Uric acid ameliorates indomethacin‐induced enteropathy in mice through its antioxidant activity

Yasutake, Yuichi; Tomita, Kengo; Higashiyama, Masaaki; Furuhashi, Hirotaka; Shirakabe, Kazuhiko; Takajo, Takeshi; Maruta, Koji; Sato, Hírokazu; Narimatsu, Kazuyuki; Yoshikawa, Kenichi; Okada, Yoshikiyo; Kurihara, Chie; Watanabe, Chikako; Komoto, Shunsuke; Nagao, Shigeaki; Miura, Soichiro; Hokari, Ryota

doi:10.1111/jgh.13785

Cited by 17 publications

(9 citation statements)

References 42 publications

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“…Evidence also indicated that uric acid has a powerful antioxidant effect (21,22). Yasutake et al found that uric acid ameliorates indomethacin-induced enteropathy in mice through its antioxidant activity (23). Additionally, systemic administration of uric acid over a range of doses is safe and can increase the body's antioxidant capacity (24).…”

Section: Discussionmentioning

confidence: 99%

Uric acid preconditioning alleviated doxorubicin induced JNK activation and Cx43 phosphorylation associated cardiotoxicity via activation of AMPK-SHP2 signaling pathway

et al. 2020

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Background: Doxorubicin is an anthracycline antibiotic, which is effective for treating various malignancies such as leukemias and lymphomas. However, its serious cumulative dose-dependent cardiotoxicity limits its clinical application. Previous studies have shown that doxorubicin-associated cardiotoxicity is closely related to adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Uric acid is known to exert a strong antioxidant function and moderate protection on the nerves. However, its cardioprotective properties have not been established. This study aimed to investigate the potential effect of uric acid preconditioning on doxorubicin-induced cardiotoxicity and the involvement of AMPK signaling in this process.Methods: An acute cardiotoxicity model of doxorubicin was established by intraperitoneal injection of a single dose of doxorubicin (20 mg/kg) in mice. Uric acid (62.5, 125, and 250 mg/kg) was intragastrically administered to mice one day before doxorubicin treatment and then continuously administered every 24 h for 8 consecutive days. The mortality rate and weight of the mice were recorded every day.Electrocardiograms (ECG) and serum biochemicals were detected with an ECG instrument and enzymelinked immunosorbent assay kit (Elisa) respectively. A real-time cell analyzer (RTCA) was used to investigate the cytotoxicity of doxorubicin in vitro. Cell signaling was assayed by western blotting. Results: Uric acid (125 mg/kg) preconditioning increased the survival rate and body weight of doxorubicintreated mice. Uric acid also effectively alleviated prolongation of the doxorubicin-induced QT interval, slowed heart rate, and reduced the plasma levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and creatine kinase (CK) in plasma in mice. Moreover, uric acid strongly activated AMPK and Src homology 2 domain-containing protein tyrosine phosphatase (SHP2), inhibiting doxorubicin-induced expression phosphorylated-c-Jun N-terminal kinases (JNK) and phosphorylated-connexin 43 (Cx43) in vitro and in vivo and effectively reversing the doxorubicin-induced decreased viability of H9C2 myocardial cells in vitro.Conclusions: We demonstrated that uric acid preconditioning alleviated doxorubicin-induced cardiotoxicity through the AMPK-SHP2-JNK-Cx43 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Uric acid preconditioning alleviated doxorubicin induced JNK activation and Cx43 phosphorylation associated cardiotoxicity via activation of AMPK-SHP2 signaling pathway

et al. 2020

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“…Humans and higher primates excrete uric acid in their urine, but other mammals convert uric acid to allantoin by uricase and then excrete it in urine ( Heinz et al, 1980 ; Kurtz et al, 1986 ; Moriwaki et al, 1999 ). Uric acid, the end product of human purine metabolism, is one of the major antioxidants ( Ames et al, 1981 ; Whiteman et al, 2002 ; Muraoka and Miura, 2003 ) and protects against neurological and intestinal diseases ( Hooper et al, 1998 ; Hooper et al, 2000 ; Toncev et al, 2002 ; Ascherio et al, 2009 ; Matsuo et al, 2015 ; Yasutake et al, 2017 ). Consequently, inosine-related metabolism should be extensively explored for its multidimensional effects on human illnesses.…”

Section: Overview Of Inosine Biologymentioning

confidence: 99%

“…in mice. Inosinic acid treatment leads to increased serum levels of uric acid, resulting in protection against intestinal injury via antioxidative effects ( Yasutake et al, 2017 ).…”

Section: Inosine and Therapeutic Implications For Inflammationmentioning

confidence: 99%

Inosine: A bioactive metabolite with multimodal actions in human diseases

Kim

2022

Front. Pharmacol.

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The nucleoside inosine is an essential metabolite for purine biosynthesis and degradation; it also acts as a bioactive molecule that regulates RNA editing, metabolic enzyme activity, and signaling pathways. As a result, inosine is emerging as a highly versatile bioactive compound and second messenger of signal transduction in cells with diverse functional abilities in different pathological states. Gut microbiota remodeling is closely associated with human disease pathogenesis and responses to dietary and medical supplementation. Recent studies have revealed a critical link between inosine and gut microbiota impacting anti-tumor, anti-inflammatory, and antimicrobial responses in a context-dependent manner. In this review, we summarize the latest progress in our understanding of the mechanistic function of inosine, to unravel its immunomodulatory actions in pathological settings such as cancer, infection, inflammation, and cardiovascular and neurological diseases. We also highlight the role of gut microbiota in connection with inosine metabolism in different pathophysiological conditions. A more thorough understanding of the mechanistic roles of inosine and how it regulates disease pathologies will pave the way for future development of therapeutic and preventive modalities for various human diseases.

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“…The first one is mediated by ROS, resulting in inflammation of the vascular endothelial cells and proliferation of vascular smooth muscle cells [ 12 ]. Previous studies reported that oxidative stress accompanied by the generation of ROS can be observed in cells exposed to uric acid [ 13 , 14 ]. Moreover, high level of uric acid could induce oxidative stress and inhibit cardiomyocytes viability through the ERK/P38 pathway [ 15 ].…”

Section: Mechanistic Frameworkmentioning

confidence: 99%

Uric Acid—An Emergent Risk Marker for Thrombosis?

Țăpoi¹,

Șalaru

Sascău

et al. 2021

JCM

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Hyperuricemia is nowadays an established cardiovascular risk factor. Experimental studies linked elevated serum uric acid (SUA) levels with endothelial dysfunction (ED), inflammation, and prothrombotic state. The purpose of this review is to summarize the current evidence that emphasizes the possible role of uric acid as a biomarker for a prothrombotic state. A large number of clinical trials correlated SUA levels with both incident and recurrent cases of venous thromboembolism (VTE), independent of other confounding risk factors. Moreover, increased SUA levels may be an important tool for the risk stratification of patients with pulmonary embolism (PE). Left atrial thrombosis was correlated with high SUA levels in several studies and its addition to classical risk scores improved their predictive abilities. In patients with acute myocardial infarction (MI), hyperuricemia was associated with increased mortality, and the idea that hyperuricemia may be able to act as a surrogate to unstable coronary plaques was advanced. Finally, SUA was correlated with an increased risk of thromboembolic events in different systemic diseases. In conclusion, uric acid has been considered a marker of a thrombotic milieu in several clinical scenarios. However, this causality is still controversial, and more experimental and clinical data is needed.

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Uric acid ameliorates indomethacin‐induced enteropathy in mice through its antioxidant activity

Abstract: Uric acid within the intestinal lumen and in serum had a protective effect against NSAID-induced enteropathy in mice, through its antioxidant activity. Uric acid could be a promising therapeutic target for NSAID-induced enteropathy.

Cited by 17 publications

References 42 publications

Uric acid preconditioning alleviated doxorubicin induced JNK activation and Cx43 phosphorylation associated cardiotoxicity via activation of AMPK-SHP2 signaling pathway

Uric acid preconditioning alleviated doxorubicin induced JNK activation and Cx43 phosphorylation associated cardiotoxicity via activation of AMPK-SHP2 signaling pathway

Inosine: A bioactive metabolite with multimodal actions in human diseases

Uric Acid—An Emergent Risk Marker for Thrombosis?

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