Relevant bibliographies by topics / TGFβ1 treatment

Academic literature on the topic 'TGFβ1 treatment'

Author: Grafiati
Published: 10 December 2022
Last updated: 28 January 2023

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Journal articles on the topic "TGFβ1 treatment"

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Budhu, Sadna, Aditi Gupta, Kelly Fitzgerald, Rachel Giese, Adam Michel, Aliya Holland, Luis Felipe Campesato, et al. "567 Isoform specific anti-TGFβ therapy enhances antitumor efficacy in mouse models of stroma poor cancers." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A596. http://dx.doi.org/10.1136/jitc-2021-sitc2021.567.

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BackgroundTGFβ is a potential target in cancer treatment due to its dual role in tumorigenesis and homeostasis. There are three isoforms of TGFβ (TGFβ1, TGFβ2 and TGFβ3), which are secreted by immune and non-immune cells as an inactive latent complex. Depending on the local context and players, TGFβ can adopt opposing roles in carcinogenesis and in modulating the immune system. However, the expression of TGFβ and its inhibition within the tumor microenvironment has mainly been investigated in stroma-rich tumors.MethodsWe examined expression of TGFβ1 and TGFβ3 isoforms on immune cells in two stroma-poor mouse tumor models (B16 melanoma and CT26 colon carcinoma) and investigated the anti-tumor efficacy of antibodies that block TGFβ1 and TGFβ3 in these two models.ResultsDepending on local expression of TGFβ isoforms, specific inhibition of either TGFβ1 or TGFβ3 may be effective. The ”TGFβ signature” of CT26 colon carcinoma is defined by TGFβ1 expression on immune cells and TGFβ1 inhibition results in tumor delay; B16 melanoma has equal expression of both TGFβ1 or TGFβ3 isoforms and inhibition of either TGFβ1 or TGFβ3 controls tumor growth. We show that the mechanism of tumor growth delay is enhanced CD8+ T cell activation and effector function. In addition, we found that combining TGFβ inhibition with immune checkpoint blockade results in improved tumor control and survival.ConclusionsOur findings suggests that expression of TGFβ isoforms in the TME is variable in different tumor types and their expression may be used to predict anti-tumor responses to TGFβ inhibition. Isoform specific TGFβ inhibition in stroma poor tumors shifts the local immune environment to favor tumor regression alone or in combination with immune checkpoint blockade.
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Budhu, Sadna, Aditi Gupta, Rachel Giese, Jacques van Snick, Catherine Uyttenhove, Gerd Ritter, Jedd D. Wolchok, and Taha Merghoub. "Isoform specific anti-TGFβ therapy enhances antitumor efficacy in mouse models of cancer." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 136.23. http://dx.doi.org/10.4049/jimmunol.202.supp.136.23.

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Abstract TGFβ is a pleotropic cytokine, which has emerged as a potential target in cancer treatment due to its dual role in tumorigenesis and homeostasis. There are three isoforms of TGFβ (TGFβ1, TGFβ2 and TGFβ3), which are secreted by immune and nonimmune cells as an inactive latent complex. Depending on the local context and players, TGFβ can adopt opposing roles in carcinogensis and in modulating the immune system. However, the expression of TGFβ isoforms within the tumor microenvironment and isoform specific inhibition remains to be investigated. The main source of TGFβ isoforms in the tumor microenvironment of B16 melanoma are infiltrating immune cells, with TGFβ1 and TGFβ3 being highly expressed on myeloid and dendritic cells. The CD45− population from B16 tumors demonstrated a lower expression of both TGFβ isoforms. Compared to untreated control animals, anti-TGFβ3 therapy resulted in the greatest delay in B16 tumor growth, followed by anti-TGFβ1 therapy and pan-TGFβ blockade. However, none of the therapies resulted in improved overall survival. Similar results were achieved in a 4T1 breast model. T cell functional assays demonstrated that anti-TGFβ3 resulted in CD8+ T cells with greater cytolytic ability as they showed higher granzyme B expression and killing against B16 cells when plated ex-vivo. Anti-TGFβ1 treatment resulted in greater interferon-γ production by CD8+ T cells, suggesting an increase in antigen-specificity. Isoform specific TGFβ inhibition in combination with immune checkpoint blockade demonstrated improved tumor control and survival. This provides rationale for the use of anti-TGFβ therapy in stroma poor tumors, such as melanoma, and for its potential to enhance the effectiveness of existing therapies.
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Shynlova, Oksana, Prudence Tsui, Anna Dorogin, B. Lowell Langille, and Stephen J. Lye. "The expression of transforming growth factor β in pregnant rat myometrium is hormone and stretch dependent." Reproduction 134, no. 3 (September 2007): 503–11. http://dx.doi.org/10.1530/rep-07-0004.

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From a quiescent state in early pregnancy to a highly contractile state in labor, the myometrium displays tremendous growth and remodeling. We hypothesize that the transforming growth factor β (TGFβ) system is involved in the differentiation of pregnant myometrium throughout gestation and labor. Furthermore, we propose that during pregnancy the mechanical and hormonal stimuli play a role in regulating myometrial TGFβs. The expression of TGFβ1-3 mRNAs and proteins was examined by real-time PCR, Western immunoblot, and localized with immunohistochemistry in the rat uterus throughout pregnancy and labor. Tgfβ1-3 genes were expressed differentially in pregnant myometrium. Tgfβ2 gene was not affected by pregnancy, whereas the Tgfβ1 gene showed a threefold increase during the second half of gestation. In contrast, we observed a dramatic bimodal change in Tgfβ3 gene expression throughout pregnancy. Tgfβ3 mRNA levels first transiently increased at mid-gestation (11-fold on day 14) and later at term (45-fold at labor, day 23). Protein expression levels paralleled the changes in mRNA. Treatment of pregnant rats with the progesterone (P4) receptor antagonist RU486 induced premature labor on day 19 and increased Tgfβ3 mRNA, whereas artificial maintenance of elevated P4 levels at late gestation (days 20–23) caused a significant decrease in the expression of Tgfβ3 gene. In addition, Tgfβ3 was up-regulated specifically in the gravid horn of unilaterally pregnant rats subjected to a passive biological stretch imposed by the growing fetuses, but not in the empty horn. Collectively, these data indicate that the TGFβ family contributes in the regulation of myometrial activation at term integrating mechanical and endocrine signals for successful labor contraction.
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Quintela, M., R. M. SeñarÍs, and C. Diéguez. "Transforming Growth Factor-βs Inhibit Somatostatin Messenger Ribonucleic Acid Levels and Somatostatin Secretion in Hypothalamic Cells in Culture*." Endocrinology 138, no. 10 (October 1, 1997): 4401–9. http://dx.doi.org/10.1210/endo.138.10.5467.

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Abstract Treatment of hypothalamic cells in monolayer culture with transforming growth factor-β1 (TGFβ1) significantly reduced both basal and cAMP-induced somatostatin messenger RNA (mRNA) levels and somatostatin secretion. This inhibitory effect was dose- and time-dependent and not mediated by glial cells, as it was also observed in glial-free hypothalamic cell cultures treated with cytosine arabinonucleoside. TGFβ2 and -β3 mimicked the actions of TGFβ1, which indicated that the three isoforms of the TGFβ family expressed in the central nervous system displayed similar effects on the somatostatinergic neurons. The blockade of synthesis of proteins with either cycloheximide or puromycin for 24 h prevented the inhibitory effect of TGFβ1 on somatostatin mRNA. This implied that the reduction of this mRNA by TGFβ1 required de novo protein synthesis. We next studied whether TGFβ1 acted at the transcriptional or posttranscriptional level by altering the stability of somatostatin mRNA. Examination of the rate of disappearance of somatostatin mRNA by Northern blot, after inhibition of mRNA transcription with either actinomycin D (AcD) or 5,6-dichloro-1β-ribofuranosyl benzimidazole revealed that TGFβ1 did reduce the stability of somatostatin mRNA. This effect was observed when we pretreated the cultures with TGFβ1 4 h before the addition of AcD, but not when we administered TGFβ1 simultaneously with AcD or 5,6-dichloro-1β-ribofuranosyl benzimidazole. Altogether these results demonstrated that the treatment of hypothalamic cells in culture with TGFβ1, TGFβ2, or TGFβ3 resulted in a decrease in somatostatin mRNA levels and somatostatin secretion. TGFβ1 reduced the steady state levels of somatostatin mRNA by inducing the synthesis of a protein (s), that appears to accelerate the degradation of the mRNA of somatostatin. Whether TGFβ1 has additional effects on the transcription of the somatostatin gene will require further study.
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Varricchio, Lilian, John Mascarenhas, Anna Rita Migliaccio, Maureen O'Connor-McCourt, Gilles Tremblay, Jean-François Denis, Camelia Iancu-Rubin, and Ronald Hoffman. "AVID200, a Potent Trap for TGF-β Ligands Inhibits TGF-β1 Signaling in Human Myelofibrosis." Blood 132, Supplement 1 (November 29, 2018): 1791. http://dx.doi.org/10.1182/blood-2018-99-116474.

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Abstract Myelofibrosis (MF) is caused by driver mutations which upregulate JAK/STAT signaling. The only curative treatment for MF is hematopoietic stem cell transplant. Ruxolitinib alleviates many of the symptoms in MF but does not significantly alter survival. There is, therefore, an urgent need for additional rational therapies for MF. Bone marrow fibrosis and collagen deposition are hallmarks of MF which have been attributed to megakaryocyte (MK) derived TGFβ, which also plays a role in myelo-proliferation. There are three isoforms of TGFβ (TGFβ1, β2, and β3). AVID200, which was constructed by fusing TGFβR ectodomains to IgG Fc regions, is a potent TGFβ trap with pM potency against two of the three TGFβ ligands, TGFβ1 and β3 (IC50 values of ~ 3 pM ). AVID200's IC50 for TGFβ2 is ~4,000-fold higher indicating that it has minimal activity against TGFβ2, which is desirable since TGFβ2 is a positive regulator of hematopoiesis. We explored the therapeutic potential of AVID200 by culturing MF or normal donor (ND) mononuclear cells (MNCs) first in the presence of stem cell factor and thrombopoietin (TPO) and then TPO alone in order to generate MK-enriched populations. Although the percentage of mature MKs from ND and MF MNCs was similar, the absolute number of CD41+/CD42+ MKs generated from MF MNCs was two-fold greater than ND MNCs. To determine the levels of TGFβ secreted by the MKs we screened MF and ND MNC conditioned media (CM). We observed significantly higher levels of TGFβ1 but not TGFβ2 and TGFβ3 in MF MK CM. The effects of AVID200 on MKs were then evaluated by measuring the levels of phosphorylated SMAD2. Treatment with 0.001 - 0.1 nM AVID200 decreased phosphorylation of SMAD2, suggesting that AVID200 blocks autocrine MK TGFβ signaling. The increased levels of TGFβ in MF patients promote the proliferation and deposition of collagen by mesenchymal stem cells (MSCs). Cellular proliferation of MSCs was evaluated following treatment with either recombinant TGFβ1 or ND/MF CM in the presence or absence of AVID200. In the absence of AVID200, both recombinant TGFβ1 and MK-derived CM increased the proliferation of MSCs by 1.4- and 1.6-fold respectively, which returned to basal levels with the addition of increasing concentrations of AVID200. These data indicate that AVID200 directly blocks the effect of TGFβ1 on MSCs. MF stroma is characterized by an increase in Type I collagen. We therefore examined if treatment with AVID200 interferes with the ability of TGFβ1 to induce collagen expression by MSCs. MSCs were cultured in presence of recombinant TGFβ1 alone or in combination with varying concentrations of AVID200 for 72 hours. Recombinant TGFβ1 alone induced an increase in COL1A1 mRNA expression as compared to untreated controls (p<0.01). Addition of AVID200 eliminated the TGFβ-mediated increase in COL1A1 expression in a dose dependent manner. ND and MF MK-derived CM also increased COL1A1 expression by MSCs as compared to un-treated controls (p<0.01) and that effect was eliminated by AVID200 treatment (p<0.01). We next demonstrated that TGFβ1 activated pSMAD2 in MSCs without affecting total SMAD2/3 expression and that SMAD2 phosphorylation was reduced by adding AVID200. Furthermore, AVID200 treatment decreased pSTAT3 which is associated with the ability of TGFβ to induce fibrosis. We next investigated the effect of AVID200 on MF hematopoiesis. Briefly, MNCs (which produce TGFβ) from two JAK2V617F+ MF patients were incubated with or without 50 nM of AVID200 and plated in semi-solid media. Treatment with AVID200 did not affect the overall number of colonies generated, but reduced the numbers of JAKV617F+ colonies while increasing the numbers of WT colonies: for PT1, there were 32% JAKV617F+ CFUs in untreated cultures (11 JAKV617F+/34 total colonies) versus 16% JAKV617F+ CFUs (7 JAKV617F+/42 total CFUs) in AVID200 treated cultures; for PT2 there were 100% JAKV617F+ CFUs in untreated cultures (37 JAKV617F+/37 total CFUs) versus 94% JAKV617F+ CFUs (49 JAK2V617F+/52 total CFUs) in AVID200 treated cultures. The in vivo effects of AVID200 on the development of MF in GATA1 low mice will be presented at the meeting. These data indicate that AVID200 selectively suppresses TGFβ1 signaling associated with the proliferation of MSCs and type I collagen synthesis, and depletes MF MNCs of JAK2V617F+progenitor cells. We conclude that AVID200 is a promising agent for treating MF patients which will be evaluated in a phase 1 clinical trial. Disclosures Mascarenhas: Novartis: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merck: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Iancu-Rubin:Incyte: Research Funding; Merck: Research Funding; Summer Road, LLC: Research Funding; Formation Biologics: Research Funding. Hoffman:Incyte: Research Funding; Summer Road: Research Funding; Merus: Research Funding; Janssen: Research Funding; Formation Biologics: Research Funding.
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Elsafadi, Mona, Muthurangan Manikandan, Sami Almalki, Mohammad Mobarak, Muhammad Atteya, Zafar Iqbal, Jamil Amjad Hashmi, et al. "TGFβ1-Induced Differentiation of Human Bone Marrow-Derived MSCs Is Mediated by Changes to the Actin Cytoskeleton." Stem Cells International 2018 (2018): 1–14. http://dx.doi.org/10.1155/2018/6913594.

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TGFβ is a potent regulator of several biological functions in many cell types, but its role in the differentiation of human bone marrow-derived skeletal stem cells (hMSCs) is currently poorly understood. In the present study, we demonstrate that a single dose of TGFβ1 prior to induction of osteogenic or adipogenic differentiation results in increased mineralized matrix or increased numbers of lipid-filled mature adipocytes, respectively. To identify the mechanisms underlying this TGFβ-mediated enhancement of lineage commitment, we compared the gene expression profiles of TGFβ1-treated hMSC cultures using DNA microarrays. In total, 1932 genes were upregulated, and 1298 genes were downregulated. Bioinformatics analysis revealed that TGFβl treatment was associated with an enrichment of genes in the skeletal and extracellular matrix categories and the regulation of the actin cytoskeleton. To investigate further, we examined the actin cytoskeleton following treatment with TGFβ1 and/or cytochalasin D. Interestingly, cytochalasin D treatment of hMSCs enhanced adipogenic differentiation but inhibited osteogenic differentiation. Global gene expression profiling revealed a significant enrichment of pathways related to osteogenesis and adipogenesis and of genes regulated by both TGFβ1 and cytochalasin D. Our study demonstrates that TGFβ1 enhances hMSC commitment to either the osteogenic or adipogenic lineages by reorganizing the actin cytoskeleton.
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Feger, Martina, Ioana Alesutan, Tatsiana Castor, Sobuj Mia, Katharina Musculus, Jakob Voelkl, and Florian Lang. "Inhibitory Effect of NH4Cl Treatment on Renal Tgfß1 Signaling Following Unilateral Ureteral Obstruction." Cellular Physiology and Biochemistry 37, no. 3 (2015): 955–64. http://dx.doi.org/10.1159/000430222.

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Background/Aims: Consequences of obstructive nephropathy include tissue fibrosis, a major pathophysiological mechanism contributing to development of end-stage renal disease. Transforming growth factor β 1 (Tgfβ1) is involved in the progression of renal fibrosis. According to recent observations, ammonium chloride (NH4Cl) prevented phosphate-induced vascular remodeling, effects involving decrease of Tgfβ1 expression and inhibition of Tgfβ1-dependent signaling. The present study, thus, explored whether NH4Cl influences renal Tgfβ1-induced pro-fibrotic signaling in obstructive nephropathy induced by unilateral ureteral obstruction (UUO). Methods: UUO was induced for seven days in C57Bl6 mice with or without additional treatment with NH4Cl (0.28 M in drinking water). Transcript levels were determined by RT-PCR as well as protein abundance by Western blotting, blood pH was determined utilizing a blood gas and chemistry analyser. Results: UUO increased renal mRNA expression of Tgfb1, Tgfβ-activated kinase 1 (Tak1) protein abundance and Smad2 phosphorylation in the nuclear fraction of the obstructed kidney tissues, effects blunted in NH4Cl treated mice as compared to control treated mice. The mRNA levels of the transcription factors nuclear factor of activated T cells 5 (Nfat5) and SRY (sex determining region Y)-box 9 (Sox9) as well as of tumor necrosis factor α (Tnfα), interleukin 6 (Il6), plasminogen activator inhibitor 1 (Pai1) and Snai1 were up-regulated in the obstructed kidney tissues following UUO, effects again significantly ameliorated following NH4Cl treatment. Furthermore, the increased protein and mRNA expression of α-smooth muscle actin (α-Sma), fibronectin and collagen type I in the obstructed kidney tissues following UUO were significantly attenuated following NH4Cl treatment. Conclusion: NH4Cl treatment ameliorates Tgfβ1-dependent pro-fibrotic signaling and renal tissue fibrosis markers following obstructive nephropathy.
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Recouvreux, M. Victoria, M. Andrea Camilletti, Daniel B. Rifkin, and Graciela Díaz-Torga. "The pituitary TGFβ1 system as a novel target for the treatment of resistant prolactinomas." Journal of Endocrinology 228, no. 3 (December 23, 2015): R73—R83. http://dx.doi.org/10.1530/joe-15-0451.

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Prolactinomas are the most frequently observed pituitary adenomas and most of them respond well to conventional treatment with dopamine agonists (DAs). However, a subset of prolactinomas fails to respond to such therapies and is considered as DA-resistant prolactinomas (DARPs). New therapeutic approaches are necessary for these tumors. Transforming growth factor β1 (TGFβ1) is a known inhibitor of lactotroph cell proliferation and prolactin secretion, and it partly mediates dopamine inhibitory action. TGFβ1 is secreted to the extracellular matrix as an inactive latent complex, and its bioavailability is tightly regulated by different components of the TGFβ1 system including latent binding proteins, local activators (thrombospondin-1, matrix metalloproteases, integrins, among others), and TGFβ receptors. Pituitary TGFβ1 activity and the expression of different components of the TGFβ1 system are regulated by dopamine and estradiol. Prolactinomas (animal models and humans) present reduced TGFβ1 activity as well as reduced expression of several components of the TGFβ1 system. Therefore, restoration of TGFβ1 inhibitory activity represents a novel therapeutic approach to bypass dopamine action in DARPs. The aim of this review is to summarize the large literature supporting TGFβ1 important role as a local modulator of pituitary lactotroph function and to provide recent evidence of the restoration of TGFβ1 activity as an effective treatment in experimental prolactinomas.
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Martin, Constance J., Abhishek Datta, Christopher Littlefield, Ashish Kalra, Christopher Chapron, Stefan Wawersik, Kevin B. Dagbay, et al. "Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape." Science Translational Medicine 12, no. 536 (March 25, 2020): eaay8456. http://dx.doi.org/10.1126/scitranslmed.aay8456.

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Despite breakthroughs achieved with cancer checkpoint blockade therapy (CBT), many patients do not respond to anti–programmed cell death-1 (PD-1) due to primary or acquired resistance. Human tumor profiling and preclinical studies in tumor models have recently uncovered transforming growth factor–β (TGFβ) signaling activity as a potential point of intervention to overcome primary resistance to CBT. However, the development of therapies targeting TGFβ signaling has been hindered by dose-limiting cardiotoxicities, possibly due to nonselective inhibition of multiple TGFβ isoforms. Analysis of mRNA expression data from The Cancer Genome Atlas revealed that TGFΒ1 is the most prevalent TGFβ isoform expressed in many types of human tumors, suggesting that TGFβ1 may be a key contributor to primary CBT resistance. To test whether selective TGFβ1 inhibition is sufficient to overcome CBT resistance, we generated a high-affinity, fully human antibody, SRK-181, that selectively binds to latent TGFβ1 and inhibits its activation. Coadministration of SRK-181-mIgG1 and an anti–PD-1 antibody in mice harboring syngeneic tumors refractory to anti–PD-1 treatment induced profound antitumor responses and survival benefit. Specific targeting of TGFβ1 was also effective in tumors expressing more than one TGFβ isoform. Combined SRK-181-mIgG1 and anti–PD-1 treatment resulted in increased intratumoral CD8+ T cells and decreased immunosuppressive myeloid cells. No cardiac valvulopathy was observed in a 4-week rat toxicology study with SRK-181, suggesting that selectively blocking TGFβ1 activation may avoid dose-limiting toxicities previously observed with pan-TGFβ inhibitors. These results establish a rationale for exploring selective TGFβ1 inhibition to overcome primary resistance to CBT.
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Peng, Fangfang, Baifang Zhang, Dongcheng Wu, Alistair J. Ingram, Bo Gao, and Joan C. Krepinsky. "TGFβ-induced RhoA activation and fibronectin production in mesangial cells require caveolae." American Journal of Physiology-Renal Physiology 295, no. 1 (July 2008): F153—F164. http://dx.doi.org/10.1152/ajprenal.00419.2007.

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Glomerular sclerosis of diverse etiologies is characterized by mesangial matrix accumulation, with transforming growth factor-β (TGFβ) an important pathogenic factor. The GTPase RhoA mediates TGFβ-induced matrix accumulation in some settings. Here we study the role of the membrane microdomain caveolae in TGFβ-induced RhoA activation and fibronectin upregulation in mesangial cells (MC). In primary rat MC, TGFβ1 time dependently increased RhoA and downstream Rho kinase activation. Rho pathway inhibition blocked TGFβ1-induced upregulation of fibronectin transcript and protein. TGFβ1-induced RhoA activation was prevented by disrupting caveolae with cholesterol depletion and rescued by cholesterol repletion. Compared with wild types, RhoA/Rho kinase activation was absent in MC lacking caveolae. Reexpression of caveolin-1 (and caveolae) restored these responses. Phosphorylation of caveolin-1 on Y14, effected by Src kinases, has been implicated in signaling responses. Overexpression of nonphosphorylatable caveolin-1 Y14A prevented TGFβ1-induced RhoA activation. TGFβ1 also activated Src, and its inhibition blocked RhoA activation. Furthermore, TGFβ1 led to association of RhoA and caveolin-1. This was prevented by Src or TGFβ receptor I inhibition, and by caveolin-1 Y14A overexpression. Last, fibronectin upregulation by TGFβ1 was blocked by Src inhibition, not seen in caveolin-1 knockout MC, and restored by caveolin-1 reexpression in the latter. TGFβ1-induced collagen I accumulation also required caveolae. TGFβ1-mediated Smad2/3 activation, however, did not require caveolae. We conclude that RhoA/Rho kinase mediates TGFβ-induced fibronectin upregulation. This requires caveolae and caveolin-1 interaction with RhoA. Interference with caveolin/caveolae or RhoA signaling thus represents a potential target for the treatment of fibrotic renal disease.
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Dissertations / Theses on the topic "TGFβ1 treatment"

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Rautenbach, Robyn Marié. "Treatment-resistant ophthalmoplegia in Myasthenia gravis: extraocular muscle pathology, the role of TGFβ1 and the derivation of induced pluripotency towards 'disease-in-a-dish' modeling." Master's thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/22782.

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Myasthenia gravis (MG) is an autoimmune disease in which pathogenic antibodies target specific neuromuscular junction proteins, most frequently acetylcholine receptors (AChR). Among those without detectable AChR-antibodies, a subgroup of patients has antibodies directed against muscle-specific tyrosine kinase (MuSK). In MG the pathogenic antibodies result in failure of neuromuscular transmission with consequent fatiguable skeletal muscle weakness. MG frequently affects the extraocular muscles (EOMs) early in the course of the disease, resulting in diplopia and ptosis, which is usually reversible with treatment. A treatment-resistant ophthalmoplegia and ptosis occurs as a complication of MG in a distinct subset of cases referred to as OP-MG. The EOMs are highly specialised muscle tissue with a unique physiological and immunological microenvironment with a large satellite cell niche, a distinct muscle fibroblast population, different transcriptional and cellular signaling pathways and fewer intrinsic complement regulatory proteins to protect them against antibody- activated complement-mediated damage. We hypothesised that in OP-MG, there is a differential response of the EOMs to the underlying MG disease process(es) on a genetic and molecular level, resulting in abnormal myofibre homeostasis. We aimed to report descriptive clinical-pathological data pertaining to EOM function and histopathological and ultrastructural EOM tissue analysis of a patient with OP- MG versus that of a non-MG control (both consented to EOM donation at ocular realignment surgery). EOM tissue from an OP-MG individual with AChR- and MuSK- antibody negative MG, demonstrated predominantly myopathic pathology and ultrastructural evidence of mitochondrial stress. The OP-MG EOM findings differ from the control EOM, which showed normal muscle histopathology in a patient undergoing strabismus surgery for a sensory exotropia in a non-seeing eye (loss of retinal stimulus for fusion) and a similar duration of deviation. These OP-MG findings appear to better correlate with previously reported histology/ultrastructure in limb muscle in MuSK-positive MG rather than AChR-positive MG. We next focussed on transforming growth factor beta-1 (TGFβ1) as a critical cytokine involved in muscle repair. An auto-induction pathway in muscle allows TGFβ1 expression to influence the transdifferentiation of satellite cells into myofibroblasts or myoblasts. In orbital fibroblasts, TGFβ1 has also been shown to upregulate decay accelerating factor (DAF), a complement regulatory protein expressed at lower levels in EOMs than other muscles, which should protect against complement-mediated injury. We established OP-MG and control-MG phenotype-specific dermal fibroblast cell lines and performed immunoblotting to evaluate TGFβ1-induced Smad3 phosphorylation and Daf expression in mouse myotubes. We demonstrated repression of phosphorylated-Smad3, a marker of the canonical TGFβ1 pathway, in OP-MG versus control MG fibroblasts after treatment with TGFβ1. We also demonstrated that TGFβ1 significantly upregulates Daf expression levels in mouse myoblasts. Taken together, these results suggest that OP-MG fibroblasts (and possibly myofibroblasts) are likely to be more susceptible to complement-mediated damage and abnormal myofibrogenesis due to their altered response to TGFβ1 stimulation and secondary DAF upregulation. Finally we investigated the feasability of establishing an in vitro disease model for MG or OP-MG by reprogramming dermal fibroblasts into disease phenotype-specific induced pluripotent stem (iPS) cells. We successfully generated and characterised iPS cells for one individual. However, this process was very labour-intensive, cost-inefficient and time-consuming, taking approximately four months to establish pluripotency in a single patient and thereby limited its further application(s). In conclusion, the EOM ultrastructural findings of an OP-MG case are novel and show similar findings to those described in limb skeletal muscle of MuSK-positive MG patients. The TGFβ1 pathway appears to be differentially regulated in OP-MG compared to control-MG cases and this may impact DAF upregulation in the EOMs in MG patients. Finally, our group is exploring an alternative method of establishing a 'disease-in-a-dish' model that is more cost-effective and practically feasible than the iPS cell route.
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Al, Maghout Tamer [Verfasser]. "P38 Kinase, SGK1 and NF-κB Dependent Up-Regulation of Na+/Ca2+ Exchanger Expression and Activity Following TGFß1 Treatment of Megakaryocytes / Tamer Al Maghout." Tübingen : Universitätsbibliothek Tübingen, 2020. http://d-nb.info/1221596780/34.

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Hsu, Yi-Chao, and 許益超. "Effects of Salvia miltiorrhiza treatment on TGFβ-1 and procollagen gene transcripts in cirrhotic rats." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/96153456417532675740.

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碩士
國立陽明大學
傳統醫藥學研究所
90
The Chinese herb, Salvia miltiorrhiza (Sm), has been shown to reduce hepatic fibrosis in rats. In this study, we investigated the effects of Sm in an experimental model of hepatic fibrosis and evaluated their effects on TGFb-1, procollagens I、III genes involved in hepatic fibrogenesis. Hepatic fibrosis was induced in male Sprague-Dawley rats (250~300 g) by common bile duct ligation (CBDL). Sham-operated (Sham) rats served as control. In part I of this study, the expression of TGFb-1, procollagens I、III mRNA was then investigated in the CBDL and Sham group at 1 day and 1, 2, 4, 6 weeks after CBDL. In part II study, effects of herbs on TGFb-1, procollagens I、III mRNA expressions in CBDL rats were investigated. The livers were analyzed by RT-PCR for the transcription of genes involved in liver fibrosis. The transcripts were normalized against that of G3PDH and analyzed statistically. There were two separate animal experimental protocols in part II study: (1) Sm crude extract study, and (2) Sm partially purified extract study. The active compound salvianolic acid B was about 80% in Study (2) and about 3%in Study (1). There were five groups in Sm crude extract study: Sham group, CBDL group, CBDL-silymarin (30 mg/kg), CBDL-low dose of Sm crude extract (30 mg/kg) and CBDL-high dose of Sm crude extract (100 mg/kg) for 4 weeks after bile duct ligation. There were six groups in Sm partially purified extract study: Sham group, Sham -high dose of Sm partially purified extract (100 mg/kg), CBDL group, CBDL-silymarin (100 mg/kg), CBDL-low dose of Sm partially purified (20 mg/kg) and CBDL-high dose of Sm partially purified extract (100 mg/kg) for 4 weeks after bile duct ligation. The results showed that TGFb-1 mRNA expression was induced in CBDL rats and procollagens I、III mRNA were up-regulated after CBDL. The results of animal experimental study showed that neither silymarin (30 mg/kg) nor Sm crude extract treatments could significantly reduce the expression of TGFb-1, procollagens I、III mRNA. On the other hand, we found that silymarin (100 mg/kg) and Sm partially purified extract could significantly reduce the expression of procollagens I、III mRNA, but had no effect on TGFb-1 mRNA expression at 4 weeks after CBDL. In conclusion, mRNA expression of TGFb-1, procollagens I、III was found increased in CBDL rats. We also found Sm crude extract and silymarin (30 mg/kg) could not reduce hepatic fibrosis in CBDL rats, and that Sm partially purified extract, which contained higher content of salvianolic acid B, and silymarin (100 mg/kg) could reduce procollagens mRNA expression and ameliorate hepatic fibrosis in CBDL rats.
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Book chapters on the topic "TGFβ1 treatment"

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Tortolina, Lorenzo, Nicoletta Castagnino, Cristina De Ambrosi, Annalisa Barla, Alessandro Verri, Gabriele Zoppoli, Luca Bagnasco, et al. "Dynamic Simulations of Pathways Downstream of TGFβ, Wnt and EGF-Family Growth Factors, in Colorectal Cancer, including Mutations and Treatments with Onco-Protein Inhibitors." In New Challenges for Cancer Systems Biomedicine, 127–42. Milano: Springer Milan, 2012. http://dx.doi.org/10.1007/978-88-470-2571-4_7.

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Wang, Yiting. "A novel theranostics nanoparticles pGGA-PTX / SPION with bifunction of diagnosis and treatment." In Is it all just an Akt - you’d be SMAD to believe it! Role of TGFβ1 in oral cancer metastasis. Science Repository Oü, 2018. http://dx.doi.org/10.31487/j.rdi.2018.10.06.

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Kuznietsova, Halyna, and Olexandr Ogloblya. "Therapy that Targets Growth Factor Receptors: Novel Approach for Liver Cirrhosis Treatment." In Advances in Hepatology. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.96552.

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The background of liver fibrous degeneration is excessive cell proliferation including hepatic stellate cells, inflammatory cells, fibroblasts and myofibroblasts. Often it is the consequence of increased growth factors and/or their receptors expression. Key contributors to the liver cell proliferation are EGFR, FGFR, PDGFR, VEGFR, TGFβR, the increased expression of which is indicated on in vitro and in vivo models of liver fibrosis and in patients who experienced fibrosis-accompanied liver diseases. Elimination of growth factors/suppression of their receptors is associated with the weakening/elimination of certain processes responsible for fibrogenesis. This chapter represents the evidences of the efficacy of growth factor receptors signaling downregulation for the suppression of liver fibrosis and cirrhosis and their individual manifestations. The data on established and experimental therapeutics – specific and multikinase growth factor receptor inhibitors which demonstrated antifibrotic and anticirrhotic activity under in vitro and in vivo models, are also presented.
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Mehmood, Sarmad, Sajjad Haider, Muhammad Naeem, Raees Khan, Muhammad Faheem, Bushra Bano, Syeda Marriam Bakhtiar, et al. "Biomaterials in Gene Therapy for Soft and Hard Tissues." In Omics Technologies for Clinical Diagnosis and Gene Therapy: Medical Applications in Human Genetics, 190–213. BENTHAM SCIENCE PUBLISHERS, 2022. http://dx.doi.org/10.2174/9789815079517122010015.

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Bone healing and formation are under the control of growth factors. Among these factors, bone morphogenetic proteins (BMPs) have a vital role in bone and cartilage maintenance and formation. BMP itself belongs to the superfamily of transforming growth factor β (TGFβ). Although, the use of recombinant BMPs has no significant association with the treatment of bone fractures, arthroplasty, pseudoarthrosis or other bone-related diseases. Recent advancements in genetic engineering have led to the foundation of gene therapy. Gene therapy uses genes to be incorporated in the living cells to replace defective genes or manipulate gene expression for therapeutic purposes. Gene therapy is emerging for the treatment of diseases with approval in Europe where it is in the marketing surveillance phase (Phase IV Clinical trial). This technique has also been tested for the incorporation of osteogenic genes in stem cells for repairing spinal fusion and recovering defects in bones in preclinical models. Therefore, gene therapy has the potential for the treatment of different diseases and has the advantage over the use of recombinant proteins. In this chapter, we have discussed gene therapy, its mechanism, delivery system and its use in tissue engineering (soft and bone tissue) for clinical application
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Conference papers on the topic "TGFβ1 treatment"

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Melchionna, Roberta, Pierluigi Iapicca, Francesca Di Modugno, Paola Trono, Novella Gualtieri, Maria Grazia Diodoro, Marcella Mottolese, et al. "Abstract A60: The hMENA Splicing Program: An important regulator of TGFβ1-driven EMT and invasiveness in pancreatic cancer." In Abstracts: AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.panca2014-a60.

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DeCant, Brian, Daniel Principe, Elizabeth Wayne, Emman Mascarinas, Hidayatullah Munshi, Barbara Jung, and Paul Grippo. "Abstract A21: Stromal-derived TGFβ facilitates pancreatic cancer development via repression of T-cell mediated cytotoxicity." In Abstracts: AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.panca2014-a21.

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Rana, Tapasi, Anwesa Chakrabarti, Michael Freeman, and Swati Biswas. "Abstract 2143: Anti-TGFβ antibody treatment rescues doxorubicin- mediated bone loss in preclinical osteolytic breast cancer metastasis models." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-2143.

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Matsueda, Satoko, Kunle Odunsi, and Richard C. Koya. "Abstract B36: TGFβ blockade and epigenetic modulation for cancer treatment: Efficient breast cancer targeted therapy with TCR-T cell transfer." In Abstracts: AACR Special Conference on Tumor Immunology and Immunotherapy; November 27-30, 2018; Miami Beach, FL. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/2326-6074.tumimm18-b36.

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Carbone, Carmine, Anna Tamburrino, Geny Piro, Marco Zanotto, Maria Mihaela Mina, Silvia Zanini, Federico Boschi, Aldo Scarpa, Giampaolo Tortora, and Davide Melisi. "Abstract 3605: Combined inhibition of IL-1, CXCR1/2, and TGFβ signaling pathways modulates in vivo acquired resistance to anti-VEGF treatment." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-3605.

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Bandyopadhyay, Abhik, Joseph Agyin, Fernando Lopez-Casillas, Long Wang, Tanuka Biswas, and Lu-Zhe Sun. "Abstract 1753: Comparison between early versus delayed treatment of breast cancer induced osteolytic bone metastasis by TGFβ inhibitors in a murine model." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-1753.

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Demaria, Sandra, Claire Vanpouille-Box, Rachael E. Hawtin, Christie Fanton, Andy Conroy, Erik Evensen, Neha Dixit, et al. "Abstract 4987: Role of the PD-1/PDL-1 pathway in resistance of patients with metastatic breast cancer to treatment with radiotherapy and TGFβ neutralization." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4987.

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Xu, Weidong, Zhenwei Zhang, Theresa Guise, Charles B. Brendler, and Prem Seth. "Abstract 723: Liver-detargeted Ad5/48 chimaeric hexon based oncolytic adenovirus targeting TGFβ signaling: A safe and effective approach for the treatment of prostate cancer bone metastases." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-723.

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Loskutoff, D. J., J. Mimuro, and C. Hekman. "PLASMINOGEN ACTIVATOR INHIBITOR." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644763.

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Plasminogen activation provides an important source of localized proteolytic activity not only during fibrinolysis, but also during ovulation, cell migration, epithelial cell differentiation, tumor invasion and a variety of other physiological processes. Precise regulation of plasminogen activator (PA) activity thus constitutes a critical feature of many biological processes. This control is achieved in large part through the action of specific PA inhibitors (PAIs). Although 4 distinct PAIs have been detected,1the endothelial cellTderived inhibitor (PAI-1) is the only one that efficiently inhibits both urokinase (Kd=2.3×10−13M; Kassoc =1.6×108 M−1s−1) and single-chaintissue-type PA (tPA; Kd=1.3×lO−15 M Kd=3.9×lO7M−1s−1). It also inhibits trypsin (Kassoc=6.8×106M−1 s−1 ) ancl Plasmin (Kassoc=7.6×l05 M−1 s5 Analysis of the effect of PAI-1 on the rate of plasminogen activation revealed a competitive type of inhibition when urokinase was employed but a linear mixed type of inhibition when single chain tPA was employed. These results suggest that the interaction of PAI-1 with tPA, in contrast to its interaction with urokinase, may involve 2 sites on the tPA molecule.PAI-1 has been purified from medium conditioned by cultured bovine aortic endothelial cells and partially characterized. It is a major biosynthetic product of these cells, accounting for as much as 12% of the total protein released by the cells in 24 h. It has an M of 50,000, an isoelectric point of 4.5-5.0, and is immunologically and biochemically related to the rapidly acting inhibitor present in human platelets and in the plasma of some patients at risk to develop thrombotic problems. Although it is relatively stable to conditions which inactivate most protease inhibitors (acid pH, SDS), it is extremely sensitive to oxidants. The molecular cloning of the PAI-1 gene revealed that the mature human protein is 379 amino acids long, contains an NH2-terminal valine, lacks cysteines and has a methionine at the Pi position of it's reactive center. The conversion of this methionine to methionine sulfoxide may be responsible for the rapid inactivation of PAI-1 by oxidants. Human PAI-1 has extensive (30%) homology with α1-antitrypsin and antithrombin III and is thus a member of the serine proteinase inhibitor (serpin) family; a group of related molecules that control the major protease cascades of the blood. The PAI-1 gene is approximately 12.2 kilobase pairs in length and is organized into nine exons and eight introns.The production of PAI-1 by endothelial cells is stimulated by endotoxin, interleukin-1, tumor necrosis factor, and transforming growth factor β(TGFβ). The cells are extremely sensitive to TGFβwith maximal effects (100-fold stimulation) observed with 1-2 ng/ml. These changes were relatively specific for PAI-1, and could be detected at both the protein and the RNA level. Interestingly, TGFgalso stimulated the amount of PAI-1 present in the extracellular matrix (ECM) of BAEs. PAI-1 was one of the primary ECM components of these cells, constituting 10-20% of the ECM proteins detected after SDS-PAGE.One of the most unusual properties of PAI-1 is that it exists in blood and in various cellular samples in both an active and an inactive (latent) form, the ratio depending on the source. The latent form can be converted into the active one by treatment with denaturants like SDS or guanidine-HCl. Although the majority of the cell-associated PAI-1 is active, it rapidly decays (t1/2=3 h) into the latent form once it is released from the cells. In contrast, the half-life of ECM associated PAI-1 was greater than 24 h. These data suggest that PAI-1 is produced by BAEs in an active form, and is then either released into the medium where it is rapidly inactivated, or released into the subendothelium where it binds to ECM. The specific binding of PAI-1 to ECM protects it from this inactivation.
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