Baicalin confers hepatoprotective effect against alcohol-associated liver disease by upregulating microRNA-205
Introduction
Alcohol-associated liver disease (ALD) is a toxic disease caused by excessive alcohol consumption [1], [2]. ALD is a multifaceted disorder which often results in fat deposition, hepatic steatosis, hepatitis or inflammation [3]. Alcohol and accompanying metabolites including reactive oxygen species (ROS), activate and exacerbate the immune system, promoting immune cell activation in response to stimuli [4]. In addition, oxidative damage induces hepatocyte apoptosis which promotes the development of ALD [5].
Interestingly, baicalin, which is a traditional Chinese herbal medicine and refers to flavonoid compound extracted from Scutellaria baicalensis Georgi, has been indicated to possess promising therapeutic effects for ALD [6]. Moreover, recently reported studies have shown antioxidant, anti-inflammatory, antidiabetic, and antibacterial properties of baicalin in vitro and in vivo [7], [8]. Accumulating studies have verified that baicalin ameliorates alcohol-associated liver injury, alleviating damaged liver function and inhibiting hepatocyte apoptosis [9].
Difficulties in the development of novel targeted therapies for ALD are largely attributed to unclear knowledge of the molecular mechanisms which underpins this disease [10]. MicroRNAs (miRNAs or miRs) are a class of small noncoding RNAs well-known for participating in post-transcriptional regulation of gene expression [11]. Interestingly, multiple miRNAs have been associated with the etiopathogenesis and progress of ALD, including in key processes such as hepatocyte damage and disrupted lipid metabolism induced by alcohol [12]. Importantly, miR-205 has been documented to repress hepatocellular carcinoma cell invasion and metastasis, suggesting the promise of miR-205 for treating hepatocellular carcinoma [13]. Moreover, miR-205 has been implicated in the control of hepatic energy metabolism during the insulin resistance process [14]. However, the overexpression of miR-205 suppresses the lipid accumulation in non-alcoholic fatty liver disease (NAFLD) via targeting neuraminidase 1 (NEU1) [15]. Intriguingly, baicalin has been indicated to upregulate miR-205 to suppress the tumor necrosis factor-α (TNF-α)-induced apoptosis and dysfunction of the pancreatic β-cell line [16].
Moreover, in this study RAID database was used to predict the presence of binding sites between miR-205 and importinα5 in humans and mice. Expression of importinα5, a protein involved in p65 translocation to the nucleus, is reported to be elevated in Kupffer cells from ethanol-fed rats [17]. Importinα5 has been verified to be involved in the nuclear transfer of the nuclear factor-kappa B (NF-κB) signaling pathway [18]. Furthermore, a prior research manifested that baicalin protected Min6 cells against TNF-α-caused injury by upregulating miR-205, which functioned at least partially by blocking the NF-κB signaling pathway [16]. Additionally, it has been indicated that inactivation of the NF-κB signaling pathway can prevent alcohol-associated liver injury and inflammation [19]. Also, it was documented in a prior work that chronic alcohol-mediated cAMP reduction triggered macrophages to enhance lipopolysaccharide (LPS)-induced NF-κB activity, which was also associated with ALD [20]. The study was designed to investigate the potential molecular mechanisms behind the hepatoprotective effects of baicalin. We hypothesized that miR-205 and importinα5 are involved in baicalin-mediated protection against ALD by regulating the NF-κB signaling pathway.
Section snippets
Ethics statement
The human experiments were implemented under the ratification of Ethics Committee of China-Japan Friendship Hospital and conforming to principles in the Declaration of Helsinki. Patients or their guardians provided written informed consents. The animal experiments were conducted under the approval of the Animal Ethics Committee of China-Japan Friendship Hospital and in compliance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.
Collection of clinical plasma samples
The
Baicalin relieves ALD and upregulates miR-205 expression in liver tissues of ALD mice
Initially, we determined the expression of miR-205 in plasma samples collected from ALD patients and healthy controls through qRT-PCR, and a down-regulated plasma miR-205 level was identified in ALD (Fig. 1). Of note, Baicalin has previously been shown to protect against ALD [21]. Thus, we established a mouse model of ALD to further explore the role of Baicalin in relation to miR-205. ALD mice presented with down-regulated miR-205 expression relative to control mice, yet Baicalin treatment
Discussion
Although multiple studies have reported the hepatoprotective effects of baicalin, the molecular mechanisms underpinning these effects have remained unclear [26], [27]. The data presented here confirmed the inhibitory effect of baicalin on ALD development and began to unpick the pathways by which baicalin altered ALD. Due to the critical role in regulating the inflammation and oxidative stress, miRNAs have been suggested to be involved in the pathogenesis of ALD [28]. Concurrently, this study
Funding
This study was supported by Beijing Natural Science Foundation (No. 7202181), China-Japan Friendship Hospital Youth Science and Technology Excellence Project (No. 2015-QNYC-B-02), and the National Natural Science Foundation (No. 91729301; No. 81630103).
Data availability
The data and materials of the study can be obtained from the corresponding author upon request.
Author contributions
Shi-Yu Du and Long Fang designed the study. Hui-Fen Wang and Yan-Ming Chen collated the data, carried out data
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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