Heat Shock Protein 60 Restricts Release of Mitochondrial dsRNA to Suppress Hepatic Inflammation and Ameliorate Non-Alcoholic Fatty Liver Disease in Mice

Huang, Ying‐Hsien; Wang, Feng‐Sheng; Wang, Pei-Wen; Lin, Hung‐Yu; Luo, Sheng‐Dean; Yang, Ya‐Ling

doi:10.3390/ijms23010577

Cited by 14 publications

(11 citation statements)

References 41 publications

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“…Overexpression of HSP60 restricted the release of mitochondrial dsRNA and ameliorated hepatocellular steatosis and liver inflammation in non-alcoholic fatty liver disease in mice [ 43 ]. Interestingly, HSP60 could bind with HDL and apoA-I with high affinity, K d.HDL = 50 nM and K d.HDL = 300 nM, respectively, to exert putative immunoregulatory activity [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Activity of CIGB-258 against Acute Toxicity of Carboxymethyllysine in Paralyzed Zebrafish via Enhancement of High-Density Lipoproteins Stability and Functionality

Cho

Kim²,

Nam³

et al. 2022

IJMS

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Background: Hyperinflammation is frequently associated with the chronic pain of autoimmune disease and the acute death of coronavirus disease (COVID-19) via a severe cytokine cascade. CIGB-258 (Jusvinza®), an altered peptide ligand with 3 kDa from heat shock protein 60 (HSP60), inhibits the systemic inflammation and cytokine storm, but the precise mechanism is still unknown. Objective: The protective effect of CIGB-258 against inflammatory stress of N-ε-carboxymethyllysine (CML) was tested to provide mechanistic insight. Methods: CIGB-258 was treated to high-density lipoproteins (HDL) and injected into zebrafish and its embryo to test a putative anti-inflammatory activity under presence of CML. Results: Treatment of CML (final 200 μM) caused remarkable glycation of HDL with severe aggregation of HDL particles to produce dysfunctional HDL, which is associated with a decrease in apolipoprotein A-I stability and lowered paraoxonase activity. Degradation of HDL3 by ferrous ions was attenuated by a co-treatment with CIGB-258 with a red-shift of the Trp fluorescence in HDL. A microinjection of CML (500 ng) into zebrafish embryos resulted in the highest embryo death rate, only 18% of survivability with developmental defects. However, co-injection of CIGB-258 (final 1 ng) caused the remarkable elevation of survivability around 58%, as well as normal developmental speed. An intraperitoneal injection of CML (final 250 μg) into adult zebrafish resulted acute paralysis, sudden death, and laying down on the bottom of the cage with no swimming ability via neurotoxicity and inflammation. However, a co-injection of CIGB-258 (1 μg) resulted in faster recovery of the swimming ability and higher survivability than CML alone injection. The CML alone group showed 49% survivability, while the CIGB-258 group showed 97% survivability (p < 0.001) with a remarkable decrease in hepatic inflammation up to 50%. A comparison of efficacy with CIGB-258, Infliximab (Remsima®), and Tocilizumab (Actemra®) showed that the CIGB-258 group exhibited faster recovery and swimming ability with higher survivability than those of the Infliximab group. The CIGB-258 group and Tocilizumab group showed the highest survivability, the lowest plasma total cholesterol and triglyceride level, and the infiltration of inflammatory cells, such as neutrophils in hepatic tissue. Conclusion: CIGB-258 ameliorated the acute neurotoxicity, paralysis, hyperinflammation, and death induced by CML, resulting in higher survivability in zebrafish and its embryos by enhancing the HDL structure and functionality.

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Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Activity of CIGB-258 against Acute Toxicity of Carboxymethyllysine in Paralyzed Zebrafish via Enhancement of High-Density Lipoproteins Stability and Functionality

Cho

Kim²,

Nam³

et al. 2022

IJMS

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“…Among these five differential proteins, P10809 (heat shock protein, HSP60) was reported to play a role in treating nonalcoholic fatty liver disease (NAFLD) and repressing hepatic inflammation possibly . A0A7H0TJC6 is a protein of Heparin cofactor II (HCII) splice isoform, and HCII is predominantly expressed in the liver and inhibits thrombin in blood plasma to influence the blood coagulation cascade .…”

Section: Resultsmentioning

confidence: 99%

Novel Strategy for Screening Target Proteins by the Common Drugs─Sofosbuvir-Specific Profiling of HCV Patient Serum

Pan,

Wang,

Yan

et al. 2024

Anal. Chem.

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It is the scientific basis of precision medicine to study all of the targets of drugs based on the interaction between drugs and proteins. It is worth paying attention to unknown proteins that interact with drugs to find new targets for the design of new drugs. Herein, we developed a protein profiling strategy based on drug−protein interactions and drug-modified magnetic nanoparticles and took hepatitis C virus (HCV) and its corresponding drug sofosbuvir (SOF) as an example. A SOFmodified magnetic separation medium (Fe 3 O 4 @POSS@SOF) was prepared, and a gradient elution strategy was employed and optimized to profile specific proteins interacted with SOF. A series of proteomic analyses were performed to profile proteins based on SOF−protein interactions (SPIs) in the serum of HCV patients to evaluate the specificity of the profiling strategy. As a result, five proteins were profiled with strong SPIs and exhibited high relevance with liver tissue, which were potentially new drug targets. Among them, HSP60 was used to confirm the highly specific interactions between the SOF and its binding proteins by Western blotting analysis. Besides, 124 and 29 differential proteins were profiled by SOF material from three HCV patient serum and pooled 20 HCV patient serum, respectively, by comparing with healthy human serum. In comparison with those profiled by the polyhedral oligomeric silsesquioxane (POSS) material, differential proteins profiled by the SOF material were highly associated with liver diseases through GO analysis and pathway analysis. Furthermore, four common differential proteins profiled by SOF material but not by POSS material were found to be identical and expressed consistently in both pooled serum samples and independent serum samples, which might potentially be biomarkers of HCV infection. Taken together, our study proposes a highly specific protein profiling strategy to display distinctive proteomic profiles, providing a novel idea for drug design and development.

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“…Hepatic lipotoxicity results in mitochondrial dysfunction with subsequent production of reactive oxygen species (ROS). One of the mitochondrial quality control mechanisms is mitochondrial unfolded protein response (UPR mt ) which generates mitochondrial chaperones, including heat shock protein Family D Member ( HSPD1 ), and proteases for repairing unfolded protein stress [ 23 ]. HSPD1 assists in proteolytic degradation of misfolded proteins and performs many physiological functions but can also be pathogenic in various conditions.…”

Section: Discussionmentioning

confidence: 99%

Rosavin Ameliorates Hepatic Inflammation and Fibrosis in the NASH Rat Model via Targeting Hepatic Cell Death

Albadawy

Hasanin

Agwa

et al. 2022

IJMS

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Background: Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease that urgently needs effective therapy. Rosavin, a major constituent of the Rhodiola Rosea plant of the family Crassulaceae, is believed to exhibit multiple pharmacological effects on diverse diseases. However, its effect on non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, and the underlying mechanisms are not fully illustrated. Aim: Investigate the pharmacological activity and potential mechanism of rosavin treatment on NASH management via targeting hepatic cell death-related (HSPD1/TNF/MMP14/ITGB1) mRNAs and their upstream noncoding RNA regulators (miRNA-6881-5P and lnc-SPARCL1-1:2) in NASH rats. Results: High sucrose high fat (HSHF) diet-induced NASH rats were treated with different concentrations of rosavin (10, 20, and 30 mg/kg/day) for the last four weeks of dietary manipulation. The data revealed that rosavin had the ability to modulate the expression of the hepatic cell death-related RNA panel through the upregulation of both (HSPD1/TNF/MMP14/ITGB1) mRNAs and their epigenetic regulators (miRNA-6881-5P and lnc-SPARCL1-1:2). Moreover, rosavin ameliorated the deterioration in both liver functions and lipid profile, and thereby improved the hepatic inflammation, fibrosis, and apoptosis, as evidenced by the decreased protein levels of IL6, TNF-α, and caspase-3 in liver sections of treated animals compared to the untreated NASH rats. Conclusion: Rosavin has demonstrated a potential ability to attenuate disease progression and inhibit hepatic cell death in the NASH animal model. The produced effect was correlated with upregulation of the hepatic cell death-related (HSPD1, TNF, MMP14, and ITGB1) mRNAs—(miRNA-6881-5P—(lnc-SPARCL1-1:2) RNA panel.

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Heat Shock Protein 60 Restricts Release of Mitochondrial dsRNA to Suppress Hepatic Inflammation and Ameliorate Non-Alcoholic Fatty Liver Disease in Mice

Cited by 14 publications

References 41 publications

Anti-Inflammatory Activity of CIGB-258 against Acute Toxicity of Carboxymethyllysine in Paralyzed Zebrafish via Enhancement of High-Density Lipoproteins Stability and Functionality

Anti-Inflammatory Activity of CIGB-258 against Acute Toxicity of Carboxymethyllysine in Paralyzed Zebrafish via Enhancement of High-Density Lipoproteins Stability and Functionality

Novel Strategy for Screening Target Proteins by the Common Drugs─Sofosbuvir-Specific Profiling of HCV Patient Serum

Rosavin Ameliorates Hepatic Inflammation and Fibrosis in the NASH Rat Model via Targeting Hepatic Cell Death

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