scholarly journals Pioglitazone attenuates hepatic inflammation and fibrosis in phosphatidylethanolamine N-methyltransferase-deficient mice

2016 ◽  
Vol 310 (7) ◽  
pp. G526-G538 ◽  
Author(s):  
Jelske N. van der Veen ◽  
Susanne Lingrell ◽  
Xia Gao ◽  
Ariel D. Quiroga ◽  
Abhijit Takawale ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Transforming Growth Factor ◽  
Body Weight Gain ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Liver Weight ◽  
Mrna Levels ◽  
Nonalcoholic Fatty Liver ◽  
Diet Induced Obesity ◽  
Important Enzyme

Phosphatidylethanolamine N-methyltransferase (PEMT) is an important enzyme in hepatic phosphatidylcholine (PC) biosynthesis. Pemt−/− mice are protected against high-fat diet (HFD)-induced obesity and insulin resistance; however, these mice develop nonalcoholic fatty liver disease (NAFLD). We hypothesized that peroxisomal proliferator-activated receptor-γ (PPARγ) activation by pioglitazone might stimulate adipocyte proliferation, thereby directing lipids from the liver toward white adipose tissue. Pioglitazone might also act directly on PPARγ in the liver to improve NAFLD. Pemt+/+ and Pemt−/− mice were fed a HFD with or without pioglitazone (20 mg·kg−1·day−1) for 10 wk. Pemt−/− mice were protected from HFD-induced obesity but developed NAFLD. Treatment with pioglitazone caused an increase in body weight gain in Pemt−/− mice that was mainly due to increased adiposity. Moreover, pioglitazone improved NAFLD in Pemt−/− mice, as indicated by a 35% reduction in liver weight and a 57% decrease in plasma alanine transaminase levels. Livers from HFD-fed Pemt−/− mice were steatotic, inflamed, and fibrotic. Hepatic steatosis was still evident in pioglitazone-treated Pemt−/− mice; however, treatment with pioglitazone reduced hepatic fibrosis, as evidenced by reduced Sirius red staining and lowered mRNA levels of collagen type Iα1 ( Col1a1), tissue inhibitor of metalloproteinases 1 ( Timp1), α-smooth muscle actin ( Acta2), and transforming growth factor-β ( Tgf-β). Similarly, oxidative stress and inflammation were reduced in livers from Pemt−/− mice upon treatment with pioglitazone. Together, these data show that activation of PPARγ in HFD-fed Pemt −/− mice improved liver function, while these mice were still protected against diet-induced obesity and insulin resistance.

scholarly journals Inhibition of p300/CBP-Associated Factor Attenuates Renal Tubulointerstitial Fibrosis through Modulation of NF-kB and Nrf2

2019 ◽  
Vol 20 (7) ◽  
pp. 1554 ◽  
Author(s):  
Sungjin Chung ◽  
Soojeong Kim ◽  
Mina Son ◽  
Minyoung Kim ◽  
Eun Koh ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Cell Damage ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Tubulointerstitial Fibrosis ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Associated Factor ◽  
Renal Tubulointerstitial Fibrosis

p300/CBP-associated factor (PCAF), a histone acetyltransferase, is involved in many cellular processes such as differentiation, proliferation, apoptosis, and reaction to cell damage by modulating the activities of several genes and proteins through the acetylation of either the histones or transcription factors. Here, we examined a pathogenic role of PCAF and its potential as a novel therapeutic target in the progression of renal tubulointerstitial fibrosis induced by non-diabetic unilateral ureteral obstruction (UUO) in male C57BL/6 mice. Administration of garcinol, a PCAF inhibitor, reversed a UUO-induced increase in the renal expression of total PCAF and histone 3 lysine 9 acetylation and reduced positive areas of trichrome and α-smooth muscle actin and collagen content. Treatment with garcinol also decreased mRNA levels of transforming growth factor-β, matrix metalloproteinase (MMP)-2, MMP-9, and fibronectin. Furthermore, garcinol suppressed nuclear factor-κB (NF-κB) and pro-inflammatory cytokines such as tumor necrosis factor-α and IL-6, whereas it preserved the nuclear expression of nuclear factor erythroid-derived 2-like factor 2 (Nrf2) and levels of Nrf2-dependent antioxidants including heme oxygense-1, catalase, superoxide dismutase 1, and NAD(P)H:quinone oxidoreductase 1. These results suggest that the inhibition of inordinately enhanced PCAF could mitigate renal fibrosis by redressing aberrant balance between inflammatory signaling and antioxidant response through the modulation of NF-κB and Nrf2.

Macrophage TNF-α contributes to insulin resistance and hepatic steatosis in diet-induced obesity

2007 ◽  
Vol 293 (3) ◽  
pp. E713-E725 ◽  
Author(s):  
Bart M. De Taeye ◽  
Tatiana Novitskaya ◽  
Owen P. McGuinness ◽  
Linda Gleaves ◽  
Mousumi Medda ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Bone Marrow ◽  
Insulin Sensitivity ◽  
Hepatic Steatosis ◽  
Relative Weight ◽  
Liver Weight ◽  
Composition Analysis ◽  
Nonalcoholic Fatty Liver ◽  
Diet Induced Obesity ◽  
Tnf Α

Obesity is commonly associated with development of insulin resistance and systemic evidence of inflammation. Macrophages contribute to inflammatory amplification in obesity and may contribute directly to insulin resistance and the development of nonalcoholic fatty liver disease through the production of inflammatory cytokines, including tumor necrosis factor (TNF)-α. To test this hypothesis, we transplanted male wild-type (WT) and TNF-α deficient (KO) mice with either TNF-α-sufficient (TNF-α+/+) or TNF-α-deficient (TNF-α−/−) bone marrow. After consuming a high-fat diet for 26 wk, metabolic and morphometric characteristics of the animals were analyzed. While there were no differences in terms of relative weight gain, body composition analysis yielded a lower relative adipose and higher relative lean mass in mice lacking TNF-α, which was partially explained by reduced epididymal fat pad and liver weight. TNF-α−/− →KO mice exhibited enhanced insulin sensitivity compared with that observed in TNF-α+/+→KO mice; remarkably, no protection against insulin resistance was provided by transplanting TNF-α−/− bone marrow in WT mice compared with TNF-α+/+→WT. The preserved insulin sensitivity seen in TNF-α−/−→KO mice provided protection against the development of hepatic steatosis. Taken together, these data indicate that macrophage-derived TNF-α contributes to the pattern and extent of fat accumulation and insulin resistance in diet-induced obesity; however, this contribution is negligible in the presence of host-derived TNF-α.

scholarly journals Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Inhibitor as a Novel Therapeutic Tool for Lung Injury

2020 ◽  
Vol 21 (20) ◽  
pp. 7761
Author(s):  
Roberta Fusco ◽  
Rosalba Siracusa ◽  
Ramona D’Amico ◽  
Marika Cordaro ◽  
Tiziana Genovese ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Tissue Injury ◽  
Body Weight Gain ◽  
Smooth Muscle Actin ◽  
Immunohistochemical Analysis ◽  
Inflammatory Cells ◽  
Transforming Growth Factor Β ◽  
Lavage Fluid ◽  
Immunomodulatory Activity

Pulmonary fibrosis is a progressive disease characterized by lung remodeling due to excessive deposition of extracellular matrix. In this study, the bleomycin experimental model of pulmonary fibrosis was employed to investigate the anti-fibrotic and immunomodulatory activity of the inhibition of MALT1 protease activity. Mice received a single intra-tracheal administration of bleomycin (1 mg/kg) in the presence or absence of MI-2, a selective MALT1 inhibitor, (a dose of 30 mg/kg administered intra-peritoneally 1 h after bleomycin and daily until the end of the experiment). Seven days after bleomycin instillation mice were sacrificed and bronchoalveolar lavage fluid analysis, measurement of collagen content in the lung, histology, molecular analysis and immunohistochemistry were performed. To evaluate mortality and body weight gain a subset of mice was administered daily with MI-2 for 21 days. Mice that received MI-2 showed decreased weight loss and mortality, inflammatory cells infiltration, cytokines overexpression and tissue injury. Moreover, biochemical and immunohistochemical analysis displayed that MI-2 was able to modulate the excessive production of reactive oxygen species and the inflammatory mediator upregulation induced by bleomycin instillation. Additionally, MI-2 demonstrated anti-fibrotic activity by reducing transforming growth factor-β (TGF-β), α-smooth muscle actin (α-SMA) and receptor associated factor 6 (TRAF6) expression. The underlying mechanisms for the protective effect of MI-2 bleomycin induced pulmonary fibrosis may be attributed to its inhibition on NF-κB pathway. This is the first report showing the therapeutic role of MALT1 inhibition in a bleomycin model of pulmonary fibrosis, thus supporting further preclinical and clinical studies.

scholarly journals Granulosal and thecal expression of bone morphogenetic protein- and activin-binding protein mRNA transcripts during bovine follicle development and factors modulating their expression in vitro

Reproduction ◽  
2011 ◽  
Vol 142 (4) ◽  
pp. 581-591 ◽  
Author(s):  
Claire Glister ◽  
Leanne Satchell ◽  
Phil G Knight
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Mrna Level ◽  
Transcript Abundance ◽  
Transforming Growth Factor Β ◽  
Follicle Development ◽  
Mrna Levels ◽  
Theca Interna

Evidence supports local roles for transforming growth factor β superfamily members including activins and bone morphogenetic proteins (BMP) in follicle development. Access of these ligands to signalling receptors is likely modulated by extracellular binding proteins (BP). In this study, we comparedex vivoexpression of four BPs (chordin, gremlin, noggin and follistatin) in granulosal (GC) and theca interna (TC) compartments of developing bovine antral follicles (1–18 mm). Effects of FSH and IGF on BMP and BP expression by cultured GC, and effects of LH and BMPs on BP expression by cultured TC were also examined. Follicular expression of all four BP transcripts was higher in GC than TC compartments (P<0.001) a finding confirmed by immunohistochemistry. Follicle category affected (P<0.01) gremlin and follistatin mRNA abundance, with a significant cell-type×follicle category interaction for chordin, follistatin and noggin. Noggin transcript abundance was lower (P<0.05) in GC of large ‘E-active’ than ‘E-inactive’ follicles while follistatin mRNA level was higher (P<0.01). FSH enhanced CYP19, FSHR, INHBA and follistatin by GC without affecting BMP or BMP–BP expression. IGF increased CYP19 and follistatin, reduced BMP4, noggin and gremlin but did not affect chordin orFSHRmRNA levels. LH increased TC androgen secretion but had no effect on BMP or BP expression. BMPs uniformly suppressed TC androgen production whilst increasing chordin, noggin and gremlin mRNA levels up to 20-fold (P<0.01). These findings support the hypothesis that extracellular BP, mostly from GC, contribute to the regulation of intrafollicular BMP/activin signalling. Enhancement of thecal BP expression by BMP implies an autoregulatory feedback role to prevent excessive signalling.

Co-activation of synovial fibroblasts by laminin-111 and transforming growth factor-β induces expression of matrix metalloproteinases 3 and 10 independently of nuclear factor-κB

2007 ◽  
Vol 67 (4) ◽  
pp. 559-562 ◽  
Author(s):  
K Warstat ◽  
T Pap ◽  
G Klein ◽  
S Gay ◽  
W K Aicher
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Synovial Fibroblasts ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
The Matrix ◽  
Specific Tissue ◽  
Significant Expression

We showed previously that the attachment of synovial fibroblasts to laminin (LM)-111 in the presence of transforming growth factor-β induces significant expression of the matrix metalloproteinase (MMP)-3. Here we go on to investigate the regulation of additional MMPs and their specific tissue inhibitors of matrix proteases (TIMPs). Changes in steady-state mRNA levels encoding TIMPs and MMPs were investigated by quantitative reverse transcription–polymerase chain reaction. Production of MMPs was monitored by a multiplexed immunoarray. Signal transduction pathways were studied by immunoblotting. Attachment of synovial fibroblasts to LM-111 in the presence of transforming growth factor-β induced significant increases in MMP-3 mRNA (12.35-fold, p<0.001) and protein (mean 62 ng/ml, sixfold, p<0.008) and in expression of MMP-10 mRNA (11.68-fold, p<0.05) and protein (54 ng/ml, 20-fold, p⩾0.02). All other TIMPs and MMPs investigated failed to show this LM-111-facilitated transforming growth factor-β response. No phosphorylation of nuclear factor-κB was observed. We conclude that co-stimulation of synovial fibroblasts by LM-111 together with transforming growth factor-β suffices to induce significant expression of MMP-3 and MMP-10 by synovial fibroblasts and that this induction is independent of nuclear factor-κB phosphorylation.

Overexpression of angiotensin type 2 receptor ameliorates glomerular injury in a mouse remnant kidney model

2004 ◽  
Vol 286 (3) ◽  
pp. F516-F525 ◽  
Author(s):  
Naoko Hashimoto ◽  
Yohei Maeshima ◽  
Minoru Satoh ◽  
Masahiro Odawara ◽  
Hitoshi Sugiyama ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Glomerular Injury ◽  
Wild Mice ◽  
Angiotensin Type 2 Receptor ◽  
Glomerular Size ◽  
Nitric Oxide Metabolites

Angiotensin II mediates the progression of renal disease through the type 1 receptor (AT1R). Recent studies have suggested that type 2 receptor (AT2R)-mediated signaling inhibits cell proliferation by counteracting the actions of AT1R. The aim of the present study was to determine the effect of AT2R overexpression on glomerular injury induced by ⅚ nephrectomy (⅚Nx). AT2R transgenic mice (AT2-Tg), overexpressing AT2R under the control of α-smooth muscle actin (α-SMA) promoter, and control wild-type mice (Wild) were subjected to ⅚Nx. In AT2-Tg mice, the glomerular expression of AT2R was upregulated after ⅚Nx. Urinary albumin excretion at 12 wk after ⅚Nx was decreased by 33.7% in AT2-Tg compared with Wild mice. Glomerular size in AT2-Tg mice was significantly smaller than in Wild mice after ⅚Nx (93.1 ± 3.0 vs. 103.3 ± 1.8 μm; P < 0.05). Immunohistochemistry revealed significant decreases in glomerular expression of platelet-derived growth factor-BB chain (PDGF-BB) and transforming growth factor-β1 (TGF-β1) in AT2-Tg with ⅚Nx compared with Wild mice. Urinary excretion of nitric oxide metabolites was increased 2.5-fold in AT2-Tg compared with Wild mice. EMSA showed that activation of early growth response gene-1, which induces the transcription of PDGF-BB and TGF-β1, was decreased in AT2-Tg mice. These changes in AT2-Tg mice at 12 wk after ⅚Nx were blocked by the AT2R antagonist PD-123319. Taken together, our findings suggest that AT2R-mediated signaling may protect from glomerular injuries induced by ⅚Nx and that overexpression of AT2R may serve as a potential therapeutic strategy for glomerular disorders.

scholarly journals Sestrin 2 Attenuates Rat Hepatic Stellate Cell (HSC) Activation and Liver Fibrosis via an mTOR/AMPK-Dependent Mechanism

2018 ◽  
Vol 51 (5) ◽  
pp. 2111-2122 ◽  
Author(s):  
Yi-Bing Hu ◽  
Xiao-Ting Ye ◽  
Qing-Qing Zhou ◽  
Rong-Quan Fu
Keyword(s):  
Liver Fibrosis ◽  
Protein Expression ◽  
Hepatic Fibrosis ◽  
Transforming Growth Factor ◽  
Histopathological Examination ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Mrna Levels ◽  
Alpha Smooth Muscle Actin

Background/Aims: Sestrin 2 is associated with the pathophysiology of several diseases. The aim of this study was to investigate the effects and potential mechanisms of Sestrin 2 in rat hepatic stellate cells (HSCs) during liver fibrogenesis. Methods: In this study, Sestrin 2 protein expression was detected in rat HSC-T6 cells challenged with transforming growth factor-β (TGF-β) and in mice treated with carbon tetrachloride (CCl4), a well-known model of hepatic fibrosis. Next, HSC-T6 cells and fibrotic mice were transfected with lentivirus. The mRNA expression levels of markers of liver fibrosis [alpha-smooth muscle actin (α-SMA) and collagen 1A1 (Col1A1)] were analyzed by quantitative reverse transcription–polymerase chain reaction (RT-PCR). Cell death and proliferation were evaluated by the MTT assay, and biochemical markers of liver damage in serum [alanine transaminase (ALT) and aspartate transaminase (AST)] were also measured using a biochemical analyzer. Histopathological examination was used to evaluate the degree of liver fibrosis, and protein expression [phospho-adenosine monophosphate-activated protein kinase (p-AMPK), AMPK, phospho-mammalian target of rapamycin (p-mTOR), and mTOR] was determined by western blotting. Results: We found that Sestrin 2 was elevated in both the HSC-T6 cell and hepatic fibrosis models. In vitro, overexpression of Sestrin 2 attenuated the mRNA levels of α-SMA and Col1A1, suppressed α-SMA protein expression, and modulated HSC-T6 cell proliferation. In vivo, overexpression of Sestrin 2 reduced the ALT and AST levels as well as the α-SMA and Col1A1 protein expression in the CCl4 model of liver fibrosis. Moreover, the degree of liver fibrosis was ameliorated. Interestingly, overexpression of Sestrin 2 increased p-AMPK but decreased p-mTOR protein expression. Conclusion: Our findings indicate that Sestrin 2 may attenuate the activation of HSCs and ameliorate liver fibrosis, most likely via upregulation of AMPK phosphorylation and suppression of the mTOR signaling pathway.

scholarly journals Inhibition of Smurf2 translation by miR-322/503 modulates TGF-β/Smad2 signaling and intestinal epithelial homeostasis

2014 ◽  
Vol 25 (8) ◽  
pp. 1234-1243 ◽  
Author(s):  
Shan Cao ◽  
Lan Xiao ◽  
Jaladanki N. Rao ◽  
Tongtong Zou ◽  
Lan Liu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cellular Responses ◽  
Mrna Levels ◽  
Intestinal Epithelial ◽  
Regulatory Factor ◽  
Epithelial Homeostasis ◽  
Repressive Effect ◽  
Single Binding Site

Smad ubiquitin regulatory factor 2 (Smurf2) is an E3 ubiquitin ligase that regulates transforming growth factor β (TGF-β)/Smad signaling and is implicated in a wide variety of cellular responses, but the exact mechanisms that control Smurf2 abundance are largely unknown. Here we identify microRNA-322 (miR-322) and miR-503 as novel factors that regulate Smurf2 expression posttranscriptionally. Both miR-322 and miR-503 interact with Smurf2 mRNA via its 3′-untranslated region (UTR) and repress Smurf2 translation but do not affect total Smurf2 mRNA levels. Studies using heterologous reporter constructs reveal a greater repressive effect of miR-322/503 through a single binding site in the Smurf2 3′-UTR, whereas point mutation of this site prevents miR-322/503–induced repression of Smurf2 translation. Increased levels of endogenous Smurf2 via antagonism of miR-322/503 inhibits TGF-β–induced Smad2 activation by increasing degradation of phosphorylated Smad2. Furthermore, the increase in Smurf2 in intestinal epithelial cells (IECs) expressing lower levels of miR-322/503 is associated with increased resistance to apoptosis, which is abolished by Smurf2 silencing. These findings indicate that miR-322/503 represses Smurf2 translation, in turn affecting intestinal epithelial homeostasis by altering TGF-β/Smad2 signaling and IEC apoptosis.

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