The Effects of RKI-1447 in a Mouse Model of Nonalcoholic Fatty Liver Disease Induced by a High-Fat Diet and in HepG2 Human Hepatocellular Carcinoma Cells Treated with Oleic Acid

Wang, Jinshan; Jiang, Wentao

doi:10.12659/msm.919220

Cited by 9 publications

(10 citation statements)

References 38 publications

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“…After the mice with NAFL acquired 5 mg/kg of H-bihistidine treatment for 7 consecutive days, the sera were obtained for transaminase activity and lipid content calculation. The results revealed that the ALT and AST levels were significantly elevated in the fatty liver mice (Figure 5A,B), suggesting that the high-fat-diet-induced liver injury in mice was in agreement with a previous report [16]. After H-bihistidine administration, transaminase activities decreased close to the control levels (Figure 5A,B).…”

Section: H-bihistidine Reduced Serum Transaminase and Lipid In Vivosupporting

confidence: 91%

Dimeric Histidine as a Novel Free Radical Scavenger Alleviates Non-Alcoholic Liver Injury

Zhao

Zhang

et al. 2021

Antioxidants

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Non-alcoholic liver injury (NLI) is a common disease worldwide. Since free radical damage in the liver is a crucial initiator leading to diseases, scavenging excess free radicals has become an essential therapeutic strategy. To enhance the antioxidant capacity of histidine, we synthesized a protonated dimeric histidine, H-bihistidine, and investigated its anti-free radical potential in several free-radical-induced NLI. Results showed that H-bihistidine could strongly scavenge free radicals caused by H2O2, fatty acid, and CCl4, respectively, and recover cell viability in cultured hepatocytes. In the animal model of nonalcoholic fatty liver injury caused by high-fat diet, H-bihistidine reduced the contents of transaminases and lipids in serum, eliminated the liver’s fat accumulation, and decreased the oxidative damage. Moreover, H-bihistidine could rescue CCl4-induced liver injury and recover energy supply through scavenging free radicals. Moreover, liver fibrosis prepared by high-fat diet and CCl4 administration was significantly alleviated after H-bihistidine treatment. This study suggests a novel nonenzymatic free radical scavenger against NLI and, potentially, other free-radical-induced diseases.

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Section: H-bihistidine Reduced Serum Transaminase and Lipid In Vivosupporting

confidence: 91%

Dimeric Histidine as a Novel Free Radical Scavenger Alleviates Non-Alcoholic Liver Injury

Zhao

Zhang

et al. 2021

Antioxidants

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“…In support of this, the experimental evidence has demonstrated that selective delivery of the ROCK inhibitor to HSCs reduces chronic carbon tetrachloride (CCl4)-induced liver fibrosis or cirrhosis by inhibiting activated HSCs in mice [ 38 , 39 ], highlighting an essential role for ROCK action in HSCs. Similar observations have been found in various animal models, including HFD-fed mice [ 40 ], HFD and streptozotocin (STZ)-treated rats [ 41 ], STZ-induced diabetic rats [ 42 ], dimethylnitrosamine- induced hepatic fibrosis rats [ 43 ], and endotoxintreated mice [ 44 , 45 ]. In animal models of CCl4-induced liver fibrosis, the ability of a ROCK inhibitor to reduce HSCs activation is greatly enhanced, leading to the prevention of liver fibrosis development [ 39 , 46 - 48 ].…”

Section: Rho-kinase Inhibitor Ameliorates Nonalcoholic Fatty Liver Diseasessupporting

confidence: 79%

“…Since the introduction of this work, numerous studies have consistently revealed that ROCK inhibition is beneficial for multiple cardiovascular-related illnesses [32][33][34]. Beyond these investigations, a pharmacotherapy with the ROCK inhibitor has also been found to be effective in treating liver diseases, including NAFLD, NASH, and fibrosis as shown in Table 1 [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53]. Data supporting a role of ROCK on liver diseases include the fact that a ROCK chemical inhibitor ameliorated hepatic steatosis and fibrosis in rats fed a choline-deficient/L-amino acid-defined (CDAA) diet and choline-deficient diet [35][36][37].…”

Section: Rho-kinase Inhibitor Ameliorates Nonalcoholic Fatty Liver Diseasesmentioning

confidence: 99%

Rho-Kinase as a Therapeutic Target for Nonalcoholic Fatty Liver Diseases

2021

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Nonalcoholic fatty liver disease (NAFLD) is a major public health problem and the most common form of chronic liver disease, affecting 25% of the global population. Although NAFLD is closely linked with obesity, insulin resistance, and type 2 diabetes mellitus, knowledge on its pathogenesis remains incomplete. Emerging data have underscored the importance of Rho-kinase (Rho-associated coiled-coil-containing kinase [ROCK]) action in the maintenance of normal hepatic lipid homeostasis. In particular, pharmacological blockade of ROCK in hepatocytes or hepatic stellate cells prevents the progression of liver diseases such as NAFLD and fibrosis. Moreover, mice lacking hepatic ROCK1 are protected against obesity-induced fatty liver diseases by suppressing hepatic de novo lipogenesis. Here we review the roles of ROCK as an indispensable regulator of obesity-induced fatty liver disease and highlight the key cellular pathway governing hepatic lipid accumulation, with focus on de novo lipogenesis and its impact on therapeutic potential. Consequently, a comprehensive understanding of the metabolic milieu linking to liver dysfunction triggered by ROCK activation may help identify new targets for treating fatty liver diseases such as NAFLD.

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“…These metabolic improvements were mediated through the activation of AMPK pathway in liver and skeletal muscle which contributed to increased whole body energy expenditure ( 47 , 48 ). In addition to systemic metabolic improvements, treatment with ROCK inhibitors ameliorates liver fibrosis in diabetic non-alcoholic steatohepatitis ( 178 – 180 ).…”

Section: Metabolic Roles Of Liver Skeletal Muscle Brain and Vascular ...mentioning

confidence: 99%

Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis

Wei

Shi

2022

Front. Endocrinol.

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Obesity and associated complications increasingly jeopardize global health and contribute to the rapidly rising prevalence of type 2 diabetes mellitus and obesity-related diseases. Developing novel methods for the prevention and treatment of excess body adipose tissue expansion can make a significant contribution to public health. Rho kinase is a Rho-associated coiled-coil-containing protein kinase (Rho kinase or ROCK). The ROCK family including ROCK1 and ROCK2 has recently emerged as a potential therapeutic target for the treatment of metabolic disorders. Up-regulated ROCK activity has been involved in the pathogenesis of all aspects of metabolic syndrome including obesity, insulin resistance, dyslipidemia and hypertension. The RhoA/ROCK-mediated actin cytoskeleton dynamics have been implicated in both white and beige adipogenesis. Studies using ROCK pan-inhibitors in animal models of obesity, diabetes, and associated complications have demonstrated beneficial outcomes. Studies via genetically modified animal models further established isoform-specific roles of ROCK in the pathogenesis of metabolic disorders including obesity. However, most reported studies have been focused on ROCK1 activity during the past decade. Due to the progress in developing ROCK2-selective inhibitors in recent years, a growing body of evidence indicates more attention should be devoted towards understanding ROCK2 isoform function in metabolism. Hence, studying individual ROCK isoforms to reveal their specific roles and principal mechanisms in white and beige adipogenesis, insulin sensitivity, energy balancing regulation, and obesity development will facilitate significant breakthroughs for systemic treatment with isoform-selective inhibitors. In this review, we give an overview of ROCK functions in the pathogenesis of obesity and insulin resistance with a particular focus on the current understanding of ROCK isoform signaling in white and beige adipogenesis, obesity and thermogenesis in adipose tissue and other major metabolic organs involved in energy homeostasis regulation.

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The Effects of RKI-1447 in a Mouse Model of Nonalcoholic Fatty Liver Disease Induced by a High-Fat Diet and in HepG2 Human Hepatocellular Carcinoma Cells Treated with Oleic Acid

Cited by 9 publications

References 38 publications

Dimeric Histidine as a Novel Free Radical Scavenger Alleviates Non-Alcoholic Liver Injury

Dimeric Histidine as a Novel Free Radical Scavenger Alleviates Non-Alcoholic Liver Injury

Rho-Kinase as a Therapeutic Target for Nonalcoholic Fatty Liver Diseases

Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis

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