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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.
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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.
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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.
ABSTRACT
This study was aimed to study the therapeutic material basis of Xiong-Shao decoction (XSD) on hepatic fi-brosis (HF), and to screen the effective parts from XSD for regulating TGF-β/Smad pathway. Male Wistar rats were randomly divided into the normal group, the model group, the Fu-Zheng Hua-Y u (FZHY) capsule group, the XSD group, the crude polysaccharide group, the total glycosides group, and the total alkaloids group. Rats of the modeling group were intraperitoneally injected with dimethylnitrosamine (DMN) to establish HF model. After modeling, FZHY capsule solution (0.105 g·mL-1), XSD crude polysaccharides extract solution (35.420 mg·mL-1), XSD total glycosides extract solution (25.725 mg·mL-1), and XSD total alkaloids extract solution (0.196 mg·mL-1) were administered to the corresponding treatment group by gavage once a day for 4 weeks, respectively. Rats of the normal group and the model group were given equivalent amount of normal saline by gavage once a day for 4 weeks. The treatment course was 4 weeks. The expression of TGF-β1 mRNA of the liver tissues was detected by FQ-PCR. And the protein ex-pressions of Smad3 and Smad7 were detected by western blotting analysis. The results showed that compared with the model group, there was no significant difference in the expression of Smad7 protein between the total glyco-sides group and the model group, as well as no significant difference between the total alkaloids group and the model group. Expressions of TGF-β1 mRNA and Smad3 protein of other treatment groups were significantly re-duced. And the expressions of their Smad7 protein were significantly increased (P < 0.05 or P < 0.01). It was concluded that crude polysaccharide an d total glycosides fractions were the effective parts of XSD for regulating TGF-β/Smad pathway.