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      Influence of Resveratrol on the Cardiovascular Health Effects of Chronic Kidney Disease

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          Abstract

          Cardiovascular disease (CVD) is closely related to chronic kidney disease (CKD), and patients with CKD have a high risk of CVD-related mortality. Traditional CVD risk factors cannot account for the higher cardiovascular risk of patients with CKD, and standard CVD interventions cannot reduce the mortality rates among patients with CKD. Nontraditional factors related to mineral and vitamin-D metabolic disorders provide some explanation for the increased CVD risk. Non-dialyzable toxins, indoxyl sulfate (IS) and p-cresol sulfate (PCS)—produced in the liver by colonic microorganisms—cause kidney and vascular dysfunction. Plasma trimethylamine-N-oxide (TMAO)—a gut microbe-dependent metabolite of dietary L-carnitine and choline—is elevated in CKD and related to vascular disease, resulting in poorer long-term survival. Therefore, the modulation of colonic flora can improve prospects for patients with CKD. Managing metabolic syndrome, anemia, and abnormal mineral metabolism is recommended for the prevention of CVD in patients with CKD. Considering nontraditional risk factors, the use of resveratrol (RSV), a nutraceutical, can be helpful for patients with CVD and CKD. This paper discusses the beneficial effects of RSV on biologic, pathophysiological and clinical responses, including improvements in intestinal epithelial integrity, modulation of the intestinal microbiota and reduction in hepatic synthesis of IS, PCS and TMAO in patients with CVD and CKD.

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          Most cited references95

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          High absorption but very low bioavailability of oral resveratrol in humans.

          The dietary polyphenol resveratrol has been shown to have chemopreventive activity against cardiovascular disease and a variety of cancers in model systems, but it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans. In this study, we examined the absorption, bioavailability, and metabolism of 14C-resveratrol after oral and i.v. doses in six human volunteers. The absorption of a dietary relevant 25-mg oral dose was at least 70%, with peak plasma levels of resveratrol and metabolites of 491 +/- 90 ng/ml (about 2 microM) and a plasma half-life of 9.2 +/- 0.6 h. However, only trace amounts of unchanged resveratrol (<5 ng/ml) could be detected in plasma. Most of the oral dose was recovered in urine, and liquid chromatography/mass spectrometry analysis identified three metabolic pathways, i.e., sulfate and glucuronic acid conjugation of the phenolic groups and, interestingly, hydrogenation of the aliphatic double bond, the latter likely produced by the intestinal microflora. Extremely rapid sulfate conjugation by the intestine/liver appears to be the rate-limiting step in resveratrol's bioavailability. Although the systemic bioavailability of resveratrol is very low, accumulation of resveratrol in epithelial cells along the aerodigestive tract and potentially active resveratrol metabolites may still produce cancer-preventive and other effects.
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            Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients.

            As a major component of uremic syndrome, cardiovascular disease is largely responsible for the high mortality observed in chronic kidney disease (CKD). Preclinical studies have evidenced an association between serum levels of indoxyl sulfate (IS, a protein-bound uremic toxin) and vascular alterations. The aim of this study is to investigate the association between serum IS, vascular calcification, vascular stiffness, and mortality in a cohort of CKD patients. One-hundred and thirty-nine patients (mean +/- SD age: 67 +/- 12; 60% male) at different stages of CKD (8% at stage 2, 26.5% at stage 3, 26.5% at stage 4, 7% at stage 5, and 32% at stage 5D) were enrolled. Baseline IS levels presented an inverse relationship with renal function and a direct relationship with aortic calcification and pulse wave velocity. During the follow-up period (605 +/- 217 d), 25 patients died, mostly because of cardiovascular events (n = 18). In crude survival analyses, the highest IS tertile was a powerful predictor of overall and cardiovascular mortality (P = 0.001 and 0.012, respectively). The predictive power of IS for death was maintained after adjustment for age, gender, diabetes, albumin, hemoglobin, phosphate, and aortic calcification. The study presented here indicates that IS may have a significant role in the vascular disease and higher mortality observed in CKD patients.
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              Properties of Resveratrol: In Vitro and In Vivo Studies about Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans

              Plants containing resveratrol have been used effectively in traditional medicine for over 2000 years. It can be found in some plants, fruits, and derivatives, such as red wine. Therefore, it can be administered by either consuming these natural products or intaking nutraceutical pills. Resveratrol exhibits a wide range of beneficial properties, and this may be due to its molecular structure, which endow resveratrol with the ability to bind to many biomolecules. Among these properties its activity as an anticancer agent, a platelet antiaggregation agent, and an antioxidant, as well as its antiaging, antifrailty, anti-inflammatory, antiallergenic, and so forth activities, is worth highlighting. These beneficial biological properties have been extensively studied in humans and animal models, both in vitro and in vivo. The issue of bioavailability of resveratrol is of paramount importance and is determined by its rapid elimination and the fact that its absorption is highly effective, but the first hepatic step leaves little free resveratrol. Clarifying aspects like stability and pharmacokinetics of resveratrol metabolites would be fundamental to understand and apply the therapeutic properties of resveratrol.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                31 August 2020
                September 2020
                : 21
                : 17
                : 6294
                Affiliations
                [1 ]Division of Cardiovascular Surgery, Department of Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; doc98017@ 123456gmail.com (J.-Y.S.); frederick_shen@ 123456hotmail.com (T.-C.S.)
                [2 ]School of Medicine, Tzu Chi University, Hualien 970, Taiwan
                [3 ]Division of Nephrology, Department of Medicine, Cardinal-Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 234, Taiwan; athletics910@ 123456gmail.com
                [4 ]Division of Nephrology, Department of Internal Medicine, En Chu Kong Hospital, New Taipei City 237, Taiwan; cjf6699@ 123456gmail.com
                [5 ]Division of Nephrology, Department of Medicine, Fu Jen Catholic University Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan; janlin0123@ 123456gmail.com
                [6 ]Division of Nephrology, Department of Medicine, Taipei Hospital, Ministry of Health and Welfare, New Taipei City 242, Taiwan; wayneliu55@ 123456gmail.com
                [7 ]Department of Pediatrics, Taoyuan Armed Forces General Hospital, Taoyuan City 325, Taiwan; mythnobody0221@ 123456gmail.com (P.-J.C.); dreamvenice@ 123456hotmail.com (B.-H.C.)
                [8 ]Taipei Medical University-Research Center of Urology and Kidney, Taipei Medical University, Taipei 110, Taiwan
                [9 ]Division of Nephrology, Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, New Taipei City 235, Taiwan
                [10 ]Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
                [11 ]Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; kuochenglu@ 123456gmail.com
                Author notes
                [* ]Correspondence: 11044@ 123456s.tmu.edu.tw
                [†]

                These authors contributed equally.

                Author information
                https://orcid.org/0000-0002-9903-7473
                https://orcid.org/0000-0002-9452-5179
                https://orcid.org/0000-0003-0370-3951
                Article
                ijms-21-06294
                10.3390/ijms21176294
                7504483
                307b3b39-5ee4-4a46-adaf-476bd94fa4a9
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 15 August 2020
                : 28 August 2020
                Categories
                Review

                Molecular biology
                cardiovascular disease,chronic kidney disease,indoxyl sulfate,microbiota,p-cresol sulfate,resveratrol,trimethylamine-n-oxide

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