A bioinformatic and mechanistic study elicits the antifibrotic effect of ursolic acid through the attenuation of oxidative stress with the involvement of ERK, PI3K/Akt, and p38 MAPK signaling pathways in human hepatic stellate cells and rat liver

He, Wenhua; Shi, Feng; Zhou, Zhi Wei; Li, Bimin; Zhang, Kun‐He; Zhang, Xinhua; Ouyang, Canhui; Zhou, Shu Feng; Zhu, Xuan

doi:10.2147/dddt.s85426

Cited by 30 publications

(16 citation statements)

References 66 publications

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“…As a traditional Chinese medicine, UA can inhibit the proliferation of activated HSCs, induce apoptosis, and protect liver cells to exert anti-fibrotic effects [ 41 ]. We conducted a preliminary exploration of the target of UA in HSCs and found that UA can inhibit the proliferation and migration of HSCs by inhibiting the NOX4/ROS and RhoA/ROCK1 signalling pathways, and this result was further verified in vivo.…”

Section: Discussionmentioning

confidence: 99%

Ursolic acid reverses liver fibrosis by inhibiting interactive NOX4/ROS and RhoA/ROCK1 signalling pathways

Wan

Luo

Huang

et al. 2020

Aging

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Liver fibrosis is the reversible deposition of extracellular matrix (ECM) and scar formation after liver damage by various stimuli. The interaction between NOX4/ROS and RhoA/ROCK1 in liver fibrosis is not yet clear. Ursolic acid (UA) is a traditional Chinese medicine with anti-fibrotic effects, but the molecular mechanism underlying these effects is still unclear. We investigated the interaction between NOX4/ROS and RhoA/ROCK1 during liver fibrosis and whether these molecules are targets for the anti-fibrotic effects of UA. First, we confirmed that UA reversed CCl4-induced liver fibrosis. In the NOX4 intervention and RhoA intervention groups, related experimental analyses confirmed the decrease in CCl4-induced liver fibrosis. Next, we determined that the expression of NOX4 and RhoA/ROCK1 was decreased in UA-treated liver fibrotic mice. Furthermore, RhoA/ROCK1 expression was decreased in the NOX4 intervention group, but there was no significant change in the expression of NOX4 in the RhoA intervention group. Finally, we found that liver fibrotic mice showed a decline in their microbiota diversity and abundance, a change in their microbiota composition, and a reduction in the number of potential beneficial bacteria. However, in UA-treated liver fibrotic mice, the microbiota dysbiosis was ameliorated. In conclusion, the NOX4/ROS and RhoA/ROCK1 signalling pathways are closely linked to the development of liver fibrosis. UA can reverse liver fibrosis by inhibiting the NOX4/ROS and RhoA/ROCK1 signalling pathways, which may interact with each other.

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Section: Discussionmentioning

confidence: 99%

Ursolic acid reverses liver fibrosis by inhibiting interactive NOX4/ROS and RhoA/ROCK1 signalling pathways

Wan

Luo

Huang

et al. 2020

Aging

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“…P38MAPK and ERK1/2 may regulate oxidative stress and inflammatory responses [34, 35]. It is known that many I/R injury models elicited the activation of p38MAPK and ERK1/2 pathways [36–38].…”

Section: Discussionmentioning

confidence: 99%

Schisandrin B Prevents Hind Limb from Ischemia-Reperfusion-Induced Oxidative Stress and Inflammation via MAPK/NF-κB Pathways in Rats

Zhu

Cai

Zhou

et al. 2017

BioMed Research International

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Schisandrin B (ScB), isolated from Schisandra chinensis (S. chinensis), is a traditional Chinese medicine with proven cardioprotective and neuroprotective effects. However, it is unclear whether ScB also has beneficial effects on rat hind limb ischemia/reperfusion (I/R) injury model. In this study, ScB (20 mg/kg, 40 mg/kg, and 80 mg/kg) was administered via oral gavage once daily for 5 days before the surgery. After 6 h ischemia and 24 h reperfusion of left hind limb, ScB reduced I/R induced histological changes and edema. ScB also suppressed the oxidative stress through decreasing MDA level and increasing SOD activity. Moreover, above changes were associated with downregulated TNF-α mRNA expression and reduced level of IL-1β in plasma. Meanwhile, ScB treatment downregulated activation of p38MAPK, ERK1/2, and NF-κB in ischemic skeletal muscle. These results demonstrate that ScB treatment could prevent hind limb I/R skeletal muscle injury possibly by attenuating oxidative stress and inflammation via p38MAPK, ERK1/2, and NF-κB pathways.

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“…Other researchers subsequently corroborated that UA selectively induces the apoptosis of activated HSCs without inducing liver or quiescent HSC apoptosis (Wang et al, 2011). Furthermore, we observed that UA inhibited the leptin-mediated expression of the NOX subunits NOX2, P67phox and NOX4 in an activated rat HSC cell line (HSC-T6), resulting in the accumulation of extracellular matrix (ECM) proteins (Wang et al, 2011; He et al, 2015). In addition, the results of another study suggested that UA attenuates experimental colitis in mice via its anti-inflammatory and antioxidant activities (Chun et al, 2014; Liu et al, 2016).…”

Section: Introductionmentioning

confidence: 98%

Protective Effect of Ursolic Acid on the Intestinal Mucosal Barrier in a Rat Model of Liver Fibrosis

et al. 2019

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Oxidative stress mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) plays an important role in intestinal mucosal barrier damage in various disease states. Recent evidence suggests that intestinal mucosal barrier damage and intestinal dysbiosis occur in mice with hepatic fibrosis induced by CCl4 or bile duct ligation. Another study showed that ursolic acid (UA) attenuates experimental colitis via its anti-inflammatory and antioxidant activities. The goal of this study was to investigate the effects of UA on the intestinal mucosal barrier in CCl4-induced hepatic fibrosis in rats and identify its associated mechanisms. Male Sprague-Dawley rats were randomly divided into the following 3 groups ( n = 10/group): the control, CCl4 model and UA treatment groups. Rats were sacrificed at 72 h after the hepatic fibrosis model was established and assessed for liver fibrosis, intestinal injury, enterocyte apoptosis, bacterial translocation, system inflammation, intestinal oxidative stress, and tight junction protein and NOX protein expression. The results demonstrated that UA attenuated the following: (i) liver and intestinal pathological injury; (ii) cleaved caspase-3 expression in the ileal epithelial cells; (iii) serum lipopolysaccharide and procalcitonin levels; (iv) intestinal malondialdehyde levels; and (v) the expression of the NOX protein components NOX2 and P67phox in ileal tissues. Furthermore, our results suggested that UA improved intestinal dysbiosis and the expression of the tight junction proteins Claudin 1 and Occludin in the ileum of rats. These results indicate that UA has protective effects on the intestinal mucosal barrier in rats with CCl4-induced liver fibrosis by inhibiting intestinal NOX-mediated oxidative stress. Our findings may provide a basis for further clinical studies of UA as a novel and adjuvant treatment to cure liver fibrosis.

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A bioinformatic and mechanistic study elicits the antifibrotic effect of ursolic acid through the attenuation of oxidative stress with the involvement of ERK, PI3K/Akt, and p38 MAPK signaling pathways in human hepatic stellate cells and rat liver

Cited by 30 publications

References 66 publications

Ursolic acid reverses liver fibrosis by inhibiting interactive NOX4/ROS and RhoA/ROCK1 signalling pathways

Ursolic acid reverses liver fibrosis by inhibiting interactive NOX4/ROS and RhoA/ROCK1 signalling pathways

Schisandrin B Prevents Hind Limb from Ischemia-Reperfusion-Induced Oxidative Stress and Inflammation via MAPK/NF-κB Pathways in Rats

Protective Effect of Ursolic Acid on the Intestinal Mucosal Barrier in a Rat Model of Liver Fibrosis

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