understood.Methods:The cytotoxic effect of OA alone or OA-5-Fluorouracil(5-FU)combination on normal and CC cells was analyzed by methyl thiazolyl diphenyl-tetrazolium bromide(MTT).Then,the impact of OA on CC cell lines(LoVo and HT-29)proliferation and stemness were measured using colon formation and tumorsphere formation assays.Octamer-binding transcription factor 4(Oct4),Prominin-1(CD133),Nanog,and transcription factor SOX-2(SOX2)are cell stemness-related indicators whose expression was assessed usingfluorescence qPCR assay,Western blotting,and immunohistochemistry.The effect of OA on the proliferative potency of CC cells was evaluated using an in vivo model.Results:The stem-like characteristics and clone production of colon cancer cells were markedly reduced by OA alone or in combination with OA-5-FU.Moreover,OA increases the susceptibility of CC cells to 5-FU by blocking the cell stemness-related markers(CD133,Nanog,SOX2,and Oct4)expression levels both in vitro and in vivo,as well as by inactivating the activator of transcription 3(STAT3 signaling)and Janus kinase 2/signal transducer(JAK2).Conclusion:Thesefindings imply that oleanolic acid,both in vitro and in vivo,suppresses the JAK2/STAT3 pathway,which in turn reverses chemoresistance and decreases colon cancer cell stemness.Therefore,by reducing the recommended amount of 5-FU,this strategy may improve chemotherapeutic effectiveness and minimize undesired side effects.展开更多
The biomolecular mechanisms that regulate tooth root development and odontoblast differentiation are poorly understood.We found that Atp6i deficient mice(Atp6i^(−/−))arrested tooth root formation,indicated by truncate...The biomolecular mechanisms that regulate tooth root development and odontoblast differentiation are poorly understood.We found that Atp6i deficient mice(Atp6i^(−/−))arrested tooth root formation,indicated by truncated Hertwig’s epithelial root sheath(HERS)progression.Furthermore,Atp6i deficiency significantly reduced the proliferation and differentiation of radicular odontogenic cells responsible for root formation.Atp6i^(−/−)mice had largely decreased expression of odontoblast differentiation marker gene expression profiles(Col1a1,Nfic,Dspp,and Osx)in the alveolar bone.Atp6i^(−/−)mice sample RNA-seq analysis results showed decreased expression levels of odontoblast markers.Additionally,there was a significant reduction in Smad2/3 activation,inhibiting transforming growth factor-β(TGF-β)signaling in Atp6i^(−/−)odontoblasts.Through treating pulp precursor cells with Atp6i^(−/−)or wild-type OC bone resorption-conditioned medium,we found the latter medium to promote odontoblast differentiation,as shown by increased odontoblast differentiation marker genes expression(Nfic,Dspp,Osx,and Runx2).This increased expression was significantly blocked by anti-TGF-β1 antibody neutralization,whereas odontoblast differentiation and Smad2/3 activation were significantly attenuated by Atp6i^(−/−)OC conditioned medium.Importantly,ectopic TGF-β1 partially rescued root development and root dentin deposition of Atp6i^(−/−)mice tooth germs were transplanted under mouse kidney capsules.Collectively,our novel data shows that the prevention of TGF-β1 release from the alveolar bone matrix due to OC dysfunction may lead to osteopetrosis-associated root formation via impaired radicular odontoblast differentiation.As such,this study uncovers TGF-β1/Smad2/3 as a key signaling pathway regulating odontoblast differentiation and tooth root formation and may contribute to future therapeutic approaches to tooth root regeneration.展开更多
Objective:To evaluate the effects of Huoxin Pill(活心丸,HXP)on cardiac fibrosis and heart failure(HF)in isoproterenol(ISO)-induced HF rats.Methods:Thirty Wistar rats were randomly divided into 5 groups including contr...Objective:To evaluate the effects of Huoxin Pill(活心丸,HXP)on cardiac fibrosis and heart failure(HF)in isoproterenol(ISO)-induced HF rats.Methods:Thirty Wistar rats were randomly divided into 5 groups including control,HF,isosorbide mononitrate(ISMN),HXP low(HXP-L),and HXP high(HXP-H)groups(n=6 for each group)according to the complete randomization method.Rats were pretreated with ISMN(5 mg/kg daily),low concentration of HXP(10 mg/kg daily)or high concentration of HXP(30 mg/kg daily)or equal volume of saline by intragastric administration for 1 week,followed by intraperitoneal injection of ISO(10 mg/kg,14 days),and continually intragastric administrated with above medicines or saline for additional 6 weeks.The effects of HXP treatment on the cardiac function,heart weight index(HWI),pathological changes,and collagen content were further assessed.Moreover,the role of HXP on activation of transforming growth factor-β1(TGF-β1)/Smads pathway was further explored using immunohistochemistry(IHC)and Westernblot assay.Results:HXP treatment significantly alleviated the decrease of ejection fraction(EF)and fractional shortening(FS),while decreased the elevation of left ventricular end-systolic volume(LVESV)in ISO-induced HF rats(P<0.05).Moreover,HXP treatment obviously attenuated the increase of HWI and serum level of creatine kinase MB(CK-MB,P<0.05),as well as pathological changes in ISO-induced HF rats.Further determination indicated that HXP treatment alleviated the elevation of collagenⅠand collagenⅢprotein expression in cardiac tissues of ISO-induced HF rats.Furthermore,HXP treatment significantly down-regulated the increase of TGF-β1 and p-Smad2/3 protein expression in cardiac tissues of HF rats(P<0.05),while did not affect the expression of total Smad2/3.Conclusions:HXP attenuated heart failure and cardiac fibrosis in ISO-induced HF rats by suppression of TGF-β1/Smad2/3 pathway.展开更多
基金funded by the National Key Research and Development Program of China(2020YFD0900902)Zhejiang Province Public Welfare Technology Application Research Project(LGJ21C20001)Zhejiang Provincial Key Research and Development Project of China(2019C02076 and 2019C02075)。
文摘Type 2 diabetes mellitus(T2DM)is a complex metabolic disease threatening human health.We investigated the effects of Tegillarca granosa polysaccharide(TGP)and determined its potential mechanisms in a mouse model of T2DM established through a high-fat diet and streptozotocin.TGP(5.1×10^(3) Da)was composed of mannose,glucosamine,rhamnose,glucuronic acid,galactosamine,glucose,galactose,xylose,and fucose.It could significantly alleviate weight loss,reduce fasting blood glucose levels,reverse dyslipidemia,reduce liver damage from oxidative stress,and improve insulin sensitivity.RT-PCR and Western blotting indicated that TGP could activate the phosphatidylinositol-3-kinase/protein kinase B signaling pathway to regulate disorders in glucolipid metabolism and improve insulin resistance.TGP increased the abundance of Allobaculum,Akkermansia,and Bifidobacterium,restored the microbiota abundance in the intestinal tracts of mice with T2DM,and promoted short-chain fatty acid production.This study provides new insights into the antidiabetic effects of TGP and highlights its potential as a natural hypoglycemic nutraceutical.
基金Natural Science Foundation of Shanxi Province(No.201801D121358)"Basic Research Special Project"of Shanxi University of Tradit Chin Med Science and Technology Innovation Ability Cultivation Program(No.2021PY-JC-13)。
文摘Objective:To investigate the mechanism of JAK2/STAT3/SOCS1 signaling pathway in electroacupuncture of different acupoints on acute colitis rats.Methods:36 SPF SD rats were randomly divided into 6 groups,with 6 rats in each group.The rat model of acute colitis was prepared by enema with glacial acetic acid solution.After the model was established,electroacupuncture was given to each acupoint group,with density wave,frequency 2Hz-50 Hz,intensity 2 mA,muscle tremor as the degree 20 min/time,1 time/day,for 3 consecutive days.Observe the general condition of rats;the pathological changes of colonic mucosa in rats were observed by HE method.The contents of serum interleukin-4(IL-4)and interleukin-8(IL-8)were detected by ELISA.Western blot and RT-PCR were used to detect the expression of JAK2,STAT3,SOCS1 protein and mRNA in rat colon tissue.Results:In contrast to the normal group,the overall condition of the model group was worse,the colonic mucosa was severely damaged,even necrotic,and the ulcer surface was obvious.The content of IL-4 in serum was obviously reduced,and the content of IL-8 was obviously go up(P<0.01).The protein content of JAK2,STAT3 and the expression of JAK2,STAT3 mRNA in colon tissue of rats were obviously go up,while the protein content of SOCS1 and the expression of SOCS1 mRNA were obviously reduced(P<0.01).In contrast to the model group,the general condition of rats in each acupoint group was significantly improved,the damage and necrosis of colonic mucosa and ulcer surface were obviously alleviated,the content of IL-4 in serum was obviously go up,and the content of IL-8 was significantly decreased(P<0.01).The protein content of JAK2,STAT3 and the expression of JAK2,STAT3 mRNA in colon tissue of rats were obviously reduced,while the protein content of SOCS1 and the expression of SOCS1 mRNA were obviously go up(P<0.05,P<0.01).Comparison of different acupoint groups,the colonic mucosal injury in the Zusanli group was significantly reduced,the content of serum IL-4 was significantly increased,and the content of IL-8 was significantly decreased(P<0.05,P<0.01).The protein content and mRNA expression of JAK2 and STAT3 in colon tissue were significantly down-regulated,while the protein content and mRNA expression of SOCS1 were significantly go up(P<0.05,P<0.01).Conclusion:Electroacupuncture at each acupoint can improve the damage of colonic mucosa and reduce the inflammatory response.The therapeutic effect of Zusanli(ST36)is better than that of Tianshu(ST25),Dachangshu(BL25)and Shangjuxu(ST37).The mechanism may be related to the regulation of JAK2/STAT3/SOCS1 signaling pathway related proteins and inflammatory cytokines IL-4 and IL-8.
基金The work was supported by grants from the Scientific Research Projects of Medical and Health Institutions of Longhua District,Shenzhen(2021016)Shenzhen Basic Research Project(JCYJ20210324125803008).
文摘Background:Oleanolic acid(OA),a pentacyclic triterpenoid exhibiting specific anti-cancer properties and highly effective antioxidant activity,was isolated from traditional Chinese medicinal herbs.Conversely,the OA that impacts colon cancer(CC)cells and its underlying mechanisms remain poorly understood.Methods:The cytotoxic effect of OA alone or OA-5-Fluorouracil(5-FU)combination on normal and CC cells was analyzed by methyl thiazolyl diphenyl-tetrazolium bromide(MTT).Then,the impact of OA on CC cell lines(LoVo and HT-29)proliferation and stemness were measured using colon formation and tumorsphere formation assays.Octamer-binding transcription factor 4(Oct4),Prominin-1(CD133),Nanog,and transcription factor SOX-2(SOX2)are cell stemness-related indicators whose expression was assessed usingfluorescence qPCR assay,Western blotting,and immunohistochemistry.The effect of OA on the proliferative potency of CC cells was evaluated using an in vivo model.Results:The stem-like characteristics and clone production of colon cancer cells were markedly reduced by OA alone or in combination with OA-5-FU.Moreover,OA increases the susceptibility of CC cells to 5-FU by blocking the cell stemness-related markers(CD133,Nanog,SOX2,and Oct4)expression levels both in vitro and in vivo,as well as by inactivating the activator of transcription 3(STAT3 signaling)and Janus kinase 2/signal transducer(JAK2).Conclusion:Thesefindings imply that oleanolic acid,both in vitro and in vivo,suppresses the JAK2/STAT3 pathway,which in turn reverses chemoresistance and decreases colon cancer cell stemness.Therefore,by reducing the recommended amount of 5-FU,this strategy may improve chemotherapeutic effectiveness and minimize undesired side effects.
基金supported by the National Institutes of Health[DE023813 and DE028264 to Y.P.L.,and AG056438 and AR070135 to W.C.]the UAB National Institutes of Health National Institute of Dental and Craniofacial Research[Dental Academic Research Training Grant(DART)5T90DE022736 to J.W.].
文摘The biomolecular mechanisms that regulate tooth root development and odontoblast differentiation are poorly understood.We found that Atp6i deficient mice(Atp6i^(−/−))arrested tooth root formation,indicated by truncated Hertwig’s epithelial root sheath(HERS)progression.Furthermore,Atp6i deficiency significantly reduced the proliferation and differentiation of radicular odontogenic cells responsible for root formation.Atp6i^(−/−)mice had largely decreased expression of odontoblast differentiation marker gene expression profiles(Col1a1,Nfic,Dspp,and Osx)in the alveolar bone.Atp6i^(−/−)mice sample RNA-seq analysis results showed decreased expression levels of odontoblast markers.Additionally,there was a significant reduction in Smad2/3 activation,inhibiting transforming growth factor-β(TGF-β)signaling in Atp6i^(−/−)odontoblasts.Through treating pulp precursor cells with Atp6i^(−/−)or wild-type OC bone resorption-conditioned medium,we found the latter medium to promote odontoblast differentiation,as shown by increased odontoblast differentiation marker genes expression(Nfic,Dspp,Osx,and Runx2).This increased expression was significantly blocked by anti-TGF-β1 antibody neutralization,whereas odontoblast differentiation and Smad2/3 activation were significantly attenuated by Atp6i^(−/−)OC conditioned medium.Importantly,ectopic TGF-β1 partially rescued root development and root dentin deposition of Atp6i^(−/−)mice tooth germs were transplanted under mouse kidney capsules.Collectively,our novel data shows that the prevention of TGF-β1 release from the alveolar bone matrix due to OC dysfunction may lead to osteopetrosis-associated root formation via impaired radicular odontoblast differentiation.As such,this study uncovers TGF-β1/Smad2/3 as a key signaling pathway regulating odontoblast differentiation and tooth root formation and may contribute to future therapeutic approaches to tooth root regeneration.
基金Supported by the National Natural Science Foundation of China(No.81774135 and No.81302884)Science and Technology Major Project of Fujian Province(No.2019YZ014004)+1 种基金Natural Science Foundations of Fujian Province(No.2018J01884)Fujian Provincial Health and Family Planning Commission(No.2018-CX-42)。
文摘Objective:To evaluate the effects of Huoxin Pill(活心丸,HXP)on cardiac fibrosis and heart failure(HF)in isoproterenol(ISO)-induced HF rats.Methods:Thirty Wistar rats were randomly divided into 5 groups including control,HF,isosorbide mononitrate(ISMN),HXP low(HXP-L),and HXP high(HXP-H)groups(n=6 for each group)according to the complete randomization method.Rats were pretreated with ISMN(5 mg/kg daily),low concentration of HXP(10 mg/kg daily)or high concentration of HXP(30 mg/kg daily)or equal volume of saline by intragastric administration for 1 week,followed by intraperitoneal injection of ISO(10 mg/kg,14 days),and continually intragastric administrated with above medicines or saline for additional 6 weeks.The effects of HXP treatment on the cardiac function,heart weight index(HWI),pathological changes,and collagen content were further assessed.Moreover,the role of HXP on activation of transforming growth factor-β1(TGF-β1)/Smads pathway was further explored using immunohistochemistry(IHC)and Westernblot assay.Results:HXP treatment significantly alleviated the decrease of ejection fraction(EF)and fractional shortening(FS),while decreased the elevation of left ventricular end-systolic volume(LVESV)in ISO-induced HF rats(P<0.05).Moreover,HXP treatment obviously attenuated the increase of HWI and serum level of creatine kinase MB(CK-MB,P<0.05),as well as pathological changes in ISO-induced HF rats.Further determination indicated that HXP treatment alleviated the elevation of collagenⅠand collagenⅢprotein expression in cardiac tissues of ISO-induced HF rats.Furthermore,HXP treatment significantly down-regulated the increase of TGF-β1 and p-Smad2/3 protein expression in cardiac tissues of HF rats(P<0.05),while did not affect the expression of total Smad2/3.Conclusions:HXP attenuated heart failure and cardiac fibrosis in ISO-induced HF rats by suppression of TGF-β1/Smad2/3 pathway.
