Analysis Of TGF-β1 Research Articles

Improvement on renal interstitial fibrosis in rats with renal failure via TLR4/NF-κB signaling pathway by means of panax notoginseng saponins

Panax notoginseng saponins (PNS) have excellent effects on treating cardiovascular and cerebrovascular diseases, tumors and organ interstitial diseases. This study assessed the effect of PNS on renal interstitial fibrosis (RIF). Four groups of models were firstly created, which included; renal failure model, healthy group, model group, PNS group, and then established TLR4 inhibitor group (TAK-242 group), TLR4 activator group (LPS group), combined PNS and TLR4 inhibitor group (PNS+ TAK-242 group) and combined PNS and TLR4 agonist (PNS+LPS group). TLR4/NF-κB signaling pathway and regulatory mechanism for PNS were observed along with analysis of TGF-β1, α-SMA, Collagen I and FN expressions in kidney tissues. The PNS significantly inhibited changes of renal interstitial fibrosis in rats with renal failure, and this process was related to decreased expressions of TLR4 and NF-κB. The PNS also inhibited the expression of TLR4, and expressions of TGF-β1, α-SMA, Collagen I and FN were down-regulated in kidney cells after using TAK-242, especially in the PNS+TAK-242 group. The PNS can thus significantly inhibit the process of renal fibrosis, and this process is due to the fact that, PNS inhibits the activity of TLR4/NF-κB signaling pathway to down-regulate the expressions of fibrosis-related factors TGF-β1, α-SMA, etc., in exerting its effects.

Glutathione S-Transferase Omega-2 and Transforming Growth Factor-β1 Polymorphisms in Iranian Glaucoma Patients.

Background To investigate the association of glutathione s-transferase omega 2 (GSTO2) (142N > D) and transforming growth factor-β1 (TGF-β1) (869T > C) gene polymorphisms on the pathogenesis of two common types of glaucoma (including primary open-angle glaucoma (POAG) and chronic angle-closure glaucoma (CACG)) in the Iranian population. Methods A total of 100 glaucoma patients (60% males and 40% females with an age mean ± SD of 34.66 ± 14.25 years; 56 cases of POAG and 44 cases of CACG) were enrolled in this study. GSTO2 (142N > D) and TGF-β1 (869T > C) polymorphisms were evaluated by PCR-based methods in patients and controls. Results At locus GSTO2 (142N > D), the odds of ND genotype with respect to DD and NN genotypes were 1.55 and 2.08 times higher in POAG and CACG patients compared to those of patients in the control group (95% CI1: 0.80–2.98; 95% CI2: 1.00–4.33) which was statistically significant in CACG patients. However, the odds of DD and NN genotypes against the reference genotype in two patients group were not statistically significant as compared to those of patients in the control group. There was a significant association between the ND genotype and male patients (OR = 2.28, 95% CI: 1.06–4.92). The analysis of TGF-β1 (869T > C) polymorphisms showed no significant difference between the genotypes of TGF-β1 (869T > C) polymorphisms in patients and control groups; however, the CT genotype of TGF-β1 significantly differed between female controls and patients (OR = 0.42, 95% CI: 0.18–0.96). Conclusion The presented results revealed that there was a significant association between the ND genotype of GSTO2 and the pathogenesis of glaucoma. Furthermore, this genotype can be considered as a sex-dependent genetic risk factor for the development of glaucoma. In contrast, the CT genotype of TGF-β1 is suggested to be a protective genetic factor against the pathogenesis of glaucoma.

Analysis of TGF-β1 and p53 Expression in The Blood of Stroke Patient

Introduction: Stroke is a dysfunction of brain tissue due to deficiency of blood circulation to the brain. This causes disruption of blood supply and oxygen in the brain. Stroke not only needs to be handled in post-event, but also needs to be understood the cause of the occurrence by molecular, so that the drug will be right on target. Inflammation is associated as a secondary injury mechanism in the case of stroke. Dendritic cells which secreted TGF-β, it functions to regulate proliferation, differentiation and activate other cytokines in cell growth. It is strongly suspected that Transforming Growth Factor-β1 (TGF-ß1) is a determinant of cytokines in nerve tissue recovery. Neural cell malfunction or nerve cell death is thought to be the role of p53 protein.Methods: The design of this research is observation. This research measures TGF and p53 expression in the stages of mRNA (RT-PCR) and protein (ELISA) in the blood of stroke patients.Results: The expression of TGF- β1 and p53 mRNA in the blood of stroke patients is higher (50 and 45 times; Unpaired p <0.01) than normal. TGF- β and p53 protein levels in the blood of stroke patients are higher than normal (20,607 vs 1,895 pg/mLx10; 44,418 vs 11.63 pg/ mL; Unpaired 0 <0.01). The correlation of both TGF- β1 and p53 shows a strong positive.Discussion: The expression of increased TGF- β1 and p53 In the blood of stroke patients.International Journal of Human and Health Sciences Vol. 05 No. 01 January’21 Page: 35-40

Miltefosine suppression of Pten null T-ALL leukemia via β-catenin degradation through inhibition of pT308-Akt and TGFβ1/Smad3

Pten deletion in the hematopoietic stem cells (HSC) causes a myeloproliferative disorder, which may subsequently develop into a T-cell acute lymphoblastic leukemia (T-ALL). β-catenin expression was dramatically increased in the c-KitmidCD3+Lin− leukemia stem cells (LSC) and was critical for T-ALL development. Therefore, the inactivation of β-catenin in LSC may have a potential to eliminate the LSC. In this study, we investigated the mechanism of enhancement of the β-catenin expression and subsequently used a drug to inactivate β-catenin expression in T-ALL. Western blot (WB) analysis revealed an increased level of β-catenin in the leukemic cells, but not in the pre-leukemic cells. Furthermore, the WB analysis of the thymic cells from different stages of leukemia development showed that increased expression of β-catenin was not via the pS9-GSK3β signaling, but was dependent on the pT308-Akt activation. Miltefosine (Hexadecylphosphocholine) is the first oral anti-Leishmania drug, which is a phospholipid agent and has been shown to inhibit the PI3K/Akt activity. Treatment of the PtenΔ/Δ leukemic mice with Miltefosine for different durations demonstrated that the pT308-Akt and the β-catenin expressions were inhibited in the leukemia blast cells. Miltefosine treatment also suppressed the TGFβ1/Smad3 signaling pathway. Analysis of TGFβ1 in the sorted subpopulations of the blast cells showed that TGFβ1 was secreted by the CD3+CD4− subpopulation and may exert effects on the subpopulations of both CD3+CD4+ and CD3+CD4− leukemia blast cells. When a TGFβR1 inhibitor, SB431542 was injected into the PtenΔ/Δ leukemic mice, the Smad3 and β-catenin expressions were down-regulated. On the basis of the results, we conclude that Miltefosine can suppress leukemia by degrading β-catenin through repression of the pT308-Akt and TGFβ1/Smad3 signaling pathways. This study demonstrates a possibility to inhibit Pten loss-associated leukemia genesis via targeting Akt and Smad3.

Pirfenidone inhibits cryoablation induced local macrophage infiltration along with its associated TGFb1 expression and serum cytokine level in a mouse model

PurposeTo investigate the effects of pirfenidone (PFD) on post-cryoablation inflammation in a mouse model. Materials and methodsIn this IACUC-approved study, eighty Balb/c mice were randomly divided into four groups (20/group): sham + vehicle, sham + PFD, cryoablation + vehicle, and cryoablation + PFD. For cryoablation groups, a 20% freeze rate cryoablation (20 s to less than −100 °C) was used to ablate normal muscle in the right flank. For sham groups, the cryoprobe was advanced into the flank and maintained for 20 s without ablation. PFD or vehicle solution was intraperitoneally injected (5 mg/kg) at days 0, 1, 2, 3, and then every other day until day 13 after cryoablation. Mice were euthanized at days 1, 3, 7, and 14. Blood samples were used for serum IL-6, IL-10, and TGFβ1 analysis using electrochemiluminescence and ELISA assays, respectively. Immunohistochemistry-stained ablated tissues were used to analyze macrophage infiltration and local TGFβ1 expression in the border region surrounding the cryoablation-induced coagulation zone. ResultsCryoablation induced macrophage infiltration and increased TGFβ1 expression in the border of the necrotic zone, and high levels of serum IL-6, peaking at days 7 (70.5 ± 8.46/HPF), 14 (228 ± 18.36/HPF), and 7 (298.67 ± 92.63), respectively. Animals receiving PFD showed reduced macrophage infiltration (35.5 ± 16.93/HPF at day 7, p < 0.01) and cytokine levels (60.2 ± 7.6/HPF at day 14, p < 0.01). PFD also significantly reduced serum IL-6 levels (p < 0.001 vs. all non-PFD groups). ConclusionsPFD mitigates cryoablation induced muscle tissue macrophage infiltration, increased IL-6 levels, and local TGFβ1 expression in a small animal model.

Analysis of TGF-β1 and TGF-β3 as regulators of encephalitogenic Th17 cells: Implications for multiple sclerosis.

The phenotype of the CD4(+) T cells that mediate the CNS pathology in multiple sclerosis is still unclear, and yet a vital question for developing therapies. One of the conundrums is the role of TGF-β in the development of encephalitogenic Th17 cells. In the present study, TGF-β1 and TGF-β3 were directly compared in their capacity to promote the differentiation of myelin-specific Th17 cells that could induce experimental autoimmune encephalomyelitis (EAE). Myelin-specific CD4(+) T cell receptor transgenic cells differentiated with antigen in the presence of IL-6+TGF-β1 or IL-6+TGF-β3 generated T cells that produced robust amounts of IL-17, but were incapable of inducing EAE when transferred into mice. Further analysis of these non-encephalitogenic Th17 cells found that they expressed lower amounts of GM-CSF or IL-23R, both molecules necessary for encephalitogenicity. Thus, TGF-β, irrespective of isoform, negatively regulates the differentiation of encephalitogenic Th17 cells.

Analysis of TGF-β1- and drug-induced epithelial–mesenchymal transition in cultured alveolar epithelial cell line RLE/Abca3

In this study, we examined the induction of epithelial–mesenchymal transition (EMT) by transforming growth factor (TGF)-β1 and drugs in genetically engineered type II alveolar epithelial cell line RLE/Abca3. Treatment of RLE/Abca3 cells with TGF-β1 induced marked changes in cell morphology from epithelial-like to elongated fibroblast-like morphology. With these morphological changes, mRNA expression of epithelial markers such as cytokeratin 19 (CK19) decreased, while that of mesenchymal markers such as α-smooth muscle actin (α-SMA) increased. TGF-β1 treatment also decreased the mRNA expression of Abca3, a type II cell marker, and formation of lamellar body structures. Interestingly, the effect of TGF-β1 on Abca3 mRNA expression was observed in RLE/Abca3 cells, but not in wild-type RLE-6TN, A549, and H441 cells. Treatment of RLE/Abca3 cells with bleomycin (BLM) and methotrexate (MTX) induced similar morphological and mRNA expression changes. In addition, the increase in α-SMA and the decrease in Abca3 mRNA expression by these drugs were observed only in RLE/Abca3 cells. These findings suggest that, like TGF-β1, BLM and MTX induce EMT in RLE/Abca3 cells, and RLE/Abca3 cells would be a good model to study drug-induced EMT. The effect of pirfenidone, an antifibrotic and anti-inflammatory drug, on EMT induced by TGF-β1 was also discussed.

MicroRNA 144 Involved in the Modulation of TGF-b Signaling and Fibrosis Is Upregulated in Lung Biopsies from Transplant Recipients Undergoing Chronic Rejection - Bronchiolitis Obliterans Syndrome (BOS)

Introduction: Development of BOS following human lung transplantation (LTx) remains a major impediment for long term function of the transplanted lungs. BOS is a fibroproliferative process resulting in progressive decline in pulmonary function and eventual allograft failure. The immune mechanisms leading to the development of BOS remains poorly defined. MicroRNAs (miR), through the regulation of gene expression, control various biological processes. Specifically, miR 144 has been reported to upregulate TGF-b signaling leading to fibrosis and therefore may play a significant role in the pathogenesis of BOS. Objective: The objective of this study was to determine whether miR 144 is upregulated in the lung biopsies from LTx recipients diagnosed with BOS and to define the role of miR 144 in the development of BOS following human LTx. Methods: Serum concentrations of TGF-β1 and IL-6 were determined by ELISA. Levels of miR 144 in the lung biopsies of BOS+ and BOS-LTx recipients (n=15 each) were analyzed by quantitative real time PCR (qPCR). The levels of downstream targets of miR 144 TGFB-induced factor homeobox 1 (TGIF-1), SMAD, TGF-b1, IL-6, and connective tissue growth factor (CTGF) were determined by qPCR using gene specific primers. Results: Analysis of the serum levels of TGF-β1 and IL-6 demonstrated a significant increase in the levels of TGF-β1 (430 vs 110 ng/ml, p< 0.05) and IL-6 (278 vs 63 ng/ml, p< 0.05) levels in BOS+ patients. Based on this we analyzed miR 144 levels in the lung biopsies from a different cohort of LTx which showed significant increase (3.4±1.2 fold) in the levels of miR 144 in the lung biopsies of BOS+ LTx when compared to the BOS- LTx (p< 0.05). qPCR analysis for the down stream targets also demonstrated significant decrease in the expression of TGIF (3.8±0.9 fold) and marked increases in SMAD (4.3±1.2 fold), TGFβ1 (5.3 fold increase), IL-6 (2.9±0.9 fold increase) and CTGF (3.9±1.1 fold increase) in comparison to BOS- LTx recipients. Analysis of TGF-β and IL-6 in serum samples from part of this cohort of BOS+ LTx also demonstrated significant increases in the levels of TGF-β (262ng/ml) and IL-6 (62.6ng/ml). Conclusion: Our results demonstrated increased levels of miR 144 in the lung biopsies from BOS+ LTx recipients. We propose that miR144 can down regulate the expression of TGIF-1, a negative regulator of SMAD which is critical for the TGF-β signaling cascade. This will result in increased expression of TGF-β1, IL-6 and CTGF which can promote the development of fibrosis, a hallmark of the lesion for the development of BOS in LTx recipients. Therefore, agents that can target miR 144 may aid in the prevention of fibrosis development and therefore BOS following LTx.

Early activation of fibrogenesis in transplanted kidneys: A study on serial renal biopsies

Background/aims In kidney transplants, the renin–angiotensin system (RAS) is involved in systemic and local changes that may induce fibrosis. Our aim was to use gene expression and immunohistochemical analysis to investigate the RAS and several factors involved in the fibrogenic cascade in allograft biopsies. Methods We considered 43 donor biopsies (T0), 18 biopsies obtained for diagnostic purposes (Td) and 24 protocol biopsies (Tp) taken 2 months after transplantation in patients with stable renal function. Morphometric αSMA and TGFβ1 analysis, and Masson's Trichrome staining were performed. mRNA levels of angiotensinogen, renin, ACE, AT1-R, AT2-R, TGFβ1, BMP-7, Coll III, fibronectin and αSMA were analyzed by real-time RT/PCR. MDRD a year after the transplant was also considered. Results Significantly higher levels of AT1-R and αSMA transcripts were found in Tp than in T0. Regression analysis showed significant TGFβ1-independent positive correlations between RAS and matrix components in T0 and Tp, but more evident in Tp, where a positive correlation between TGFβ1 and Masson's Trichrome stained areas was also seen. Conclusion Our results suggest that RAS and TGFβ1-related fibrogenic loops are activated as early as 2 months after kidney transplantation.

Analysis of TGF-β 1 gene polymorphisms in Hong Kong Chinese patients with asthma

The C-509T polymorphism of TGF-beta(1) gene has been associated with asthma and atopy in white populations. We investigated the association between asthma and previously identified polymorphisms at C-509T and T869C of the TGF-beta(1) gene among 250 Chinese patients with asthma and 308 healthy controls in Hong Kong. Genotyping was performed on peripheral blood genomic DNA by using PCR-RFLP. There were no differences in the frequencies of genotypes and alleles between patients and controls. The C-509T and T869C polymorphisms were in tight linkage disequilibrium (P < .01). Among atopic subjects, significant differences were found in genotype and allele frequencies for T869C polymorphism between patients and controls (P = .014 and P = .019, respectively), and individuals bearing the CC genotype were associated with increased risk for the development of asthma (odds ratio, 2.58; 95% CI, 1.17-5.66; P = .018) after adjusting for age, sex, and smoking status. Individuals with asthma bearing the CT genotype of the C-509T polymorphism had significantly increased risk for severe airflow obstruction compared with individuals who had mild obstruction (odds ratio, 4.00; 95% CI, 1.06-15.08; P = .035). Our results indicate that the polymorphisms at C-509T and T869C of the TGF-beta(1) gene are associated with asthma susceptibility in atopic subjects of the Hong Kong Chinese population, and the C-509T polymorphism may play a role in the pathogenesis of airflow obstruction.

Identification of the Prelinitis Condition in Gastric Cancer and Analysis of TGF-β, TGF-β RII and pS2 Expression

In the present study, we performed an immunohistochemical examination of the expression of transforming growth factor-β (TGF-β), TGF-β type II receptor (TGF-β RII) and a trefoil peptide, pS2, in the several types of gastric cancer. The TGF-β:TGF-β RII ratios of IIc-like type and Ménétrier type closely resembled that of linitis type. pS2 was intensely expressed in cytoplasm of the superficial and foveolar epithelium, as well as in scirrhous type gastric cancers which retained the gastric or intestinal phenotype. However, pS2 expression was significantly (p < 0.05) reduced in linitis type gastric cancers (1 of 6; 17%) when compared with other scirrhous types of gastric cancers (13 of 22; 59%). A decrease in the TGF-β:TGF-β RII ratios in linitis type, IIc-like type and Ménétrier type gastric cancers may be associated with the fibrosis seen in these types of cancer. Furthermore, reduction of pS2 expression in linitis type gastric cancer may represent a dedifferentiation of the cancer from gastric or intestinal phenotype. Judging by the expression patterns of TGF-β, TGF-β RII and pS2, it is possible that IIc-like type and Ménétrier type gastric cancers are precursor lesions of linitis type gastric cancer.

Osteogenic evaluation of glutaraldehyde crosslinked gelatin composite with fetal rat calvarial culture model.

The cytotoxicity of the synthetic bone substitute composed of tricalcium phosphate and glutaraldehyde crosslinked gelatin (GTG) were evaluated by osteoblast cell culture. In a previous study, the GTG composites were soaked in distilled water for 1, 2, 4, 7, 14, 28, and 42 days, and then the solutions (or extracts) were cocultured with osteoblasts to evaluate the cytotoxicity of GTG composites by alive cell counting. In this study, the extracts were cocultured with the osteoblasts; thereafter, the concentration of transforming growth factor-beta (TGF-beta1) and prostaglandin E2 (PGE2) in the medium was analyzed to strictly reflect the biological effects of GTG composites on the growth of osteoblasts. In order to investigate the osteoconductive potential of the GTG composites on new bone formation in a relative short term, a model of neonatal rat calvarial organ culture was designed prior to animal experiments. Three experimental materials of 4, 8, and 12% GTG composites were evaluated by fetal rat calvarial organ culture for their ability for bone regeneration. Deproteinized bovine and porcine cancellous bone matrixes were used as the controlled materials. All the organ culture units were maintained in cultured medium for 5 weeks. Following the culture period, the morphology of tissue was observed under an optical microscope, and the quantitative evaluation of the new generation bone was determined by using a semiautomatic histomorphometeric method. Except in the initial 4 days, the concentration of TGF-beta1 of 4% and 8% GTG composites was higher than that of the blank group for all the other experimental time periods. The PGE2 concentration for 4% and 8% GTG composites was lower than that of the blank group. It revealed that the 4% and 8% GTG composites would not lead to inflammation and would promote osteoblast growth. The morphology and activity of the osteoblasts were not transformed or changed by the 2 GTG composites. For the 12% GTG composite, the performance of the in vitro condition was inferior to the blank group and the other 2 GTG composites. Although the concentration of TGF-beta1 and PGE2 was gradually back to normal after 14 days, the morphology of the osteoblasts was abnormal with features such as contracted cytoplast structures. The osteoblast was damaged perhaps in the initial stage. We suggested that the 4% and 8% GTG composites should be soaked in distilled water at least for 4 days before medical applications. The 12% GTG composite and the composites with a concentration of glutaraldehyde solution higher than 12% were not recommended as a medical prostheses in any condition. The fetal rat calvaria culture also showed the same results with the analysis of TGF-beta1 and PGE2. From the study, we could predict the results of animal experiments in the future.

Evolutionary Trace analysis of TGF-β and related growth factors

Evolutionary Trace analysis of TGF-β and related growth factors