Mechanism of HMGB1 in scarring after glaucoma drainage valve implantation / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To explore the dynamic expression of high mobility group box 1(HMGB1)in scar tissues after glaucoma drainage valve implantation, and to further reveal the role and possible mechanism of HMGB1 in scarring after glaucoma surgery.METHODS: A total of 60 New Zealand white rabbits were randomly divided into control group(n=20), model group(n=20, silicone implantation under conjunctival sac)and model with drug administration group(n=20, silicone implantation under conjunctival sac combined with 5-fluorouracil injection). The conjunctival tissues were collected at 4 and 8 wk after surgery. HE staining and Masson staining were used to detect the proliferation and distribution of fibroblasts and collagen fibers in conjunctival tissues. Immunohistochemistry was utilized to detect the distribution and changes of HMGB1, transforming growth factor(TGF)-β1, Smad3 and α-smooth muscle actin(SMA)in conjunctival tissues. RT-PCR and Western blot were adopted to detect the mRNA and protein expression of HMGB1, TGF-β1, Smad3 and α-SMA in conjunctival tissues.RESULTS: HE staining and Masson staining showed that the proliferation of inflammatory cells, fibroblasts and collagen fibers in the model group was significantly higher than that in the control group at both 4 and 8 wk. Meanwhile, the proliferation of fibroblasts and collagen fibers in the model with drug administration group was significantly lower than that in the model group. Immunohistochemical staining showed that the expression of HMGB1, TGF-β1, Smad3 and α-SMA protein was observed in the conjunctival tissues of the model group both 4 and 8 wk, with brown and significantly deeper staining of the model group at 8 wk. Meanwhile, the positive staining in the model with drug administration group at both 4 and 8 wk was significantly lower than that in the model group. There was positive correlations between the number of fibroblasts stained with HE and the expression of HMGB1 in the conjunctival tissue of the model group at both 4 and 8 wk(r=0.602, 0.703, all P<0.05). RT-PCR and Western blot revealed that the mRNA and protein expression levels of HMGB1, TGF-β1, Smad3 and α-SMA in the model group were significantly higher than those in the control group at both 4 and 8 wk(all P<0.05). Meanwhile, the mRNA and protein expression levels of HMGB1, TGF-β1, Smad3 and α-SMA in the model with drug administration group were significantly lower than those in the model group(all P<0.05). There was positive correlations between mRNA expressions of HMGB1 and TGF-β1, Smad3 in the model group and the model with drug administration group(all P<0.05).CONCLUSION: The expression of HMGB1 increased at a time-dependent manner after glaucoma valve implantation. HMGB1 acts an indispensable role in the initiation and progression of scar formation after glaucoma surgery, which may be involved in the regulation of TGF-β/Smad signaling pathway.

Transforming growth factor beta/Smad signaling pathway and targeted therapy of keloid scars / 中国组织工程研究

BACKGROUND:There are many studies focusing on keloid scars,but the pathogenesis is not fully understood.In recent years,there have been some new research advances in the pathogenesis of keloids,including transforming growth factor-β(TGF-β)/Smad signaling pathway,ischemic hypoxia,hypoxia-inducible factor 1(HIF-1),and mitogen-activated protein kinase(MAPK)pathway.The TGF-β/Smad pathway is now more clearly studied,and activation of the TGF-β/Smad pathway promotes the development of keloid scars. OBJECTIVE:To review the TGF-β/Smad signaling pathway and evaluate the main therapeutic strategies targeting this pathway,with the aim of contributing to the development of more effective clinical treatments. METHODS:PubMed and Web of Science,CNKI and WanFang databases were searched by computer for relevant literature published from January 2017 to April 2023 with the search terms of"keloid,fibroblasts,TGF-β/Smad,extracellular matrix,collagen,treatment measures"in English and Chinese.Seventy-two articles were finally included according to the inclusion and exclusion criteria. RESULTS AND CONCLUSION:The mechanism of TGF-β/Smad signaling pathway in the occurrence and development of keloids is summarized:TGF-β1 and TGF-β2 are overexpressed in keloids,while TGF-β3 shows antifibrotic effects.Smad2/3 and Smad1/5/8 are combined with Smad4 to form a complex that enters the nucleus and plays a fibrotic role,while Smad6/7 can inhibit keloid hyperplasia.The TGF-β/Smad signaling pathway is currently the most clearly studied pathway in keloids,and there are many pathways targeted to inhibit the activation of this pathway,which can inhibit the occurrence and development of keloids to a greater extent.Currently,there is no single clinical gold standard treatment for keloids,and inhibition of the TGF-β/Smad pathway alone cannot completely inhibit the development of keloids.A comprehensive consideration of the association between all systemic systems and keloids is needed.Although many promising targets have been identified in the fibrosis cascade,more research is needed to translate this into targeted therapies in the clinic.

Role of TGF-β/Smad signaling pathway in diabetic kidney disease and research progress of traditional Chinese medicine intervention / 中国中药杂志

Diabetic kidney disease is an important microvascular complication of diabetes and the leading cause of end-stage renal disease. Its pathological characteristics mainly include epithelial mesenchymal transition(EMT) in glomerulus, podocyte apoptosis and autophagy, and damage of glomerular filtration barrier. Transforming growth factor-β(TGF-β)/Smad signaling pathway is specifically regulated by a variety of mechanisms, and is a classic pathway involved in physiological activities such as apoptosis, proliferation and differentiation. At present, many studies have found that TGF-β/Smad signaling pathway plays a key role in the pathogenesis of diabetic kidney disease. Traditional Chinese medicine has significant advantages in the treatment of diabetic kidney disease for its multi-component, multi-target and multi-pathway characteristics, and some traditional Chinese medicine extracts, traditional Chinese medicines and traditional Chinese medicine compound prescription improve the renal injury of diabetic kidney disease by regulating TGF-β/Smad signaling pathway. This study clarified the mechanism of TGF-β/Smad signaling pathway in diabetic kidney disease by expounding the relationship between the key targets of the pathway and diabetic kidney disease, and summarized the research progress of traditional Chinese medicine in the treatment of diabetic kidney disease by interfering with TGF-β/Smad signaling pathway in recent years, to provide reference for drug research and clinical treatment of diabetic kidney disease in the future.

Amygdalin Ameliorates Liver Fibrosis through Inhibiting Activation of TGF-β/Smad Signaling / 中国结合医学杂志

OBJECTIVE@#To observe the effect of amygdalin on liver fibrosis in a liver fibrosis mouse model, and the underlying mechanisms were partly dissected in vivo and in vitro.@*METHODS@#Thirty-two male mice were randomly divided into 4 groups, including control, model, low- and high-dose amygdalin-treated groups, 8 mice in each group. Except the control group, mice in the other groups were injected intraperitoneally with 10% carbon tetrachloride (CCl4)-olive oil solution 3 times a week for 6 weeks to induce liver fibrosis. At the first 3 weeks, amygdalin (1.35 and 2.7 mg/kg body weight) were administered by gavage once a day. Mice in the control group received equal quantities of subcutaneous olive oil and intragastric water from the fourth week. At the end of 6 weeks, liver tissue samples were harvested to detect the content of hydroxyproline (Hyp). Hematoxylin and eosin and Sirius red staining were used to observe the inflammation and fibrosis of liver tissue. The expressions of collagen I (Col-I), alpha-smooth muscle actin (α-SMA), CD31 and transforming growth factor β (TGF-β)/Smad signaling pathway were observed by immunohistochemistry, quantitative real-time polymerase chain reaction and Western blot, respectively. The activation models of hepatic stellate cells, JS-1 and LX-2 cells induced by TGF-β1 were used in vitro with or without different concentrations of amygdalin (0.1, 1, 10 µmol/L). LSECs. The effect of different concentrations of amygdalin on the expressions of liver sinusoidal endothelial cells (LSECs) dedifferentiation markers CD31 and CD44 were observed.@*RESULTS@#High-dose of amygdalin significantly reduced the Hyp content and percentage of collagen positive area, and decreased the mRNA and protein expressions of Col-I, α-SMA, CD31 and p-Smad2/3 in liver tissues of mice compared to the model group (P<0.01). Amygdalin down-regulated the expressions of Col-I and α-SMA in JS-1 and LX-2 cells, and TGFβ R1, TGFβ R2 and p-Smad2/3 in LX-2 cells compared to the model group (P<0.05 or P<0.01). Moreover, 1 and 10 µmol/L amygdalin inhibited the mRNA and protein expressions of CD31 in LSECs and increased CD44 expression compared to the model group (P<0.05 or P<0.01).@*CONCLUSIONS@#Amygdalin can dramatically alleviate liver fibrosis induced by CCl4 in mice and inhibit TGF-β/Smad signaling pathway, consequently suppressing HSCs activation and LSECs dedifferentiation to improve angiogenesis.

Regulation of the TGF-β type I Receptor/Smad Pathway Inhibits Renal Fibrosis by Shenkang Injection / 世界科学技术-中医药现代化

Objective Chinese herbal injections called Shenkang injections(SKI)have become widely used for treating chronic kidney disease in the clinic.An investigation into the underlying mechanisms of SKI inhibition of renal tubular epithelial cell trans differentiation treated with TGF-β1 was carried out in this study.Methods To create an in vitro model of RF,HK-2 cells were treated with TGF-1(10 ng·mL-1)at 37℃for 48 h.After the cells were treated with SKI for 48 h,the morphology of the cells was observed by electron microscope.And Western blot,RT-PCR and immunofluorescence techniques were used to detect α-Smooth muscle actin(α-SMA),type III collagen(COI-Ⅲ),TGF-β1,Smad3,Smad7 and TβR-I expression changes of proteins and genes.Results SKI can significantly reduce expressed proteins and genes related to renal fibrosis,such as α-Smooth muscle actin(α-SMA)and type Ⅲ collagen(COI-Ⅲ).SKI control the production of proteins associated with the TGF-β/Smad signaling pathway.By downregulating TGF-β1,Smad3,and TβR-I protein expression,as well as upregulating Smad7 protein expression,it is able to prevent cell trans differentiation.Conclusions SKI can inhibit renal tubular epithelial cell mesenchymal trans differentiation.In addition,this drug may prevent chronic kidney disease by downregulating the expression of TβR-I and regulating the TGF-β/Smad pathway-related molecules.

Research progress on the influence of TGF-β/Smad signaling pathway on host T cell immune responses in parasite infection / 中华地方病学杂志

Parasitic infection are an important global public health issue, and parasites can modulate and evade host immune attacks through various ways. In recent years, studies have shown that in the process of parasite infection, transforming growth factor-β (TGF-β)/Smad signaling pathway participates in host T cell immune response, induce T cells to proliferate and differentiate towards regulatory cells (Treg) and helper T cells (Th), regulate Treg/Th17 cell balance, inhibit Th1 cell proliferation and differentiation, and play an important role in the occurrence and development of parasitic diseases and their interactions with the host. This article reviews the research progress of T cell immune responses mediated by TGF-β/Smad signaling pathway in the process of parasite infection.

Mechanism study of IGHG1 on proliferation,apoptosis,and invasion of THP-1 cells in acute myeloid leukemia / 中国比较医学杂志

Objective To investigate the expression of immunoglobulin γ-1 heavy chain constant region(IGHG1)in acute myeloid leukemia(AML)THP-1 cells and its influence on cell proliferation,apoptosis,and invasion via its regulation of the transforming growth factor β(TGF-β)/Smad pathway.Methods Bone marrow specimens from nine children with AML and eight children with fractures,human bone marrow stromal HS-5 cells,and human AML THP-1 and HL60 cells were used in the research.Western blot was used to detect IGHG1 protein expression.THP-1 cells were divided into a blank group(without any treatment),si-NC group,si-IGHG1-1 group,si-IGHG1-2 group,si-IGHG1-3 group,TGF-β group,si-IGHG1-1+TGF-β group,and si-IGHG1-1+TGF-β +LY364947 group.Cell proliferation was measured by CCK-8 method.Flow cytometry and Transwell experiment were performed to measure apoptosis and invasion.Western blot was used to detect the protein expression of IGHG1,TGF-β,p-Smad2 and p-Smad3 in each group of cells.Results Compared with the bone marrow of children with fractures,the bone marrow of children with AML(P<0.05)had significantly higher expression levels of IGHG1((0.24±0.03)vs(0.87±0.12)).Compared with HS-5 cells,human AML THP-1 and HL60 cells had significantly increased expression levels of IGHG1((0.89±0.14)(0.75±0.08)vs(0.21±0.02))(P<0.05).Compared with the blank group,the si-IGHG1-1 group of THP-1 cells showed significantly reduced OD450 values(24 h,48 h,72 h),invading cell numbers and protein expression of TGF-β,p-Smad2,p-Smad3 and their apoptosis rate was increased(P<0.05),while the corresponding indexes showed the opposite trend in the TGF-β group(P<0.05).TGF-β reversed the effects of silencing IGHG1 on the proliferation,apoptosis and invasion of THP-1 cells.Compared with the si-IGHG1-1+TGF-β group,the si-IGHG1-1+TGF-β+LY364947 group had significantly decreased TGF-β,p-Smad2,p-Smad3 and protein levels,OD450 values and cell invasion numbers and the apoptosis rate was increased(P<0.05).Conclusions IGHG1 is highly expressed in AML cells.Silencing the IGHG1 gene can inhibit the proliferation and invasion of AML cells and promote the apoptosis of AML cells.This mechanism may be related to the inhibition of the TGF-β/Smad pathway.

Functions of key genes involved in TGF-β/Smad signaling pathway in progression of pulmonary fibrosis / 环境与职业医学

Background Although transforming growth factor-β (TGF-β)/Smad signaling pathway is important in regulating the occurrence and development of pulmonary fibrosis, the pathogenesis of pulmonary fibrosis remains elusive. Objective To explore the functions of genes associated with TGF-β/Smad signaling pathway in the progression of pulmonary fibrosis. Methods A NIH-3T3 fibroblast model induced by TGF-β1 was established. The experiment samples were divided into a control group and a TGF-β1 treatment group. The control group was exposed to normal saline, while the TGF-β1 treatment group was exposed to 10 ng·mL−1 TGF-β1 for 12 h. The RNAs of the two groups were extracted, sequenced, and analyzed by bioinformatics methods to identify seven key genes in TGF-β pathway, including Dcn, Smad3, Smad7, Fbn1, Thbs1, TGF-β1, and TGF-β3. The gene expression levels of five markers [Collagen1α1, Collagen1α2, α-smooth muscle actin (α-SMA), TGF-β1, and TGF-β3] and the seven key genes were detected by quantitative real-time PCR (qRT-PCR). The proteins of the two groups were extracted. The important marker protein expression levels of Smad3, the phosphorylation of Smad3 (P-Smad3), and α-SMA were detected by Western blotting. At the same time, 30 healthy SPF-grade C57BL/6 mice were randomly divided into three groups, with 10 mice in each group: a control group, a SiO2 inhalation exposure group for 28 d (10 mice), and a SiO2 inhalation exposure group for 56 d (10 mice). The mice in the two treatment groups were exposed to a natural SiO2 environment for 4 h per day with a 10-min pause for breathing fresh air at 2 h intervals. The lung tissues of the mice were taken after execution. The changes of pulmonary fibrosis were detected by Masson staining, and mRNAs and proteins were extracted to detect the expression of the above key genes and proteins. Results The expression levels of the five marker genes Collagen1α1, Collagen1α2, α-SMA, TGF-β1, and TGF-β3 were significantly increased in the TGF-β1-induced NIH-3T3 fibroblasts than those in the control group (P < 0.01); the expression levels of P-Smad3 and α-SMA proteins increased significantly (P < 0.01); the expression results of the seven key genes screened in the TGF pathway were that Dcn and Smad3 were obviously down-regulated (P < 0.01), and Smad7, Fbn1, Thbs1, TGF-β1, and TGF-β3 were obviously up-regulated (P < 0.01). The changes in gene expression levels of the transcriptome sequencing showed the same trend. The results of Masson staining showed that the content of collagen fibers in the lung tissues also increased in the SiO2 inhalation exposure groups over time. In the mouse experiment, five marker genes were obviously up-regulated compared with the control group (P < 0.01); no obvious change was found in the expression of Smad3 protein, and the expression levels of P-Smad3 and α-SMA were obviously higher in the SiO2 exposure groups than those in the control group (P < 0.01); the expression levels of Dcn and Smad3 showed a down-regulated trend, while the expression levels of Smad7, Fbn1, Thbs1, TGF-β1, and TGF-β3 showed an up-regulated trend with the increase of SiO2 inhalation exposure days (P < 0.01). The expression levels of the above five marker genes, three important marker proteins, and seven key genes were consistent with the expression trends of TGF-β1-induced NIH-3T3 fibroblasts. Conclusion The expression levels of pulmonary fibrosis-related marker genes and proteins change significantly in TGF-β1-induced fibroblast cells, and the lung tissues of mice under natural SiO2 inhalation exposure has obvious fibrosis characteristics. Seven genes (Dcn, Smad3, Smad7, Fbn1, Thbs1, TGF-β1, and TGF-β3) may be involved in the regulation of pulmonary fibrosis by the TGF-β/Smad signaling pathway.

Sanwubai San Inhibits TGF-β1 Induced Epithelial Mesenchymal Transition of Human Gastric Cancer SGC-7901 Cells Through TGF-β/ Smad Pathway / 中国实验方剂学杂志

ObjectiveTo study the effect of serum containing Sanwubai San on TGF-β1 induced epithelial mesenchymal transition （EMT） of human gastric cancer SGC-7901 cells and its mechanism in vitro based on transforming growth factor-β/Smad（TGF-β/Smad）signaling pathway. MethodTwenty-eight male SD rats （SPF grade， three months） were randomly divided into blank group and Sanwubai low （0.031 25 g·kg-1·d-1， ig）， medium （0.062 5 g·kg-1·d-1， ig） and high （0.125 g·kg-1·d-1， ig） dose groups， seven in each group. The blank group was given the same volume of ultrapure water （ig）. The gavage was performed once a day for seven consecutive days. The serum containing the drug was taken from the abdominal aorta 45 min after the last administration. Cell counting kit-8 （CCK-8） method was used to detect the effect of serum in Sanwubai San high dose group on the activity of SGC-7901 cells. Changes of cell morphology after treatment with TGF-β1 and serum containing Sanwubai San were observed by microscopy， and the migration rate and invasion rate of the SGC-7901 cells were detected by cell scratch assay and transwell assay， respectively. Western blot was used to detect the expression of E-cadherin， snail， TGF-β1， Smad3， p-Smad3 and Smad7 proteins. ResultCompared with the blank group， 10%， 15% and 20% high-dose Sanwubai San inhibited the activity of SGC-7901 cells in a concentration and time dependent manner. Compared with the conditions in the blank group， the cells in the model group lost spindle shape， and most cells became round and long. Compared with the model group， the Sanwubai San groups had decreased pseudopodia and small cells with the morphology returning to normal. Compared with the conditions in the blank group， enhanced ability of cell migration and invasion （P<0.01）， lowered expression of E-cadherin and Smad7 （P<0.01）， and increased expression of Snail， p-Smad3 and TGF-β1 （P<0.01） were found in the model group， with the total protein level of Smad3 remaining unchanged. Compared with the conditions in the model group， the cell migration ability was inhibited in the Sanwubai San high and medium dose groups （P<0.01） after 24 h， and the ability was inhibited in all three Sanwubai San groups after 48 h （P<0.01）， while the invasion ability was enhanced. In addition， the Sanwubai San high and medium dose groups had elevated expression of E-cadherin （P<0.01） and Smad7 （P<0.01）， and decreased expression of Snail （P<0.01）， and the expression of TGF-β1 and p-Smad3 was down-regulated in the three Sanwubai San groups （P<0.01）. ConclusionSanwubai San could inhibit TGF-β1 induced EMT in SGC-7901 cells， and its mechanism might be related to the regulation of TGF-β/Smad signaling pathway.

Ligustroflavone ameliorates CCl / 中国天然药物

Liver fibrosis is a pathological process characterized by excess deposition of extracellular matrix (ECM) that are mainly derived from activated hepatic stellate cells. Previous studies suggested that ligustroflavone (LF) was an ingredient of Ligustrum lucidum Ait. with activities of anti-inflammation and anti-oxidation. In this study, we investigated whether LF had any effect on liver fibrosis. In our study, we established a mouse model of carbon tetrachloride (CCl

Study on the Effect and Mechanism of Total Flavonoids from Marchantia convoluta on the Anti-hepatic Fibrosis in Mice / 中国药房

OBJECTIVE：To study the effect and potential mechanism of the total flavonoids from Marchantia convoluta on anti-hepatic fibrosis in the mice. METHODS ：Seventy-two mice were randomly divided into blank group ，model group ，positive control group （colchicine 0.2 mg/kg）and M. convoluta total flavonoids high-dose ，medium-dose and low-dose groups （300，150， 75 mg/kg），with 12 mice in eac group. Except for blank group ，other groups were subcutaneously given 25％ CCl4-peanut oil solution on the back to induce liver fibrosis model. At the same time ，blank group and model group were given water intragastrically，while other groups were given relevant medicine intragastrically 20 mL/kg，once a day ，for consecutive 10 weeks. After last administration ，the serum levels of ALT and AST were detected . Histopathological changes of liver tissue in mice was observed. The levels of COL- Ⅰ，COL-Ⅲ and TGF-β1 in liver tissue were detected . The protein expression levels of α-SMA and TGF-β1，Smad2，Smad4 and Smad 7 in liver tissue were detected . The expression levels of TGF-β1，Smad2，Smad4 and Smad 7 mRNA in liver tissue were detected . RESULTS ：Compared with blank group ，the serum levels of ALT and AST in model group，the levels of COL- Ⅰ，COL-Ⅲ and TGF-β1 in liver tissue，protein expression levels of α-SMA，TGF-β1，Smad2 and Smad 4，mRNA expression levels of TGF-β1，Smad2 and Smad4 were increased significantly （P＜0.05 or P＜0.01）.The mRNA and protein expression levels of Smad 7 in liver tis sue were decreased significantly （P＜0.05）. The degree of liver tissue injury and collagen fiber hyperplasia were serious. Compared with model group ，above indexes of mice were reversed significantly in positive control group and M. convoluta total flavonoids high-dose group （P＜0.05 or P＜0.01）. Serum level of ALT ，the levels of COL- Ⅰ，mRNA and protein expression of TGF-β1，Smad2 and Smad 4 in liver tissue were decreased significantly in M. convoluta total flavonoids medium-dose group （P＜0.05 or P＜0.01）. Protein expression of Smad 2 and Smad 4 in liver tissue were decreased significantly in M. convoluta total flavonoids low-dose group （P＜0.05）. The liver injury and fibrosis of mice were relieved in administration groups. CONCLUSIONS ：M. convoluta total flavonoids possess the effect of anti-hepatic fibrosis ，the mechanism of which is related to the regulation of mRNA and protein expression of TGF-β1，Smad2，Smad4 and Smad 7 in the signaling pathway of TGF-β/Smad.

Role of osteogenic signaling pathway in non-traumatic femoral head necrosis / 中国组织工程研究

BACKGROUND: In recent years, the incidence of non-traumatic femoral head necrosis has increased gradually. It has the characteristics of insidious onset, rapid development of disease and high disability rate, bringing a great burden to patients, their families and society. Confirming its pathogenesis is of great significance for the early effective treatment of non-traumatic femoral head necrosis. OBJECTIVE: To review the relevant literature worldwide and to summarize the research progress of osteogenic signaling pathways in the pathogenesis of non-traumatic femoral head necrosis. METHODS: PubMed, Embase, Medline, CNKI, VIP and WanFang databases were retrieved with the keywords of “non-traumatic osteonecrosis of femoral head, osteogenesis, signaling pathways, pathogenesis, Wnt/β-catenin, PPARy, TGF-β/Smad, PI3K/AKT, MAPK, Notch” in English and Chinese, respectively. The articles concerning mechanism and application of osteogenic signaling pathways associated with avascular necrosis of the femoral head were included. RESULTS AND CONCLUSION: Recently, the role of osteogenic signaling pathways in non-traumatic femoral head necrosis has received increasing attentions. The abnormal differentiation of bone marrow mesenchymal stem cells in the development of non-traumatic femoral head necrosis has also become an issue of concern. Abnormal differentiation of bone marrow mesenchymal stem cells, inhibition of osteogenic differentiation, increased bone destruction, and imbalance of bone metabolism may be the main cause of non-traumatic femoral head necrosis, and Wnt/β-catenin, PPARy, TGF-β/Smad, PI3K/AKT, MAPK, Notch and other osteogenic signaling pathways may be a viable approach to intervention for non-traumatic femoral head necrosis. Although a large number of in vitro and animal studies have confirmed that osteogenic signaling pathway may have the potential to regulate bone marrow mesenchymal stem cell differentiation and reverse femoral head necrosis, its specific mechanism of action remains unclear and little is reported on its clinical applications. Therefore, exploring the mechanism of signaling pathways and accelerating its clinical use are the directions of the future research.

Transcriptional co-activator p300 participates in atrial fibrosis induced by high hydrostatic pressure by regulating TGF-β/Smad3 signaling pathway / 中国药理学通报

Aim To investigate the role and potential mechanism of transcriptional co-activator p300 in atrial fibrosis caused by high hydrostatic pressure. Methods The left atrial appendage tissues of humans in three groups of sinus rhythm, atrial fibrillation (AF), hypertension and AF were collected. The expressions of p300 protein and TGF-β/Smad3 signaling pathway and fibrotic factors as type I/III collagen Alphal chain (Col-lAl/Col-3Al), matrix metalloproteinase 2/9 (MMP-2/9) were tested by Western blot. Mouse atrial appendage fibroblasts were cultured under hydrostatic pressures of 0, 20 and 40 mmHg. The fibroblasts cultured under 40 mmHg pressure were treated with curcumin and p300 interference RNA. Western blot was used to test changes in the expression of p300 and the above fibrosis indicators. CCK-8 method was used to test changes of cell proliferation. Results The expressions of p300 and TGF-β/Smad3 signaling pathway proteins and fibrotic factors in AF group and hypertension combined with AF group were significantly higher than those in sinus rhythm group (P < 0. 05). 40 mmHg high hydrostatic pressure stimulation in vitro could increase the expression of p300 and fibrotic factors in fibroblasts (P < 0. 0 5) and enhance the proliferation ability (P < 0. 05). Both curcumin and p300 interfering RNA could reverse the increased expression of p300 and fibrotic factors (P < 0. 05) and decrease cell proliferation (P < 0. 05) induced by hydrostatic pressure. Conclusions High hydrostatic pressure can induce atrial fibrosis, which involves the participation of p300 in this process by regulating the TGF-β/Smad3 signaling pathway.

Mechanism of Biejia Jianwan in Suppressing Epithelial-mesenchymal Transition in DEN-induced Rat Hepatocellular Carcinoma via TGF-β/Smad Pathway / 中国实验方剂学杂志

Objective:To study the effect of Biejia Jianwan on expressions of signal molecules and target genes of transforming growth factor-β (TGF-β)/Smad pathway in diethylnitrosamine (DEN)-induced rat hepatocellular carcinoma, and explore the mechanisms of Biejia Jianwan suppressing the invasion of hepatocellular carcinoma. Method:The rats were divided into three group, namely normal group, model group and Biejia Jianwan group (2.2 g·kg-1·d-1). Rats in Biejia Jianwan group and model group received intraperitoneal injections of DEN to induce sequential chronic inflammation, cirrhosis and hepatocellular carcinoma. At the sign of cirrhosis, rats in Biejia Jianwan group began taking Biejia Jianwan by gavage for 6 weeks. Rat blood was collected to measure serum levels of biochemical markers of liver function tests, including alanine aminotransferase(ALT), aspartate aminotransferase(AST), total bilirubin(TBIL), albumin(Alb), γ-glutamyl transpeptadase(GGT), alkaline phosphatase(ALP). Rat livers were fixed in formalin and stained with hematoxylin-eosin (HE)staining， quantitative real-time PCR was used to test the mRNA expressions of TGF-β1， and Western blot was used to test protein expressions of TGF-β1, Smad2/3, p-Smad2/3, N-cadherin, E-cadherin and Vimentin. Result:All of the levels of biochemical markers showed no difference in Biejia Jianwan group and model group. Biejia Jianwan could improve the pathological changes of balloon-like degeneration, edema, and necrosis in liver cancer tissues. Importantly, the treatment dramatically decreased the mRNA expression of TGF-β1(P<0.01), and the protein expressions of TGF-β1, p-Smad2(P<0.01). Besides, the protein expression of N-cadherin and Vimentin were decreased significantly (P<0.01). Conclusion:Biejia Jianwan can inhibit epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma cells activated via TGF-β/Smad pathway by reducing TGF-β1 expression, so as to suppress the metastasis and invasion of hepatocellular carcinoma.

Study on the Protective Effects of Schisandrin A on Hepatic Fibrosis Induced by Carbon Tetrachloride in Mice and Its Mechanism / 中国药房

OBJECTIVE：To study the pr otective effect of schisandrin A （SA）on CCl 4-induced liver fibrosis model mice and its mechanism. METHODS ：Mice were randomly divided into blank control group ，model group ，silymarin group （positive control，100 mg/kg），SA low-dose and high-dose groups （20，40 mg/kg），with 10 mice in each group. Except for blank control group，other groups were given CCl 4 subcutaneously to induce liver fibrosis model. After successful modeling ，administration groups were given relevant medicine intragastrically ，once a day ，for consecutive 6 weeks；blank control group and model group were given constant volume of 0.5％sodium carboxymethyl cellulose solution intragastrically by the same way. HE staining was used to observe the pathological changes of liver tissue in mice. UV spectrophotometry and ELISA assay were adopted to detect the serum levels of liver injury indexes （ALT and AST ）and the contents of inflammatory factors （TNF-α，IL-1β，IL-6）. Western blotting assay was used to detect the expression of NOD like receptor protein 3（NLRP3）/NF-κB and TGF-β/Smad signaling pathway protein. RESULTS ：Compared with blank control group ，obvious pathological changes of liver fibrosis were observed in model group. The serum levels of liver injury indexes and contents of inflammatory factors were significantly increased （P＜0.01）. The expression of NLRP 3，apoptosis associated spot-like protein ，Caspase-1 and IL- 1β，TGF-β1 and ratios ofp-NF-κB p65/NF-κB p65，p-IκBα/IκBα，p-Samd3/Smad3 were increased significantly （P＜0.01）. Compared with model group ，SA could significantly relieve hepatic fibrosis in mice ，reduce serum levels of liver injury indexes and contents of inflammatory factors ，as well as the expression of NLRP 3/NF-κB and TGF-β/Smad signaling pathway protein and phosphorylation level（P＜0.01）. CONCLUSIONS ： SA can effectively relieve liver injury and inflammation of CCl 4-induced hepatic fibrosis model mice ，which may be through the regulation of NLRP 3/NF-κB and TGF-β/Smad3 signaling pathways ，thus inhibiting the process of liver fibrosis.

Research progress on the promoting effect of interleukin-11 on tumors / 上海交通大学学报（医学版）

According to the lastest statistics, the overall morbidity and mortality of cancer in China still show an upward trend compared with historical data. An in-depth understanding of the molecular mechanisms of tumorigenesis and development is important to formulate future treatment strategies. Interleukin 11 (IL-11) is a member of cytokines that traditionally promote megakaryocyte maturation and regulate immune activity. In recent years, the promoting effect of IL-11 on tumor has been gradually discovered. This review mainly expounds that IL-11 is regu-lated by transforming growth factor-β/drosophila mothers against decapentaplegic protein (TGF-β/Smad) pathway, and may play a role in tumor-igenesis, drug resistance, metastasis and tumor microenvironment through signal transduction pathways such as Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) pathway, and explores the application prospect of interfering IL-11 signal transduction in tumor therapy.

Comparison of in-vitro anti-fibrotic effects of pirfenidone and nintedanib / 中国药理学通报

Aim To compare the mechanism of action of currently marketed pulmonary fibrosis drugs at the cellular level by evaluating the inhibitory effects of pirfenidone and nintedanib on the proliferation, migration and activation of human embryonic lung fibroblast HFL1. Methods The inhibitory effects of pirfenidone and nintedanib on TGF-β1/PDGF-induced HFL1 proliferation, migration and activation were evaluation of by MTT, scratch test,Q-PCR and Western blot. Results MTT, scratch test results showed that both pirfenidone and nintedanib could inhibit TGF-β1-induced fibroblast proliferation and migration, in which nintedanib had a higher titer than pirfenidone. In anti-activation experiments, both pirfenidone and nintedanib inhibited the expression of fibroblast activation markers mRNA and protein, and both inhibited the phosphorylation of Smad3 and inhibited the activation of TGF-β/ Smad3 signaling pathway. Nintedanib had a stronger inhibitory effect on TGF-β/Smad3 signaling pathway, which exerted 51 % inhibitory rate on Smad3 phosphorylation compared with 13% inhibitory rate of pirfenidone. Conclusions Both pirfenidone and nintedanib can inhibit the proliferation, migration and activation of myofibroblasts, where nintedanib has a higher inhibitory potency than pirfenidone does, and the inhibition of TGF-β/Smad3 signaling pathway is stronger.

Effects of Ivermectin on Migration and Invasion of Human Gastric Cancer Cells BGC- 823 and MGC- 803 and Its Mechanism / 中国药房

OBJECTIVE： To study the effects of ivermectin on the migration and invasion of human gastric cancer cell lines BGC-823 and MGC-803 and its mechanism. METHODS： After treated with 0， 2.5， 5， 10， 20， 40 μmol/L ivermectin for 24 h， inhibitory rate of human gastric cancer cell lines BGC-823 and MGC-803 were detected by MTT assay. Effects of 5 μmol/L ivermectin and phosphate buffercontaining 0.67‰ dimethyl sulfoxide （control group） for 24 h on the migration and invasion of` gastric cancer cells BGC-823 and MGC-803 were observed by Transwell chamber invasion assay.Western blot assay was used to detect the protein expression of TGF-β1， TGF-βR， Smad2 and Smad3 in epithelial-mesenchymal transition （EMT） markers E-cadherin， N-cadherin， Vimentin， Snail and EMT transduction pathway TGF-β/smad of BGC-823 and MGC-803 cells after treated with 5， 10 μmol/L ivermectin and phosphate buffercontaining 0.67‰ dimethyl sulfoxide （control group） for 24 h. RESULTS： Ivermectin could inhibit the growth of BGC-823 and MGC-803， inhibitory rate of it was positively correlated with its concentration. Compared with control group， the number of migration and invasion BGC-823 and MGC-803 cells were decreased significantly after treated with 5 μmol/L ivermectin （P＜0.01 or P＜0.001）； the expression of E-cadherin protein was enhanced significantly in BGC-823 and MGC-803 cells after treated with 5 and 10 μmol/L ivermectin （P＜0.05 or P＜0.01 or P＜0.001）； the protein expression of N-cadherin， Vimentin， Snail， TGF-βR， Smad2 and Smad3 were decreased significantly （P＜0.05， P＜0.01 or P＜0.001）； protein expression of TGF-β1 was decreased significantly after treated with 10 μmol/L ivermectin （P＜0.05）. CONCLUSIONS： Ivermectin can significantly inhibit the migration and invasion of gastric cancer cells BGC-823 and MGC-803， and inhibiting the biological activity of EMT by reducing the expression of TGF-β/smad pathway is one of the mechanisms that inhibit the migration and invasion of gastric cancer cells.

Licochalcone A in Inhibiting Bleomycin-induced Pulmonary Fibrosis Through TGF-β/Smad Pathway / 中国实验方剂学杂志

Objective: To explore the therapeutic effect of licochalcone A (Lico A) on pulmonary fibrosis (PF). Method: Thirty mice were divided into five group, namely sham, model, Lico A (15, 30 mg·kg-1) and pirfenidone (300 mg·kg-1) groups. All of the groups except for sham group were intratracheally given bleomycin (BLM, 5 mg·kg-1). The sham group was given normal saline. On day 2, the mice were treated with Lico A and pirfenidone, respectively. On day 28, all of the mice were put to death. Then, lung tissues were collected and weighted. Pathological changes in lung tissue were measured by htoxylin eosin(HE) and Masson staining. The α-smooth muscle actin(α-SMA), Collagen I, fibronectin p-Smad2/3 and Smad2/3 were analyzed by Western blot. Then, transforming growth factor-β1 (TGF-β1)-induced MRC-5 cells were employed for evaluating the inhibitory activity of Lico A in vitro. Result: Compared with normal group, several pathological changes, including alveolar space collapse, emphysema, infiltration of inflammatory cells, and collagen deposition were observed in the BLM-treated mice, and these pathological changes were markedly attenuated by subsequent treatment with Lico A. Lico A could significantly inhibit BLM-induced up-regulation of α-SMA and Collagen I and phosphorylation of Smad2/3 in lung tissues of mice(PPβ-induced α-SMA and fibronectin expression in MRC-5 cells(PPConclusion: The preliminary mechanisms of the anti-fibrosis effect of Lico A may inhibit TGF-β/Smad pathway.

Recent advances in signaling pathways related to choroidal neovascularization / 国际眼科杂志(Guoji Yanke Zazhi)

@#Choroid neovascularization is the characteristic pathological change of many fundus diseases and is the most common cause for severe vision loss and metamorphopsia. Among the pathogenic factors, VEGF is considered to be the most important and treatment targeting VEGF showed promising results. However, anti-VEGF agents need to be administrated frequently and they are usually expensive. Also, some patients got no response to this treatment. These facts force us to find other pathway that involves in the formation of CNV. This article reviews the latest research on CNV-related signaling pathways so as to provide a deeper look into CNV and hopefully point out new directions for treating diseases that share similar pathogenesis.