Mesenchymal stem cells(MSCs)are critical for immune regulation.Although several microRNAs(miRNAs)have been shown to participate in autoimmune pathogenesis by affecting lymphocyte development and function,the roles of ...Mesenchymal stem cells(MSCs)are critical for immune regulation.Although several microRNAs(miRNAs)have been shown to participate in autoimmune pathogenesis by affecting lymphocyte development and function,the roles of miRNAs in MSC dysfunction in autoimmune diseases remain unclear.Here,we show that patients with systemic lupus erythematosus(SLE)display a unique miRNA signature in bone marrow-derived MSCs(BMSCs)compared with normal controls,among which miR-663 is closely associated with SLE disease activity.MiR-663 inhibits the proliferation and migration of BMSCs and impairs BMSC-mediated downregulation of follicular T helper(Tfh)cells and upregulation of regulatory T(Treg)cells by targeting transforming growth factorβ1(TGF-β1).MiR-663 overexpression weakens the therapeutic effect of BMSCs,while miR-663 inhibition improves the remission of lupus disease in MRL/lpr mice.Thus,miR-663 is a key mediator of SLE BMSC regulation and may serve as a new therapeutic target for the treatment of lupus.展开更多
Paconiflorin(Pae)is a monoterpenoid glycoside compound and has many biological activitics,such as immunosuppression,anti-inflammation and anti-cell proliferation.However,the effects and mechanisms of Pae on chronic he...Paconiflorin(Pae)is a monoterpenoid glycoside compound and has many biological activitics,such as immunosuppression,anti-inflammation and anti-cell proliferation.However,the effects and mechanisms of Pae on chronic heart failure(CHF)remain unclear.This study was conducted to assess the effects and mechanisms of Pae on myocardial fibrosis in isoprenaline(Iso)-induced CHF rats.Pae(20 mgkg)was intragastrically administrated to CHF rats for 6 weeks.Cardiac structure and function were assessed.The protein and mRNA levels of transforming growth factorβ1(TGF-β1)and p38 were detected.C ompared to Iso group,Pae could alleviate myocardial fbrosis and improve cardiac function in CHF rats.The levels of collagen volume fraction(13.75%+3.77%vs.30.97%+4.22%,P<0.001)and perivascular collagen volume area(14.32%+2.50%v8.28.31%+3.16%,P<0.001)were significantly reduced in Pae group as compared with those in Iso group.The expression of TGF-BI protein(0.30+0.07 vs.0.66+0.07,P<0.05)and mRNA(3.51+0.44 vs.7.58+0.58,P<0.05)decreased significantly in Pac group as compared with that in Iso group.The expression of p38 protein(0.36+0.12 vs.0.81+0.38,P<0.05)and mRNA(3.84+0.05 vs.4.40+0.17,P<0.05)also decreased markedly in Pae group as compared with that in Iso group.Pae could attenuate myocardial fibrosis and improve cardiac function in CHF rats by down-regulating the p38 MAPK signaling pathway.展开更多
Objective：To study the protective effect of the Mixture of Shengmai Powder and Danshen Decoction（生脉散丹参饮合剂,abbreviated as the Mixture） in the rat model with type 2 diabetic cardiomyopathy （DCM）.Methods：Fo...Objective：To study the protective effect of the Mixture of Shengmai Powder and Danshen Decoction（生脉散丹参饮合剂,abbreviated as the Mixture） in the rat model with type 2 diabetic cardiomyopathy （DCM）.Methods：Forty-two SD rats with DCM model,established by the combination of insulin resistance by a high-fat diet with the damage of pancreatic islet p cells by intraperitoneal injection of high dose streptozotocin （50 mg/kg） once,were evaluated in the damage of the myocardium by electrocardiogram at the end of 12 weeks of grouping and intervention administration;the extent of damage in the myocardial subcellular structure was observed by electron microscopy;the content of myocardial collagen in the left cardiac ventricle was quantified by Masson staining test;the myocardial cell apoptosis was determined by TUNEL;the changes in the mRNA expression levels of thrombospodin-1（TSP-1） and tribbles homolog 3（TRB-3） by real-time quantitative PCR,the expression levels of myocardial TSP-1,tumor growth factorβ1（TGF-β1）,TRB-3,and chymase were detected by immunohistochemistry,and the changes in the expression levels of myocardial TSP-1,active-TGF-β1 （A-TGF-β1） and latent-TGF-β1（L-TGF-β1） protein were tested by Western blotting.Results：Compared with the control group,the myocardial tissue was less damaged,and the extent of damage in the myocardial subcellular structure was less;the collagen fiber content and the cell apoptosis were reduced;the expression levels of TSP-1 mRNA and TRB-3 mRNA,the expression levels of myocardial TSP-1,TGF-β1,TRB-3,and chymase,as well as the average expression levels of the myocardial TSP-1,A-TGFβ1,and L-TGF-β1 protein were decreased in the Mixture group.Conclusion：The Mixture of Shengmai Powder and Danshen Decoction could inhibit the process of myocardial fibrosis in the rat myocardium of DCM through multiple pathways and significantly delay the genesis and progress of DCM in hyperglycemic rats.展开更多
Summary： In order to investigate whether Yinchenhao decoction （YCHD） attenuates hepatic fibro- genesis in the bile duct ligation （BDL） model via recovering and restoring the self-regulation and bal- ance of the r...Summary： In order to investigate whether Yinchenhao decoction （YCHD） attenuates hepatic fibro- genesis in the bile duct ligation （BDL） model via recovering and restoring the self-regulation and bal- ance of the renin-angiotensin system （RAS）, 33 specific-pathogen-free （SPF） male Sprague-Dawley rats with common BDL and scission were randomly divided into five groups as follows： G1, the sham group （n=4）; G2, BDL 7-day group （n=5）; G3, BDL＋YCHD 430 mg/mL （n=8）; G4, BDL＋losartan 0.65 mg/mL （ARB group, n=8）; G5, model group （BDL without any treatment, n=8）. YCHD and losartan （10 mL.kgl.day-1） were given by gastric gavage for 16 days following BDL in G3 and G4 groups, respec- tively. The effect of YCHD on liver fibrosis and the detailed molecular mechanisms were assessed by liver function including total bilirubin （TBIL）, direct bilirubin （DBIL）, indirect bilirubin （IDBIL）, alanine aminotransferase （ALT）, and aspartate aminotransferase （AST）. Histological changes were ob-. served by transmission electron microscopy （TEM） and Masson trichrome staining. Western blotting was used to detect the protein expression level of the renin-angiotensin system （RAS） components in- cluding angiotensin converting enzyme （ACE）, angiotensin II type 1 receptor （AT1R）, ACE2, angio- tensin II （Ang II） as well as transforming growth factor 131 （TGF131）. The experimental data were ana- lyzed by principle component analytical method of pattern recognition. The results showed that bio- chemically, serum TBIL, DBIL, IDBIL, ALT and AST levels were markedly increased following BDL as compared with the sham group （P〈0.05）. Serum TBIL, IDBIL and DBIL levels in G3 group were dramatically decreased as compared with G5 and G4 groups （P〈0.05）. Serum AST level in G3 was sig- nificantly lowered than in G5 group （P〈0.05）, but there was no significant difference in ALT among G3, G4 and G5 groups （P〉0.05）. Histologically, livers in G3 group sh展开更多
In the central nervous system, the formation of fibrotic scar after injury inhibits axon regeneration and promotes repair. However, the mechanism underlying fibrotic scar formation and regulation remains poorly unders...In the central nervous system, the formation of fibrotic scar after injury inhibits axon regeneration and promotes repair. However, the mechanism underlying fibrotic scar formation and regulation remains poorly understood. M2 macrophages regulate fibrotic scar formation after injury to the heart, lung, kidney, and central nervous system. However, it remains to be clarified whether and how M2 macrophages regulate fibrotic scar formation after cerebral ischemia injury. In this study, we found that, in a rat model of cerebral ischemia induced by middle cerebral artery occlusion/reperfusion, fibrosis and macrophage infiltration were apparent in the ischemic core in the early stage of injury(within 14 days of injury). The number of infiltrated macrophages was positively correlated with fibronectin expression. Depletion of circulating monocyte-derived macrophages attenuated fibrotic scar formation. Interleukin 4(IL4) expression was strongly enhanced in the ischemic cerebral tissues, and IL4-induced M2 macrophage polarization promoted fibrotic scar formation in the ischemic core. In addition, macrophage-conditioned medium directly promoted fibroblast proliferation and the production of extracellular matrix proteins in vitro. Further pharmacological and genetic analyses showed that sonic hedgehog secreted by M2 macrophages promoted fibrogenesis in vitro and in vivo, and that this process was mediated by secretion of the key fibrosis-associated regulatory proteins transforming growth factor beta 1 and matrix metalloproteinase 9. Furthermore, IL4-afforded functional restoration on angiogenesis, cell apoptosis, and infarct volume in the ischemic core of cerebral ischemia rats were markedly impaired by treatment with an sonic hedgehog signaling inhibitor, paralleling the extent of fibrosis. Taken together, our findings show that IL4/sonic hedgehog/transforming growth factor beta 1 signaling targeting macrophages regulates the formation of fibrotic scar and is a potential therapeutic target for ischemic stroke.展开更多
To construct the antisense transforming growth factorβ1 (TGFβ1) gene and investigate the effect of TGFβ1 autocrine loop blockage on the proliferation of osteosarcoma cells. TGFβ1 cDNA was cloned by RT-PCR from hum...To construct the antisense transforming growth factorβ1 (TGFβ1) gene and investigate the effect of TGFβ1 autocrine loop blockage on the proliferation of osteosarcoma cells. TGFβ1 cDNA was cloned by RT-PCR from human osteosarcoma cells (MG-63) and inserted into pcDNA3 to construct an antisense expression vector, which was dubbed pcDNA3-TGFβ1(-). MTT was used to detect the proliferation of osteosarcoma cells transfected by antisense TGFβl gene. Our results showed that the proliferation of the transfected osteosarcoma cells was suppressed markedly. It is concluded that TGFβ1 autocrine loop blockage in osteosarcoma cells could inhibit cell proliferation, which might be helpful for gene therapy of osteosarcoma.展开更多
BACKGROUND Phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1(PREX1)was reported to be overexpressed in some cancers and involved in cancer development,but its expression and significance in gast...BACKGROUND Phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1(PREX1)was reported to be overexpressed in some cancers and involved in cancer development,but its expression and significance in gastric cancer remain unclear.AIM To evaluate the expression of PREX1 in gastric cancer and its significance in the development of gastric cancer,especially to evaluate the potential mechanism of PREX1 in gastric cancer.METHODS Bioinformatic analysis was performed in order to examine the expression of PREX1 in gastric cancer.The relationship between the survival rate of gastric cancer patients and PREX1 expression was assessed by Kaplan Meier portal.The Gene Set Enrichment Analysis and the correlation between PREX1 and transforming growth factor(TGF)β1 pathway-related mediators were evaluated by cBioPortal for Cancer Genomics.Western blotting and reverse transcriptase polymerase chain reaction assay were used to test the role of TGFβ1 on the expression of PREX1.Western blotting and dual-luciferase reporter system was used to evaluate the effect of PREX1 on the activation of TGFβ1 pathway.Wound healing and Transwell assay were used to assess the effect of PREX1 on the metastasis activity of gastric cancer cells.RESULTS PREX1 was overexpressed in the gastric tumors,and the expression levels were positively associated with the development of gastric cancer.Also,the high expression of PREX1 revealed poor prognosis,especially for those advanced and specific intestinal gastric cancer patients.PREX1 was closely involved in the positive regulation of cell adhesion and positively correlated with TGFβ1-related mediators.Furthermore,TGFβ1 could induce the expression of PREX1 at both the protein and mRNA level.Also,PREX1 could activate the TGFβ1 pathway.The induced PREX1 could increase the migration and invasion activity of gastric cancer cells.CONCLUSION PREX1 is overexpressed in gastric cancer,and the high level of PREX1 predicts poor prognosis.PREX1 is closely associated with TGFβsignaling and promotes the展开更多
The cornea is a highly specialized and unique organ in the human body. Its main function is to project light from the external environment onto the retina, and it has a specific transparency to perform its function pr...The cornea is a highly specialized and unique organ in the human body. Its main function is to project light from the external environment onto the retina, and it has a specific transparency to perform its function properly. The transparency and integrity of the cornea is of vital importance. The corneal wound, especially laceration deep to Bowman＇s membrane and stroma, which will inevitably cause scar formation, may cause the degeneration or even loss of sight.展开更多
Sarcomatoid carcinoma of the pancreas(SCP)is a very rare pathological type of carcinoma that usually has a poor prognosis.Its pathogenesis has not been elucidated.We herein report a case of an early-stage SCP involvin...Sarcomatoid carcinoma of the pancreas(SCP)is a very rare pathological type of carcinoma that usually has a poor prognosis.Its pathogenesis has not been elucidated.We herein report a case of an early-stage SCP involving successful treatment and a good prognosis.The patient was a 48-year-old Chinese man with a5-mo history of vague abdominal pain.Ultrasonography revealed a 93 mm×94 mm×75 mm mass of mixed echogenicity in the tail of the pancreas.Laboratory test results were within the normal range,with the exception of an obviously increased pretreatment neuron-specific enolase level.The plasma transforming growth factor(TGF)β1 and interleukin-11 levels were obviously increased according to enzyme-linked immunosorbent assay.Microscopically,the excised tumor tissue comprised cancer cells and mesenchymal cells.Immunohistochemical analysis was positive forα-1-antichymotrypsin,pan-cytokeratin,cytokeratin 19,cytokeratin 8/18,and vimentin and negative for CD68and lysozyme.The pathogenetic mechanism of this case shows that TGFβ1 may regulate the epithelial-tomesenchymal transition in SCP.With early eradication of the tumor and systemic therapy,this patient has been alive for more than 3 years without tumor recurrence or distant metastasis.This case is also the first to show that TGFβ1 may regulate the epithelial-tomesenchymal transition in early-stage SCP.展开更多
OBJECTIVE: To investigate the role of tongue coating fluid protein in regulation of congestive heart failure(CHF) in Qi-deficiency-blood-stasis syndrome.METHODS: We studied patients with CHF(3 patients with Qi-deficie...OBJECTIVE: To investigate the role of tongue coating fluid protein in regulation of congestive heart failure(CHF) in Qi-deficiency-blood-stasis syndrome.METHODS: We studied patients with CHF(3 patients with Qi-deficiency-blood-stasis syndrome and 3 without Qi-deficiency-blood-stasis syndrome) to investigate differentially expressed proteins. We also included a control group. A biotin label-based antibody array was used for testing tongue coating fluid samples from patients. Net-work analysis of these differentially expressed proteins was conducted using the STRING database,which can predict the relations between differentially expressed proteins and CHF with Qi-deficiency-blood-stasis syndrome.RESULTS: A total of seven differentially expressed proteins were identified, and among these, transforming growth factor β1(TGF-β1) gets a particular attention for us has drawn specific attention.Network analysis showed a homologous relationship of TGF-β1 with bone morphogenetic protein15, which is associated with myocardial fibrosis.CONCLUSION: Occurrence and development of CHF may result from certain DE-proteins and associated signaling pathways. TGF-β1 protein may be a candidate marker for assessing the risk of CHF in Qideficiency-blood-stasis syndrome.展开更多
Liver fibrosis is the deposition of extracellular matrix(ECM)in the liver caused by persistent chronic injury,which can lead to more serious diseases such as cirrhosis or cancer.Blocking the effect of transforming gro...Liver fibrosis is the deposition of extracellular matrix(ECM)in the liver caused by persistent chronic injury,which can lead to more serious diseases such as cirrhosis or cancer.Blocking the effect of transforming growth factorβ1(TGF-β1),one of the most important cytokines in liver fibrosis,may be one of the effective ways to inhibit liver fibrosis.As a kind of natural nano-scale vesicles,small extracellular vesicles(sEvs)have displayed excellent delivery vehicle properties.Herein,we prepared hepatic stellate cell(HSC)-derived sEvs loading left-right determination factor 1(lefty1)mRNA(sEvLs)and we wanted to verify whether they can inhibit fibrosis by blocking the TGF-β1 signaling pathway.The results showed that sEvLs had effective cell uptake and reduced activation of HSCs.Rats that were injected with CCl 4 by intraperitoneal injection for 6 weeks exhibited obvious symptoms of liver fibrosis and were treated with systemically administered sEvLs and free sEvs for 4 weeks.Rats injected with olive oil alone served as sham controls.Administration of sEvLs significantly reduced the area of fibrosis compared with free sEvs.We demonstrated that sEvLs inhibited HSCs activation and ECM production,and promote ECM degradation by downregulatingα-smooth muscle actin(α-SMA),collagen I,tissue inhibitor of metalloproteinase(TIMP)-1 and upregulating matrix metalloprotease(MMP)-1.In summary,as an endogenous delivery vehicle,sEvs could deliver mRNA to attenuate hepatic fibrosis by blocking the TGF-β/Smad signaling pathway.展开更多
This study aimed to investigate the effect and mechanism of valproic acid(VPA)on the neurosphere formation in rat embryonic cortical cells.We used free-floating neurosphere formation as a model system to evaluate the ...This study aimed to investigate the effect and mechanism of valproic acid(VPA)on the neurosphere formation in rat embryonic cortical cells.We used free-floating neurosphere formation as a model system to evaluate the VPA on the proliferation of neural stem cells(NSCs).We found a time-and dose-dependent increase in neurosphere formation and NSC proliferation after VPA treatment.Further RNA-seq analysis demonstrated that the upregulated TGFβ1 signaling might attribute to the effect of VPA on the neurosphere formation and NSC proliferation.Consistently,the neurosphere formation and NSC proliferation were blocked by the treatment with SB431542,an inhibitor of TGFβ1 receptor.Moreover,in a coculture system,NSCs treated with VPA significantly reduced the oxygen-glucose deprivation-induced neuronal apoptosis.Taken together,our results showed that VPA could enhance neurosphere formation and NSC proliferation by activating TGFβ1,which might be a novel therapeutic strategy for neurological disorders.展开更多
In order to investigate the effect of paeoniflorin(PAE)on hepatic fibrosis of mice with Schistosomiasis japonica in vivo and in vitro,a model of hepatic fibrosis caused by schistosomiasis was established in mice infec...In order to investigate the effect of paeoniflorin(PAE)on hepatic fibrosis of mice with Schistosomiasis japonica in vivo and in vitro,a model of hepatic fibrosis caused by schistosomiasis was established in mice infected with cercariae of Schistosoma japonicum.Then,PAE was orally administered before and after praziquantel treat-ment and both therapeutics were given simultaneously at different time points after the infection.The concentra-tion of serum hyaluronic acid(HA)was determined by radioimmunoassay(RIA).Hepatic granuloma and fib-rosis were evaluated via HE and Masson staining.The expression of α-smooth muscle actin(α-SMA),transform-ing growth factor β1(TGF-β1)and collagen I(Col I)protein was detected by immunohistochemistry.The effect of soluble egg antigen(SEA)and PAE on the pro-duction of TGF-β1 from mouse peritoneal macrophages(PMQs)was investigated by RT-PCR,Western blotting and ELISA.The effect of TGF-β1 in optimum macro-phage-conditioned medium(OPMCM)on the prolifera-tion of hepatic stellate cells(HSCs)and collagen secretion from HSCs with anti-TGF-β1 antibody was explored by MTT assay and ELISA.The results show that PAE could significantly reduce the concentration of serum HA,the size of egg granuloma,the severity of hepatic fibrosis and the expression of a-SMA,TGF-β1 and Col I protein in the pre-treatment group.However,in sim-or post-treatment group,PAE did not have any significant therapeutic effect.TGF-β1 could be secreted from PMQs stimulated by SEA.Meanwhile,the production of TGF-β1 from PMQs could be depressed significantly by PAE in a con-centration-dependent manner.TGF-β1 could promote the proliferation of HSCs and the secretion of collagens.In a word,PAE can prevent hepatic granuloma and fib-rosis caused by schistosomiasis japonica through the inhibition of the secretion of TGF-β1 from PMQs,the proliferation and activation of HSCs and the secretion of collagens from HSCs.展开更多
BACKGROUND Collagen is one of the most commonly used natural biomaterials for tendon tissue engineering.One of the possible practical ways to further enhance tendon repair is to combine a porous collagen sponge scaffo...BACKGROUND Collagen is one of the most commonly used natural biomaterials for tendon tissue engineering.One of the possible practical ways to further enhance tendon repair is to combine a porous collagen sponge scaffold with a suitable growth factor or cytokine that has an inherent ability to promote the recruitment,proliferation,and tenogenic differentiation of cells.However,there is an incomplete understanding of which growth factors are sufficient and optimal for the tenogenic differentiation of rat bone marrow mesenchymal stem cells(BMSCs)in a collagen sponge-based 3D culture system.AIM To identify one or more ideal growth factors that benefit the proliferation and tenogenic differentiation of rat BMSCs in a porous collagen sponge scaffold.METHODS We constructed a 3D culture system based on a type I collagen sponge scaffold.The surface topography of the collagen sponge scaffold was observed by scanning electron microscopy.Primary BMSCs were isolated from Sprague-Dawley rats.Cell survival on the surfaces of the scaffolds with different growth factors was assessed by live/dead assay and CCK-8 assay.The mRNA and protein expression levels were confirmed by quantitative real-time polymerase chain reaction and Western blot,respectively.The deposited collagen was assessed by Sirius Red staining.RESULTS Transforming growth factorβ1(TGF-β1)showed great promise in the tenogenic differentiation of BMSCs compared to growth differentiation factor 7(GDF-7)and insulin-like growth factor 1(IGF-1)in both the 2D and 3D cultures,and the 3D culture enhanced the differentiation of BMSCs into tenocytes well beyond the level of induction in the 2D culture after TGF-β1 treatment.In the 2D culture,the proliferation of the BMSCs showed no significant changes compared to the control group after TGF-β1,IGF-1,or GDF-7 treatment.However,TGF-β1 and GDF-7 could increase the cell proliferation in the 3D culture.Strangely,we also found more dead cells in the BMSC-collagen sponge constructs that were treated with TGF-β1.Moreover,TGF-β1 展开更多
基金by the Major International(Regional)Joint Research Project(No.81720108020)National Natural Science Foundation of China(No.81373199,81501347 and 81370730,81273304)+2 种基金National Natural Science Foundation of Jiangsu(BK20150098)Jiangsu Province Major Research and Development Program(BE2015602)Jiangsu Province 333 Talant Grant(BRA2016001).
文摘Mesenchymal stem cells(MSCs)are critical for immune regulation.Although several microRNAs(miRNAs)have been shown to participate in autoimmune pathogenesis by affecting lymphocyte development and function,the roles of miRNAs in MSC dysfunction in autoimmune diseases remain unclear.Here,we show that patients with systemic lupus erythematosus(SLE)display a unique miRNA signature in bone marrow-derived MSCs(BMSCs)compared with normal controls,among which miR-663 is closely associated with SLE disease activity.MiR-663 inhibits the proliferation and migration of BMSCs and impairs BMSC-mediated downregulation of follicular T helper(Tfh)cells and upregulation of regulatory T(Treg)cells by targeting transforming growth factorβ1(TGF-β1).MiR-663 overexpression weakens the therapeutic effect of BMSCs,while miR-663 inhibition improves the remission of lupus disease in MRL/lpr mice.Thus,miR-663 is a key mediator of SLE BMSC regulation and may serve as a new therapeutic target for the treatment of lupus.
基金This study was supported by grants from Scientific Research Development Program of North Sichuan Medical College(No.CBY16-A-ZD10)Nanchong Government-University Strategic Cooperation Project in Science and Technology(No.18SXHZ0505).
文摘Paconiflorin(Pae)is a monoterpenoid glycoside compound and has many biological activitics,such as immunosuppression,anti-inflammation and anti-cell proliferation.However,the effects and mechanisms of Pae on chronic heart failure(CHF)remain unclear.This study was conducted to assess the effects and mechanisms of Pae on myocardial fibrosis in isoprenaline(Iso)-induced CHF rats.Pae(20 mgkg)was intragastrically administrated to CHF rats for 6 weeks.Cardiac structure and function were assessed.The protein and mRNA levels of transforming growth factorβ1(TGF-β1)and p38 were detected.C ompared to Iso group,Pae could alleviate myocardial fbrosis and improve cardiac function in CHF rats.The levels of collagen volume fraction(13.75%+3.77%vs.30.97%+4.22%,P<0.001)and perivascular collagen volume area(14.32%+2.50%v8.28.31%+3.16%,P<0.001)were significantly reduced in Pae group as compared with those in Iso group.The expression of TGF-BI protein(0.30+0.07 vs.0.66+0.07,P<0.05)and mRNA(3.51+0.44 vs.7.58+0.58,P<0.05)decreased significantly in Pac group as compared with that in Iso group.The expression of p38 protein(0.36+0.12 vs.0.81+0.38,P<0.05)and mRNA(3.84+0.05 vs.4.40+0.17,P<0.05)also decreased markedly in Pae group as compared with that in Iso group.Pae could attenuate myocardial fibrosis and improve cardiac function in CHF rats by down-regulating the p38 MAPK signaling pathway.
基金Supported by the First Grade of China Postdoctoral Science Foundation(No.20070410129)the Special Fund by China Postdoctoral Science Foundation(No.200801166)+1 种基金the Major Project of Beijing Municipal Science and Technology Committee (No.H020920010330)the Subject of Science and Technology Plan of Beijng Municipal Science and Technology Committee(No.D08050703020802)
文摘Objective：To study the protective effect of the Mixture of Shengmai Powder and Danshen Decoction（生脉散丹参饮合剂,abbreviated as the Mixture） in the rat model with type 2 diabetic cardiomyopathy （DCM）.Methods：Forty-two SD rats with DCM model,established by the combination of insulin resistance by a high-fat diet with the damage of pancreatic islet p cells by intraperitoneal injection of high dose streptozotocin （50 mg/kg） once,were evaluated in the damage of the myocardium by electrocardiogram at the end of 12 weeks of grouping and intervention administration;the extent of damage in the myocardial subcellular structure was observed by electron microscopy;the content of myocardial collagen in the left cardiac ventricle was quantified by Masson staining test;the myocardial cell apoptosis was determined by TUNEL;the changes in the mRNA expression levels of thrombospodin-1（TSP-1） and tribbles homolog 3（TRB-3） by real-time quantitative PCR,the expression levels of myocardial TSP-1,tumor growth factorβ1（TGF-β1）,TRB-3,and chymase were detected by immunohistochemistry,and the changes in the expression levels of myocardial TSP-1,active-TGF-β1 （A-TGF-β1） and latent-TGF-β1（L-TGF-β1） protein were tested by Western blotting.Results：Compared with the control group,the myocardial tissue was less damaged,and the extent of damage in the myocardial subcellular structure was less;the collagen fiber content and the cell apoptosis were reduced;the expression levels of TSP-1 mRNA and TRB-3 mRNA,the expression levels of myocardial TSP-1,TGF-β1,TRB-3,and chymase,as well as the average expression levels of the myocardial TSP-1,A-TGFβ1,and L-TGF-β1 protein were decreased in the Mixture group.Conclusion：The Mixture of Shengmai Powder and Danshen Decoction could inhibit the process of myocardial fibrosis in the rat myocardium of DCM through multiple pathways and significantly delay the genesis and progress of DCM in hyperglycemic rats.
基金supported by grants from the National Natural Science Foundation of China(No.81102692)the Natural Science Foundation of Hubei Province,China(No.JX6B09)the Fundamental Research Funds for the Central Universities,China(No.2015QN203)
文摘Summary： In order to investigate whether Yinchenhao decoction （YCHD） attenuates hepatic fibro- genesis in the bile duct ligation （BDL） model via recovering and restoring the self-regulation and bal- ance of the renin-angiotensin system （RAS）, 33 specific-pathogen-free （SPF） male Sprague-Dawley rats with common BDL and scission were randomly divided into five groups as follows： G1, the sham group （n=4）; G2, BDL 7-day group （n=5）; G3, BDL＋YCHD 430 mg/mL （n=8）; G4, BDL＋losartan 0.65 mg/mL （ARB group, n=8）; G5, model group （BDL without any treatment, n=8）. YCHD and losartan （10 mL.kgl.day-1） were given by gastric gavage for 16 days following BDL in G3 and G4 groups, respec- tively. The effect of YCHD on liver fibrosis and the detailed molecular mechanisms were assessed by liver function including total bilirubin （TBIL）, direct bilirubin （DBIL）, indirect bilirubin （IDBIL）, alanine aminotransferase （ALT）, and aspartate aminotransferase （AST）. Histological changes were ob-. served by transmission electron microscopy （TEM） and Masson trichrome staining. Western blotting was used to detect the protein expression level of the renin-angiotensin system （RAS） components in- cluding angiotensin converting enzyme （ACE）, angiotensin II type 1 receptor （AT1R）, ACE2, angio- tensin II （Ang II） as well as transforming growth factor 131 （TGF131）. The experimental data were ana- lyzed by principle component analytical method of pattern recognition. The results showed that bio- chemically, serum TBIL, DBIL, IDBIL, ALT and AST levels were markedly increased following BDL as compared with the sham group （P〈0.05）. Serum TBIL, IDBIL and DBIL levels in G3 group were dramatically decreased as compared with G5 and G4 groups （P〈0.05）. Serum AST level in G3 was sig- nificantly lowered than in G5 group （P〈0.05）, but there was no significant difference in ALT among G3, G4 and G5 groups （P〉0.05）. Histologically, livers in G3 group sh
基金supported by the National Natural Science Foundation of China,Nos.82171456 (to QY),81971229 (to QY)the Natural Science Foundation of Chongqing,No.cstc2021jcyj-msxmX0263 (to QY)the Postgraduate Research and Innovation Project of Chongqing,Nos.CYB20151 (to QY),CYS19182 (to YC)。
文摘In the central nervous system, the formation of fibrotic scar after injury inhibits axon regeneration and promotes repair. However, the mechanism underlying fibrotic scar formation and regulation remains poorly understood. M2 macrophages regulate fibrotic scar formation after injury to the heart, lung, kidney, and central nervous system. However, it remains to be clarified whether and how M2 macrophages regulate fibrotic scar formation after cerebral ischemia injury. In this study, we found that, in a rat model of cerebral ischemia induced by middle cerebral artery occlusion/reperfusion, fibrosis and macrophage infiltration were apparent in the ischemic core in the early stage of injury(within 14 days of injury). The number of infiltrated macrophages was positively correlated with fibronectin expression. Depletion of circulating monocyte-derived macrophages attenuated fibrotic scar formation. Interleukin 4(IL4) expression was strongly enhanced in the ischemic cerebral tissues, and IL4-induced M2 macrophage polarization promoted fibrotic scar formation in the ischemic core. In addition, macrophage-conditioned medium directly promoted fibroblast proliferation and the production of extracellular matrix proteins in vitro. Further pharmacological and genetic analyses showed that sonic hedgehog secreted by M2 macrophages promoted fibrogenesis in vitro and in vivo, and that this process was mediated by secretion of the key fibrosis-associated regulatory proteins transforming growth factor beta 1 and matrix metalloproteinase 9. Furthermore, IL4-afforded functional restoration on angiogenesis, cell apoptosis, and infarct volume in the ischemic core of cerebral ischemia rats were markedly impaired by treatment with an sonic hedgehog signaling inhibitor, paralleling the extent of fibrosis. Taken together, our findings show that IL4/sonic hedgehog/transforming growth factor beta 1 signaling targeting macrophages regulates the formation of fibrotic scar and is a potential therapeutic target for ischemic stroke.
基金This work was supported by a grant from Chenguang Project of Wuhan(Serial No.20025001028).
文摘To construct the antisense transforming growth factorβ1 (TGFβ1) gene and investigate the effect of TGFβ1 autocrine loop blockage on the proliferation of osteosarcoma cells. TGFβ1 cDNA was cloned by RT-PCR from human osteosarcoma cells (MG-63) and inserted into pcDNA3 to construct an antisense expression vector, which was dubbed pcDNA3-TGFβ1(-). MTT was used to detect the proliferation of osteosarcoma cells transfected by antisense TGFβl gene. Our results showed that the proliferation of the transfected osteosarcoma cells was suppressed markedly. It is concluded that TGFβ1 autocrine loop blockage in osteosarcoma cells could inhibit cell proliferation, which might be helpful for gene therapy of osteosarcoma.
文摘BACKGROUND Phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1(PREX1)was reported to be overexpressed in some cancers and involved in cancer development,but its expression and significance in gastric cancer remain unclear.AIM To evaluate the expression of PREX1 in gastric cancer and its significance in the development of gastric cancer,especially to evaluate the potential mechanism of PREX1 in gastric cancer.METHODS Bioinformatic analysis was performed in order to examine the expression of PREX1 in gastric cancer.The relationship between the survival rate of gastric cancer patients and PREX1 expression was assessed by Kaplan Meier portal.The Gene Set Enrichment Analysis and the correlation between PREX1 and transforming growth factor(TGF)β1 pathway-related mediators were evaluated by cBioPortal for Cancer Genomics.Western blotting and reverse transcriptase polymerase chain reaction assay were used to test the role of TGFβ1 on the expression of PREX1.Western blotting and dual-luciferase reporter system was used to evaluate the effect of PREX1 on the activation of TGFβ1 pathway.Wound healing and Transwell assay were used to assess the effect of PREX1 on the metastasis activity of gastric cancer cells.RESULTS PREX1 was overexpressed in the gastric tumors,and the expression levels were positively associated with the development of gastric cancer.Also,the high expression of PREX1 revealed poor prognosis,especially for those advanced and specific intestinal gastric cancer patients.PREX1 was closely involved in the positive regulation of cell adhesion and positively correlated with TGFβ1-related mediators.Furthermore,TGFβ1 could induce the expression of PREX1 at both the protein and mRNA level.Also,PREX1 could activate the TGFβ1 pathway.The induced PREX1 could increase the migration and invasion activity of gastric cancer cells.CONCLUSION PREX1 is overexpressed in gastric cancer,and the high level of PREX1 predicts poor prognosis.PREX1 is closely associated with TGFβsignaling and promotes the
基金THIS STUDY WAS SUPPORTED BY A GRANT FROM THE NATIONAL NATURAL SCIENCE FOUNDATION OF CHINA (NO. 30571997) AND SHANDONG SCIENTIFIC AND TECHNOLOGICAL COMMITTEE.
文摘The cornea is a highly specialized and unique organ in the human body. Its main function is to project light from the external environment onto the retina, and it has a specific transparency to perform its function properly. The transparency and integrity of the cornea is of vital importance. The corneal wound, especially laceration deep to Bowman＇s membrane and stroma, which will inevitably cause scar formation, may cause the degeneration or even loss of sight.
基金Supported by China Postdoctoral Science Foundation,No.2013M541699Social Development of Jiangsu Province,No.BE2012705the Foundation of Northern Jiangsu People’s Hospital,No.Yzucms201213
文摘Sarcomatoid carcinoma of the pancreas(SCP)is a very rare pathological type of carcinoma that usually has a poor prognosis.Its pathogenesis has not been elucidated.We herein report a case of an early-stage SCP involving successful treatment and a good prognosis.The patient was a 48-year-old Chinese man with a5-mo history of vague abdominal pain.Ultrasonography revealed a 93 mm×94 mm×75 mm mass of mixed echogenicity in the tail of the pancreas.Laboratory test results were within the normal range,with the exception of an obviously increased pretreatment neuron-specific enolase level.The plasma transforming growth factor(TGF)β1 and interleukin-11 levels were obviously increased according to enzyme-linked immunosorbent assay.Microscopically,the excised tumor tissue comprised cancer cells and mesenchymal cells.Immunohistochemical analysis was positive forα-1-antichymotrypsin,pan-cytokeratin,cytokeratin 19,cytokeratin 8/18,and vimentin and negative for CD68and lysozyme.The pathogenetic mechanism of this case shows that TGFβ1 may regulate the epithelial-tomesenchymal transition in SCP.With early eradication of the tumor and systemic therapy,this patient has been alive for more than 3 years without tumor recurrence or distant metastasis.This case is also the first to show that TGFβ1 may regulate the epithelial-tomesenchymal transition in early-stage SCP.
基金Supported by the Natural Science Foundation of China(No.81803996)the Major Clinical Research Project of the Army(No.2006021003)+1 种基金the Training Plan on Excellent Academic Leader of Shanghai Health System(No.XBR2011070)Construction of Clinical Basic Discipline of TCM(No.A1-Z183020110)。
文摘OBJECTIVE: To investigate the role of tongue coating fluid protein in regulation of congestive heart failure(CHF) in Qi-deficiency-blood-stasis syndrome.METHODS: We studied patients with CHF(3 patients with Qi-deficiency-blood-stasis syndrome and 3 without Qi-deficiency-blood-stasis syndrome) to investigate differentially expressed proteins. We also included a control group. A biotin label-based antibody array was used for testing tongue coating fluid samples from patients. Net-work analysis of these differentially expressed proteins was conducted using the STRING database,which can predict the relations between differentially expressed proteins and CHF with Qi-deficiency-blood-stasis syndrome.RESULTS: A total of seven differentially expressed proteins were identified, and among these, transforming growth factor β1(TGF-β1) gets a particular attention for us has drawn specific attention.Network analysis showed a homologous relationship of TGF-β1 with bone morphogenetic protein15, which is associated with myocardial fibrosis.CONCLUSION: Occurrence and development of CHF may result from certain DE-proteins and associated signaling pathways. TGF-β1 protein may be a candidate marker for assessing the risk of CHF in Qideficiency-blood-stasis syndrome.
基金received from National Natural Science Foundation of China(No.82073784)Jilin Province Science and Technology Development Program(No.20200801012GH)Industrial Technology Research and Development Projects from the Development and Reform Commission of Jilin Province(2019C050-4).
文摘Liver fibrosis is the deposition of extracellular matrix(ECM)in the liver caused by persistent chronic injury,which can lead to more serious diseases such as cirrhosis or cancer.Blocking the effect of transforming growth factorβ1(TGF-β1),one of the most important cytokines in liver fibrosis,may be one of the effective ways to inhibit liver fibrosis.As a kind of natural nano-scale vesicles,small extracellular vesicles(sEvs)have displayed excellent delivery vehicle properties.Herein,we prepared hepatic stellate cell(HSC)-derived sEvs loading left-right determination factor 1(lefty1)mRNA(sEvLs)and we wanted to verify whether they can inhibit fibrosis by blocking the TGF-β1 signaling pathway.The results showed that sEvLs had effective cell uptake and reduced activation of HSCs.Rats that were injected with CCl 4 by intraperitoneal injection for 6 weeks exhibited obvious symptoms of liver fibrosis and were treated with systemically administered sEvLs and free sEvs for 4 weeks.Rats injected with olive oil alone served as sham controls.Administration of sEvLs significantly reduced the area of fibrosis compared with free sEvs.We demonstrated that sEvLs inhibited HSCs activation and ECM production,and promote ECM degradation by downregulatingα-smooth muscle actin(α-SMA),collagen I,tissue inhibitor of metalloproteinase(TIMP)-1 and upregulating matrix metalloprotease(MMP)-1.In summary,as an endogenous delivery vehicle,sEvs could deliver mRNA to attenuate hepatic fibrosis by blocking the TGF-β/Smad signaling pathway.
基金This work was supported by grants from the Key R&D Program of Jiangsu Province(Grant No.2017CX010)the National Natural Science Foundation of China(Grant No.81973308)to J.G.the Nanjing Science and Technology Development Program(Grant No.201402021)to H.L.
文摘This study aimed to investigate the effect and mechanism of valproic acid(VPA)on the neurosphere formation in rat embryonic cortical cells.We used free-floating neurosphere formation as a model system to evaluate the VPA on the proliferation of neural stem cells(NSCs).We found a time-and dose-dependent increase in neurosphere formation and NSC proliferation after VPA treatment.Further RNA-seq analysis demonstrated that the upregulated TGFβ1 signaling might attribute to the effect of VPA on the neurosphere formation and NSC proliferation.Consistently,the neurosphere formation and NSC proliferation were blocked by the treatment with SB431542,an inhibitor of TGFβ1 receptor.Moreover,in a coculture system,NSCs treated with VPA significantly reduced the oxygen-glucose deprivation-induced neuronal apoptosis.Taken together,our results showed that VPA could enhance neurosphere formation and NSC proliferation by activating TGFβ1,which might be a novel therapeutic strategy for neurological disorders.
基金supported by the National Natural Science Foundation of China(Grant No.30571631).
文摘In order to investigate the effect of paeoniflorin(PAE)on hepatic fibrosis of mice with Schistosomiasis japonica in vivo and in vitro,a model of hepatic fibrosis caused by schistosomiasis was established in mice infected with cercariae of Schistosoma japonicum.Then,PAE was orally administered before and after praziquantel treat-ment and both therapeutics were given simultaneously at different time points after the infection.The concentra-tion of serum hyaluronic acid(HA)was determined by radioimmunoassay(RIA).Hepatic granuloma and fib-rosis were evaluated via HE and Masson staining.The expression of α-smooth muscle actin(α-SMA),transform-ing growth factor β1(TGF-β1)and collagen I(Col I)protein was detected by immunohistochemistry.The effect of soluble egg antigen(SEA)and PAE on the pro-duction of TGF-β1 from mouse peritoneal macrophages(PMQs)was investigated by RT-PCR,Western blotting and ELISA.The effect of TGF-β1 in optimum macro-phage-conditioned medium(OPMCM)on the prolifera-tion of hepatic stellate cells(HSCs)and collagen secretion from HSCs with anti-TGF-β1 antibody was explored by MTT assay and ELISA.The results show that PAE could significantly reduce the concentration of serum HA,the size of egg granuloma,the severity of hepatic fibrosis and the expression of a-SMA,TGF-β1 and Col I protein in the pre-treatment group.However,in sim-or post-treatment group,PAE did not have any significant therapeutic effect.TGF-β1 could be secreted from PMQs stimulated by SEA.Meanwhile,the production of TGF-β1 from PMQs could be depressed significantly by PAE in a con-centration-dependent manner.TGF-β1 could promote the proliferation of HSCs and the secretion of collagens.In a word,PAE can prevent hepatic granuloma and fib-rosis caused by schistosomiasis japonica through the inhibition of the secretion of TGF-β1 from PMQs,the proliferation and activation of HSCs and the secretion of collagens from HSCs.
基金Supported by Natural National Science Foundation of China,No.31700810 and No.11772073Science and Technology Research Program of Chongqing Municipal Education Commission,No.KJQN201800601+1 种基金Natural Science Foundation of Chongqing,China,No.cstc2020jcyj-msxmX0760Visiting Scholar Foundation of Key Laboratory of Biorheological Science and Technology(Chongqing University),Ministry of Education,No.CQKLBST-2018-007.
文摘BACKGROUND Collagen is one of the most commonly used natural biomaterials for tendon tissue engineering.One of the possible practical ways to further enhance tendon repair is to combine a porous collagen sponge scaffold with a suitable growth factor or cytokine that has an inherent ability to promote the recruitment,proliferation,and tenogenic differentiation of cells.However,there is an incomplete understanding of which growth factors are sufficient and optimal for the tenogenic differentiation of rat bone marrow mesenchymal stem cells(BMSCs)in a collagen sponge-based 3D culture system.AIM To identify one or more ideal growth factors that benefit the proliferation and tenogenic differentiation of rat BMSCs in a porous collagen sponge scaffold.METHODS We constructed a 3D culture system based on a type I collagen sponge scaffold.The surface topography of the collagen sponge scaffold was observed by scanning electron microscopy.Primary BMSCs were isolated from Sprague-Dawley rats.Cell survival on the surfaces of the scaffolds with different growth factors was assessed by live/dead assay and CCK-8 assay.The mRNA and protein expression levels were confirmed by quantitative real-time polymerase chain reaction and Western blot,respectively.The deposited collagen was assessed by Sirius Red staining.RESULTS Transforming growth factorβ1(TGF-β1)showed great promise in the tenogenic differentiation of BMSCs compared to growth differentiation factor 7(GDF-7)and insulin-like growth factor 1(IGF-1)in both the 2D and 3D cultures,and the 3D culture enhanced the differentiation of BMSCs into tenocytes well beyond the level of induction in the 2D culture after TGF-β1 treatment.In the 2D culture,the proliferation of the BMSCs showed no significant changes compared to the control group after TGF-β1,IGF-1,or GDF-7 treatment.However,TGF-β1 and GDF-7 could increase the cell proliferation in the 3D culture.Strangely,we also found more dead cells in the BMSC-collagen sponge constructs that were treated with TGF-β1.Moreover,TGF-β1
