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.

Transforming growth factor-β1 and vascular endothelial growth factor levels in senile acute myeloid leukemia and correlation with prognosis

BACKGROUND Acute myeloid leukemia(AML)is a disease in which immature hematopoietic cells accumulate in the bone marrow and continuously expand,inhibiting hematopoiesis.The treatment and prognosis of this disease have always been unsatisfactory.AIM To investigate the correlation between vascular endothelial growth factor(VEGF)and transforming growth factor-β1(TGFβ1)expression and prognosis in older adults with AML.METHODS This study enrolled 80 patients with AML(AML group),including 36 with complete response(AML-CR),23 with partial response(AML-PR),and 21 with no response(AML-NR).The expression levels of VEGF and TGFβ1 were detected by reverse transcription polymerase chain reaction in bone marrow mononuclear cells isolated from 56 healthy controls.Kaplan-Meier analysis was performed to assess overall survival(OS)and progression-or disease-free survival(DFS).Prognostic risk factors were analyzed using a Cox proportional hazards model.RESULTS The AML group showed a VEGF level of 2.68±0.16.VEGF expression was lower in patients with AML-CR than those with AML-PR or AML-NR(P<0.05).TGFβ1 expression in the AML group was 0.33±0.05.Patients with AML-CR showed a higher TGFβ1 expression than those with AML-PR or AML-NR(P<0.05).VEGF and TGFβ1 expression in patients with AML was significantly correlated with the counts of leukocytes,platelets,hemoglobin,and peripheral blood immature cells(P<0.05);Kaplan-Meier survival analysis revealed that patients with high TGFβ1 expression had better OS and DFS than those with low TGFβ1 expression(P<0.05),whereas patients with low VEGF levels showed better OS and DFS than those with high VEGF levels(P<0.05).VEGF,TGFβ1,and platelet count were identified by the Cox proportional hazards model as independent risk factors for OS(P<0.05),while VEGF,TGFβ1,and white blood cell count were independent risk factors for DFS(P<0.05).CONCLUSION Decreased VEGF expression and increased TGFβ1 expression in patients with AML provide valuable references for determining and individualizing clinical treatment strategies.

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)

Roles of Smad3 and Smad7 in rat pancreatic stellate cells activated by transforming growth factor-beta 1

BACKGROUND: Pancreatic stellate cells (PSCs) play a major role in promoting pancreatic fibrosis. Transforming growth factor beta 1 (TGF-beta 1) is a critical mediator of this process. This study aimed to determine the expression of the Smad3 and Smad7 genes in the process of PSC activation, and explore the mechanisms of chronic pancreatitis. METHODS: The expressions of Smad3 and Smad7 in PSCs before and after TGF-beta 1 treatment were detected by reverse transcription-polymerase chain reaction and Western blotting analysis. Smad3 expression was detected in PSCs after treatment with 5 ng/ml of TGF-beta 1 for 24 hours. RESULTS: Smad7 expression was decreased in TGF-beta 1 -activated PSCs (P<0.05) in a dose-dependent manner. When TGF-beta 1 concentration reached 10 ng/ml, the expression of p-Smad3, Smad3, and Smad7 was inhibited (P<0.05). CONCLUSIONS: TGF-beta 1 promotes the expression of Smad3 and inhibits the expression of Smad7 during the activation of PSCs. In contrast, high-dose TGF-beta 1 downregulates the expression of Smad3 in completely activated PSCs.

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.

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.

Molecular Tissue Engineering: Applications for Modulation of Mesenchymal Stem Cells Proliferation by Transforming Growth Factor β_1 Gene Transfer

The effect of transforming growth factor β 1 (TGF β 1 ) gene transfection on the proliferation of bone marrow derived mesenchymal stem cells (MSC S ) and the mechanism was investigated to provide basis for accelerating articular cartilage repairing using molecular tissue engineering technology. TGF β 1 gene at different doses was transduced into the rat bone marrow derived MSCs to examine the effects of TGF β 1 gene transfection on MSCs DNA synthesis, cell cycle kinetics and the expression of proliferating cell nuclear antigen (PCNA). The results showed that 3 μl lipofectamine mediated 1 μg TGF β 1 gene transfection could effectively promote the proliferation of MSCs best; Under this condition (DNA/Lipofectamine=1μg/3μl), flow cytometry and immunohistochemical analyses revealed a significant increase in the 3 H incorporation, DNA content in S phase and the expression of PCNA. Transfection of gene encoding TGF β 1 could induce the cells at G0/G1 phase to S1 phase, modulate the replication of DNA through the enhancement of the PCNA expression, increase the content of DNA at S1 phase and promote the proliferation of MSCs. This new molecular tissue engineering approach could be of potential benefit to enhance the repair of damaged articular cartilage, especially those caused by degenerative joint diseases.

Dab2 attenuates brain injury in APP/PS1 mice via targeting transforming growth factor-beta/SMAD signaling

Transforming growth factor-beta （TGF-β） type II receptor （TβRⅡ） levels are extremely low in the brain tissue of patients with Alzheimer＇s disease. This receptor inhibits TGF-β1/SMAD signaling and thereby aggravates amyolid-beta deposition and neuronal injury. Dab2, a specific adapter protein, protects T RII from degradation and ensures the effective conduction of TGF-β 1/SMAD signaling. In this study, we used an adenoviral vector to overexpress the Dab2 gene in the mouse hippocampus and investigated the regulatory effect of Dab2 protein on TGF-β1/SMAD signaling in a mouse model of Alzheimer＇s disease, and the potential neuroprotective effect. The results showed that the TβRⅡ level was lower.in APP/PS1 mouse hippocampus than in normal mouse hippocampus. After Dab2 expression, hippocampal TβRⅡ and p-SMAD2/3 levels were signifi- cantly increased, while amyloid-beta deposition, microglia activation, tumor necrosis factor- and interleulin-6 levels and neuronal loss were significantly attenuated in APP/PS1 mouse brain tissue. These results suggest that Dab2 can exhibit neuroprotective effects in Alzheimer＇s disease by regulating TGF-β1/SMAD signaling.

TGF-β_(1)基因rs1800469、rs4803455位点单核苷酸多态性与肝细胞癌易感性及预后的关系

目的探讨转化生长因子β_(1)(TGF-β_(1))基因rs1800469、rs4803455位点单核苷酸多态性(SNP)与肝细胞癌(HCC)遗传易感性及患者预后的关系。方法选择202例HCC患者作为HCC组、健康体检者176例作为对照组。用质谱法检测TGF-β_(1)基因rs1800469、rs4803455位点SNP;对患者进行电话随访,末次随访截至2015年12月,记录死亡和存活情况。用拟合优度χ2检验分析基因型分布的Hardy-Weinberg遗传平衡,用非条件Logistic回归分析法分析TGF-β_(1)基因rs1800469、rs4803455位点SNP对HCC遗传易感性的影响,用Cox比例风险模型分析TGF-β_(1)基因rs1800469、rs4803455位点SNP与HCC患者预后的关系。结果Hardy-Weinberg遗传平衡检验结果表明,两组各基因型频率差异无统计学意义(P>0.05)。与rs1800469 AA基因型比较,携带GG、GA+GG基因型个体HCC发病风险低(P均<0.05),携带GA基因型个体HCC发病风险低,但差异无统计学意义(P>0.05)。与rs480345 CC基因型比较,携带CA、AA、CA+AA基因型个体HCC发病风险低,但差异无统计学意义(P均>0.05)。以性别、HBV感染为分层变量进行分层分析,女性人群中,与rs1800469 AA基因型比较,携带GA+GG基因型个体HCC发病风险低(P<0.05);与rs4803455 CC基因型比较,携带CA+AA基因型个体HCC发病风险低(P均<0.05)。男性人群中,rs1800469、rs4803455各基因型个体HCC发病风险差异无统计学意义(P均<0.05);HBV感染对rs1800469、rs4803455各基因型个体HCC发病风险无影响(P>0.05)。202例患者死亡106例、存活96例。rs1800469位点各基因型、rs4803455位点各基因型的生存时间比较差异无统计学意义(P均>0.05)。TGF-β_(1)基因rs1800469、rs4803455位点SNP对HCC患者预后无影响(P均>0.05)。结论携带TGF-β_(1)基因rs1800469 GG、GA+GG基因型的个体HCC发病风险低;在女性人群中,携带GA+GG基因型的个体HCC发病风险低;未发现rs1800469、rs4803455位点SNP与HCC患者预后有关。

Correlation between expression of two transforming growth factor-beta 1 receptors and microvascular density in a rat model of cerebral ischemia and reperfusion injury

The effects of transforming growth factor-β1 （TGF-β1） are currently controversial. Whether TGF-β1 promotes or inhibits revascularization under different conditions remains poorly understood. Based on previous studies, the current experiment established rat models of cerebral ischemia and reperfusion injury （IRI）, and demonstrated that pathological and functional damage was also increased after IRI. The most serious damage was observed at 3 days after reperfusion, at which time microvascular density fell to its lowest level. Soon afterwards, microvascular density increased, new collateral circulation was gradually established at 4 to 7 days after reperfusion, and pathological damage and neurological deficits were improved. TGF-β1, activin receptor-like kinase 5 （ALK5） mRNA and protein expression levels increased gradually over time. In contrast, ALK1 mRNA and protein expression decreased over the same period. A significant negative correlation was detected between microvascular density and expression of the ALK5 gene transcript. There was no correlation between microvascular density and ALK1 gene transcriptional expression following cerebral IRI in a rat model. These findings suggest that ALK5, rather than ALK1, is the critical receptor in the TGF-β1 signal pathways after cerebral IRI.

Effects of Heparin on Transforming Growth Factor-β_1 and Extracellular Matrix Components in the Glomeruli of Diabetic Rats

The effects of heparin on the expression of transforming growth factor-β 1 (TGF-β 1) and two extracellular matrix components laminin (LN) and fibronectin (FN) in diabetic rat glomeruli were investigated. Twenty-six rats were randomly divided into control group (C, n=8), diabetic group (D, n=9), and diabetes+heparin group (DH, n=9). After 8-week therapy of heparin (200 U once daily by abdominal injection), TGF-β 1, LN and FN expression in glomeruli was detected by immunohistochemical method. The results showed that the expression levels of TGF-β 1, LN and FN were higher in group D than in group C. It was found that heparin could reduce 24-h urinary albumin excretion and inhibit overexpression of TGF-β 1, LN and FN in glomeruli of diabetic rats. It suggested that the inhibitory effect of heparin on diabetic glomerular sclerosis was at least partly related with the inhibition of TGF-β 1 expression.

Osteogenic Potential of Cultured Bone Marrow Stromal Cells Transfected with Transforming Growth Factor β_1 Gene in vitro

To study the osteogenic potential of cultured bone marrow stromal cells transfected with transforming growth factor β 1 gene in vitro , cultured BMSCs were transfected with the complexes of pcDNA 3 TGF β 1 and Lipofectamine Reagent in vitro . The cell proliferation was detected by MTT method and the morphological features of transfected BMSCs was observed. ALP stains and PNP method were used to measure ALP activity. In addition, the collagen type Ⅰ propeptides and mineralized matrixes were examined by immunohistochemical staining and tetracycline fluorescence labeling respectively. The morphological and biological characters of the transfected BMSCs were similar to those of osteoblasts and the cell proliferation was promoted. The cell layer displayed strong positive reaction for ALP stains and immunohistochemical staining. ALP activity and collagen type Ⅰ expression increased remarkably after transfection. Mineralized matrixes formed earlier and more in transfected BMSCs as compared with control group. It is concluded that transfecting with TGF β 1 gene could promote the osteogenic potential of cultured BMSCs.

Expression of transforming growth factor-β_1 and its typeⅠ receptor in different phases of post-burn hypertrophic scars

Objective: To analyze and compare the expression pattern of the transforming growth factor-β1(TGF-β1) and its type I receptor (TGF-β RI ) in nounal human skin and various phases of post-burn hypertrophic scars (HTS). Method: The immunohistochemical ABC method was employed. Results: In nounal human skin, no evident immunoreactivity of TGF-β1 and TGF-β R I was observed. In activation phase of post-burn HTS, TGF-β R I and TGF-β1 were highly expressed in most dermal fibroblasts which seemed to be the same subset. However, in remission phase, no staining was seen in der mal fibroblasts. Conclusion: The formation of all may involve the increase of TGF-β responsiveness in fibroblasts The ac cumulation at the wound site and failure of apoptosis of over-resposive fibroblasts may contribute to the formation of HTS.

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.

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.

Expression of Mesenger RNA for Transforming Growth Factor-β_1 in Bovine Trabecular Meshwork

Purpose: To investigate the relationship between transforming growth factor-β1(TGF-β1) and primary open-angle glaucoma, we have determined whether trabec-ular tissues have the expression of messenger RNA for TGF-β1.Methods: Total RNA of 24 newborn bovine trabecular tissue were extracted byGuanidine isothiocyanate method. The TGF-β33 plasmid was brought into E. col-ibacillius HB101 and amplificated. After Bam HI endolase degradation and labelwith a-32p-dATP the RNA was hybridized with the cDNA (complementary DNA)probe and examined by autoradiography.Results: The presence of mRNA for TGF-β1 in bovine trabecular meshwork wasconfirmed.Conclusions: The TGF-β1 present in normal aqueous humor must be at least partlyderived from the trabecular meshwork. It offered a basis for understanding therelationship between abnormal synthesis, activation and clearance of TGF-β1 andthe pathogenesis of primary open-angle glaucoma (POAG) in molecular biology.Eye Science 1996; 12:1-4.

益肾养阴固精方对2型糖尿病肾病气阴两虚证患者TGF-β1、S1P、NLRP3炎症小体及胰岛β细胞功能的影响

【目的】探讨益肾养阴固精方(左归丸化裁)在2型糖尿病肾病气阴两虚证治疗中的应用价值,观察其对炎症反应、胰岛β细胞功能及肾功能的影响。【方法】将2020年5月至2023年7月在陕西中医药大学附属医院就诊的162例2型糖尿病肾病气阴两虚证患者按随机数字表法随机分为观察组和对照组,每组各81例。对照组给予降压、护肾等西医常规治疗,观察组在对照组的基础上联合益肾养阴固精方治疗,疗程为12周。观察2组患者治疗前后中医证候总积分、胰岛素敏感指数、胰岛素分泌指数、24 h尿蛋白定量(24hUTP)及血清糖化血红蛋白(HbA1c)、空腹胰岛素(FINS)、空腹血糖(FBG)、血肌酐(SCr)、尿素氮(BUN)、转化生长因子β1(TGF-β1)、NLRP3炎症小体、白细胞介素6(IL-6)、超氧化物歧化酶(SOD)、1-磷酸鞘氨醇(S1P)水平的变化情况,并比较2组患者的临床疗效。【结果】(1)治疗12周后,观察组的总有效率为93.83%(76/81),对照组为83.95%(68/81),组间比较,观察组的疗效明显优于对照组(χ^(2)=9.163,P<0.05)。(2)治疗后,2组患者的胰岛素敏感指数、胰岛素分泌指数均较治疗前升高(P<0.05),中医证候总积分均较治疗前降低(P<0.05),且观察组对胰岛素敏感指数、胰岛素分泌指数的升高幅度及对中医证候总积分的降低幅度均明显优于对照组(P<0.05)。(3)治疗后,2组患者的血清HbA1c、FINS、FBG、SCr、BUN及24hUTP水平均较治疗前降低(P<0.05),且观察组对血清HbA1c、FINS、FBG、SCr、BUN及24hUTP水平的降低幅度均明显优于对照组(P<0.05)。(4)治疗后,2组患者的血清TGF-β1、IL-6、NLRP3炎症小体水平均较治疗前降低(P<0.05),血清S1P、SOD水平均较治疗前升高(P<0.05),且观察组对血清TGF-β1、IL-6、NLRP3炎症小体水平的降低幅度及对血清S1P、SOD水平的升高幅度均明显优于对照组(P<0.05)。【结论】对于2型糖尿病肾病气阴两虚证患者而言,联合益肾养阴固精方治疗有助于减轻炎症反应,改善胰岛β细胞功能,调节血糖水平,改善肾功能,提高临床疗效。

Vascular endothelial growth factor A, secreted in response to transforming growth factor-β1 under hypoxic conditions, induces autocrine effects on migration of prostate cancer cells

Hypoxia and transforming growth factor-β1 （TGF-β1） increase vascular endothelial growth factor A （VEGFA） expression in a number of malignancies. This effect of hypoxia and TGF-β1 might be responsible for tumor progression and metastasis of advanced prostate cancer. In the present study, TGF-β1 was shown to induce VEGFA165 secretion from both normal cell lines （HPV7 and RWPE1） and prostate cancer cell lines （DU 145 and PC3）. Conversely, hypoxia-stimulated VEGFA165 secretion was observed only in prostate cancer cell lines. Hypoxia induced TGF-β1 expression in PC3 prostate cancer cells, and the TGF-β1 type I receptor （ALK5） kinase inhibitor partially blocked hypoxia-mediated VEGFA16s secretion. This effect of hypoxia provides a novel mechanism to increase VEGFA expression in prostate cancer cells. Although autocrine signaling of VEGFA has been implicated in prostate cancer progression and metastasis, the associated mechanism is poorly characterized. VEGFA activity is mediated via VEGF receptor （VEGFR） 1 （Fit-l） and 2 （FIk-I/KDR）. Whereas VEGFR-1 mRNA was detected in normal prostate epithelial cells, VEGFR-2 mRNA and VEGFR protein were expressed only in PC3 cells. VEGFA165 treatment induced phosphorylation of extracellular signal-regulated kinase 1/2 （ERKI/2） in PC3 cells but not in HPV7 cells, suggesting that the autocrine function of VEGFA may be uniquely associated with prostate cancer. Activation of VEGFR-2 by VEGFA165 was shown to enhance migration of PC3 cells. A similar effect was also observed with endogenous VEGFA induced by TGF-β1 and hypoxia. These findings illustrate that an autocrine loop of VEGFA via VEGFR-2 is critical for the tumorigenic effects of TGF-β1 and hypoxia on metastatic prostate cancers.

LOW DOSE PIRFENIDONE SUPPRESSES TRANSFORMING GROWTH FACTOR BETA-1 AND TISSUE INHIBITOR OF METALLOPROTEINASE-1, AND PROTECTS RATS FROM LUNG FIBROSIS INDUCED BY BLEOMYCIN

Objective To investigate the optimal dosage of pirfenidone for the treatment of pulmonary fibrosis induced by bleomycin in Wistar rats, and the alteration of expressions of transforming growth factor beta-1 （ TGF-β1 ）, tissue inhibitor of metalloproteinase-1 （ TIMP-1 ）, and matrix metalloproteinase-13 （ MMP-13 ） in lung tissue. Methods Male Wistar rats were endotracheally instilled with bleomycin or normal saline. Pirfenidone （25-800 mg · kg^-l · d^-1 ）, dexamethasone （3 mg/kg）, or 1% carboxymethylcellulose sodium were given daily by feed 2 days before instillation of bleomycin. Groups T7 and T14 were fed pirfenidone 50 mg · kg^-1 · d^-1 at 7 days or 14 daYs after bleomycin instillation. Lungs were harvested at 28 days after bleomycin instillation. Patholological changes in luffg tissues were evaluated with HE staining. Lung collagen was stained by sirius red and measured by content of hydroxypro- line. Expression of proteins of TGF-β1 TIMP-1, and MMP-13 were detected by Western blotting. Results At doses of 25, 50, and 100 mg· kg^- 1 · d ^- 1, pirfenidone had significant anti-fibrotic effects for bleomy- cin-induced rat pulmonary fibrosis, and these effects were most significantly attenuated at the dosage of 50 mg · kg^-1 ·d^ -1（ HE： P 〈 0. 01, P 〈 0.01, and P = 0.064; sirius red： P 〈0.05, P 〈 0.01, and P 〈 0.05 ; hydroxyproline： P = 0.595, P 〈 0.01, and P = 0.976）. Pirfenidone at a dosage of 50 mg · kg^- l · d^-1 inhibited protein expression of TGF-131 and TIMP-1 in lung tissue in the early phase （0.79 and 0.75 times of control group）, but had no effect on ex- nr^eelnn nf MMP-13. Conclusion Low dose pirfenidone, especially at dosage of 50 mg · kg^-1 · d^-1, has significant anti-fibrotic effects on bleomycin-induced rat pulmonary fibrosis. Pirfenidone partially inhibits the enhancement of the expression of TGF-131 and TIMP-β1 in lung tissue.

儿童慢性粒细胞白血病慢性期红细胞参数及血清bFGF、TGF-β1、VEGF表达变化分析

目的探究儿童慢性粒细胞白血病(CML)慢性期红细胞参数及血清碱性成纤维细胞生长因子(bFGF)、转化生长因子β1(TGF-β1)及血管内皮生长因子(VEGF)表达变化。方法前瞻性选取2020年1月至2023年1月在首都医科大学附属北京儿童医院进行治疗的54例CML慢性期患儿为研究组,另随机抽取46名同期在本院进行体检的健康儿童为健康对照组。研究组给予酪氨酸激酶抑制剂治疗。比较两组间红细胞参数及血清bFGF、TGF-β1、VEGF表达变化,并比较研究组治疗前后红细胞参数及血清bFGF、TGF-β1、VEGF表达水平。结果研究组的RBC、血红蛋白、红细胞压积(HCT)及平均红细胞血红蛋白浓度(MCHC)水平分别为(3.45±0.04)×10^(12)/L、(102.33±1.15)g/L、(32.03±0.61)%、322.15±2.58,均显著低于对照组[(4.98±0.03)×10^(12)/L、(149.78±1.88)g/L、(44.33±0.31)%、334.12±0.77],平均红细胞体积(MCV)、平均红细胞血红蛋白含量(MCH)及红细胞体积分布宽度(RDW)水平分别为(91.44±0.77)fL、(33.15±2.55)pg、(17.55±0.12)%,均显著高于对照组[(89.88±0.34)fL、(30.24±0.16)pg、(12.66±0.11)%],差异均有统计学意义(P<0.05)。研究组的血清bFGF、VEGF水平分别为(30.66±9.66)、(128.68±30.58)pg/mL,均显著高于对照组[(5.26±1.54)、(70.66±11.26)pg/mL],TGF-β1水平为(38.22±8.06)μg/L,显著低于对照组[(78.66±8.13)μg/L],差异均有统计学意义(P<0.05)。治疗后,研究组患儿的RBC、血红蛋白、HCT、MCV及MCH水平均较治疗前显著降低,MCHC及RDW水平均较治疗前显著升高,差异均有统计学意义(P<0.05)。研究组治疗后的血清bFGF、VEGF水平均较治疗前显著降低,TGF-β1水平较治疗前显著升高,差异均有统计学意义(P<0.05)。结论在儿童CML慢性期患儿中可见血细胞参数明显异常,血清bFGF、VEGF水平显著升高,TGF-β1水平显著降低。酪氨酸激酶抑制剂治疗CML慢性期能有效改善患儿红细胞形态及功能,抑制肿瘤细胞生长,临床疗效显著,值得临床推广使用。