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Micronutrients
Published in Chuong Pham-Huy, Bruno Pham Huy, Food and Lifestyle in Health and Disease, 2022
Chuong Pham-Huy, Bruno Pham Huy
Molybdenum (Mo) is an essential micro-mineral and acts as a cofactor for the activities of several enzymes in the human body including xanthine oxidase, aldehyde oxidase, sulfite oxidase, nitrate reductase, and hydrogenase (4, 6, 8–9). Xanthine oxidase and aldehyde oxidase play a role in iron utilization as well as in cellular metabolism and electron transport. Xanthine oxidase is also used in the uptake and release of iron from ferritin in the intestinal mucosa and in the release of iron from ferritin in the liver, placenta, and erythropoietic tissues to the ferrous form (8). Xanthine oxidase and hydrogenase play a role in the production of uric acid from hypoxanthine and xanthine (4). Aldehyde oxidase oxidizes and detoxifies purines and pyrimidines, while sulfite oxidase containing molybdenum incorporated as part of the molecule, is used for the conversion of sulfite to sulfate (4).
Cellular and Molecular Mechanisms of Ischemic Acute Renal Failure and Repair
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Joseph V. Bonventre, Ralph Witzgall
Despite a large amount of investigation, the role of ROS in ischemic kidney injury remains somewhat controversial. Not all investigators agree on protective effects of antioxidants (Greene and Paller, 1991) nor do all agree on the presence of enhanced lipid peroxidation or ROS generation with ischemia (Gamelin and Zager, 1988; Greene and Paller, 1991). Some have reported protection with exogenously administered superoxide dismutase, or catalase. Allopurinol, which has been used to inhibit xanthine oxidase, has also had mixed success as a protective agent (Borkan and Schwartz, 1989). Furthermore, the human kidney likely has very little xanthine oxidase (Southard, et al., 1987). Glutathione, normally present in high amounts in tubular cells, can neutralize ROS. Cellular glutathione levels fall with hypoxia and reduced cellular glutathione levels sensitize cells to oxidative stress (Arrick, et al., 1982). As with other ROS scavengers, results with glutathione are conflicting (Paller, 1988; Yang, et al., 1990). It has been argued that protective effects of this compound are due to the generation of glycine, its metabolic product, which is protective independent of any effect on ROS (Weinberg, 1991).
Role of Vasoactive Intestinal Peptide in Myocardial Ischemia Reperfusion Injury
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Dipak K. Das, Nilanjana Maulik, Richard M. Engelman
VIP also possesses free-radical scavenging properties in in-vivo systems. One of the biological sources of the reactive oxygen species is the xanthine/xanthine oxidase system. The addition of this oxygen free-radical-generating system to perfused rat lungs increased both peak airway pressure and perfusion pressure, simultaneously resulting in pulmonary edema and increased protein content in broncho-alveolar lavage fluid (73). Treatment with 1–10 mg/kg/min of VIP significantly inhibited or completely abolished all signs of injury and reduced or abolished the generation of arachidonic acid products, suggesting that VIP may function as a physiological modulator of inflammatory tissue damage resulting from toxic oxygen species. Another, related study demonstrated that VIP does not cause generation of oxygen free radicals in any form and that the vasodilatory actions of VIP is not mediated through the generation of reactive oxygen species (74).
Engineered Escherichia coli Nissle 1917 with urate oxidase and an oxygen-recycling system for hyperuricemia treatment
Published in Gut Microbes, 2022
Rui Zhao, Zimai Li, Yuqing Sun, Wei Ge, Mingyu Wang, Huaiwei Liu, Luying Xun, Yongzhen Xia
Hyperuricemia could be treated either by reducing UA production or promoting UA excretion through the kidney, which are two major factors leading to the development of hyperuricemia.6 There are four clinical treatment options. First, diet control is used to reduce the intake of purines and nucleosides.7 Second, xanthine oxidase inhibitors such as allopurinol, oxypurinol, and febuxostat, are used to inhibit the activity of xanthine oxidase to reduce UA production.8 Third, URAT1 (human urate transporter 1), which is a key UA transporter and is responsible for reabsorbing UA from the renal tubule into cells,9,10 is inhibited by drugs such as probenecid, benzbromarone, and losartan to reduce UA absorption in the renal tubules.11 Fourth, UA is degraded in the blood by supplementing exogenous UOX.12
In vitro enzyme inhibition and in vivo anti-hyperuricemic potential of eugenol: an experimental approach
Published in Drug Development and Industrial Pharmacy, 2021
V. Vijeesh, A. Vysakh, Ninan Jisha, M. S. Latha
The global index of the hyperuricemia incidence has reached 1.13 billion in 2015 [16]. The incidence of hyperuricemia and its associated diseases were increased in many countries during the last decades [17]. When the serum urate levels exceed the normal threshold, it leads to the hyperuricemia [18]. Exogenous purine intake, a source of uric acid production ranges from 100 to 200 mg per day, with the majority of serum uric acid coming from endogenous sources such as nucleic acid breakdown and de novo purine production [19]. That is why the elevated levels of uric acid in an individual with preoperative condition are considered as a potential risk factor for the development of postoperative hyperuricemia linked complications [20]. Hyperuricemia is one of the signs of tumor lysis syndrome [21]. The frequent consumption of organ meat, seafood, alcohol, etc. also increases the risk of hyperuricemia condition [22]. The recent studies proposed that the fructose metabolism, high intracellular glucose and excess fat storage are positively correlated with high level of uric acid production [23–25]. Xanthine oxidase is a therapeutic target in humans because it catalyzes the conversion of purines to uric acid. The hyperuricemia condition can be induced in rat model by inhibiting the uricase enzyme. PO is a well-known uricase inhibiting agent commonly used to induce hyperuricemia condition.
Recent approaches to gout drug discovery: an update
Published in Expert Opinion on Drug Discovery, 2020
Naoyuki Otani, Motoshi Ouchi, Hideo Kudo, Shuichi Tsuruoka, Ichiro Hisatome, Naohiko Anzai
Considering these challenges, new therapies are needed for patients with hyperuricemia who cannot achieve sufficient urate reduction with current therapies. Recent progress on molecularly targeted therapies has generated interest in drug discovery targeting transporters. Lesinurad is an orally administered selective inhibitor of the kidneys’ URAT1 and OAT4, via which it inhibits urate reabsorption and thus increases renal urate excretion and lowers serum urate levels. Currently, it is indicated for use in combination with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone. FYU-981(Dotinurad) is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by selective inhibition of URAT1, and was approved in Japan on November 2019. Possible drug discovery targets include not only URAT1 but also other transporters, such as URATv1/GLUT9 and NPT4. Furthermore, the urate transportsome is pivotal as a new concept for regulating urate excretion; if its functional and molecular characterization progresses, it may also become a new target for drug discovery. Drug discovery targeting other transporters, such as URATv1/GLUT9 and NPT4 are being developed in early phase. However, results from pivotal trials are waited for some novel agents.