Autophagy inhibition attenuates the induction of anti-inflammatory effect of catalpol in liver fibrosis

doi:10.1016/j.biopha.2018.04.156

Biomedicine & Pharmacotherapy

Volume 103, July 2018, Pages 1262-1271

https://doi.org/10.1016/j.biopha.2018.04.156 Get rights and content

Highlights

•
Catalpol protected the liver against CCl₄-induced injury.
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Catalpol suppressed inflammation in the CCl₄-caused liver fibrosis in rats.
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Catalpol promoted autophagy in CCl₄-caused liver fibrosis in rats.
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Autophagy inhibition attenuates the induction of anti-inflammatory effect of Catalpol.

Abstract

Autophagy has been regarded as an inflammation-associated defensive mechanism against chronic liver disease, which has been highlighted as a novel therapeutic target for the treatment of liver fibrosis. We herein aimed to study the effects of catalpol on liver fibrosis in vivo and in vitro, and to elucidate the role of autophagy in catalpol-induced anti-inflammation. Catalpol protected the liver against CCl₄-induced injury, as evidenced by mitigated hepatic steatosis, necrosis, and fibrotic septa. Catalpol decreased the serum levels of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase and bilirubin as well as the liver/body weight ratio. Masson and sirius red staining along with hydroxyproline detection showed that catalpol decreased collagen deposition significantly compared to that of the model group. Catalpol inhibited CCl₄-induced liver fibrosis, manifested as decreased expressions of α-SMA, fibronectin and α1(I)-procollagen at both transcriptional and translational levels. Inflammatory factors, such as IL-1β, TNF-α, IL-18, IL-6 and COX-2, were significantly elevated in rats receiving CCl₄ and down-regulated by catalpol in a dose-dependent manner in vivo. Western blot and immunofluorescence assay revealed that catalpol activated the autophagy of rats with CCl₄-caused liver fibrosis, as indicated by up-regulation of LC3-II and beclin1 and down-regulation of P62. The results of in vitro experiments were consistent. Interestingly, inhibition or depletion of autophagy by LY294002 or Atg5 siRNA significantly attenuated catalpol-induced anti-inflammatory effects on activated hepatic stellate cells in vitro. In conclusion, catalpol relieved liver fibrosis mainly by inhibiting inflammation, and autophagy inhibition attenuated the catalpol-induced anti-inflammatory effect on liver fibrosis.

Graphical abstract

Schema of the underlying mechanism of catalpol in ameliorating CCl₄ induced liver fibrosis. CCl₄ treatment with rats induces the activation of autophagy and the accumulation of inflammatory factors in the liver, and catalpol could inhibit the expression of inflammatory factors by promoting autophagy. Using Atg5 siRNA or LY294002 to inhibit autophagy could attenuate the induction of anti-inflammatory effect of Catalpol in liver fibrosis.

Introduction

Hepatic fibrosis occurs in response to different etiologies of chronic liver injury, which is mainly accompanied by pathological diffusion of excessive extracellular matrix (ECM) of the liver, as the common reaction of multiple chronic liver diseases to liver cirrhosis [1,2]. Without effective management, liver fiber nodules are produced soon and normal liver structure and function are disrupted [3]. Therefore, hepatic fibrosis has become a major public health issue, and currently, effective anti-fibrotic strategies are still lacking in clinical practice.

Inflammation is involved in the pathophysiological process of liver fibrosis [[4], [5], [6]]. Fibrotic liver is in the inflammatory microenvironment and surrounded by different inflammatory factors [[7], [8], [9]]. In normal liver, pro- and anti-inflammatory factors are kept balanced, which is broken upon injury [10,11]. Hence, it is feasible to fight against liver fibrosis by suppressing inflammation. Zhang et al. reported that dihydroartemisinin(DHA) alleviated liver fibrosis by inhibiting the expressions of pro-inflammatory factors and promoting those of anti-inflammatory factors, and such process was dependent on activation of autophagy in vivo and in vitro [7]. Li et al. showed that quercetin mitigated liver fibrosis in mice through modulating of HMGB1-TLR2/4-NF-κB signaling pathways [12]. Autophagy mediates the regulation of inflammation and plays a key role in the pathophysiology of many human disorders including hepatic fibrosis [[13], [14], [15], [16]]. It directly suppresses proinflammatory complexes, and also indirectly allows efficient clearance of damaged organelles or intracellular pathogenic microorganisms that both constitute potent inflammatory stimuli [7,17]. Therefore, targeting autophagy may be able to combat liver fibrosis. Wang et al. found that 3-methyladenine, a selective type III phosphatidylinositol 3-kinase inhibitor, relieved liver fibrosis mainly through inhibiting the autophagy of hepatic stellate cells (HSCs) regulated by the NF-κB signaling pathways [13]. Besides, Zhang et al. showed that ROS-JNK1/2-dependent activation of autophagy was required to induce the anti-inflammatory effects of DHA on liver fibrosis [7]. In this study, we thus focused on the above two aspects.

CCl₄ is a commonly used carcinogen, not only anesthetizing effect on the central nervous system but also seriously damaging to the liver and kidney [18]. It has been widely used to induce liver injury or fibrosis in animals including rats [19,20]. Due to short experimental period and stability, the in vivo model of CCl₄-induced liver fibrosis was employed in this study. The key role of HSCs in liver fibrosis is well-documented [[21], [22], [23]]. HSCs activation is a critical process in the pathogenesis of liver fibrosis, because ECM deposit mainly originates from activated HSCs [24]. Therefore, PDGF-BB-activated HSCs were used herein to perform in vitro experiments.

Natural products have attracted worldwide attention and are now important sources for anti-fibrotic agents. Catalpol, an iridoid glycoside extracted from traditional Chinese medicine Rehmannia glutinosa, has anti-asthma [25], antioxidant, anti-inflammatory [26], antidiabetic [27,28], antitumor [29] and other remarkable pharmacological effects. However, its effects on liver fibrosis remain largely unknown. In this study, the in vitro and in vivo anti-fibrotic effects of catalpol were assessed for the first time. Meanwhile, the mechanisms were clarified by examining the expressions of autophagy associated proteins and inflammatory factors in vitro and in vivo. Finally, the influence of autophagy inhibition on the anti-inflammatory effects of catalpol on liver fibrosis was evaluated in vitro. A new mechanism by which catalpol resisted fibrosis was confirmed. By regulating autophagy-mediated inflammation, catalpol alleviated liver fibrosis in vivo and in vitro.

Section snippets

Chemicals and reagents

Catalpol (No. 2415-24-9, purity ≥ 99%) was purchased from Xi’an Helin Biological Engineering Co., Ltd. (Xi’an, China), and the examination report was provided as a supplementary data (Supplementary Fig. 1). Primary antibodies against α-SMA (14395-1-AP), fibronectin (15613-1-AP), α1(I)-procollagen (14695-1-AP), Beclin1(11306-1-AP), P62 (18420-1-AP), IL-18(10663-1-AP) and LC3(14600-1-AP) were purchased from Proteintech. IL-1β (12,703), TNF-α (6945), IL-6 (12,912), β-actin (4970) were obtained

Catalpol protected the liver from CCl₄-induced injury and suppressed hepatic fibrogenesis in the rat model

We first assessed the ameliorative effects of catalpol on hepatic injury in vivo. Morphological changes pathologically occurred in the rat liver injected with CCl₄ compared to the normal liver, which, however, were relieved by catalpol treatment (Fig. 1A). HE staining showed that catalpol treatment remarkably improved the liver pathology by mitigating hepatic steatosis, necrosis and fibrotic septa owing to CCl₄ injection (Fig. 1B). Abnormalities of some well-established biomarkers, such as

Discussion

Recent studies have highlighted inflammation and autophagy as novel targets for the treatment of liver fibrosis [7,14]. In this study, we demonstrated that catalpol protected the rat liver from CCl₄-caused injury and fibrogenesis in vivo and in vitro for the first time. In particular, inhibition of inflammation played an important role in mediating the protective effects of catalpol on CCl₄-induced injury and liver fibrosis. Notably, catalpol was a potent inducer of autophagy in vivo and in

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81703884; 81670243; 81403260); the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (No. 17KJB360012; 17KJB360015); Natural Science Foundation of Jiangsu Province (No. BK20140493; BK20151276); China Postdoctoral Science Foundation (No. 2014M551639); Postdoctoral Funding in Jiangsu Province (No.1401138C); The Technical Project of Yangzhou City(YZ2017090); Nantong University

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Wu et al. found that hispidulin enhanced autophagy and alleviated high glucose-induced podocyte apoptosis by inhibiting the Pim1-p21-mTOR signaling axis[123]. Catalpol is a natural iridoid glycoside compound extracted from the Rehmannia glutinosa, which has pharmacological activities, such as hypoglycemic, anti-inflammatory, and neuroprotective effects[85,130]. Chen et al. found that catalpol promoted TFEB nuclear translocation by inhibiting mTOR activity, ameliorated high glucose-induced podocyte autophagy inhibition, and attenuated podocyte injury[14].
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Citation Excerpt :
Rehmannia glutinosa is a traditional Chinese medicine which has been widely applied in clinical therapy (Bai et al., 2019). Catalpol (Fig. 1C), an iridoid glycoside, which is derived from Rehmannia glutinosa, exhibits a wide range of biological characters, such as anti-diabetic (Chen et al., 2020), anti-inflammatory (Liu et al., 2018) and neuroprotective effect (Yang et al., 2020). Additionally, it is well documented that catalpol possessed anti-tumor properties in gastric cancer cells (Wang and Zhan-Sheng, 2018), colon cancer cells (Qiao et al., 2020), bladder cancer cells (Jin et al., 2015), ovarian cancer cells (Yan et al., 2020), non-small-cell lung cancer (Wang et al., 2018) and osteosarcoma cancer cells (Wang and Xue, 2018).
Breast cancer is a fatal cancer with the highest mortality in female. New strategies for anti-breast cancer are still urgently needed. Catalpol, an iridoid glycoside extracted from the traditional Chinese medicinal plant Rehmannia glutinosa, has shown anticancer efficacy in various cancer cells. However, its effect on breast cancer remains unclear. In this study, we aim to investigate the anti-breast cancer activity of catalpol and elucidate its underlying mechanism. Cell counting kit-8 (CCK-8) and morphology change showed that catalpol could inhibit the proliferation and viability of MCF-7 cells. Catalpol administration reduced the tumor volume in xenograft model. Catalpol induced apoptosis in MCF-7 cells confirmed by Hoechst 33342 staining and Annexin V-FITC/PI double staining. In vivo, catalpol also induced apoptosis as seen from the increased level of terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) in tumor. According to JC-1 and Dichlorodi-hydrofluorescein Diacetate (DCFH-DA) staining, loss of mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) generation was found in MCF-7 cells treated with catalpol. Furthermore, catalpol also increased the level of cytoplasmic cytochrome c and activity of caspase-3 in MCF-7 cells. Likewise, histopathological and immunohistochemical (IHC) assay also found that catalpol enhanced the levels of cytochrome c and caspase-3 in breast cancer tissues. Ultimately, acetylation, 2-hydroxyisobutyrylation and lactylation were dramatically increased, whereas succinylation, malonylation and phosphorylation were markedly decreased in the breast cancer tumor treated with catalpol. Taken together, catalpol inhibited breast cancer in vitro and in vivo through induction of apoptosis via mitochondria apoptosis pathway and regulation of protein post-translational modifications (PTMs). Thus, it can be considered as an excellent candidate compound for treatment of breast cancer.
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¹: These authors contributed equally to these work.

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Autophagy inhibition attenuates the induction of anti-inflammatory effect of catalpol in liver fibrosis

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Chemicals and reagents

Catalpol protected the liver from CCl4-induced injury and suppressed hepatic fibrogenesis in the rat model

Discussion

Conflict of interest

Acknowledgements

Redox Biol.

Free Radical Bio. Med.

Toxicol. Lett.

Eur. J. Pharmacol.

Exp. Toxicol. Pathol.

Eur. J. Pharmacol.

Cell. Signal.

Eur. J. Pharm. Sci.

Int. Immunopharmacol.

Chin. Med.

Biomed. Pharmacother. Biomed. Pharmacother.

Biomed. Pharmacother. Biomed. Pharmacother.

J. Hepatol.

Toxicol. Lett.

Nat. Prod. Res.

Toxicol. Appl. Pharmacol.

Int. Immunopharm.

Biochim. Biophys. Acta

Life Sci.

J. Hepatol.

J. Hepatol.

Neurotoxicology

Curcumin attenuates angiogenesis in liver fibrosis and inhibits angiogenic properties of hepatic stellate cells

J. Cell. Mol. Med.

Liver fibrosis: a compilation on the biomarkers status and their significance during disease progression

Future Sci. OA

A20 attenuates liver fibrosis in NAFLD and inhibits inflammation responses

Inflammation

Tyrosine kinase inhibitor BIBF1120 ameliorates inflammation, angiogenesis and fibrosis in CCl4-induced liver fibrogenesis mouse model

Sci. Rep.

Catalpol protected the liver from CCl₄-induced injury and suppressed hepatic fibrogenesis in the rat model