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      Modified Chuanhu anti-gout mixture, a traditional Chinese medicine, protects against potassium oxonate-induced hyperuricemia and renal dysfunction in mice

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          Abstract

          Objective

          Acute gout is a painful, inflammatory arthritis that features a rapidly escalating inflammatory response resulting from the formation of monosodium urate crystals in the affected joint space. Previously, we found that Chuanhu anti-gout mixture (CAGM) had similar effects as colchicine against gout in the clinic. Subsequently, to improve its effectiveness and efficacy, we modified the original formulation of CAGM. The current study evaluated the effectiveness of the modified formulation in mice.

          Methods

          Potassium oxonate (PO) was used to establish a mouse model of hyperuricemia. Plasma levels of uric acid and creatine were determined using the respective test kits. Hepatic xanthine oxidase (XOD) expression was examined by enzyme-linked immunosorbent assay. To explore the underlying mechanism, renal urate transporter 1 (URAT1) mRNA levels were evaluated by quantitative real-time PCR. Allopurinol and benzbromarone were used as reference drugs.

          Results

          The original CAGM and its modified high-dose formulation significantly reduced serum uric acid and creatine levels in hyperuricemic mice. In addition, the CAGM-treated groups displayed lower mRNA levels of hepatic XOD and renal URAT1.

          Conclusions

          CAGM and its modified formulation significantly ameliorated PO-induced hyperuricemia in mice, which might be partially attributable to reductions of hepatic XOD and renal URAT1 levels.

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          Molecular identification of a renal urate anion exchanger that regulates blood urate levels.

          Atsushi Enomoto, Hiroaki Kimura, Arthit Chairoungdua … (2002)
          Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes, as demonstrated by its capacity of neuroprotection. It is present at higher levels in human blood (200 500 microM) than in other mammals, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences. Here we identify the long-hypothesized urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate anion exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.
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            Hyperuricemia and coronary heart disease: a systematic review and meta-analysis.

            S. H. Kim, Ivana K. Kim, Daniel Heitjan … (2010)
            The role of serum uric acid as an independent risk factor for cardiovascular disease remains unclear, although hyperuricemia is associated with cardiovascular disease such as coronary heart disease (CHD), stroke, and hypertension. A systematic review and meta-analysis using a random-effects model was conducted to determine the risk of CHD associated with hyperuricemia in adults. Studies of hyperuricemia and CHD were identified by searching major electronic databases using the medical subject headings and keywords without language restriction (through February 2009). Only prospective cohort studies were included if they had data on CHD incidences or mortalities related to serum uric acid levels in adults. Twenty-six eligible studies of 402,997 adults were identified. Hyperuricemia was associated with an increased risk of CHD incidence (unadjusted risk ratio [RR] 1.34, 95% confidence interval [95% CI] 1.19-1.49) and mortality (unadjusted RR 1.46, 95% CI 1.20-1.73). When adjusted for potential confounding, the pooled RR was 1.09 (95% CI 1.03-1.16) for CHD incidence and 1.16 (95% CI 1.01-1.30) for CHD mortality. For each increase of 1 mg/dl in uric acid level, the pooled multivariate RR for CHD mortality was 1.12 (95% CI 1.05-1.19). Subgroup analyses showed no significant association between hyperuricemia and CHD incidence/mortality in men, but an increased risk for CHD mortality in women (RR 1.67, 95% CI 1.30-2.04). Hyperuricemia may marginally increase the risk of CHD events, independently of traditional CHD risk factors. A more pronounced increased risk for CHD mortality in women should be investigated in future research.
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              Hyperuricemia and risk of stroke: a systematic review and meta-analysis.

              Arlene Albert, J. Choi, Ivana K. Kim … (2009)
              To assess the association between hyperuricemia and risk of stroke incidence and mortality because hyperuricemia is hypothesized to be a risk factor for stroke and other cardiovascular disease, but, to date, results from observational studies are conflicting. A systematic review and meta-analysis were conducted. Studies were identified by searching major electronic databases using the Medical Subject Headings and keywords without restriction in languages. Prospective cohort studies were included only if they contained data on stroke incidences or mortalities related to serum uric acid levels in adults. Pooled risk ratios (RRs) for the association of stroke incidence and mortality with serum uric acid levels were calculated. A total of 16 studies including 238,449 adults were eligible and abstracted. Hyperuricemia was associated with a significantly higher risk of both stroke incidence (6 studies; RR 1.41, 95% confidence interval [95% CI] 1.05, 1.76) and mortality (6 studies; RR 1.36, 95% CI 1.03, 1.69) in our meta-analyses of unadjusted study estimates. Subgroup analyses of studies adjusting for known risk factors such as age, hypertension, diabetes mellitus, and cholesterol still showed that hyperuricemia was significantly associated with both stroke incidence (4 studies; RR 1.47, 95% CI 1.19, 1.76) and mortality (6 studies; RR 1.26, 95% CI 1.12, 1.39). The pooled estimate of multivariate RRs did not differ significantly by sex. Hyperuricemia may modestly increase the risks of both stroke incidence and mortality. Future research is needed to determine whether lowering uric acid level has any beneficial effects on stroke.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Int Med Res
                Journal ID (iso-abbrev): J. Int. Med. Res
                Journal ID (publisher-id): IMR
                Journal ID (hwp): spimr
                Title: The Journal of International Medical Research
                Publisher: SAGE Publications (Sage UK: London, England )
                ISSN (Print): 0300-0605
                ISSN (Electronic): 1473-2300
                Publication date (Electronic): 05 March 2019
                Publication date (Print): May 2019
                Volume: 47
                Issue: 5
                Pages: 1927-1935
                Affiliations
                [1 ]Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
                [2 ]Department of Endocrinology, Jining First People’s Hospital, Jining, Shandong, China
                [3 ]Department of Endocrinology, Heze Hospital of Traditional Chinese Medicine, Heze, Shandong, China
                [4 ]Department of Endocrinology, Rizhao First People’s Hospital, Rizhao, Shandong, China
                Author notes
                [*]Yangang Wang, Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao266003, Shandong, China. Email: 15668186286@ 123456163.com
                Author information
                https://orcid.org/0000-0002-5367-0425
                Article
                Publisher ID: 10.1177_0300060519831182
                DOI: 10.1177/0300060519831182
                PMC ID: 6567774
                PubMed ID: 30832523
                SO-VID: e819c043-61c3-45fa-931b-31b6c3798818
                Copyright © © The Author(s) 2019
                License:

                Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Date received : 5 September 2018
                Date accepted : 24 January 2019
                Categories
                Subject: Clinical Research Reports

                Keywords: chuanhu anti-gout mixture,hyperuricemia,renal dysfunction,traditional chinese medicine,xanthine oxidase,urate transporter 1
                Data availability:
                Keywords: chuanhu anti-gout mixture, hyperuricemia, renal dysfunction, traditional chinese medicine, xanthine oxidase, urate transporter 1

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