Gardeniae Fructus Attenuates Thioacetamide-Induced Liver Fibrosis in Mice via Both AMPK/SIRT1/NF-κB Pathway and Nrf2 Signaling

Liver fibrosis, which means a sort of the excessive accumulation of extracellular matrices (ECMs) components through the liver tissue, is considered as tissue repair or wound-healing status. This pathological stage potentially leads to cirrhosis, if not controlled, it progressively results in hepatocellular carcinoma. Herein, we investigated the pharmacological properties and underlying mechanisms of Gardeniae Fructus (GF) against thioacetamide (TAA)-induced liver fibrosis of mice model. GF not only attenuated hepatic tissue oxidation but also improved hepatic inflammation. We further confirmed that GF led to ameliorating liver fibrosis by ECMs degradations. Regarding the possible underlying mechanism of GF, we observed GF regulated epigenetic regulator, Sirtuin 1 (SIRT1), in TAA-injected liver tissue. These alterations were well supported by SIRT1 related signaling pathways through regulations of its downstream proteins including, AMP-activated protein kinase (AMPK), p47phox, NADPH oxidase 2, nuclear factor erythroid 2–related factor 2 (Nrf2), and heme oxygenase-1, respectively. To validate the possible mechanism of GF, we used HepG2 cells with hydrogen peroxide treated oxidative stress and chronic exposure conditions via deteriorations of cellular SIRT1. Moreover, GF remarkably attenuated ECMs accumulations in transforming growth factor–β1-induced LX-2 cells relying on the SIRT1 existence. Taken together, GF attenuated liver fibrosis through AMPK/SIRT1 pathway as well as Nrf2 signaling cascades. Therefore, GF could be a clinical remedy for liver fibrosis patients in the future.

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Effect of nanopolysaccharide (BSEPS) from Bacillus subtilis sp. on thioacetamide-induced liver fibrosis in rats

Bulletin of the National Research Centre ◽

10.1186/s42269-019-0244-1 ◽

2019 ◽

Vol 43 (1) ◽

Author(s):

Manal G. Mahmoud ◽

Mohsen S. Asker ◽

Mohamed E. El Awady ◽

Amal I. Hassan ◽

Nadia A. R. Zaharan ◽

...

Keyword(s):

Bacillus Subtilis ◽

Liver Fibrosis ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Periodate Oxidation ◽

Hepatic Tissue ◽

Albino Rats ◽

Gamma Glutamyl Transferase ◽

Glutamyl Transferase ◽

Tgf Β1

Abstract Background Nanomedicine contributes to the efficiency of pharmacological treatments and progresses rapidly. The present study was designed to produce exopolysaccharide (BSEPS) from Bacillus subtilis sp. strain reported in our previous study was further characterized, and its BSEPS for synthesis of the nanoparticle Ag-BSEPS using microwave heating to determine the possible effects of a prepared solution containing Ag-BSEPS versus thioacetamide (TAA) evoked liver fibrosis in Wister albino rats. Nanoparticles with silver (Ag) core have been synthesized in an aqueous solution after exposure of BSEPS to periodate oxidation. Animals were split into four groups: I - control rats, water ad libitum for 6 weeks; II - rats were injected with TAA 200 mg/kg-1 3 times/week for 4 weeks IP; III - Ag-BSEPS 100 mg/kg-1 IP twice a week for 6 weeks; and IV - TAA, as group II followed by Ag-BSEPS as group III. The antifibrotic effects of Ag-BSEPS were appraised by determining different hepatotoxicity indices, oxidative stress, and inflammatory and liver fibrosis markers. Results Nanoparticles were obtained with a diameter size range of 50–100 nm characterized by SEM and TEM without using any harmful reagents. Results evinced considerably reduced activity of liver functions such as transaminases (AST, ALT), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP) in the group which received TAA followed by Ag-BSEPS compared to the other group which received only TAA. In the current results, the administration of Ag-BSEPS showed an improvement in the proinflammatory cytokines. On the contrary, the antioxidant enzymes in liver homogenates revealed significant improvement (concentration of glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), and catalase (CAT) increases) in animals with TAA-induced liver damage followed by Ag-BSEPS. Moreover, the activities of the fibrotic markers transforming growth factor-beta 1(TGF-β1) and type III pro-collagen (PCIII) were increased in liver tissues in the group which was given TAA alone as compared to the controls. The percentage of fibrosis of hepatic tissue had a positive correlation with the levels of PCIII and TGF-β1, followed by Ag-BSEPS compared to the TAA group without nanocomposite treatment. Microscopic examinations revealed inhibitory effects of Ag-BSEPS on inflammatory changes and deterrent of liver fibrosis. Conclusion It was suggested that the biochemical and histological amelioration observed in Ag-BSEPS (100 mg/kg-1 twice a week for 6 weeks) treated the fibrotic rats.

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Specificity protein 1 and Smad-dependent regulation of human heme oxygenase-1 gene by transforming growth factor-β1 in renal epithelial cells

AJP Renal Physiology ◽

10.1152/ajprenal.00519.2006 ◽

2007 ◽

Vol 293 (3) ◽

pp. F885-F894 ◽

Cited By ~ 16

Author(s):

Amie Traylor ◽

Thomas Hock ◽

Nathalie Hill-Kapturczak

Keyword(s):

Growth Factor ◽

Heme Oxygenase ◽

Transforming Growth Factor ◽

Tissue Injury ◽

Transforming Growth Factor Β1 ◽

Molecular Regulation ◽

Heme Oxygenase 1 ◽

Specificity Protein 1 ◽

Specificity Protein ◽

Tgf Β1

Excess transforming growth factor-β1 (TGF-β1) in the kidney leads to increased cell proliferation and deposition of extracellular matrix, resulting in progressive kidney fibrosis. TGF-β1, however, stabilizes and attenuates tissue injury through the activation of cytoprotective proteins, including heme oxygenase-1 (HO-1). HO-1 catabolizes pro-oxidant heme into substances with anti-oxidant, anti-apoptotic, anti-fibrogenic, vasodilatory and immune modulatory properties. Little is known regarding the molecular regulation of human HO-1 induction by TGF-β1 except that it is dependent on de novo RNA synthesis and requires a group of structurally related proteins called Smads. It is not known whether other DNA binding proteins are required to initiate transcription of HO-1 and, furthermore, the promoter region(s) involved in TGF-β1-mediated induction of HO-1 has not been identified. The purpose of this study was to further delineate the molecular regulation of HO-1 by TGF-β1 in human renal proximal tubular cells. Actinomycin D and nuclear run-on studies demonstrate that TGF-β1 augments HO-1 expression by increased gene transcription and does not involve increased mRNA stability. Using transient transfection, mithramycin A, small interfering RNA, electrophoretic mobility shift assays, and decoy oligonucleotide experiments, a TGF-β1-responsive region is identified between 9.1 and 9.4 kb of the human HO-1 promoter. This ∼280-bp TGF-β1-responsive region contains a putative Smad binding element and specificity protein 1 binding sites, both of which are required for human HO-1 induction by TGF-β1.

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Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice

Biology ◽

10.3390/biology10020082 ◽

2021 ◽

Vol 10 (2) ◽

pp. 82

Author(s):

Isabela A. Finamor ◽

Caroline A. Bressan ◽

Isabel Torres-Cuevas ◽

Sergio Rius-Pérez ◽

Marcelo da Veiga ◽

...

Keyword(s):

Liver Fibrosis ◽

Liver Damage ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Elevated Serum ◽

Inflammasome Activation ◽

Related Factor ◽

Type I ◽

Artificial Sweetener

Background: Aspartame is an artificial sweetener used in foods and beverages worldwide. However, it is linked to oxidative stress, inflammation, and liver damage through mechanisms that are not fully elucidated yet. This work aimed to investigate the effects of long-term administration of aspartame on the oxidative and inflammatory mechanisms associated with liver fibrosis progression in mice. Methods: Mice were divided into two groups with six animals each: control and aspartame. Aspartame (80 mg/kg, via oral) or vehicle was administrated for 12 weeks. Results: Aspartame caused liver damage and elevated serum transaminase levels. Aspartame also generated liver fibrosis, as evidenced by histology analysis, and pro-fibrotic markers’ upregulation, including transforming growth factor β 1, collagen type I alpha 1, and alpha-smooth muscle actin. Furthermore, aspartame reduced nuclear factor erythroid 2-related factor 2 (Nrf2) activation and enzymatic antioxidant activity and increased lipid peroxidation, which triggered NOD-like receptor containing protein 3 (NLRP3) inflammasome activation and p53 induction. Furthermore, aspartame reduced peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) levels, possibly through p53 activation. This PGC-1α deficiency could be responsible for the changes in lipid profile in serum, total lipid accumulation, and gluconeogenesis impairment in liver, evidenced by the gluconeogenic enzymes’ downregulation, thus causing hypoglycemia. Conclusions: This work provides new insights to understand the mechanisms related to the adverse effects of aspartame on liver tissue.

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Abstract 3054: Comparison of Transforming Growth Factor-β1 Expression in Aortic Wall of Thoracic Aortic Aneurysm Versus Dissection

Circulation ◽

10.1161/circ.116.suppl_16.ii_684-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Shouguo Yang ◽

Guanggen Cui ◽

Ramin Beygui ◽

Fardad Esmailian ◽

Abbas Ardehali ◽

...

Keyword(s):

Aortic Aneurysm ◽

Thoracic Aortic Aneurysm ◽

Aortic Wall ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Underlying Mechanism ◽

Transforming Growth Factor Β1 ◽

Fluorescent Intensity ◽

Nucleus Density ◽

Tgf Β1

Background The underlying mechanism of thoracic aortic aneurysm (TAA) and dissection(TAD) was undetermined, and one controversy lies in whether they represent the different dvelopement period of the same disorder or totally diferent diseases. This study is in aim to compare the expression and distribution of Transforming Growth Factors(TGF) β1 in the aortic wall of TAA versus TAD patients. Method Aortic specimens were obtained from patients underwent to aortic procedures for TAA (n=38) and TAD (n=20) at UCLA , and control aorta (CN) from organ donnor (n=20). Double immunofluorescent stainning of TGF-β1 and α-smooth muscle actin were performed with paraffin embeded slides for all aortic samples and semiquantified by fluorescent intensity analysis. Histopathologic examination were performed with HE, Verhoeff van-Gieson and Masson’s trichrome stain. Results TAA and TAD patients exhibited an up-regulation of TGF-β1 to 120.3% and 109.6% compared with CN separately (P<0.05), with TAA higher than TAD (P<0.05). TGF-β1 distributed unevenly across aortic wall with the highest levels expression in tunica media, followed by intima then adventitia. In intima, TGF-β1 was expressed at the same level for TAD as CN, but was increased to 115.2% for TAA compared to CN (P<0.05). In media, TGF-β1 increased by 127.2% in TAA and 116.1% in TAD compared to CN (P<0.01), with TAA being higher than TAD (P<0.05). In adventitia, TGF- β1 was up-regulated to 119.6% and 116.7% for TAA and TAD compared to CN (P<0.05). Nucleus density analysis showed cellular plasia in adventitia of TAA and TAD than CN (P<0.05 ), while TAD patients demonstrated a higher nucleus density than TAA in intima and adventitia (P<0.05). α-actin was increased in media of TAA and TAD to 164.5% and 120% than CN (P<0.01 and P<0.05). Attenuated and interrupted elastin and mild to severe cystic medial degeneration were characteristic histopathologic finding in 29 (76.3%) TAA and 17(85%) TAD patients. Conclusions TGF- β1 expression was up-regulated in aortic wall of TAA and TAD compared to CN. The significant higher levels of TGF- β1 in intima and media in TAA versus TAD patients implicated a probable positive effect of TGF- β1 to maintain aortic wall integrity, and/or greater comsamption of TGF- β1 in the aortic dissection.

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Targeting ER protein TXNDC5 in hepatic stellate cell mitigates liver fibrosis by repressing non-canonical TGFβ signalling

Gut ◽

10.1136/gutjnl-2021-325065 ◽

2021 ◽

pp. gutjnl-2021-325065

Author(s):

Chen-Ting Hung ◽

Tung-Hung Su ◽

Yen-Ting Chen ◽

Yueh-Feng Wu ◽

You-Tzung Chen ◽

...

Keyword(s):

Extracellular Matrix ◽

Liver Fibrosis ◽

Liver Injury ◽

Transforming Growth Factor ◽

Stellate Cell ◽

Transforming Growth Factor Β1 ◽

Duct Ligation ◽

Extracellular Matrix Production ◽

Matrix Production

Background and objectivesLiver fibrosis (LF) occurs following chronic liver injuries. Currently, there is no effective therapy for LF. Recently, we identified thioredoxin domain containing 5 (TXNDC5), an ER protein disulfide isomerase (PDI), as a critical mediator of cardiac and lung fibrosis. We aimed to determine if TXNDC5 also contributes to LF and its potential as a therapeutic target for LF.DesignHistological and transcriptome analyses on human cirrhotic livers were performed. Col1a1-GFPTg, Alb-Cre;Rosa26-tdTomato and Tie2-Cre/ERT2;Rosa26-tdTomato mice were used to determine the cell type(s) where TXNDC5 was induced following liver injury. In vitro investigations were conducted in human hepatic stellate cells (HSCs). Col1a2-Cre/ERT2;Txndc5fl/fl (Txndc5cKO) and Alb-Cre;Txndc5fl/fl (Txndc5Hep-cKO) mice were generated to delete TXNDC5 in HSCs and hepatocytes, respectively. Carbon tetrachloride treatment and bile duct ligation surgery were employed to induce liver injury/fibrosis in mice. The extent of LF was quantified using histological, imaging and biochemical analyses.ResultsTXNDC5 was upregulated markedly in human and mouse fibrotic livers, particularly in activated HSC at the fibrotic foci. TXNDC5 was induced by transforming growth factor β1 (TGFβ1) in HSCs and it was both required and sufficient for the activation, proliferation, survival and extracellular matrix production of HSC. Mechanistically, TGFβ1 induces TXNDC5 expression through increased ER stress and ATF6-mediated transcriptional regulation. In addition, TXNDC5 promotes LF by redox-dependent JNK and signal transducer and activator of transcription 3 activation in HSCs through its PDI activity, activating HSCs and making them resistant to apoptosis. HSC-specific deletion of Txndc5 reverted established LF in mice.ConclusionsER protein TXNDC5 promotes LF through redox-dependent HSC activation, proliferation and excessive extracellular matrix production. Targeting TXNDC5, therefore, could be a potential novel therapeutic strategy to ameliorate LF.

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OL-004 Suppression of liver fibrosis is associated with the decrease of transforming growth factor-β1 and increase of matrix metalloproteinase-1 expression after interferon-α therapy in chronic hepatitis C patients

International Journal of Infectious Diseases ◽

10.1016/s1201-9712(09)60333-7 ◽

2009 ◽

Vol 13 ◽

pp. S32

Author(s):

Yun-ru Li

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C ◽

Growth Factor ◽

Liver Fibrosis ◽

Matrix Metalloproteinase ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Interferon Α ◽

Matrix Metalloproteinase 1 ◽

Chronic Hepatitis C Patients

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Transforming growth factor-β1 up-regulates connexin43 expression in osteocytes via canonical Smad-dependent signaling pathway

Bioscience Reports ◽

10.1042/bsr20181678 ◽

2018 ◽

Vol 38 (6) ◽

Cited By ~ 8

Author(s):

Wenjing Liu ◽

Yujia Cui ◽

Jianxun Sun ◽

Linyi Cai ◽

Jing Xie ◽

...

Keyword(s):

Growth Factor ◽

Connexin 43 ◽

Transforming Growth Factor ◽

Bone Cells ◽

Underlying Mechanism ◽

Transforming Growth Factor Β1 ◽

Type I ◽

Gap Junctional Intercellular Communication ◽

Cx43 Expression ◽

Tgf Β1

Connexin 43 (Cx43)-mediated gap junctional intercellular communication (GJIC) has been shown to be important in regulating multiple functions of bone cells. Transforming growth factor-β1 (TGF-β1) exhibited controversial effects on the expression of Cx43 in different cell types. To date, the effect of TGF-β1 on the Cx43 expression of osteocytes is still unknown. In the present study, we detected the expression of TGF-β1 in osteocytes and bone tissue, and then used recombinant mouse TGF-β1 to elucidate its effect on gap junctions (GJs) of osteocytes. Our data indicated that TGF-β1 up-regulated both mRNA and protein expression of Cx43 in osteocytes. Together with down-regulation of Cx43 expression after being treated with TGF-β type I receptor inhibitor Repsox, we deduced that TGF-β1 can positively regulate Cx43 expression in osteocytes. Thus we next focussed on the downstream signals of TGF-β and found that TGF-β1-mediated smads, Smad3 and Smad4, to translocate into nucleus. These translocated signal proteins bind to the promoter of Gja1 which was responsible for the changed expression of Cx43. The present study provides evidence that TGF-β1 can enhance GJIC between osteocytes through up-regulating Cx43 expression and the underlying mechanism involved in the activation of Smad-dependent pathway.

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Crocin attenuates CCl4-induced liver fibrosis via PPAR-γ mediated modulation of inflammation and fibrogenesis in rats

Human & Experimental Toxicology ◽

10.1177/0960327120937048 ◽

2020 ◽

Vol 39 (12) ◽

pp. 1639-1649 ◽

Cited By ~ 1

Author(s):

J Chhimwal ◽

S Sharma ◽

P Kulurkar ◽

V Patial

Keyword(s):

Liver Fibrosis ◽

Liver Tissue ◽

Transforming Growth Factor ◽

Liver Enzymes ◽

Pathological Condition ◽

Smooth Muscle Actin ◽

Intraperitoneal Administration ◽

Crocus Sativus ◽

Mrna Levels ◽

Ppar Γ

Background: Liver fibrosis is a chronic pathological condition with a leading cause of liver-related mortality worldwide. In the present study, we have evaluated the antifibrotic effect of crocin, a carotenoid present in the stigma of Crocus sativus, and also explored its putative mechanism of action. Methods: Liver fibrosis was induced by intraperitoneal administration of 30% carbon tetrachloride (CCl4). The crocin was administered orally at 20, 40 and 80 mg/kg body weight along with CCl4 up to 8 weeks. Results: Chronic exposure to CCl4 resulted in elevated levels of liver enzymes and reduced cytochrome P450 2E1 (CYP2E1) activity in the liver. The liver tissue showed cellular swelling, vacuolization, necrosis, infiltration of inflammatory cells and fibrotic changes. The crocin treatment significantly lowered the levels of liver enzymes in serum and improved the liver CYP2E1 mRNA levels. The pathological changes in the liver were also lowered by crocin treatment. The level of pro-inflammatory cytokines, nuclear factor-kappa B, interleukin-6 and tumor necrosis factor α and fibrogenic factor, transforming growth factor β, and α-smooth muscle actin were elevated by the CCl4 in the liver tissue. However, crocin treatment at different doses significantly reduced the expression of these factors. The increased caspase 3/7 activity was also lowered by crocin. CCl4 administration decreased the expression of peroxisome proliferator-activated receptor γ (PPAR-γ) in liver tissue. The improved PPAR-γ expression in the liver by crocin treatment indicates its role in the therapeutic effect of crocin. Conclusions: Crocin attenuated the various events in the progression of liver fibrosis via PPAR-γ mediated modulation of inflammatory and fibrogenic pathways.

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