Adiponectin-derived active peptide ADP355 exerts anti-inflammatory and anti-fibrotic activities in thioacetamide-induced liver injury

Wang, Huafeng; Zhang, Huan; Zhang, Zimu; Huang, Biao; Cheng, Xixi; Wang, Dan; Gahu, Zha la; Xue, Zhenyi; Da, Yurong; Li, Daiqing; Yao, Zhi; Gao, Fei; Xu, Aimin; Zhang, Rongxin

doi:10.1038/srep19445

Cited by 53 publications

(57 citation statements)

References 47 publications

(78 reference statements)

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“…J. Morphol., 36(2):661-669, 2018. infiltration, and Macrophagocytus stellatus (Kupffer cells) proliferation were noticeable and identical to findings of Nada et al (2015) and Wang et al (2016a). Both inflammatory and Kupffer cells play a critical role in the regulation of liver inflammation (Wynn & Barron, 2010).…”

Section: Discussionsupporting

confidence: 70%

The Ameliorative Potential of Probiotics and/or Silymarin on Thioacetamide Induced Hepatotoxicity in Rats: Histological and Immunohistochemical Study

2018

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EMAM, M. A.; FAROUK, S. M. & ABDO, M. The ameliorative potential of probiotics and/or silymarin on thioacetamide induced hepatotoxicity in rats: histological and immunohistochemical study. Int. J. Morphol., 36(2): 661-669, 2018. SUMMARY: Thioacetamide (TAA) is one of the common fungicidal agents that induce liver injury varying from inflammation, necrosis, and fibrosis to cirrhosis. Many recent studies reported the beneficial effect of probiotics and silymarin on hepatotoxicity regardless the causative agents. Therefore, the present study aimed to evaluate the ameliorative role of probiotics and/or silymarin on TAA induced hepatotoxicity in rats via histological, and immunohistochemical methods. Twenty five male albino rats were used for this experiment and were divided into five groups (n=5 rats/group); group I acts as negative control, group II was orally administrated distilled water for six weeks, then injected with TAA (200 mg/kg b.wt./ 5 ml physiological saline/ I.P.) twice a week for another six weeks, group III was treated with probiotics at a dose of 135 mg/ kg b.wt. orally in drinking water daily for six weeks, then injected with TAA (dosage of group II), twice weekly for another six weeks, group IV was treated with silymarin at a dose of 200 mg/ kg b.wt orally 4 times per week for six weeks, then injected with TAA (dosage of group II), twice weekly for another six weeks and group V was treated with combination of both probiotics and silymarin, at the same dosage in groups III and IV respectively then injected with TAA (dosage of group II), twice weekly for another six weeks. Histologically, TAA induced hepatocytes degeneration, inflammatory cells infiltration, and pseudolobular parenchyma as well as, high apoptosis and low proliferation rates that were proved by immunohistochemical staining for caspase 3 and ki-67 respectively. Probiotics and/or silymarin improved the histological feature of hepatocytes, reduced apoptosis and stimulated proliferation. Based on these results, we concluded that the use of probiotics and silymarin combination ameliorates the hepatotoxic effect of TAA in rats more than the use of probiotics or silymarin alone. KEY WORDS: Thioacetamide; Probiotics; Silymarin; Liver; Histology; Immunohistochemistry. EMAM, M. A.; FAROUK, S. M. & ABDO, M. The ameliorative potential of probiotics and/or silymarin on thioacetamide induced hepatotoxicity in rats: histological and immunohistochemical study. EMAM, M. A.; FAROUK, S. M. & ABDO, M. The ameliorative potential of probiotics and/or silymarin on thioacetamide induced hepatotoxicity in rats: histological and immunohistochemical study.

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Section: Discussionsupporting

confidence: 70%

The Ameliorative Potential of Probiotics and/or Silymarin on Thioacetamide Induced Hepatotoxicity in Rats: Histological and Immunohistochemical Study

2018

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“…Adiponectin induces expression of aquaglyceroporin (known to be down-regulated in association with obesity) and inactivates HSCs [193]. Adiponectin-derived synthetic short peptide, ADP355, suppresses focal adhesion kinase (FAK) activity and TGFβ1/SMAD2 signaling and promotes AMPK and STAT3 signaling, and inactivates HSCs in mice [194, 195]. …”

Section: Mechanisms Of Hsc Activationmentioning

confidence: 99%

Hepatic stellate cells as key target in liver fibrosis

Higashi

Friedman

Hoshida

2017

Advanced Drug Delivery Reviews

1,036

894

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Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.

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“…[14][15][16] Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the most attractive targets for atherosclerosis and lipid management. 17 It is mainly produced by the liver and subsequently cleaved for secretion to circulation.…”

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confidence: 99%

Activation of Adiponectin Receptor Regulates Proprotein Convertase Subtilisin/Kexin Type 9 Expression and Inhibits Lesions in ApoE-Deficient Mice

Sun

Yang

et al. 2017

ATVB

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Objective— The reduced adiponectin levels are associated with atherosclerosis. Adiponectin exerts its functions by activating adiponectin receptor (AdipoR). Proprotein convertase subtilisin kexin type 9 (PCSK9) degrades LDLR protein (low-density lipoprotein receptor) to increase serum LDL-cholesterol levels. PCSK9 expression can be regulated by PPARγ (peroxisome proliferator–activated receptor γ) or SREBP2 (sterol regulatory element-binding protein 2). The effects of AdipoR agonists on PCSK9 and LDLR expression, serum lipid profiles, and atherosclerosis remain unknown. Approach and Results— At cellular levels, AdipoR agonists (ADP355 and AdipoRon) induced PCSK9 transcription/expression that solely depended on activation of PPAR-responsive element in the PCSK9 promoter. AdipoR agonists induced PPARγ expression; thus, the AdipoR agonist-activated PCSK9 expression/production was impaired in PPARγ deficient hepatocytes. Meanwhile, AdipoR agonists transcriptionally activated LDLR expression by activating SRE in the LDLR promoter. Moreover, AMP-activated protein kinase α (AMPKα) was involved in AdipoR agonist-activated PCSK9 expression. In wild-type mice, ADP355 increased PCSK9 and LDLR expression and serum PCSK9 levels, which was associated with activation of PPARγ, AMPKα and SREBP2 and reduction of LDL-cholesterol levels. In contrast, ADP355 reduced PCSK9 expression/secretion in apoE-deficient (apoE −/− ) mice, but it still activated hepatic LDLR, PPARγ, AMPKα, and SREBP2. More importantly, ADP355 inhibited lesions in en face aortas and sinus lesions in aortic root in apoE −/− mice with amelioration of lipid profiles. Conclusions— Our study demonstrates that AdipoR activation by agonists regulated PCSK9 expression differently in wild-type and apoE −/− mice. However, ADP355 activated hepatic LDLR expression and ameliorated lipid metabolism in both types of mice and inhibited atherosclerosis in apoE −/− mice.

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Adiponectin-derived active peptide ADP355 exerts anti-inflammatory and anti-fibrotic activities in thioacetamide-induced liver injury

Cited by 53 publications

References 47 publications

The Ameliorative Potential of Probiotics and/or Silymarin on Thioacetamide Induced Hepatotoxicity in Rats: Histological and Immunohistochemical Study

The Ameliorative Potential of Probiotics and/or Silymarin on Thioacetamide Induced Hepatotoxicity in Rats: Histological and Immunohistochemical Study

Hepatic stellate cells as key target in liver fibrosis

Activation of Adiponectin Receptor Regulates Proprotein Convertase Subtilisin/Kexin Type 9 Expression and Inhibits Lesions in ApoE-Deficient Mice

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