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Pulmonary fibrosis(PF)is an irreversible lung disease that is characterized by excessive scar tissue with a poor median survival rate of 2-3 years.The inhibition of transforming growth factor-β receptor type-Ⅰ(TGF-β RI)by an appropriate drug may provide a promising strategy for the treatment of this disease.Polygonum cuspidatum(PC)is a well-known traditional Chinese herbal medicine which has an anti-PF effect.Accordingly,a combination of high resolution mass spectrometry with an in silico strategy was developed as a new method to search for potential chemical ingredients of PC that target the TGF-β RI.Based on this strategy,a total of 24 ingredients were identified.Then,absorption,distribution,meta-bolism,and excretion(ADME)-related properties were subsequently predicted to exclude compounds with potentially undesirable pharmacokinetics behaviour.Molecular docking studies on TGF-β RI were adopted to discover new PF inhibitors.Eventually,a compound that exists in PC known as resveratrol was proven to have excellent biological activity on TGF-β RI,with an ICso of 2.211 μM in vitro.Furthermore,the complex formed through molecular docking was tested via molecular dynamics simulations,which revealed that resveratrol had strong interactions with residues of TGF-β RI.This study revealed that resveratrol has significant potential as a treatment for PF due to its ability to target TGF-β RI.In addition,this research demonstrated the exploration of natural products with excellent biological activities toward specific targets via high resolution mass spectrometry in combination with in silico technology is a promising strategy for the discovery of novel drugs.
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The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon-
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Transforming growth factor-β (TGF-β) belongs to a group of biologically active cytokines that bind to its receptors to activate Smad signaling and non-Smad signaling pathways. The biological functions of TGF-β include promoting cell epithelial-mesenchymal transition, tissue fibrosis, angiogenesis and tumor immune evasion, as well as dual effects of cancer suppression and cancer promotion. Given the fact that the ligand- and receptors-mediated abnormal activation of TGF-β signaling pathways play an important role in the pathogenesis of multiple diseases such as malignant tumors and tissue fibrosis, more than a dozen small-molecule inhibitors have been developed to block the TGF-β signaling pathways, providing a novel method for controlling the development of these diseases. At present, pirfenidone, an inhibitor for TGF-β production, has been approved for treatment of idiopathic pulmonary fibrosis, while the inhibitors of TGFβRI/ALK5 for therapeutics of tumors or myelodysplastic syndromes, including LY2157299, EW-7197 and LY3200882, are in the phase I to III clinical trials, with additional ones inhibiting TGFβRs such as SB-431542, LY2109761, TP-0427736, and IN-1130 being in the preclinical phase. This paper reviews recent advances in research of small-molecule inhibitors targeting TGF-β and its receptors.
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Aim To investigate the role of TGF-β/Smads signaling pathway in the improvement of myo-cardial fibrosis in diabetes mellitus by curcumin. Methods A model of type 2 diabetes mellitus was in-duced by intraperitoneal injection of small dose of streptozotocin (STZ) 35 mg·kg-1with a high glucose and high fat diet, and then intervened by drinking of 300 mg·kg·d-1curcumin. The expression of myo-cardial collagen in rats was detected by Sirius red stai-ning. The expressions of Collange I and Collagen III in myocardium of rats were detected by immunofluores-cence. Cardiac fibroblasts(CFs) in neonatal rats were stimulated by different concentrations of glucose(5.5, 20,25, 30, 35, 50 mmol·L-1) for 24 h to deter-mine the optimum concentration of high glucose model, and rat CFs were stimulated for 24 h by 30 mmol·L-1 high glucose plus different concentrations of curcumin (10,25,50,100,200 μmol·L-1) to determine the optimal concentration of curcumin. The expressions of type Ⅰ and Ⅲ collagen,TGF-β1,p-Smad2,Smad2, p-Smad3,Smad3 and TβR-Ⅲin CFs were detected by Western blot. Results Compared with the control rats,the collagen deposition in the myocardium of the diabetic rats was more obvious and the expression of Collagen Ⅰ and Collagen Ⅲ significantly increased. After treatment of curcumin,the collagen deposition in the myocardium and the expression of Collagen I and CollagenⅢof diabetic rats remarkably decreased. The CFs under the condition of 30 mmol·L-1high glucose and 24 h had the highest survival rate (P <0.05);10μmol·L-1curcumin could obviously inhibit the proliferation of myocardial fibroblasts induced by high glucose (P<0.05). After induced by 30 mmol·L-1 high glucose for 24 h, the expression of Collagen Ⅰand Collagen Ⅲ, TGF-β1, p-Smad2, Smad2, p-Smad3,Smad3 and TβR-Ⅲ proteins in CFs markedly increased(P <0.05), and the expression levels of these proteins were obviously reduced when treated with 25 μmol·L-1curcumin. Conclusion Curcumin could ameliorate myocardial fibrosis in diabetic rats through TGF-β/Smads signaling pathway, exerting the protective effect on myocardium in diabetic rats.
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Objective: The effect of Codonopsis Radix was significantly different before and after being cooked, and to study the content of polysaccharide and 5-hydroxymethyl furfural (5-HMF) in Codonopsis Radix after cooked with rice and its impact on rabbit gastrointestinal smooth muscle in vitro. Methods: Before and after being cooked, the content of polysaccharide and 5-HMF were determined with phenol sulfuric method and HPLC. BL-420F bio-functional experiment was applied to observe the impact of Codonopsis Radix processing with rice on rabbit gastrointestinal smooth muscle in vitro. Tests showed that acetylcholine (Ach), neostigmine, barium chloride (BaCl2), atropine, and adrenaline (Adr) intervened the relaxation of rabbit gastrointestinal smooth muscle in vitro. Results: The content of polysaccharide was significantly lower than pieces after cooked with rice, and the content of 5-HMF was significantly higher. After processing it can further excite spontaneous activity of gastrointestinal smooth muscle in vitro. It can enhance bowel neostigmine and BaCI2 caused intestinal excitement and tension, objecting Adr caused intestinal relaxation. Conclusion: 5-HMF was abundantly produced after Codonopsis Radix cooked with rice, caused excitability contraction on rabbit gastrointestinal smooth muscle in vitro, reproducing 5-HMF effect of gastrointestinal smooth muscle in vitro. It may be one of the material basis of Codonopsis Radix cooked with rice enhanced spleen. Its mechanism may be its collaborative control of N2R and βR results.
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Aim To investigate the effects of curcumol on the contractile activity of isolated duodenal smooth muscle in rats and explore its underlying mechanisms. Methods The isolated duodenum specimens of rats were made. The effects of different concentrations of curcumol on the contraction of isolated duodenal smooth muscle were observed using BL-420F biological and functional experimental system with constant tem-perature perfusion method. A certain concentration of curcumol was combined with atropine,isoproterenol, norepinephrine,calcium-free Krebs solution,verapam-il respectively to observe its effect on smooth muscle contraction. Results Curcumol could stimulate duo-denal smooth muscle in vitro,and increase its contrac-tile amplitude and tension significantly. It could be an-tagonized partly by atropine,isoprenaline,norepineph-rine,verapamil. Conclusion Curcumol can promote the contraction of isolated duodenal smooth muscle in rats,which may be achieved by stimulating M recep-tor,inhibiting α and β receptors,and promoting the extracellular calcium influx.
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Objective To compare the efficacy and safety of endoscopic variceal ligation (EVL) and β-receptor blockers (βB) administration for prophylaxis of primary esophageal variceal bleeding. Methods EMBASE, PubMed, CENTRAL, Wan-fang Database, CNKI database and Google Scholar were comprehensively searched in May 2015 for eligible full-text randomized controlled trials (RCTs). Endpoints of interest were first variceal bleeding, all-cause mortality, bleeding-related mortality and main adverse events. A fixed-effect model was firstly utilized to calculate the pooled odds risk (OR) with 95% confidence intervals (CIs). Results Fourteen studies involving 1 280 patients were identified fulfilled the inclusion criteria in this analysis. Compared with βB, EVL significantly reduced the incidence rate of first variceal bleeding (OR=0.67, 95%CI: 0.49-0.91,P=0.010, I2=21%). All-cause and bleeding-related mortality had no significant difference in the two groups (all-cause mortality [OR=1.14, 95%CI: 0.87-1.50, P=0.35, I2=0%] and bleeding-related mortality [OR=0.72, 95%CI: 0.44-1.17,P=0.19, I2=0%]). EVL had lower incidence rate of main adverse events than non-selective βB (OR=0.43, 95%CI: 0.29-0.64, P<0.000 1, I2=40%). However, compared with EVL, the incidence rate of main adverse events in Carvedilol was significantly lower (OR=10.59, 95%CI: 2.37-47.27, P=0.002). Conclusion EVL is more effective in preventing the primary esophageal variceal bleeding compared with βB, but the two methods have no differences in all-cause mortality or bleeding-related mortality.
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Objective To investigate the mechanism and prevention of syncope on patients with hypertrophic cardiomyopathy (HCM). Methods Seventy-six cases of HOCM (obstruction group) were successfully operated by PTSMA and oral ACEI/ARB. After six months , they were treated with β-receptor blocker. Another 29 patients (control group) with LVOTPG < 50 mmHg or < 70 mmHg after pharmacologic stress test (PST), have being treated with β-receptor blocker. The results was observed as follow: (1) the difference of between syncope incidence and positive incidence induced by PST in control group; (2) the difference of syncope incidence at half year, a year and admission in control group; (3) the difference of syncope incidence in obstruction group before and after operation; (4) the difference of syncope incidence after six months between two groups at same period; (5) the difference of syncope incidence one year between two groups. Results In control group, the syncope positive incidence induced PST was 55.5%. Treating with medications for half a year , syncope incidence significantly dropped than that on admission (P < 0.05); Obstruction group syncope incidence in the history obviously lower than the control group syncope positive induced PST (P < 0.05), and half a year after takingβ-receptor blocker syncope incidence was significantly dropped than before (P < 0.01). Conclusions The mechanism of syncope with HOCM is not only obstruction but also neuronal reflex. PST is an very useful inspection item for screening the ablation indication, analysis syncope mechanism, and guiding clinical medication.β-receptor blocker is an effective drug on treating and preventing syncope with HCM.
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ObjectiveTo observe the chronological and spatial expressions of transforming growth factor-β receptor typeⅡ(TGF-βRⅡ)and fibronectin (Fn )in developing mouse kidney and investigate the relationship between the expressions and kidney development. Methods Immunohistochemistry and Western blotting were used to observe and measure the expression of TGF-βRⅡ and Fn in embryos and postnatal mouse kidneys. Results The expression of TGF-βRⅡ was noticed in all stages of glomeruli, renal tubes and collecting ducts, and increased gradually with ages; The expression of Fn was noticed too in all stages of glomeruli, renal tubes and collecting ducts, except for the comma-shaped bodies, and also increased gradually with ages. Conclusion TGF-β and Fn might play an important role in the development and maturation of mouse kidney.
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Objective To investigate the spatiotemporal expression patterns of transforming growth factor-β(TGF-β) receptors type Ⅰ and type Ⅱ and their relationships with development of outflow tract(OFT) in mouse embryonic heart. Methods Serial sections of mouse embryos from embryonic day 9 (E9d) to embryonic day 14 (E14d) were stained using PAP immunohistochemical methods. Results Expressions of TGF-β receptors type Ⅰ (TGF-βRⅠ) and type II(TGF-βRⅡ) in the myocardial wall of OFT started at E10d, reached the reflection with splanchnic epithelium on the dorsal wall of the pericardial cavity at E11d. At E12d, expression intensity of TGF-βRⅠ and TGF-βRⅡ in myocardium increased to its highest level, and TGF-βRⅡ positive mesenchymal cells in OFT ridges could be detected. After E13d the staining intensity of TGF-βRⅠ and TGF-βRⅡ decreased rapidly,and at E14d,their expressions had fallen at the lowest.Conclusion The expressions of TGF-βRⅠ and TGF-βRⅡ in OFT are confined to the period of E10d to E14d, they may play important roles in regulating the myocardial cell proliferation, remodeling and septation of OFT, and promoting the differentiation from mesenchymal cells in the secondary heart field into smooth muscle cells in the distal end of OFT.
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AIM: To quantitatively investigate transforming growth factor-β type Ⅰ receptor (TβRⅠ) and transforming growth factor-β type Ⅱ receptor (TβRⅡ) gene expressions in rat retina.METHODS: Sprague-Dawley rats were chosen in this research. Gene expression was detected quantitatively by reverse transcription polymerase chain reaction (RT-PCR) analysis. RESULTS: The expression level of TβRⅠ and TβRⅡ were 0.00034±0.00013 and 0.0001±0.00005, respectively. The expression level of TβRⅠ was obviously higher than that of TβRⅡ in the rat retina with statistical significance (P<0.01). The ratio of TβRⅠ/TβRⅡ was 3.9±1.7.CONCLUSION: Real time quantitative RT-PCR is an effective method to detect differential expression genes in retina. The change of TβRⅠ/TβRⅡ expression may play an important role in the pathogenesis of retinopathy, which could be further investigated in its significance in the development of proliferation retinopathy.
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· AIM: To quantitatively detect gene expression level of transforming growth factor-β type 1 receptor (Tβ R 1) and transforming growth factor-β type 2 receptor (Tβ R 2) in different stage of diabetic rats' retina. To observe and analyze the effect of transforming growth factor-βreceptors on the retina of rat diabetic animal model.· METHODS: 28 healthy adult Sprague-Dawley rats were chosen and randomly divided into two groups of normal control (CON) and diabetes mellitus (DM). Diabetes was induced by streptozotocin (STZ) intraperitoneal injection.Gene expression was detected quantitatively with real-time fluorescence quantitative reverse transcription polymerase chain reaction (QRT-PCR).· RESULTS: The mRNA level of Tβ R 1 and Tβ R 2 was 0.000493± 0.000133 and 0.000166± 0.000057 at 4wk. The mRNA level of Tβ R 1 and Tβ R 2 was 0.000608± 0.000232 and 0.000113± 0.000049 at 12wk. Tβ R 1 expression was gradually elevated during the progression of diabetic retinopathy, Tβ R 2 expression was up-regulated at 4wk,but down-regulated at 12wk.Tβ R 2) may play important role in the pathogenesis of diabetic retinopathy.