Diosmin attenuates radiation-induced hepatic fibrosis by boosting PPAR-γ expression and hampering miR-17-5p-activated canonical Wnt–β-catenin signaling

2017 ◽  
Vol 95 (3) ◽  
pp. 400-414 ◽  
Author(s):  
Hesham Farouk Hasan ◽  
Mohamed Khairy Abdel-Rafei ◽  
Shereen Mohamed Galal
Keyword(s):  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Stellate Cell ◽  
Antioxidant Defenses ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Radiation Induced ◽  
Canonical Wnt

Background: Liver fibrosis is one of the major complications from upper right quadrant radiotherapy. MicroRNA-17-5p (miR-17-5p) is hypothesized to act as a regulator of hepatic stellate cell (HSCs) activation by activation of the canonical Wnt–β-catenin pathway. Diosmin (Dios), a citrus bioflavonoid, is known to possess potent antioxidant, anti-inflammatory, and anti-apoptotic properties. Purpose: To explore the molecular mechanisms that underlie radiation-induced liver fibrosis, and to evaluate the possible influence of Dios on the miR-17-5p–Wnt–β-catenin signaling axis during fibrogenesis provoked by irradiation (IRR) in rats. Also, the effect of Dios on hepatic peroxisome proliferator activated receptor-γ (PPAR-γ) expression as a regulator for HSC activation was considered. Methods: We administered 100 mg·(kg body mass)–1·day–1(per oral) of Dios were administered to IRR-exposed rats (overall dose of 12 Gy on 6 fractions of 2 Gy each) for 6 successive weeks. Results: Data analysis revealed that Dios treatment mitigated oxidative stress, enhanced antioxidant defenses, alleviated hepatic inflammatory responses, abrogated pro-fibrogenic cytokines, and stimulated PPAR-γ expression. Dios treatment repressed the miR-17-5p activated Wnt–β-catenin signaling induced by IRR. Moreover, Dios treatment restored the normal hepatic architecture and reversed pathological alterations induced by IRR. Conclusion: We hypothesize that the stimulation of PPAR-γ expression and interference with miR-17-5p activated Wnt–β-catenin signaling mediates the antifibrotic properties of Dios.

The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules

2013 ◽  
Vol 305 (2) ◽  
pp. F143-F154 ◽  
Author(s):  
Harshini Mudaliar ◽  
Carol Pollock ◽  
Muralikrishna Gangadharan Komala ◽  
Steven Chadban ◽  
Huiling Wu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Inflammatory Responses ◽  
Proximal Tubules ◽  
Peroxisome Proliferator ◽  
Tlr2 Expression ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Diagnostic Threshold

Inflammatory responses are central to the pathogenesis of diabetic nephropathy. Toll-like receptors (TLRs) are ligand-activated membrane-bound receptors which induce inflammatory responses predominantly through the activation of NF-κB. TLR2 and 4 are present in proximal tubular cells and are activated by endogenous ligands upregulated in diabetic nephropathy, including high-mobility group box-1 (HMGB1) and fibronectin. Human proximal tubules were exposed to 5 mM (control), 11.2 mM (approximating the clinical diagnostic threshold for diabetes mellitus), and 30 mM (high) glucose for 72 h or 7 days. Cells were harvested for protein, mRNA, and nuclear extract to assess for TLR2, 4, and inflammatory markers. Glucose (11.2 mM) maximally increased TLR2 and 4 expression, HMGB1 release, and NF-κB activation with increased expression of cytokines. However, only TLR2 expression and subsequent NF-κB binding were sustained at 7 days. Recombinant HMGB1 induced NF-κB activation, which was prevented by both TLR2 silencing [small interfering (si)RNA] and TLR4 inhibition. Peroxisome proliferator-activated receptor-γ (PPAR-γ) transcription was reduced by exposure to 11.2 mM glucose with an increase observed at 30 mM glucose at 24 h. This may reflect a compensatory increase in PPAR-γ induced by exposure to 30 mM glucose, limiting the inflammatory response. Therefore, short-term moderate increases in glucose in vitro increase HMGB1, which mediates NF-κB activation through both TLR2 and 4. Furthermore, in vivo, streptozotocin-induced diabetic mice exhibited an increase in tubular TLR2 and HMGB1 expression. These results collectively suggest that TLR2 is likely to be the predominant long-term mediator of NF-κB activation in transducing inflammation in diabetic nephropathy.

Peroxisome proliferator-activated receptor-γ inhibits cigarette smoke solution-induced mucin production in human airway epithelial (NCI-H292) cells

2006 ◽  
Vol 291 (1) ◽  
pp. L84-L90 ◽  
Author(s):  
Sung Yong Lee ◽  
Eun Joo Kang ◽  
Gyu Young Hur ◽  
Ki Hwan Jung ◽  
Hye Cheol Jung ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Inflammatory Responses ◽  
Cigarette Smoke Exposure ◽  
Etiologic Factor ◽  
Peroxisome Proliferator ◽  
Cell Hyperplasia ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mucin Production ◽  
Ppar Γ ◽  
Anti Inflammatory

The main etiologic factor for chronic bronchitis is cigarette smoke. Exposure to cigarette smoke is reported to induce goblet cell hyperplasia and mucus production. Mucin synthesis in airways has been reported to be regulated by the EGFR system. Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a member of the ligand-activated nuclear receptor superfamily. PPAR-γ is implicated in anti-inflammatory responses, but mechanisms underlying these varied roles remain ill-defined. Recently, reports have shown that upregulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) might be one of the mechanisms through which PPAR-γ agonists exert their anti-inflammatory actions. However, no data are available on the role of PPAR-γ in smoke-induced mucin production. In this study, we investigated the effect of PPAR-γ agonist (rosiglitazone) on smoke-induced mucin production in NCI-H292 cells. Exposure to cigarette smoke causes a significant decrease in PTEN expression and increases dose-dependent EGFR-specific tyrosine phosphorylation, resulting in MUC5AC mucin production in NCI-H292 cells. PPAR-γ agonists or specific inhibitors of phosphoinositide 3-kinase exert inhibition of cigarette smoke-induced mucin production, with the upregulation of PTEN signaling and downregulation of Akt expression. This study demonstrates that PPAR-γ agonist functions as a regulator of epithelial cell inflammation that may result in reduction of mucin-producing cells in airway epithelium.

Disruption of transforming growth factor-β signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-γ in rat hepatic stellate cells

2007 ◽  
Vol 292 (1) ◽  
pp. G113-G123 ◽  
Author(s):  
Shizhong Zheng ◽  
Anping Chen
Keyword(s):  
Gene Expression ◽  
Hepatic Stellate Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Gene Promoter ◽  
Stellate Cells ◽  
Transforming Growth Factor Β ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Activation of hepatic stellate cells (HSC), the major effectors of hepatic fibrogenesis, is coupled with sequential alterations in gene expression, including an increase in receptors for transforming growth factor-β (TGF-β) and a dramatic reduction in the peroxisome proliferator-activated receptor-γ (PPAR-γ). The relationship between them remains obscure. We previously demonstrated that curcumin induced gene expression of PPAR-γ in activated HSC, leading to reducing cell proliferation, inducing apoptosis and suppressing expression of extracellular matrix genes. The underlying molecular mechanisms are largely unknown. We recently observed that stimulation of PPAR-γ activation suppressed gene expression of TGF-β receptors in activated HSC, leading to the interruption of TGF-β signaling. This observation supported our assumption of an antagonistic relationship between PPAR-γ activation and TGF-β signaling in HSC. In this study, we further hypothesize that TGF-β signaling might negatively regulate gene expression of PPAR-γ in activated HSC. The present report demonstrates that exogenous TGF-β1 inhibits gene expression of PPAR-γ in activated HSC, which is eliminated by the pretreatment with curcumin likely by interrupting TGF-β signaling. Transfection assays further indicate that blocking TGF-β signaling by dominant negative type II TGF-β receptor increases the promoter activity of PPAR-γ gene. Promoter deletion assays, site-directed mutageneses, and gel shift assays localize two Smad binding elements (SBEs) in the PPAR-γ gene promoter, acting as curcumin response elements and negatively regulating the promoter activity in passaged HSC. The Smad3/4 protein complex specifically binds to the SBEs. Overexpression of Smad4 dose dependently eliminates the inhibitory effects of curcumin on the PPAR-γ gene promoter and TGF-β signaling. Taken together, these results demonstrate that the interruption of TGF-β signaling by curcumin induces gene expression of PPAR-γ in activated HSC in vitro. Our studies provide novel insights into the molecular mechanisms of curcumin in the induction of PPAR-γ gene expression and in the inhibition of HSC activation.

Regulation of dectin-1–mediated dendritic cell activation by peroxisome proliferator–activated receptor-gamma ligand troglitazone

Blood ◽  
2011 ◽  
Vol 117 (13) ◽  
pp. 3569-3574 ◽  
Author(s):  
Grethe Kock ◽  
Anita Bringmann ◽  
Stefanie Andrea Erika Held ◽  
Solveig Daecke ◽  
Annkristin Heine ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Peroxisome Proliferator ◽  
Nuclear Factor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Mitogen Activated Protein

Abstract Dectin-1 is the major receptor for fungal β-glucans. The activation of Dectin-1 leads to the up-regulation of surface molecules on dendritic cells (DCs) and cytokine secretion. Furthermore, Dectin-1 is important for the recruitment of leukocytes and the production of inflammatory mediators. Peroxisome proliferator–activated receptor-γ (PPAR-γ) and its ligands, cyclopentenone prostaglandins or thiazolidinediones, have modulatory effects on B-cell, T-cell, and DC function. In the present study, we analyzed the effects of troglitazone (TGZ), a high-affinity synthetic PPAR-γ ligand, on the Dectin-1–mediated activation of monocyte-derived human DCs. Dectin-1–mediated activation of DCs was inhibited by TGZ, as shown by down-regulation of costimulatory molecules and reduced secretion of cytokines and chemokines involved in T-lymphocyte activation. Furthermore, TGZ inhibited the T-cell–stimulatory capacity of DCs. These effects were not due to a diminished expression of Dectin-1 or to a reduced phosphorylation of spleen tyrosine kinase; they were mediated by the inhibition of downstream signaling molecules such as mitogen-activated protein kinases and nuclear factor-κB. Furthermore, curdlan-mediated accumulation of caspase recruitment domain 9 (CARD9) in the cytosol was inhibited by TGZ. Our data demonstrate that the PPAR-γ ligand TGZ inhibits Dectin-1–mediated activation by interfering with CARD9, mitogen-activated protein kinase, and nuclear factor-κB signaling pathways. This confirms their important role as negative-feedback regulators of potentially harmful inflammatory responses.

Activation of peroxisome proliferator-activated receptor-γ contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth

2003 ◽  
Vol 285 (1) ◽  
pp. G20-G30 ◽  
Author(s):  
Jianye Xu ◽  
Yumei Fu ◽  
Anping Chen
Keyword(s):  
Gene Expression ◽  
Liver Injury ◽  
Hepatic Fibrosis ◽  
Stellate Cell ◽  
Healing Process ◽  
Wound Healing Process ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Hepatic fibrogenesis occurs as a wound-healing process after many forms of chronic liver injury. Hepatic fibrosis ultimately leads to cirrhosis if not treated effectively. During liver injury, quiescent hepatic stellate cells (HSC), the most relevant cell type, become active and proliferative. Oxidative stress is a major and critical factor for HSC activation. Activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) inhibits the proliferation of nonadipocytes. The level of PPAR-γ is dramatically diminished along with activation of HSC. Curcumin, the yellow pigment in curry, is a potent antioxidant. The aims of this study were to evaluate the effect of curcumin on HSC proliferation and to begin elucidating underlying mechanisms. It was hypothesized that curcumin might inhibit the proliferation of activated HSC by inducing PPAR-γ gene expression and reviving PPAR-γ activation. Our results indicated that curcumin significantly inhibited the proliferation of activated HSC and induced apoptosis in vitro. We demonstrated, for the first time, that curcumin dramatically induced the gene expression of PPAR-γ and activated PPAR-γ in activated HSC. Blocking its trans-activating activity by a PPAR-γ antagonist markedly abrogated the effects of curcumin on inhibition of cell proliferation. Our results provide a novel insight into mechanisms underlying the inhibition of activated HSC growth by curcumin. The characteristics of curcumin, including antioxidant potential, reduction of activated HSC growth, and no adverse health effects, make it a potential antifibrotic candidate for prevention and treatment of hepatic fibrosis.

Peroxisome proliferator-activated receptor-γ ligands regulate endothelial membrane superoxide production

2005 ◽  
Vol 288 (4) ◽  
pp. C899-C905 ◽  
Author(s):  
Jinah Hwang ◽  
Dean J. Kleinhenz ◽  
Bernard Lassègue ◽  
Kathy K. Griendling ◽  
Sergey Dikalov ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nadph Oxidase ◽  
Molecular Mechanisms ◽  
Pcr Analysis ◽  
Resonance Spectroscopy ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Endothelial Nitric Oxide

Recently, we demonstrated that the peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands, either 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) or ciglitazone, increased endothelial nitric oxide (·NO) release without altering endothelial nitric oxide synthase (eNOS) expression ( 4 ). However, the precise molecular mechanisms of PPAR-γ-stimulated endothelial·NO release remain to be defined. Superoxide anion radical (O2−·) combines with ·NO to decrease·NO bioavailability. NADPH oxidase, which produces O2−·, and Cu/Zn-superoxide dismutase (Cu/Zn-SOD), which degrades O2−·, thereby contribute to regulation of endothelial cell·NO metabolism. Therefore, we examined the ability of PPAR-γ ligands to modulate endothelial O2−· metabolism through alterations in the expression and activity of NADPH oxidase or Cu/Zn-SOD. Treatment with 10 μM 15d-PGJ2 or ciglitazone for 24 h decreased human umbilical vein endothelial cell (HUVEC) membrane NADPH-dependent O2−· production detected with electron spin resonance spectroscopy. Treatment with 15d-PGJ2 or ciglitazone also reduced relative mRNA levels of the NADPH oxidase subunits, nox-1, gp91 phox (nox-2), and nox-4, as measured using real-time PCR analysis. Concordantly, Western blot analysis demonstrated that 15d-PGJ2 or ciglitazone decreased nox-2 and nox-4 protein expression. PPAR-γ ligands also stimulated both activity and expression of Cu/Zn-SOD in HUVEC. These data suggest that in addition to any direct effects on endothelial·NO production, PPAR-γ ligands enhance endothelial·NO bioavailability, in part by altering endothelial O2−· metabolism through suppression of NADPH oxidase and induction of Cu/Zn-SOD. These findings further elucidate the molecular mechanisms by which PPAR-γ ligands directly alter vascular endothelial function.

Suppression of PPAR-γ attenuates insulin-stimulated glucose uptake by affecting both GLUT1 and GLUT4 in 3T3-L1 adipocytes

2007 ◽  
Vol 293 (1) ◽  
pp. E219-E227 ◽  
Author(s):  
Wei Liao ◽  
M. T. Audrey Nguyen ◽  
Takeshi Yoshizaki ◽  
Svetlana Favelyukis ◽  
David Patsouris ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Insulin Signaling ◽  
Adipocyte Differentiation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Tnf Α ◽  
Interfering Rna

Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays a critical role in regulating insulin sensitivity and glucose homeostasis. In this study, we identified highly efficient small interfering RNA (siRNA) sequences and used lentiviral short hairpin RNA and electroporation of siRNAs to deplete PPAR-γ from 3T3-L1 adipocytes to elucidate its role in adipogenesis and insulin signaling. We show that PPAR-γ knockdown prevented adipocyte differentiation but was not required for maintenance of the adipocyte differentiation state after the cells had undergone adipogenesis. We further demonstrate that PPAR-γ suppression reduced insulin-stimulated glucose uptake without affecting the early insulin signaling steps in the adipocytes. Using dual siRNA strategies, we show that this effect of PPAR-γ deletion was mediated by both GLUT4 and GLUT1. Interestingly, PPAR-γ-depleted cells displayed enhanced inflammatory responses to TNF-α stimulation, consistent with a chronic anti-inflammatory effect of endogenous PPAR-γ. In summary, 1) PPAR-γ is essential for the process of adipocyte differentiation but is less necessary for maintenance of the differentiated state, 2) PPAR-γ supports normal insulin-stimulated glucose transport, and 3) endogenous PPAR-γ may play a role in suppression of the inflammatory pathway in 3T3-L1 cells.

scholarly journals Short hairpin RNA attenuates liver fibrosis by regulating the peroxisome proliferator-activated receptor-γ and nuclear factor-κB pathways in hepatitis B virus-induced liver fibrosis in mice

2019 ◽  
Author(s):  
Lei Ye ◽  
Jiaqi Cao ◽  
Liying Sun ◽  
Ting Chen ◽  
Wuping Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Fibrosis ◽  
Signaling Pathway ◽  
Nuclear Factor Κb ◽  
Differentially Expressed ◽  
Peroxisome Proliferator ◽  
Differentially Expressed Proteins ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Ppar Signaling

Abstract Background: Progressive liver fibrosis, caused by chronic viral infection and metabolic disorders, results in the development of cirrhosis and hepatocellular carcinoma. However, no antifibrotic therapies have been approved to date. In our previous study, adeno-associated virus (AAV) short hairpin RNAs (shRNAs) targeting hepatitis B virus (HBV) and transforming growth factor (TGF)-β administration could persistently inhibit HBV replication and concomitantly prevent liver fibrosis. However, the differentially expressed proteins and critical regulatory networks of AAVshRNA treatment remain unclear. Accordingly, in this study, our major goal was we aimed to analyze differentially expressed proteins in the liver of AAV-shRNAs-treated mice with HBV infection and liver fibrosis using isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics and to elucidate the underlying antifibrotic mechanisms. Results: In total 2743 proteins were recognized by iTRAQ-based quantitative proteomics analysis. Gene ontology analysis suggested that the differentially expressed proteins were mostly participated in peptide metabolism in the biological process category, cytosolic ribosomes in the cell component category, and structural constituents of ribosomes in the molecular function category. Kyoto Encyclopedia of Genes and Genomespathway analysis indicated that oxidative stress and the peroxisome proliferator-activated receptor (PPAR) signaling pathway were actived after treatment. Verification studies showed that AAVshRNAs inhibited hepatic stellate cell activation and inflammation by suppressing nuclear factor-κB p65 phosphorylation and α-smooth muscle actin expression via upregulation of PPAR-γ. Hepatocytes steatosis was also decreased by activating PPAR signaling pathway and improving lipid metabolism. TGF-β level was decreased owning to increase PPAR-γ expression and directly inhibition using AAVshRNAs targeting TGF-β. TGF-β-induced oxidative stress was suppressed by increasing glutathione S-transferase Pi 1 and reducing peroxiredoxin 1. Conclusions: Our results indicated that AAV-shRNAs were effective for modulating liver fibrosis by reducing oxidative stress, inflammation and activating PPAR signaling pathway.

scholarly journals Peroxisome Proliferator-Activated Receptor γ Activation Restores Islet Function in Diabetic Mice through Reduction of Endoplasmic Reticulum Stress and Maintenance of Euchromatin Structure

2009 ◽  
Vol 29 (8) ◽  
pp. 2053-2067 ◽  
Author(s):  
Carmella Evans-Molina ◽  
Reiesha D. Robbins ◽  
Tatsuyoshi Kono ◽  
Sarah A. Tersey ◽  
George L. Vestermark ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Molecular Mechanisms ◽  
Serum Insulin ◽  
Peroxisome Proliferator ◽  
Islet Function ◽  
Direct Role ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

ABSTRACT The nuclear receptor peroxisome proliferator-activated receptor γ (PPAR-γ) is an important target in diabetes therapy, but its direct role, if any, in the restoration of islet function has remained controversial. To identify potential molecular mechanisms of PPAR-γ in the islet, we treated diabetic or glucose-intolerant mice with the PPAR-γ agonist pioglitazone or with a control. Treated mice exhibited significantly improved glycemic control, corresponding to increased serum insulin and enhanced glucose-stimulated insulin release and Ca2+ responses from isolated islets in vitro. This improved islet function was at least partially attributed to significant upregulation of the islet genes Irs1, SERCA, Ins1/2, and Glut2 in treated animals. The restoration of the Ins1/2 and Glut2 genes corresponded to a two- to threefold increase in the euchromatin marker histone H3 dimethyl-Lys4 at their respective promoters and was coincident with increased nuclear occupancy of the islet methyltransferase Set7/9. Analysis of diabetic islets in vitro suggested that these effects resulting from the presence of the PPAR-γ agonist may be secondary to improvements in endoplasmic reticulum stress. Consistent with this possibility, incubation of thapsigargin-treated INS-1 β cells with the PPAR-γ agonist resulted in the reduction of endoplasmic reticulum stress and restoration of Pdx1 protein levels and Set7/9 nuclear occupancy. We conclude that PPAR-γ agonists exert a direct effect in diabetic islets to reduce endoplasmic reticulum stress and enhance Pdx1 levels, leading to favorable alterations of the islet gene chromatin architecture.

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