Transforming growth factor-beta 1 enhances discharge activity of cortical neurons

Transforming growth factor-beta 1(TGF-β1)has been extensively studied for its pleiotropic effects on central nervous system diseases.The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may depend on the pathological process and cell types involved.Voltage-gated sodium channels(VGSCs)are essential ion channels for the generation of action potentials in neurons,and are involved in various neuroexcitation-related diseases.However,the effects of TGF-β1 on the functional properties of VGSCs and firing properties in cortical neurons remain unclear.In this study,we investigated the effects of TGF-β1 on VGSC function and firing properties in primary cortical neurons from mice.We found that TGF-β1 increased VGSC current density in a dose-and time-dependent manner,which was attributable to the upregulation of Nav1.3 expression.Increased VGSC current density and Nav1.3 expression were significantly abolished by preincubation with inhibitors of mitogen-activated protein kinase kinase(PD98059),p38 mitogen-activated protein kinase(SB203580),and Jun NH2-terminal kinase 1/2 inhibitor(SP600125).Interestingly,TGF-β1 significantly increased the firing threshold of action potentials but did not change their firing rate in cortical neurons.These findings suggest that TGF-β1 can increase Nav1.3 expression through activation of the ERK1/2-JNK-MAPK pathway,which leads to a decrease in the firing threshold of action potentials in cortical neurons under pathological conditions.Thus,this contributes to the occurrence and progression of neuroexcitatory-related diseases of the central nervous system.

Expression patterns of transforming growth factor-beta and its receptors in gastric mucosa of patients with refractory gastric ulcer

AIM: Transforming growth factor-β (TGF-β) plays a regulatory role in tissue repair. In a previous study, we found that TGF-β and its receptors were expressed in gastric mucosa of patients with well-healed gastric ulcers, as demonstrated by immunohistochemistry. To further characterize the role of TGF-β and its receptors in repairing gastric ulcers, we investigated the expression patterns of TGF-β and its receptors in gastric mucosa by in situ hybridization and reverse transcriptase-polymerase chain reaction (RT-PCR).METHODS: Seventy-four patients with endoscopically proven gastric ulcers were eligible for participation in this study. All patients had routine biopsies on initial endoscopy and were then treated for 12 wk with an H2 blocker. Repeat endoscopy was then performed. There were 8 patients with poorly healed ulcers, and biopsies were taken from the margin of the residual ulcers. These tissue samples, along with biopsy of gastric mucosa near the original ulcers from 8 randomly selected patients with well-healed ulcers were examined for TGF-β and TGF-β receptor Ⅱ mRNA by RT-PCR and in situ hybridization, as well as immunohistochemistry.RESULTS: TGF-β and TGF-β receptor Ⅱ were strongly expressed in tissues from patients with well-healed ulcers.Four of the 8 patients with poor healing had low or absent expression of TGF-β or TGF-β receptor Ⅱ mRNA. All cases positive by RT-PCR assay were confirmed by in situ hybridization as well as immunohistochemistry.CONCLUSION: It is suggested that TGF-β and its receptors are important for gastric ulcer healing. These results may have implications for further investigation of the healing process and in predicting response to therapy.

Platelet-rich plasma increases transforming growth factor-beta1 expression at graft-host interface following autologous osteochondral transplantation in a rabbit model

AIM: To explore the effect of platelet-rich plasma on protein expression patterns of transforming growth factor-beta1(TGF-β1) in cartilage following autologous osteochondral transplantation(AOT) in a rabbit knee cartilage defect model.METHODS: Twelve New Zealand white rabbits received bilateral AOT. In each rabbit, one knee was randomized to receive an autologous platelet rich plasma(PRP) injection and the contralateral knee received saline injection. Rabbits were euthanized at 3, 6 and 12 wk post-operatively. Articular cartilage sections were stained with TGF-β1 antibody. Histological regions of interest(ROI)(left, right and center of the autologous grafts interfaces) were evaluated using Meta Morph. Percentage of chondrocytes positive for TGF-β1 was then assessed.RESULTS: Percentage of chondrocytes positive for TGF-β1 was higher in PRP treated knees for selected ROIs(left; P = 0.03, center; P = 0.05) compared to control and was also higher in the PRP group at each post-operative time point(P = 6.6 × 10^(-4), 3.1 × 10^(-4) and 7.3 × 10^(-3) for 3, 6 and 12 wk, respectively). TGF-β1 expression was higher in chondrocytes of PRP-treated knees(36% ± 29% vs 15% ± 18%)(P = 1.8 × 10^(-6)) overall for each post-operative time point and ROI. CONCLUSION: Articular cartilage of rabbits treated with AOT and PRP exhibit increased TGF-β1 expression compared to those treated with AOT and saline. Our findings suggest that adjunctive PRP may increase TGF-β1 expression, which may play a role in the chondrogenic effect of PRP in vivo.

Effects of RNA interference targeting transforming growth factor-beta 1 on immune hepatic fibrosis induced by Concanavalin A in mice

BACKGROUND: Previous studies have shown that transforming growth factor-beta 1 (TGF-beta 1) is the most potent means of stimulating liver fibrogenesis by myofibroblast-like cells derived from hepatic stellate cells. Thus, TGF-beta 1 could be a target for treating hepatic fibrosis. This study aimed to investigate the inhibitory effects of specific TGF-beta 1 small interference RNA (siRNA) on immune hepatic fibrosis induced by Concanavalin A (Con A) in mice. METHODS: Three short hairpin RNAs targeting different positions of TGF-beta 1 were designed and cloned to the plasmid pGenesil-1 to obtain three recombinant expression vectors (pGenesil-TGF-beta 1-ml, pGenesil-TGF-beta 1-m2 and pGenesil-TGF-beta 1-m3). Thirty male Kunming mice were randomly divided into 6 groups: normal, model, control, and three treatment groups. The immune hepatic fibrosis models were constructed by injecting Con A via the tail vein at 8 mg/kg per week for 6 weeks. At weeks 2, 4 and 6, pGenesil-TGF-beta 1-ml, pGenesil-TGF-beta 1-m2 or pGenesi1-TGF-beta 1-m3 was injected by a hydrodynamics-based transfection method via the tail vein at 0.8 ml/10 g within 24 hours after injection of Con A in each of the three treatment groups. The mice in the control group were injected with control plasmid pGenesil-HK at the same dose. All mice were sacrificed at week 7. The levels of hydroxyproline in liver tissue were determined by biochemistry. Liver histopathology was assessed by Van Gieson staining. The expression levels and localization of TGF-beta 1, Smad3, and Smad7 in liver tissue were detected by immunohistochemistry. The expression of TGF-beta 1, Smad3, Smad7 and alpha-smooth muscle actin (alpha-SMA) mRNAs in the liver were assessed by semi-quantitative RT-PCR. RESULTS: The levels of hydroxyproline in the liver tissue of the treatment groups were lower than those of the model group (P<0.01). Histopathologic assay showed that liver fibrogenesis was clearly improved in the treatment groups compared with the model group. The expression levels of TGF-beta 1 and Smad3 of liver tissue were also markedly lower in the treatment groups than in the model group (P<0.01), while the levels of Smad7 were higher in the treatment groups than in the model group (P<0.01). RT-PCR further showed that the expression of TGF-beta 1, Smad3 and alpha-SMA mRNA was significantly inhibited in the treatment groups compared with the model group, while the levels of Smad7 were increased. There was no difference in the above parameters among the three treatment groups or between the control and model groups (P>0.05), but the inhibitory effect of pGenesil-TGF-beta 1-ml was the highest among the treatment groups. CONCLUSIONS: Specific siRNA targeting of TGF-beta 1 markedly inhibited the fibrogenesis of immune hepatic fibrosis induced by Con A in mice. The anti-fibrosis mechanisms of siRNAs may be associated with the down-regulation of TGF-beta 1, Smad3 and alpha-SMA expression and up-regulation of Smad7 expression in liver tissue, which resulted in suppressing the activation of hepatic stellate cells. (Hepatobiliary Pancreat Dis Int 2009; 8: 300-308)

Deciphering the role of transforming growth factor-beta 1 as a diagnostic-prognostic-therapeutic candidate against hepatocellular carcinoma

Transforming growth factor-beta(TGF-β)is a multifunctional cytokine that performs a dual role as a tumor suppressor and tumor promoter during cancer progression.Among different ligands of the TGF-βfamily,TGF-β1 modulates most of its biological outcomes.Despite the abundant expression of TGF-β1 in the liver,steatosis to hepatocellular carcinoma(HCC)progression triggers elevated TGF-β1 levels,contributing to poor prognosis and survival.Additionally,elevated TGF-β1 levels in the tumor microenvironment create an immunosuppressive stage via various mechanisms.TGF-β1 has a prime role as a diagnostic and prognostic biomarker in HCC.Moreover,TGF-β1 is widely studied as a therapeutic target either as monotherapy or combined with immune checkpoint inhibitors.This review provides clinical relevance and up-to-date information regarding the potential of TGF-β1 in diagnosis,prognosis,and therapy against HCC.

Role of transforming growth factor-beta signaling pathway in pathogenesis of benign biliary stricture

AIM: To characterize the expression of members of the transforming growth factor-beta (TGF-β)/Smad/ connective tissue growth factor (CTGF) signaling pathway in the tissue of benign biliary stricture, and to investigate the effect of TGF-β signaling pathway in the pathogenesis of benign biliary stricture. METHODS: Paraffin embedded materials from 23 cases of benign biliary stricture were analyzed for members of the TGF-β/Smad/CTGF signaling pathway. TGF-β_1, TβRⅠ, TβRⅡ, Smad4, Smad7 and CTGF protein were detected by immunohistochemical strepto-advidinbiotin complex method, and CTGF mRNA was evaluated by hybridization in situ, while 6 cases of normal bile duct served as controls. The percentages of positive cells were counted. The correlation between TGF-β_1, Smad4 and CTGF was analyzed. RESULTS: The positive expression ratios of TGF-β_1, TβRⅠ , TβRⅡ , Smad4, CTGF and CTGF mRNA in 23 cases with benign biliary stricture were 91.3%, 82.6%, 87.0%, 78.3%, 82.6% and 65.2%, respectively, signifi cantly higher than that in 6 cases of normal bile duct respectively (vs 33.3%, 16.7%, 50.0%, 33.3%, 50.0%, 16.7%, respectively, P < 0.05). The positiveexpression ratio of Smad7 in cases with benign biliary stricture was 70.0%, higher than that in normal bile duct, but this difference is not statistically signifi cant 70.0% vs 50%, P > 0.05). There was a positive correlation between positive expression of TGF-β_1, Smad4 and CTGF in cases with benign biliary stricture. CONCLUSION: The high expression of TGF-β/Smad/ CTGF signaling pathway plays an important role in the pathogenesis of benign biliary stricture.

Pre-ischemia electro-acupuncture potentiates the expression of Bcl-2 and transforming growth factor-beta 1 in rat brains

The expression of the anti-apoptotic molecules Bcl-2 and transforming growth factor-beta 1 is known to confer protective effects on the cerebral ischemia-reperfusion injury.The current study investigated the expression levels of Bcl-2 and transforming growth factor-beta 1 in response to multiple pre-ischemia electro-acupuncture at acupoints Zusanli（ST36）and Fengchi（GB20） stimulation.Rats were divided into five groups：uninjured,control,non-acupoint,GB20 and ST36. Rats in the non-acupoint,GB20 and ST36 groups received 30 minutes（3 times or 18 times）of electro-acupuncture stimulation before experimental cerebral ischemia was induced.Bcl-2 and transforming growth factor-beta 1 were found to be significantly increased in the ST36 groups with either 3 or 18 electro-acupuncture treatments（P〈0.05）.The production was higher with 18 electro-acupuncture treatments in the ST36 groups（P〈0.05）.In the GB20 groups,significant increase was only observed in transforming growth factor-beta 1 with 18 electro-acupuncture treatments（P〈0.05）.No significant elevation of the level of transforming growth factor-beta 1 was observed in the non-acupoint groups.However,the production of Bcl-2 increased with 18 treatments in the non-acupoint groups（P〈0.05）.The data suggest that multiple pre-ischemia electro-acupuncture at ST36 was effective in conferring neuroprotective effect on the brain by means of upregulation of Bcl-2 and transforming growth factor-beta 1 and the effect was increase with the number of treatment.

Influence of HBcAg in liver cell plasma on expression of transforming growth factor-beta 1 in liver tissue of low-grade chronic hepatitis B patients

AIM： To study the influence of HBcAg on the expression of transforming growth factor-beta 1 （TGF-131） in liver tissue of low-grade chronic hepatitis B （CHB） patients. METHODS： The expression of T（3F-β1 and HBcAg in liver samples from 93 low-grade CHB patients was detected by immunohistochemistry and valuated by semi-quantitative scoring. RESULTS： In the 93 low-grade CHB patients, HBcAg was expressed in cell plasma but not in the liver tissue. There was no significant difference between the two groups. CONCLUSION： The expression of TGF-β1 is not related with HBcAg expressed as plasma type in the tissues of low-grade CHB patients.

Expression and clinical significance of dendritic cell and transforming growth factor-beta 1 in cervical cancer

Objective:To explore the density and mature status of Dendritic cell(DC) in cervical cancer and correlation with the expression of transforming growth factor-beta 1(TGF-β1).Methods:Streptavidin-peroxidase(SP) immunohistochemistry methods were used to detect S-100 DC and the expression of TGF-β1 in 20 normal cervical tissues and 53 cervical cancer tissues without any sort of chemotherapy or radiation therapy prior to resection.Medical records were reviewed,clinicopathological variables were retrieved and used for analysis.Results:Two types of DC were observed under the microscope.The expression of DC in cervical cancer was significantly higher than that in normal tissues(23.34 cells/mm^2 vs 29.91 cells/mm^2,P<0.05),and significantly higher in early stage than that in advanced stage(P<0.05).The expression of TGF-β1 was significantly higher in cervical cancer than that in normal tissues (P<0.025).However,there was no correaction between TGF-β1 and lymph nodes metastasis.The index of DC in cervical cancer was negatively correlated to the expression of TGF-β1 in tumor cells (r=-0.8875,P=0.0001).Conclusion:Maturation of DC in cervical cancer is inhibited.The decreased number of DC and the higher expression of TGF-β1 are due to the failure of the immunity,these may play an important role in the development of the cervical cancer.

Tousled-like kinase 1 promotes gastric cancer progression by regulating the tumor growth factor-beta signaling pathway

BACKGROUND The role of Tousled-like kinase 1(TLK1)in in gastric cancer(GC)remains unclear.AIM To investigate the expression,biological function,and underlying mechanisms of TLK1 in GC.METHODS We measured TLK1 protein expression levels and localized TLK1 in GC cells and tissues by western blot and immunofluorescence,respectively.We transfected various GC cells with lentiviruses to create TLK1 overexpression and knockdown lines and established the functional roles of TLK1 through in vitro colony formation,5-ethynyl-2`-deoxyuridine,and Transwell assays as well as flow cytometry.We applied bioinformatics to elucidate the signaling pathways associated with TLK1.We performed in vivo validation of TLK1 functions by inducing subcutaneous xenograft tumors in nude mice.RESULTS TLK1 was significantly upregulated in GC cells and tissues compared to their normal counterparts and was localized mainly to the nucleus.TLK1 knockdown significantly decreased colony formation,proliferation,invasion,and migration but increased apoptosis in GC cells.TLK1 overexpression had the opposite effects.Bioinformatics revealed,and subsequent experiments verified,that the tumor growth factor-beta signaling pathway was implicated in TLK1-mediated GC progression.The in vivo assays confirmed that TLK1 promotes tumorigenesis in GC.CONCLUSION The findings of the present study indicated that TLK1 plays a crucial role in GC progression and is,therefore,promising as a therapeutic target against this disease.

Expression of Cyclooxygenase-2 and Transforming Growth Factor-Beta 1 in Patients with the Early Recurrence of Hepatocellular Carcinoma Following Hepatectomy

Background: Cyclooxygenase-2 (COX-2) and transforming growth factor-beta1 (TGF-β1) are modulated in variety cancers including Hepatocellular carcinoma (HCC). However, there is a paucity of data concerning their role in the pathologic process of recurrence of HCC following hepatectomy. We herein assessed the role of the hepatic expression of COX-2 and TGF-β as predictors for patients with early recurrence within 2 years of HCC diagnosis. Methods: Sixty patients with HCC who underwent curative hepatectomy between 2000 and 2003 were entered in the present study. The immunoreactivity and distribution patterns of COX-2 and TGF-β1 were examined in both the HCC and the adjacent nonHCC tissues of the liver. Risk factors of tumor recurrence within 2 years, including COX-2 and TGF-β1 expression, were investigated by univariate and multivariate analyses. Results: Among 60 patients, 31 patients had early recurrences within 2 years and 14 patients recurred after 2 years following surgery. Patients with low COX-2 expression in the HCC tissues and adjacent nonHCC tissues had favorable disease-free survival (p = 0.002 and p β1 expression in the nonHCC tissues had also longer disease-free survival (p = 0.045). Based on the expression patterns of COX-2 and TGF-β1, patients with low COX-2 and positive TGF-β1 expression in the nonHCC tissues had favorable overall and disease-free survival (p β1 signaling in nontumor tissues suggested high risk of recurrence and poor survival to the HCC patients following hepatectomy.

Plasma Levels of Transforming Growth Factor-Beta 1 in Women with Pelvic Organ Prolapse

Objective: In women with pelvic organ prolapse (POP), decreased expression of transforming growth factor-beta 1 (TGF-β1) has been shown in POP tissues. However, no studies have evaluated plasma TGF-β1 levels in patients with POP, so it is unknown whether they are also changed or not. Therefore, we compared plasma TGF-β1 levels in women with and without POP. Methods: Participants were 49 women with POP and 23 healthy control women. All participants were postmenopausal. We measured plasma TGF-β1 and compared data between patients with POP and controls, and between patients with uterine prolapse (UP, n = 19) and those with a cystocele (CC, n = 30). In addition, in patients, we assessed the POP quantification system (POP-Q) stage. Results: Plasma TGF-β1 levels were significantly lower in patients than in healthy controls. POP-Q stage was not significantly different between the UP and CC subgroups, but POP-Q stage IV was diagnosed in 63% of patients with UP and 7% of those with CC. Plasma TGF-β1 levels were significantly lower in the CC subgroup than in the UP subgroup. Conclusion: Plasma TGF-β1 is decreased in POP. It remains unclear whether the lower levels indicate a reduction in systemic TGF-β1 activity, but they can be assumed to reflect reduced TGF-β1 expression in POP tissues.

C23 ameliorates carbon tetrachloride-induced liver fibrosis in mice

BACKGROUND C23,an oligo-peptide derived from cold-inducible RNA-binding protein(CIRP),has been reported to inhibit tissue inflammation,apoptosis and fibrosis by binding to the CIRP receptor;however,there are few reports on its role in liver fibrosis and the underlying mechanism is unknown.AIM To explore whether C23 plays a significant role in carbon tetrachloride(CCl4)-induced liver fibrosis.METHODS CCl4 was injected for 6 weeks to induce liver fibrosis and C23 was used beginning in the second week.Masson and Sirius red staining were used to examine changes in fiber levels.Inflammatory factors in the liver were detected and changes inα-smooth muscle actin(α-SMA)and collagen I expression were detected via immu-nohistochemical staining to evaluate the activation of hematopoietic stellate cells(HSCs).Western blotting was used to detect the activation status of the trans-forming growth factor-beta(TGF-β)/Smad3 axis after C23 treatment.RESULTS CCl4 successfully induced liver fibrosis in mice,while tumor necrosis factor-alpha(TNF-α),IL(interleukin)-1β,and IL-6 levels increased significantly and the IL-10 level decreased significantly.Interestingly,C23 inhibited this process.On the other hand,C23 significantly inhibited the activation of HSCs induced by CCl4,which inhibited the expression ofα-SMA and the synthesis of collagen I.In terms of mechanism,C23 can block Smad3 phosphorylation significantly and inhibits INTRODUCTION At present there is no specific and effective drug for treating liver fibrosis caused by acute or chronic injury.Although preclinical research has made breakthroughs,their suitability as clinical treatments is still unknown.The activation of hepatic stellate cells(HSCs)caused by chronic inflammation is a key process in the development of liver fibrosis and activated HSCs expressα-smooth muscle actin(α-SMA)and transdifferentiate into myofibroblasts with proliferation,migration and secretion abilities,synthesizing the extracellular matrix to deposit in the hepatocyte space and subse-quently forming liver fibrosis[1].Although therapeutic strategies have improved due to past few efforts there is no ideal treatment for hepatic fibrosis[2].Extracellular cold inducible RNA binding protein(CIRP)has been shown to play a role in various acute and chronic inflammatory diseases by promoting tissue inflammation and apoptosis and inducing fibrosis through its receptor Toll-like receptor 4(TLR4)[3].C23 is a recognized competitive inhibitor of CIRP that can competitively bind to CIRP receptors and reduce tissue damage in inflammatory diseases[4].C23 has been shown to significantly reduce serum tumor necrosis factor-alpha(TNF-α),IL(interleukin)-6 and IL-1βlevels.In addition,it can reduce tissue TLR4,TNF-α,IL-6 and IL-1βlevels and inhibit the colocalization of CIRP and TLR4,which plays a significant role in systemic inflammation[5].Re-search has shown that CIRP induces the inflammatory phenotype of lung fibroblasts in a TLR4-dependent manner[6].On the other hand,CIRP is associated with markers of fibrosis andα-SMA is significantly positively correlated with CIRP.Cirp-/-mice exhibit attenuated expression ofα-SMA and collagen(COL1A1 and COL3A1),decreased hydroxyproline content,decreased histological fibrosis scores,and improved pulmonary hypertension[7].C23 inhibited the release of TNF-α,the degradation of IκB and the nuclear translocation of NF-κB in CIRP-stimulated macrophages in a dose-dependent manner and C23 treatment significantly increased the serum levels of lactic dehydrogenase,alanine ami-notransferase,IL-6,TNF-αand IL-1βin septic CLP mice[8].Based on previous research we hypothesized that C23 might alleviate liver fibrosis by inhibiting acute and chronic inflammation.As a selective hepatotoxic chemical carbon tetrachloride(CCl4).can induce inflammation and activate HSCs,promoting liver fibrosis.This study reveals the role and mechanism of C23 in CCl4-induced liver fibrosis in mice.at room temperature for 30 minutes.The gray value of each group was calculated after chemiluminescence.

TIMP-1mRNA表达在病毒性心肌炎小鼠心肌胶原重构中的作用及其与TGF-β_1的关系

目的探讨TIMP-1mRNA表达在病毒性心肌炎小鼠心肌胶原重构中的作用及其与转化生长因子(TGF-β1)的关系。方法4周龄雄性BALB/c鼠腹腔接种0.1ml100TCID50CVB3m,周龄、性别相同小鼠为对照,分别于接种后3、7、9、14、21、28、56d断脊处死小鼠,心肌标本经常规制片,VG染色观察心肌组织胶原的改变,原位杂交观察TIMP-1mRNA和TGF-β1mRNA的表达,免疫组织化学观察TGF-β1的表达。结果感染后28d小鼠心肌组织血管周围胶原明显沉积,感染后56d心肌组织血管周围及心肌细胞间隙胶原沉积均明显增加;感染后7d可见TIMP-1mRNA表达,14～21d最为明显,此后减弱,直到56d。感染后3d可见TGF-β1mRNA及TGF-β1表达,7～21d最为明显,此后减弱,持续至感染后56d;TIMP-1mRNA和TGF-β1表达等级间存在正相关关系(P<0.001)。结论TGF-β1表达增加及其上调TIMP-1mRNA的表达可能在病毒性心肌炎心肌胶原重构中起重要作用。

艾塞那肽通过下调p22phox、NOX4和TGF-β1减轻1型糖尿病大鼠主动脉的氧化应激损伤

目的观察胰高血糖素样肽1(GLP-1)受体激动剂艾塞那肽对1型糖尿病大鼠主动脉NADPH氧化酶亚单位表达及其氧化应激损伤作用的影响。方法 30只雄性SD大鼠随机分为正常对照组(n=7)和造模组(n=23)。采用链脲佐菌素(STZ)制备1型糖尿病大鼠模型。将造模成功的19只1型糖尿病大鼠随机分为糖尿病对照组(n=10)和艾塞那肽治疗组(n=9)。艾塞那肽治疗组给予艾塞那肽5μg/kg皮下注射,2次/天;正常对照组和糖尿病对照组给予等量的生理盐水皮下注射。药物干预8周后,处死动物。用实时荧光定量聚合酶链反应法(RTPCR)检测主动脉p22phox和NOX4 mRNA的表达,用免疫组织化学法检测主动脉的转化生长因子β1(TGF-β1)的表达。标本切片用HE染色后,行组织形态学检查。结果与正常对照组比较,糖尿病对照组大鼠主动脉p22phox和NOX4 mRNA表达显著升高,TGF-β1蛋白表达显著升高(P<0.05)。与糖尿病对照组比较,艾塞那肽治疗组大鼠主动脉p22phox和NOX4 mRNA表达降低(P<0.05),主动脉TGF-β1蛋白表达降低(P<0.05)。与正常对照组比较,糖尿病对照组大鼠主动脉内膜和中膜明显增厚,内膜不光滑,内皮细胞突起,形态不规则,平滑肌细胞排列紊乱;与糖尿病对照组比较,艾塞那肽治疗组大鼠主动脉内膜仅局限性增厚不光滑,内皮细胞与平滑肌细胞排列较整齐,中膜轻度增厚。结论艾塞那肽通过下调1型糖尿病大鼠主动脉p22phox、NOX4和TGF-β1的表达,减轻氧化应激对主动脉的损伤,对糖尿病大鼠血管产生保护作用。

γ干扰素和转化生长因子β水平与支气管结核治疗效果的关联性研究

目的探讨血清和支气管灌洗液中γ干扰素(IFN-γ)和转化生长因子β(TGF-β)水平与支气管结核(EBTB)治疗效果之间的关联性。方法采用酶联免疫吸附(ELISA)方法测定78例EBTB患者支气管镜下介入治疗前后血清和支气管灌洗液中IFN-γ和TGF-β的水平,以及50名健康对照血清中IFN-γ和TGF-β的水平。EBTB患者被分成2组:一组治疗后表现为支气管狭窄,另一组治疗后未表现为支气管狭窄。结果研究显示:(1)与对照组相比,EBTB患者组支气管灌洗液中IFN-γ和TGF-β水平升高。(2)78例EBTB患者治疗后,27例患者显示有支气管的纤维狭窄,51例患者没有支气管狭窄。支气管狭窄组治疗前血清TGF-β水平[(783.21±478.67)pg/ml]比无支气管狭窄组[(1258.60±573.29)pg/ml]低(U=3.8905,P<0.01),而支气管灌洗液中TGF-β[(1219.54±439.27)pg/ml]和IFN-γ[(2152±1594.33)pg/ml]水平明显高于无狭窄组[(779.24±395.91)pg/ml,(1006.30±752.57)pg/ml](U值分别为4.3553和3.5315,P值均<0.01)。结论 (1)EBTB患者支气管灌洗液中IFN-γ和TGF-β水平升高可能与支气管结核发病机制有关。(2)初始血清TGF-β低水平和支气管灌洗液IFN-γ和TGF-β高水平与治疗后支气管纤维狭窄有关。

桃红芪术软肝煎基于TGF-β/Smad信号通路逆转上皮-间质转化抗肝纤维化作用

目的:观察桃红芪术软肝煎从(transforming growth factor beta,TGF-β)/Smad信号通路逆转上皮-间充质细胞转化(e p i t h e l i a lmesenchymal transition,EMT)抗肝纤维化的作用.方法:取对数生长期的HepG2细胞进行试验,将细胞分为7组:空白组、TGF-β诱导EMT组、TGF-β+中药[低剂量组(p e a c h stilbene low dose group,THQL)、中剂量组(peach stilbene middle dose group,THQM)、高剂量组(peach stilbene high dose group,THQH)]、TGF-β+扶正祛瘀胶囊组(Fuzheng Huayu recipe,FZHY组)、TGF-β+秋水仙碱组(c o l c h i c i n e g r o u p,QSXJ组),采用免疫荧光和Western blot方法检测E-cadherin、Vimentin、Smad2、TGF-βR1表达情况,并检测细胞上清液中的谷丙转氨酶(alanine aminotransferase,ALT)、谷草转氨酶(aspartate transaminase,AST)、甲胎蛋白(alpha fetoprotein,AFP)表达情况.结果:诱导组AFP诱导第3天浓度明显降低,差异具有统计学意义(P<0.05);用药干预后,用药组ALT、AST水平均低于模型组,差异具有统计学意义(P<0.05),THQL及TRQM的ALT水平均低于FZHY和QSXJ,差异具有统计学意义(P<0.05),THQM及THQH的AST水平均低于FZHY和QSXJ,差异具有统计学意义(P<0.05);桃红芪术软肝煎可以改善HepG2细胞被诱导发生EMT的形态,其中THQM组和THQH组形态改变较为明显;桃红芪术软肝煎可以上调E-cadherin表达,下调Smad2、TGF-βR1、Vimentin表达.结论:桃红芪术软肝煎可以通过作用于TGF-β/Smad信号通路逆转上皮-间质转化,从而起到抗肝纤维化的作用.

COX-2、VEGF及TGF-β1在慢性粒细胞白血病中的表达及临床意义

目的观察慢性粒细胞白血病(chronic myeloid leukemia,CML)患者血清环氧合酶-2(COX-2)、血管内皮生长因子(VEGF)及转化生长因子β1(TGF-β1)的水平变化,探讨各指标在临床中的指导意义。方法选取我院2014年1月—2015年8月确诊的CML 50例(白血病组),予甲磺酸伊马替尼治疗3个月;同时选择在我院体检健康的40例(对照组)。比较两组血清COX-2、VEGF及TGF-β1的水平变化,并观察白血病组治疗前后血清COX-2、VEGF及TGF-β1的变化。结果与对照组比较,白血病组治疗前后血清COX-2及VEGF水平显著升高,TGF-β1水平显著降低,差异有统计学意义(P<0.01);与治疗前比较,白血病组治疗后血清COX-2、VEGF水平显著降低,TGF-β1水平显著升高,差异有统计学意义(P<0.01)。白血病组治疗前急变期、加速期血清VEGF及COX-2水平均较慢性期显著升高,TGF-β1水平则降低,差异有统计学意义(P<0.01);治疗后完全缓解(CR)者血清COX-2、VEGF及TGF-β1水平逐渐恢复正常,与未缓解(NR)者比较差异有统计学意义(P<0.01)。白血病组血清COX-2、VEGF水平与TGF-β1水平呈负相关(R=-0.632,P<0.01;R=-0.315,P=0.026)。结论 COX-2、VEGF及TGF-β1与CML患者病情密切相关,可作为CML病情评估的重要参考依据。

昆明山海棠对实验性肾炎的干预作用及机制

目的探讨昆明山海棠治疗大鼠系膜增生性肾小球肾炎模型的有效性及作用机制。方法应用兔抗大鼠胸腺细胞免疫血清(ATS)复制大鼠MsPGN模型,将实验大鼠分为对照组(A组)、模型组(B组)、昆明山海棠治疗组(C组)、泼尼松治疗组(D组)、昆明山海棠与泼尼松联合治疗组(E组),分别于第1、2及4周测定肝肾功能,并采用免疫组织化学、RT-PCR技术及计算机图像分析系统,观察各组肝肾功能变化、系膜区TGF-β1蛋白及肾皮质mRNA表达以及Smad3mRNA表达的变化。结果各组在观察期间均无明显肝肾功能不良。模型组系膜区TGF-β1蛋白表达及肾皮质TGF-β1,Smad3mRNA表达增高,3个治疗组TGF-β1蛋白表达及肾皮质TGF-β1和Smad3mRNA表达均较模型组显著降低(均P<0.01),以联合治疗组降低最明显。结论昆明山海棠可能是通过抑制TGF-β1的表达,改善肾小球系膜的增殖,达到减少蛋白尿,延缓肾功能的进展。其作用机制可能通过TGF-β1/Smads通路。昆明山海棠与泼尼松有协同作用,两种药物合用治疗效果更明显,且不增加肝肾损害的发生。

头针抗大鼠急性脑缺血再灌注炎症损伤的作用机制

目的:探讨头针治疗脑缺血的可能作用机制。方法:采用线栓法制备大脑中动脉闭塞(middle cerebral artery occlusion,MCAO)再灌注模型。60只MCAO再灌注模型大鼠分为模型组和头针组,再根据缺血再灌注时间(24、48、72h)的不同,将模型组和头针组各随机分为3个亚组。另选10只大鼠行假手术作为假手术组。采用头针治疗,接穴位神经刺激仪,疏密波,频率2Hz/100Hz,强度2mA,每次30min,每天1次。应用神经功能缺损评分(neurological severity score,NSS)、苏木精和伊红(hematoxylin and eosin,HE)染色、聚合酶链反应及酶联免疫吸附测定法观察急性脑缺血再灌注后头针治疗对模型大鼠神经功能缺损,缺血脑组织环氧化酶2(cyclooxygenase-2,COX-2)、核因子κB(nuclear factor-kappaB,NF-κB)、转化生长因子β1(transforming growth factor-beta1,TGF-β1)mRNA及蛋白含量的影响。结果:头针组各时相的NSS与模型组比较,差异均有统计学意义(P<0.05,P<0.01),以脑缺血再灌注72h后较明显。HE染色提示,头针组各时相脑组织白细胞浸润较模型组减轻,以脑缺血再灌注72h后最为明显。头针治疗组COX-2和NF-κB含量在24、48、72h均低于模型组(P<0.01,P<0.05),而头针治疗组TGF-β1含量在24、48、72h均显著高于模型组(P<0.01)。结论:头针有利于脑缺血大鼠神经功能的恢复,可减轻急性脑缺血再灌注后神经元的损害,并在一定范围内降低损伤脑组织中COX-2和NF-κB的表达,增强TGF-β1的表达,从而减缓免疫炎症反应,减轻脑缺血再灌注损伤。