Hydroxysafflor Yellow A Attenuates Carbon Tetrachloride-Induced Hepatic Fibrosis in Rats by Inhibiting Erk5 Signaling

2012 ◽  
Vol 40 (03) ◽  
pp. 481-494 ◽  
Author(s):  
Ying-Bo Zhang ◽  
Han-Ying Dong ◽  
Xue-Ming Zhao ◽  
Li Fan ◽  
Yu Zou ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Messenger Rna ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Sprague Dawley ◽  
Hydroxysafflor Yellow A ◽  
Sprague Dawley Rats ◽  
Polymerase Chain

Hepatic stellate cells (HSCs) undergo activation during the development of liver fibrosis. Transcription factor myocyte enhancer factor (MEF2) 2C plays a key role in this process. In the present study, we investigated the effect of hydroxysafflor yellow A (HSYA) on hepatic fibrosis and further investigated potential mechanisms in vivo. Sprague-Dawley rats were administered with CCl4 together with or without HYSA for 12 weeks. The effect of HYSA on hepatic fibrosis was evaluated using hematoxylin-eosin and Van Gieson staining. Messenger RNA expression was quantified by real-time polymerase chain reaction, and protein was quantified by Western blot or immunohistochemistry. Our results revealed that CCl4 treatment induced micronodular hepatic fibrosis with a pronounced deposition of collagen fibers. Treatment with HYSA resulted in a significant decrease in fibrosis, protein expression of α-SMA, and MEF-2C gene expression. This was accompanied by a decreased expression of Tβ-RI, Tβ-RII, MEKK3, MEK5, and phosphorylation of ERk5. HYSA alone had no effect on the measured parameters. Our findings demonstrate that HSYA protected, at least in part, the rat liver from CCl 4-caused fibrogenesis through inhibition of hepatic stellate cell (HSC) activation, attenuation of transforming growth factor beta (TGF-β) signaling. HSYA may become a novel and promising agent for the inhibition of hepatic fibrosis.

scholarly journals Sedum sarmentosum Total Flavonoids Alleviate Schistosomiasis-Induced Liver Fibrosis by Altering TGF-β1 and Smad7 Expression

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Peng-chun Yang ◽  
Wei-zhe Bai ◽  
Jing Wang ◽  
Cai-hua Yan ◽  
Wei-feng Huang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Protein Expression ◽  
Hepatic Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Schistosomiasis Japonica ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Tgf Β1 ◽  
Liver Tissues

Objectives. Schistosomiasis is a parasitic disease that affects over 142 million people worldwide. The main causes of death of schistosomiasis include liver granuloma and secondary hepatic cirrhosis resulting from severe fibrosis. Despite intensive research, controlling liver fibrosis associated with schistosomiasis remains challenging. Sedum sarmentosum total flavonoid (SSTF) is a promising agent to reduce liver fibrosis with an unknown mechanism. Thus, the objectives of this study are to validate its effect on the liver fibrosis caused by schistosomiasis and to explore the underlying molecular mechanism. Methods. Sixty male Sprague-Dawley rats were randomly divided into six groups: one group of normal control and five groups of liver fibrosis induced by schistosomiasis japonica with or without SSTF or colchicine treatment, the latter serving as the positive control. Liver tissues from each animal were harvested to observe the degree and grade of hepatic fibrosis. We also measured the expression of transforming growth factor-beta 1 (TGF-β1) and Smad7 using RT-qPCR, Western blot, and immunohistochemistry. Results. Compared with the untreated model group, groups treated with SSTF at all three tested doses had significantly reduced hepatic fibrosis ( P < 0.05 ). Each dose of SSTF also significantly reduced TGF-β1 protein expression and mRNA levels in the liver tissues ( P < 0.05 ). In contrast, the middle and high doses of SSTF significantly increased Smad7 protein expression and mRNA levels ( P < 0.05 ). Immunohistochemistry showed that each dose of SSTF reduced TGF-β1 protein expression ( P < 0.05 ). Conclusion. Our results demonstrated that SSTF alleviated schistosomiasis japonica-induced hepatic fibrosis by inhibiting the TGF-β1/Smad7 pathway.

Tissue hypoxygenation activates the adrenomedullin system in vivo

2000 ◽  
Vol 278 (2) ◽  
pp. R513-R519 ◽  
Author(s):  
Karl-Heinz Hofbauer ◽  
Boye L. Jensen ◽  
Armin Kurtz ◽  
Peter Sandner
Keyword(s):  
Intracellular Signaling ◽  
Messenger Rna ◽  
Rnase Protection Assay ◽  
Tissue Hypoxia ◽  
Mrna Abundance ◽  
Sprague Dawley ◽  
Rnase Protection ◽  
Sprague Dawley Rats ◽  
Intracellular Signaling Cascade

Our study aimed to investigate the influence of tissue hypoxygenation on the adrenomedullin (ADM) system in vivo. For this purpose, male Sprague-Dawley rats were exposed to normobaric hypoxia (8% oxygen) or to functional anemia [0.1% carbon monoxide (CO)] or to cobalt chloride (60 mg/kg) for 6 h. Messenger RNA levels for ADM and its receptor (ADM-R) were assessed in diverse organs by RNase protection assay. Additionally, ADM protein concentrations in these organs, as in plasma, were determined by a RIA. We found that ADM mRNA abundance increased in response to hypoxia and to CO inhalation up to 15-fold in all organs examined. Similarly, ADM-R mRNA abundance increased during hypoxia and CO inhalation in all organs examined with exception of the liver. The effects of hypoxia and of CO inhalation on ADM and ADM-R mRNAs were mimicked by injection of cobaltous chloride. Hypoxia also significantly increased ADM protein content in all organs, and plasma levels of ADM rose twofold in response to hypoxia and CO inhalation. These findings indicate that tissue hypoxia leads to a widespread activation of the ADM system, which comprises a parallel stimulation of ADM and ADM receptor mRNA as enhanced ADM protein synthesis and secretion. The ADM system may, therefore, play a significant role in the physiological response to tissue hypoxia. It appears that ADM and ADM-R belong to the family of classic oxygen-regulated genes, which are activated by a decrease of the pericellular oxygen tension through the same intracellular signaling cascade.

scholarly journals Human Liver Stem Cell-Derived Extracellular Vesicles Target Hepatic Stellate Cells and Attenuate Their Pro-fibrotic Phenotype

2021 ◽  
Vol 9 ◽  
Author(s):  
Giulia Chiabotto ◽  
Elena Ceccotti ◽  
Marta Tapparo ◽  
Giovanni Camussi ◽  
Stefania Bruno
Keyword(s):  
Stem Cells ◽  
Hepatic Fibrosis ◽  
Extracellular Vesicles ◽  
Transforming Growth Factor Beta ◽  
Hepatic Stellate Cells ◽  
Human Liver ◽  
Adult Stem Cells ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Stellate Cells

Liver fibrosis occurs in response to chronic liver injury and is characterized by an excessive deposition of extracellular matrix. Activated hepatic stellate cells are primarily responsible for this process. A possible strategy to counteract the development of hepatic fibrosis could be the reversion of the activated phenotype of hepatic stellate cells. Extracellular vesicles (EVs) are nanosized membrane vesicles involved in intercellular communication. Our previous studies have demonstrated that EVs derived from human liver stem cells (HLSCs), a multipotent population of adult stem cells of the liver with mesenchymal-like phenotype, exert in vivo anti-fibrotic activity in the liver. However, the mechanism of action of these EVs remains to be determined. We set up an in vitro model of hepatic fibrosis using a human hepatic stellate cell line (LX-2) activated by transforming growth factor-beta 1 (TGF-β1). Then, we investigated the effect of EVs obtained from HLSCs and from human bone marrow-derived mesenchymal stromal cells (MSCs) on activated LX-2. The incubation of activated LX-2 with HLSC-EVs reduced the expression level of alpha-smooth muscle actin (α-SMA). Conversely, MSC-derived EVs induced an increase in the expression of pro-fibrotic markers in activated LX-2. The analysis of the RNA cargo of HLSC-EVs revealed the presence of several miRNAs involved in the regulation of fibrosis and inflammation. Predictive target analysis indicated that several microRNAs (miRNAs) contained into HLSC-EVs could possibly target pro-fibrotic transcripts. In particular, we demonstrated that HLSC-EVs shuttled miR-146a-5p and that treatment with HLSC-EVs increased miR-146a-5p expression in LX-2. In conclusion, this study demonstrates that HLSC-EVs can attenuate the activated phenotype of hepatic stellate cells and that their biological effect may be mediated by the delivery of anti-fibrotic miRNAs, such as miR-146a-5p.

scholarly journals The Expression of BNP, ET-1, and TGF-β1 in Myocardium of Rats with Ventricular Arrhythmias

2019 ◽  
Vol 20 (23) ◽  
pp. 5845 ◽  
Author(s):  
Tian ◽  
Xiao ◽  
Xue ◽  
Zhang ◽  
Jia ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Quantitative Polymerase Chain Reaction ◽  
Type I ◽  
Rat Myocardium ◽  
Novel Biomarkers ◽  
Growth Factor Beta ◽  
Polymerase Chain ◽  
Tgf Β1

Ventricular arrhythmia (VA) is a major component of sudden cardiac death (SCD). To investigate the expression of brain natriuretic peptide (BNP), endothelin-1 (ET-1), and transforming growth factor-beta 1 (TGF-β1) during VA, we established a rat model of VA induced by BaCl2 solution through a microinjector pump. PD142893 (ET-1 receptor blocker) and SB431542 (TGF-β1 receptor type I blocker) were used to explore the effect of ET-1 and TGF-β1 on BNP expression in the myocardium after VA. BNP, ET-1, and TGF-β1 in rat myocardium were assayed by western blot and immunohistochemical staining for proteins, and real-time quantitative polymerase chain reaction for mRNAs. We found increased expression of BNP and ET-1 in rat myocardium that was associated with the duration of VA. However, TGF-β1 protein expression remained unchanged. Such early increases in BNP and ET-1 may be attributed to fatal arrhythmias associated with SCD, suggesting these may be novel biomarkers of this disease. After intraperitoneal injection of PD142893 and SB431542, respectively, BNP was downregulated in the myocardium of the left ventricle; however, this was abrogated by co-application of the two inhibitors. These results suggested that both ET-1 and TGF-β1, by specifically binding to their receptors, might be involved in the myocardial synthesis of BNP during VA in vivo.

A traditional formula, Chunggan extract, attenuates thioacetamide-induced hepatofibrosis via GSH system in rats

2010 ◽  
Vol 30 (9) ◽  
pp. 1322-1332 ◽  
Author(s):  
Kyeong-Gue Kwak ◽  
Jing-Hua Wang ◽  
Jang-Woo Shin ◽  
Dong-Soo Lee ◽  
Chang-Gue Son
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Sprague Dawley ◽  
Necrosis Factor Alpha ◽  
Antifibrotic Effect ◽  
Sprague Dawley Rats ◽  
Tnf Α ◽  
Factor Alpha ◽  
Per Oral ◽  
Oxide Synthase

Chunggan extract (CGX) is a hepatotherapeutic herbal formula which has been traditionally used for patients suffering from various hepatic disorders. This study aimed to elucidate antifibrotic effect and mechanisms of CGX in thioacetamide (TAA) model. Hepatic fibrosis was induced in 45 Sprague-Dawley rats by TAA (200 mg kg–1, intraperitoneally [ip]) on twice per week for 12 weeks. CGX (100 or 200 mg kg–1, per oral [po]) was administrated once a day throughout the experiment. CGX treatment ameliorated serum biomarkers. CGX administration significantly attenuated distortion of histopathologic finding, and accumulation of hydroxyproline and malondialdehyde (MDA). CGX treatment significantly decreased transforming growth factor-beta (TGF-β) concentrations and inactivated hepatic stellate cells (HSCs). CGX treatment drastically restored glutathione (GSH) system, while inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α) significantly down-regulated in liver tissue. CGX showed antifibrotic effect in thioacetamide-induced chronic liver injury model. Its corresponding mechanisms may be mediated via anti-oxidative stress property sustaining GSH system and inhibition of ROS production.

Toxicokinetic and Genotoxicity Study of NNK in Male Sprague-Dawley Rats Following Nose-Only Inhalation Exposure, Intraperitoneal Injection, and Oral Gavage

2021 ◽  
Author(s):  
Shu-Chieh Hu ◽  
Matthew S Bryant ◽  
Estatira Sepehr ◽  
Hyun-Ki Kang ◽  
Raul Trbojevich ◽  
...  
Keyword(s):  
Human Lung ◽  
Inhalation Exposure ◽  
Systemic Exposure ◽  
Sprague Dawley ◽  
Oral Gavage ◽  
Sd Rats ◽  
New Information ◽  
Sprague Dawley Rats ◽  
Tissue Specimens

Abstract The tobacco-specific nitrosamine NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] is found in tobacco products and tobacco smoke. NNK is a potent genotoxin and human lung carcinogen; however, there are limited inhalation data for the toxicokinetics (TK) and genotoxicity of NNK in vivo. In the present study, a single dose of 5x10−5, 5x10−3, 0.1, or 50 mg/kg body weight (BW) of NNK, 75% propylene glycol (vehicle control), or air (sham control) was administered to male Sprague-Dawley (SD) rats (9-10 weeks age) via nose-only inhalation (INH) exposure for 1 hour. For comparison, the same doses of NNK were administered to male SD rats via intraperitoneal (IP) injection and oral gavage (PO). Plasma, urine, and tissue specimens were collected at designated timepoints and analyzed for levels of NNK and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and tissue levels of DNA adduct O6-methylguanine by LC/MS/MS. TK data analysis was performed using a non-linear regression program. For the genotoxicity subgroup, tissues were collected at 3 hours post-dosing for comet assay analysis. Overall, the TK data indicated that NNK was rapidly absorbed and metabolized extensively to NNAL after NNK administration via the three routes. The IP route had the greatest systemic exposure to NNK. NNK metabolism to NNAL appeared to be more efficient via INH than IP or PO. NNK induced significant increases in DNA damage in multiple tissues via the three routes. The results of this study provide new information and understanding of the toxicokinetics and genotoxicity of NNK.

scholarly journals Effect of valproic acid on functional bleb morphology in a rabbit model of minimally invasive surgery

2021 ◽  
pp. bjophthalmol-2020-318691
Author(s):  
Zhu Li Yap ◽  
Li-Fong Seet ◽  
Stephanie WL Chu ◽  
Li Zhen Toh ◽  
Farah Ilyana Ibrahim ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Cell Growth ◽  
Minimally Invasive ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Rabbit Model ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Label Free ◽  
Collagen Fibres

AbstractPurposeTo determine the effect of valproic acid (VPA) on bleb morphology and scar characteristics in a rabbit model of minimally invasive glaucoma surgery (MIGS).MethodsNine New Zealand white rabbits were subjected to MIGS with intraoperative implantation of the PreserFlo MicroShunt. Rabbits were then administered with subconjunctival injections of phosphate buffered saline (PBS) (n=4) or with VPA (n=5). Bleb morphology was examined by slit-lamp biomicroscopy and in vivo confocal microscopy. Postoperative day 28 tissues were examined by immunohistochemical evaluation and label-free multiphoton microscopy to visualise the collagen matrix, by terminal deoxynucleotidyl transferase dUTP nick-end labelling assay and immunofluorescent labelling for Ki67 expression to detect apoptosis and cell growth, and by real-time quantitative PCR to measure Col1a1, Fn, and Smad6 transcript expression.ResultsVPA-treated blebs were detectable on day 28, while the PBS-treated blebs were not detectable by day 14. VPA-treated blebs were diffuse, extended posteriorly with near normal conjunctival vascularity and featured a combination of reticular/blurred stromal pattern with evidence of relatively large stromal cysts. Instead of the deposition of thick, disorganised collagen fibres characteristic of the PBS bleb, the VPA bleb contained conspicuously thinner collagen fibres which were associated with similarly thinner fibronectin fibres. In corroboration, Col1a1 and Fn mRNA expression was reduced in the VPA blebs, while increased Smad6 expression implicated the disruption of the transforming growth factor beta pathway. Apoptosis and cell growth profiles appeared similar with both treatments.ConclusionsThe results support the application of VPA to enhance bleb morphology associated with good bleb function in MIGS with no apparent cytotoxicity.

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