SIRT1 Controls Acetaminophen Hepatotoxicity by Modulating Inflammation and Oxidative Stress

Rada, Patricia; Pardo, Virginia; Mobasher, Maysa A.; García-Martínez, Irma; Ruiz, Laura; González-Rodrı́guez, Águeda; Sánchez‐Ramos, Cristina; Muntané, Jordi; Alemany, Susana; James, Laura P.; Simpson, Kenneth J.; Monsalve, Marı́a; Valdecantos, M. Pilar; Valverde, Ángela M.

doi:10.1089/ars.2017.7373

Cited by 115 publications

(88 citation statements)

References 62 publications

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“…Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase important in regulating cell apoptosis (25). Studies have also indicated that SIRT1 plays critical roles in the regulation of inflammatory responses (26)(27)(28)(29). Notably, potential binding sites between SirT1 and mir-138-5p were detected in the present study via bioinformatics software analysis.…”

Section: Introductionmentioning

confidence: 61%

MicroRNA‑138‑5p regulates the development of spinal cord injury by targeting SIRT1

Chen

Qin

2020

Mol Med Report

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Micrornas (mirs) play an important role in the development and progression of spinal cord injury (Sci). The role of mir-138-5p in Sci was investigated in the present study. The anti-inflammatory effects of miR-138-5p and underlying mechanisms were investigated in an Sci rat model and in vitro model. reverse transcription-quantitative Pcr (rT-qPcr) was used to examine the expression of mir-138-5p in the Sci in vivo and in vitro models, as well as patients with Sci; it was found that miR-138-5p was significantly upregulated in Sci. Bioinformatics and dual-luciferase reporter assays were performed to predict and confirm the binding sites between mir-138-5p and the 3'untranslated region of sirtuin 1 (SirT1). Then, the expression of SirT1 was detected via rT-qPcr and western blotting, indicating downregulation of SIRT1 in SCI. PC12 cells were transfected with miR-138-5p inhibitor, inhibitor control or miR-138-5p inhibitor + SIRT1 small interfering RNA for 48 h, and then subjected to lipopolysaccharide (100 ng/ml) treatment for 4 h. Then, MTT assay, flow cytometry and eliSa experiments were performed to analyze cell viability, apoptosis, and the levels of tumor necrosis factor-α, interleukin (il)-1β and il-6. Findings suggested that downregulation of miR-138-5p increased PC12 cell viability, inhibited cell apoptosis and attenuated proinflammatory responses, which may result in amelioration of Sci. However, all these effects were reversed by SIRT1 knockdown. Finally, it was observed that miR-138-5p altered the related protein expression of the PTen/aKT pathway. These results indicated that miR-138-5p could regulate inflammatory responses and cell apoptosis in SCI models by modulating the PTEN/AKT signaling pathway via SirT1, thus playing an important role in the development of Sci. collectively, the present study demonstrated that miR-138-5p may be a novel therapeutic target for the treatment of Sci. Materials and methodsClinical samples. a total of 18 serum specimens from patients with Sci (age range, 27-58 years; 12 male patients and 6 female MicroRNA-138-5p regulates the development of spinal cord injury by targeting SIRT1 JincHuan cHen and ruJie Qin department of Spine Surgery, The First People's Hospital of lianyungang, lianyungang, Jiangsu 222000, P.r. china

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Section: Introductionmentioning

confidence: 61%

MicroRNA‑138‑5p regulates the development of spinal cord injury by targeting SIRT1

Chen

Qin

2020

Mol Med Report

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“…Hepatoxicity induced by APAP was accompanied by an inflammatory response containing stimulation of resident macrophages like Kupffer cells (Liu and Kaplowitz, 2006;Laskin, 2009;Williams et al, 2011). Patricia et al (Rada et al, 2018) found that conditioned media from RAW 264.7 macrophages co-cultured with APAP reduced protein levels of SIRT1 in hepatocytes. Thus, in future studies, we will focus on the correlation between Kupffer cells, APAP and API.…”

Section: Discussionmentioning

confidence: 99%

“…Sirtuin 1 (SIRT1) regulates protein deacetylation, participates in protein transcription and translation, regulates cell proliferation, oxidative stress, and metabolism, and plays an important role in metabolic diseases, tumors, and cardiac function (Consiglio et al, 2014;Cui et al, 2016;Qin et al, 2016). Rada et al found that overexpression of SIRT1 ameliorated hepatoxicity induced by APAP, and inhibits inflammation responses and oxidative stress (Rada et al, 2018). A previous study also reported that SIRT1 suppresses p53 acetylation in ischemia/reperfusion liver injury (Nakamura et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Apigenin Prevents Acetaminophen-Induced Liver Injury by Activating the SIRT1 Pathway

Zhao

Zhang

et al. 2020

Front. Pharmacol.

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Acetaminophen (APAP) overdose is the main cause of acute liver failure. Apigenin (API) is a natural dietary flavonol with high antioxidant capacity. Herein, we investigated protection by API against APAP-induced liver injury in mice, and explored the potential mechanism. Cell viability assays and mice were used to evaluate the effects of API against APAPinduced liver injury. Western blotting, immunofluorescence staining, RT-PCR, and Transmission Electron Microscope were carried out to determine the signalling pathways affected by API. Analysis of mouse serum levels of alanine/aspartate aminotransferase (ALT/AST), malondialdehyde (MDA), liver myeloperoxidase (MPO) activity, glutathione (GSH), and reactive oxygen species (ROS) revealed that API (80 mg/kg) owned protective effect on APAP-induced liver injury. Meanwhile, API ameliorated the decreased cell viability in L-02 cells incubated by APAP with a dose dependent. Furthermore, API promoted SIRT1 expression and deacetylated p53. Western blotting showed that API promoted APAP-induced autophagy, activated the NRF2 pathway, and inhibited the transcriptional activation of nuclear p65 in the presence of APAP. Furthermore, SIRT1 inhibitor EX-527 reduced protection by API against APAP-induced hepatotoxicity. Molecular docking results indicate potential interaction between API and SIRT1. API prevents APAP-induced liver injury by regulating the SIRT1-p53 axis, thereby promoting APAP-induced autophagy and ameliorating APAP-induced inflammatory responses and oxidative stress injury.

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“…SirT1, an nad + -dependent deacetylase, is involved in apoptosis (21) and serves important roles in the regulation of inflammatory responses (22)(23)(24)(25). For example, SIRT1 protein levels are downregulated by IL1β/nFκB signaling in acetaminophen hepatotoxicity, resulting in inflammation and oxidative stress (23). The inhibition of SIRT1 leads to oxidative stress and inflammation in patients with coronary artery disease (24).…”

Section: Discussionmentioning

confidence: 99%

“…Sirtuin 1 (SIRT1), an NAD + -dependent deacetylase, plays an important role in the regulation of apoptosis and inflammatory responses (21)(22)(23)(24)(25). A recent report indicated that the inhibition of SIRT1 may promote atherosclerosis (26).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‑217 is involved in the progression of atherosclerosis through regulating inflammatory responses by targeting sirtuin 1

Zhang

Chen

et al. 2019

Mol Med Report

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Atherosclerosis is a chronic inflammatory disease, and it is a global clinical problem. The development of new and effective therapeutic targets for atherosclerosis is necessary. A number of microRNAs (miRNAs) have been demonstrated to serve a crucial role in atherosclerosis. However, the role of miRNA (miR)-217 in atherosclerosis remains unclear. Therefore, the aim of the present study was to investigate the role and mechanism of miR-217 in atherosclerosis. The level of miR-217 was detected in the blood of patients with atherosclerosis using reverse transcription-quantitative PCR. THP-1 acute monocytic leukemia cells were treated with oxidized low-density lipoprotein (ox-LDL) to develop an atherosclerotic cell model of macrophages. The relationship between miR-217 and sirtuin 1 (SIRT1) was determined by TargetScan and dual luciferase reporter assay. Cell apoptosis was measured by flow cytometry. Production of pro-inflammatory factors and triglyceride (TG) and total cholesterol (TC) levels were also determined. The results demonstrated that miR-217 was significantly upregulated in atherosclerosis. SIRT1 was demonstrated to be a direct target of miR-217 and was downregulated in atherosclerosis. Downregulation of miR-217 significantly inhibited ox-LDL-induced TG and TC level increase, cell apoptosis and the upregulation of the pro-inflammatory factors tumor necrosis factor α, interleukin (IL)-6 and IL-1β. Additionally, the SIRT1/AMP-activated protein kinase α/NF-κB pathway was at least partially involved in modulating the effects of miR-217 inhibition on THP-1 cells treated with ox-LDL. In addition, the effects of miR-217 downregulation on ox-LDL-treated THP-1 cells were eliminated by SIRT1 silencing. In conclusion, the results of the present study indicated that miR-217 downregulation may relieve atherosclerosis through the inhibition of macrophage apoptosis and inflammatory response by targeting SIRT1.

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SIRT1 Controls Acetaminophen Hepatotoxicity by Modulating Inflammation and Oxidative Stress

Cited by 115 publications

References 62 publications

MicroRNA‑138‑5p regulates the development of spinal cord injury by targeting SIRT1

MicroRNA‑138‑5p regulates the development of spinal cord injury by targeting SIRT1

Apigenin Prevents Acetaminophen-Induced Liver Injury by Activating the SIRT1 Pathway

MicroRNA‑217 is involved in the progression of atherosclerosis through regulating inflammatory responses by targeting sirtuin 1

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