Evaluation of antifibrotic and antifungal combined therapies in experimental pulmonary paracoccidioidomycosis

2019 ◽  
Vol 58 (5) ◽  
pp. 667-678 ◽  
Author(s):  
Angela C Finato ◽  
Débora F Almeida ◽  
Amanda R dos Santos ◽  
Dejair C Nascimento ◽  
Ricardo S Cavalcante ◽  
...  
Keyword(s):  
Weight Loss ◽  
Transforming Growth Factor ◽  
Systemic Mycosis ◽  
Fungal Burden ◽  
Reticulin Fibers ◽  
Lung Functions ◽  
Ifn Γ ◽  
Tgf Β1

Abstract Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the Paracoccidioides genus. Most of the patients with chronic form present sequelae, like pulmonary fibrosis, with no effective treatment, leading to impaired lung functions. In the present study, we aimed to investigate the antifibrotic activity of three compounds: pentoxifylline (PTX), azithromycin (AZT), and thalidomide (Thal) in a murine model of pulmonary PCM treated with itraconazole (ITC) or cotrimoxazole (CMX). BALB/c mice were inoculated with P. brasiliensis (Pb) by the intratracheal route and after 8 weeks, they were submitted to one of the following six treatments: PTX/ITC, PTX/CMX, AZT/ITC, AZT/CMX, Thal/ITC, and Thal/CMX. After 8 weeks of treatment, the lungs were collected for determination of fungal burden, production of OH-proline, deposition of reticulin fibers, and pulmonary concentrations of cytokines and growth factors. Pb-infected mice treated with PTX/ITC presented a reduction in the pulmonary concentrations of OH-proline, associated with lower concentrations of interleukin (IL)-6, IL-17, and transforming growth factor (TGF)-β1 and higher concentrations of IL-10 compared to the controls. The Pb-infected mice treated with AZT/CMX exhibited decreased pulmonary concentrations of OH-proline associated with lower levels of TGF-β1, and higher levels of IL-10 compared controls. The mice treated with ITC/Thal and CMX/Thal showed intense weight loss, increased deposition of reticulin fibers, high pulmonary concentrations of CCL3, IFN-γ and VEGF, and decreased concentrations of IL-6, IL-1β, IL-17, and TGF-β1. In conclusion, our findings reinforce the antifibrotic role of PTX only when associated with ITC, and AZT only when associated with CMX, but Thal did not show any action upon addition.

scholarly journals Proline-rich tyrosine kinase 2 mediates transforming growth factor-beta-induced hepatic stellate cell activation and liver fibrosis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jonghwa Kim ◽  
Wonseok Kang ◽  
So Hee Kang ◽  
Su Hyun Park ◽  
Ji Young Kim ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Tyrosine Kinase ◽  
Focal Adhesion ◽  
Transforming Growth Factor ◽  
Family Members ◽  
Type I ◽  
Tyrosine Kinase 2 ◽  
The Impact ◽  
Tgf Β1

AbstractHepatic fibrogenesis is characterized by activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix (ECM). The impact of ECM on TGF-β-mediated fibrogenic signaling pathway in HSCs has remained obscure. We studied the role of non-receptor tyrosine kinase focal adhesion kinase (FAK) family members in TGF-β-signaling in HSCs. We used a CCl4-induced liver fibrosis mice model to evaluate the effect of FAK family kinase inhibitors on liver fibrosis. RT-PCR and Western blot were used to measure the expression of its target genes; α-SMA, collagen, Nox4, TGF-β1, Smad7, and CTGF. Pharmacological inhibitors, siRNA-mediated knock-down, and plasmid-based overexpression were adopted to modulate the function and the expression level of proteins. Association of PYK2 activation with liver fibrosis was confirmed in liver samples from CCl4-treated mice and patients with significant fibrosis or cirrhosis. TGF-β treatment up-regulated expression of α-SMA, type I collagen, NOX4, CTGF, TGF-β1, and Smad7 in LX-2 cells. Inhibition of FAK family members suppressed TGF-β-mediated fibrogenic signaling. SiRNA experiments demonstrated that TGF-β1 and Smad7 were upregulated via Smad-dependent pathway through FAK activation. In addition, CTGF induction was Smad-independent and PYK2-dependent. Furthermore, RhoA activation was essential for TGF-β-mediated CTGF induction, evidenced by using ROCK inhibitor and dominant negative RhoA expression. We identified that TGF-β1-induced activation of PYK2-Src-RhoA triad leads to YAP/TAZ activation for CTGF induction in liver fibrosis. These findings provide new insights into the role of focal adhesion molecules in liver fibrogenesis, and targeting PYK2 may be an attractive target for developing novel therapeutic strategies for the treatment of liver fibrosis.

scholarly journals Identification of a microRNA signature in renal fibrosis: role of miR-21

2011 ◽  
Vol 301 (4) ◽  
pp. F793-F801 ◽  
Author(s):  
Abolfazl Zarjou ◽  
Shanzhong Yang ◽  
Edward Abraham ◽  
Anupam Agarwal ◽  
Gang Liu
Keyword(s):  
Epithelial Cells ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Response To Treatment ◽  
Tubular Epithelial Cells ◽  
Altered Expression ◽  
Tnf Α ◽  
Tgf Β1

Renal fibrosis is a final stage of many forms of kidney disease and leads to impairment of kidney function. The molecular pathogenesis of renal fibrosis is currently not well-understood. microRNAs (miRNAs) are important players in initiation and progression of many pathologic processes including diabetes, cancer, and cardiovascular disease. However, the role of miRNAs in kidney injury and repair is not well-characterized. In the present study, we found a unique miRNA signature associated with unilateral ureteral obstruction (UUO)-induced renal fibrosis. We found altered expression in UUO kidneys of miRNAs that have been shown to be responsive to stimulation by transforming growth factor (TGF)-β1 or TNF-α. Among these miRNAs, miR-21 demonstrated the greatest increase in UUO kidneys. The enhanced expression of miR-21 was located mainly in distal tubular epithelial cells. miR-21 expression was upregulated in response to treatment with TGF-β1 or TNF-α in human renal tubular epithelial cells in vitro. Furthermore, we found that blocking miR-21 in vivo attenuated UUO-induced renal fibrosis, presumably through diminishing the expression of profibrotic proteins and reducing infiltration of inflammatory macrophages in UUO kidneys. Our data suggest that targeting specific miRNAs could be a novel therapeutic approach to treat renal fibrosis.

scholarly journals Role of Vitamin D in Premature Atherosclerosis in Adolescents Type 1 Diabetes through Transforming Growth Factor-β1, Interferon-γ, Interleukin-10, and Interleukin-17

2020 ◽  
Vol 8 (B) ◽  
pp. 738-746
Author(s):  
Haryudi Aji Cahyono ◽  
Wisnu Barlianto ◽  
Dian Handayani ◽  
Handono Kalim
Keyword(s):  
Vitamin D ◽  
Type 1 Diabetes ◽  
Transforming Growth Factor ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Transforming Growth Factor Β1 ◽  
Premature Atherosclerosis ◽  
Ifn Γ ◽  
Tgf Β1

BACKGROUND: Cardiovascular disease (CVD) is one the cause of mortality in patients with type 1 diabetes (T1D). The development of CVD is mainly triggered by atherosclerosis, which is associated with the inflammatory process. AIM: The current study was aimed to investigate the association of Vitamin D level and premature atherosclerosis in adolescents with T1D, mainly through the regulation of various cytokines (interferon-γ [IFN-γ], IL-17, interleukin-10 [IL-10], and transforming growth factor-β1 [TGF-β1]). METHODS: This study was designed as a cross-sectional study involving 40 T1D and 40 healthy control who came to the outpatient clinic, Saiful Anwar Hospital, Malang, Indonesia, within the study period (January 2019-July 2019). RESULTS: Our data demonstrated that the IFN-γ and IL-17 levels were significantly higher (p < 0.001), whereas the TGF-β1 and IL-10 levels were significantly lower (p < 0.001) in T1D group compared with control. Furthermore, T1D also has higher carotid intima-media thickness (cIMT) value and lower flow-mediated dilatation (FMD) value compared to the control group (p < 0.001). Level of 25(OH)D3 was strongly associated with reduced cIMT and elevated FMD (p < 0.005). The direct effect of 25(OH)D3 on cIMT and FMD was higher than the indirect effect of Vitamin D through TGF-β1, IL-10, IL-17, and IFN-γ. The cutoff value of 25(OH)D3 levels for the risk of atherosclerosis was 12.8 ng/dL (sensitivity 85.7% and specificity 86.7%). CONCLUSION: The level of Vitamin D in the T1D group was significantly lower than those in healthy children and Vitamin D deficiency substantially influences the formation of premature atherosclerosis.

scholarly journals The role of TGF-β2 in cartilage development and diseases

2021 ◽  
Vol 10 (8) ◽  
pp. 474-487
Author(s):  
Mengmeng Duan ◽  
Qingxuan Wang ◽  
Yang Liu ◽  
Jing Xie
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Vital Role ◽  
Cartilage Defects ◽  
Cartilage Development ◽  
Physiological Processes ◽  
Cartilage Diseases ◽  
Autologous Mesenchymal Stem Cells ◽  
Tgf Β1

Transforming growth factor-beta2 (TGF-β2) is recognized as a versatile cytokine that plays a vital role in regulation of joint development, homeostasis, and diseases, but its role as a biological mechanism is understood far less than that of its counterpart, TGF-β1. Cartilage as a load-resisting structure in vertebrates however displays a fragile performance when any tissue disturbance occurs, due to its lack of blood vessels, nerves, and lymphatics. Recent reports have indicated that TGF-β2 is involved in the physiological processes of chondrocytes such as proliferation, differentiation, migration, and apoptosis, and the pathological progress of cartilage such as osteoarthritis (OA) and rheumatoid arthritis (RA). TGF-β2 also shows its potent capacity in the repair of cartilage defects by recruiting autologous mesenchymal stem cells and promoting secretion of other growth factor clusters. In addition, some pioneering studies have already considered it as a potential target in the treatment of OA and RA. This article aims to summarize the current progress of TGF-β2 in cartilage development and diseases, which might provide new cues for remodelling of cartilage defect and intervention of cartilage diseases.

Acceleration of Palatal Wound Healing in Smad3-deficient Mice

2009 ◽  
Vol 88 (8) ◽  
pp. 757-761 ◽  
Author(s):  
K. Jinno ◽  
T. Takahashi ◽  
K. Tsuchida ◽  
E. Tanaka ◽  
K. Moriyama
Keyword(s):  
Wound Healing ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Monocyte Chemoattractant Protein 1 ◽  
Inflammatory Protein ◽  
Complex Process ◽  
Dermal Cells ◽  
Macrophage Inflammatory Protein ◽  
Tgf Β1

Wound healing is a well-orchestrated complex process leading to the repair of injured tissues. It is suggested that transforming growth factor (TGF)-β/Smad3 signaling is involved in wound healing. The purpose of this study was to investigate the role of TGF-β/Smad3 signaling in palatal wound healing in Smad3-deficient (Smad3−/−) mice. Histological examination showed that wound closure was accelerated by the proliferation of epithelium and dermal cells in Smad3−/− mice compared with wild-type (WT) mice. Macrophage/monocyte infiltration at wounded regions in Smad3−/− mice was decreased in parallel with the diminished production of TGF-β1, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1α compared with WT mice. Fibrocytes, expressing hematopoietic surface marker and fibroblast products, were recruited and produced α-smooth-muscle actin in WT mice, but were not observed in Smad3−/− mice. These results suggest that TGF-β/Smad3 signaling may play an important role in the regulation of palatal wound healing.

Abstract 17285: A Selective Transforming Growth Factor-β and Growth Differentiation Factor-15 Ligand Trap Attenuates Pulmonary Hypertension

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Lai-Ming Yung ◽  
Samuel D Paskin-Flerlage ◽  
Ivana Nikolic ◽  
Scott Pearsall ◽  
Ravindra Kumar ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Rna Seq ◽  
Differentiation Factor ◽  
Group I ◽  
Tgf Β1

Introduction: Excessive Transforming Growth Factor-β (TGF-β) signaling has been implicated in pulmonary arterial hypertension (PAH), based on activation of TGF-β effectors and transcriptional targets in affected lungs and the ability of TGF-β type I receptor (ALK5) inhibitors to improve experimental PAH. However, clinical use of ALK5 inhibitors has been limited by cardiovascular toxicity. Hypothesis: We tested whether or not selective blockade of TGF-β and Growth Differentiation Factor (GDF) ligands using a recombinant TGFβ type II receptor extracellular domain Fc fusion protein (TGFBRII-Fc) could impact experimental PAH. Methods: Male SD rats were injected with monocrotaline (MCT) and received vehicle or TGFBRII-Fc (15 mg/kg, twice per week, i.p.). C57BL/6 mice were treated with SU-5416 and hypoxia (SUGEN-HX) and received vehicle or TGFBRII-Fc. RNA-Seq was used to profile transcriptional changes in lungs of MCT rats. Circulating levels of GDF-15 were measured in 241 PAH patients and 41 healthy controls. Human pulmonary artery smooth muscle cells were used to examine signaling in vitro . Results: TGFBRII-Fc is a selective ligand trap, inhibiting the ability of GDF-15, TGF-β1, TGF-β3, but not TGF-β2 to activate SMAD2/3 in vitro . In MCT rats, prophylactic treatment with TGFBRII-Fc normalized expression of TGF-β transcriptional target PAI-1, attenuated PAH and vascular remodeling. Delayed administration of TGFBRII-Fc in rats with established PAH at 2.5 weeks led to improved survival, decreased PAH and remodeling at 5 weeks. Similar findings were observed in SUGEN-HX mice. No valvular abnormalities were found with TGFBRII-Fc treatment. RNA-Seq revealed GDF-15 to be the most highly upregulated TGF-β ligand in the lungs of MCT rats, with only modest increases in TGF-β1 and no change in TGF-β2/3 observed, suggesting a dominant role of GDF-15 in the pathophysiology of this model. Plasma levels of GDF-15 were significantly increased in patients with diverse etiologies of WHO Group I PAH. Conclusions: These findings demonstrate that a selective TGF-β/GDF-15 trap attenuates experimental PAH, remodeling and mortality, without causing valvulopathy. These data highlight the potential role of GDF-15 as a pathogenic molecule and therapeutic target in PAH.

scholarly journals FOXO3a is stabilized by USP18-mediated de-ISGylation and inhibits TGF-β1-induced fibronectin expression

2019 ◽  
Vol 68 (3) ◽  
pp. 786-791 ◽  
Author(s):  
Ban Wang ◽  
Yanhui Li ◽  
Heather Wang ◽  
Jing Zhao ◽  
Yutong Zhao ◽  
...  
Keyword(s):  
Half Life ◽  
Transforming Growth Factor ◽  
Fibroblast Cells ◽  
Post Translational Modification ◽  
Human Lung Fibroblast ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Fibronectin Expression ◽  
Tgf Β1

FOXO3a belongs to a family of transcription factors characterized by a conserved forkhead box DNA-binding domain. It has been known to regulate various cellular processes including cell proliferation, apoptosis and differentiation. Post-translational modifications of FOXO3a and their roles in the regulation of FOXO3a activity have been well-documented. FOXO3a can be phosphorylated, acetylated and ubiquitinated, however, the ISGylation of FOXO3a has not been reported. Protein overexpression, ISGylation and half-life were measured to determine the post-translational modification of FOXO3a. Human fibroblast cells were treated with transforming growth factor (TGF)-β1 to determine the role of FOXO3a ISGylation in TGF-β1 signaling. FOXO3a’s half-life is around 3.7 hours. Inhibition of the proteasome, not lysosome, extends its half-life. ISGylation, but not ubiquitination of FOXO3a, is increased in the presence of the proteasome inhibitor. Overexpression of ISG15 increases FOXO3a degradation, while overexpression of USP18 stabilizes FOXO3a through de-ISGylation. These results suggest that FOXO3a is degraded in the ISGylation and proteasome system, which can be reversed by USP18, an ISG15-specific deubiquitinase. This study reveals a new molecular mechanism by which ISGylation regulates FOXO3a degradation. Furthermore, we show that the overexpression of FOXO3a attenuated TGF-β1-induced fibronectin expression in human lung fibroblast cells without altering Smad2/3 expression and activation. FOXO3a can be ISGylated, which can regulate FOXO3a stability. USP18/FOXO3a pathway is a potential target for treating TGF-β1-mediated fibrotic diseases such as idiopathic pulmonary fibrosis.

TGF-β1-Induced Long-Term Changes in Neuronal Excitability in Aplysia Sensory Neurons Depend on MAPK

2006 ◽  
Vol 95 (5) ◽  
pp. 3286-3290 ◽  
Author(s):  
Jeannie Chin ◽  
Rong-Yu Liu ◽  
Leonard J. Cleary ◽  
Arnold Eskin ◽  
John H. Byrne
Keyword(s):  
Sensory Neuron ◽  
Transforming Growth Factor Beta ◽  
Neuronal Excitability ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Camp Response Element Binding ◽  
Long Term Changes ◽  
Tgf Β1

Transforming growth factor beta-1 (TGF-β1) plays important roles in the early development of the nervous system and has been implicated in neuronal plasticity in adult organisms. It induces long-term increases in sensory neuron excitability in Aplysia as well as a long-term enhancement of synaptic efficacy at sensorimotor synapses. In addition, TGF-β1 acutely regulates synapsin phosphorylation and reduces synaptic depression induced by low-frequency stimuli. Because of the critical role of MAPK in other forms of long-term plasticity in Aplysia, we examined the role of MAPK in TGF-β1-induced long-term changes in neuronal excitability. Prolonged (6 h) exposure to TGF-β1 induced long-term increases in excitability. We confirmed this finding and now report that exposure to TGF-β1 was sufficient to activate MAPK and increase nuclear levels of active MAPK. Moreover, TGF-β1 enhanced phosphorylation of the Aplysia transcriptional activator cAMP response element binding protein (CREB)1, a homologue to vertebrate CREB. Both the TGF-β1-induced long-term changes in neuronal excitability and the phosphorylation of CREB1 were blocked in the presence of an inhibitor of the MAPK cascade, confirming a role for MAPK in long-term modulation of sensory neuron function.

scholarly journals Treatment of Experimental (Trinitrobenzene Sulfonic Acid) Colitis by Intranasal Administration of Transforming Growth Factor (Tgf)-β1 Plasmid

2000 ◽  
Vol 192 (1) ◽  
pp. 41-52 ◽  
Author(s):  
Atsushi Kitani ◽  
Ivan J. Fuss ◽  
Kazuhiko Nakamura ◽  
Owen M. Schwartz ◽  
Takashi Usui ◽  
...  
Keyword(s):  
Growth Factor ◽  
Sulfonic Acid ◽  
Transforming Growth Factor ◽  
Intraperitoneal Administration ◽  
Experimental Colitis ◽  
Inhibitory Effect ◽  
Transforming Growth Factor Β1 ◽  
Trinitrobenzene Sulfonic Acid ◽  
Ifn Γ ◽  
Tgf Β1

In this study, we show that a single intranasal dose of a plasmid encoding active transforming growth factor β1 (pCMV-TGF-β1) prevents the development of T helper cell type 1 (Th1)-mediated experimental colitis induced by the haptenating reagent, 2,4,6-trinitrobenzene sulfonic acid (TNBS). In addition, such plasmid administration abrogates TNBS colitis after it has been established, whereas, in contrast, intraperitoneal administration of rTGF-β1 protein does not have this effect. Intranasal pCMV-TGF-β1 administration leads to the expression of TGF-β1 mRNA in the intestinal lamina propria and spleen for 2 wk, as well as the appearance of TGF-β1–producing T cells and macrophages in these tissues, and is not associated with the appearances of fibrosis. These cells cause marked suppression of interleukin (IL)-12 and interferon (IFN)-γ production and enhancement of IL-10 production; in addition, they inhibit IL-12 receptor β2 (IL-12Rβ2) chain expression. Coadministration of anti–IL-10 at the time of pCMV-TGF-β1 administration prevents the enhancement of IL-10 production and reverses the suppression of IL-12 but not IFN-γ secretion. However, anti–IL-10 leads to increased tumor necrosis factor α production, especially in established colitis. Taken together, these studies show that TGF-β1 inhibition of a Th1-mediated colitis is due to: (a) suppression of IL-12 secretion by IL-10 induction and (b) inhibition of IL-12 signaling via downregulation of IL-12Rβ2 chain expression. In addition, TGF-β1 may also have an inhibitory effect on IFN-γ transcription.

scholarly journals Tetrahydrobiopterin and alkylglycerol monooxygenase substantially alter the murine macrophage lipidome

2015 ◽  
Vol 112 (8) ◽  
pp. 2431-2436 ◽  
Author(s):  
Katrin Watschinger ◽  
Markus A. Keller ◽  
Eileen McNeill ◽  
Mohammad T. Alam ◽  
Steven Lai ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lipid Metabolism ◽  
Transforming Growth Factor ◽  
Ether Lipid ◽  
Mouse Bone Marrow ◽  
Monooxygenase Activity ◽  
Lipid Species ◽  
Primary Mouse ◽  
Ifn Γ

Tetrahydrobiopterin is a cofactor synthesized from GTP with well-known roles in enzymatic nitric oxide synthesis and aromatic amino acid hydroxylation. It is used to treat mild forms of phenylketonuria. Less is known about the role of tetrahydrobiopterin in lipid metabolism, although it is essential for irreversible ether lipid cleavage by alkylglycerol monooxygenase. Here we found intracellular alkylglycerol monooxygenase activity to be an important regulator of alkylglycerol metabolism in intact murine RAW264.7 macrophage-like cells. Alkylglycerol monooxygenase was expressed and active also in primary mouse bone marrow-derived monocytes and “alternatively activated” M2 macrophages obtained by interleukin 4 treatment, but almost missing in M1 macrophages obtained by IFN-γ and lipopolysaccharide treatment. The cellular lipidome of RAW264.7 was markedly changed in a parallel way by modulation of alkylglycerol monooxygenase expression and of tetrahydrobiopterin biosynthesis affecting not only various ether lipid species upstream of alkylglycerol monooxygenase but also other more complex lipids including glycosylated ceramides and cardiolipins, which have no direct connection to ether lipid pathways. Alkylglycerol monooxygenase activity manipulation modulated the IFN-γ/lipopolysaccharide–induced expression of inducible nitric oxide synthase, interleukin-1β, and interleukin 1 receptor antagonist but not transforming growth factor β1, suggesting that alkylglycerol monooxygenase activity affects IFN-γ/lipopolysaccharide signaling. Our results demonstrate a central role of tetrahydrobiopterin and alkylglycerol monooxygenase in ether lipid metabolism of murine macrophages and reveal that alteration of alkylglycerol monooxygenase activity has a profound impact on the lipidome also beyond the class of ether lipids.

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