Paraquat (PQ, 1,1'-dimethyl-4-4'-bipyridinium dichloride) is a highly toxic quaternary ammonium herbicide widely used in agriculture, it exerts its toxic effects mainly because of its redox cycle through the production of superoxide anions in organisms, leading to an imbalance in the redox state of the cell causing oxidative damage and finally cell death. The contribution of mitochondrial dysfunction including increased production of reactive oxygen species besides the reduction in oxygen consumption as well as in the activity of some respiratory complexes has emerged as a key component in the mechanisms through which PQ induces cell death. Although several aspects of PQ-mitochondria interaction remain to be clarified, recent advances have been conducted with reproducible results. Currently, there is no treatment for PQ poisoning; however, several studies taking into account oxidative stress as the main mechanism of PQ-induced toxicity suggest an antioxidant therapy as a viable alternative. In fact, it has been shown that the antioxidants naringin, sylimarin, edaravone, Bathysa cuspidata extracts, alpha-lipoic acid, pirfenidone, lysine acetylsalicylate, selenium, quercetin, C-phycocyanin, bacosides, and vitamin C may be useful in the treatment against PQ toxicity. The main mechanisms involved in the protective effect of these antioxidants include the reduction of oxidative stress and inflammation and the induction of antioxidant defenses. Interestingly, recent findings suggest that the induction of nuclear factor erythroid like-2 (Nrf2), a major regulator of the antioxidant response, by some of the above-mentioned antioxidants, has been involved in the protective effect against PQ-induced toxicity.
Oxidative stress (OS) has greatly interested the research community in understanding damaging processes occurring in cells. OS is triggered by an imbalance between reactive oxygen species (ROS) production and their elimination by the antioxidant system; however, ROS function as second messengers under physiological conditions. ROS are produced from endogenous and exogenous sources. Endogenous sources involve mitochondria, nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), oxidases (NOXs), endoplasmic reticulum (ER), xanthine oxidases (XO), endothelial nitric oxide synthase (eNOs), and others. In contrast, exogenous ROS might be generated through ultraviolet (UV) light, ionizing radiation (IR), contaminants, and heavy metals, among others. It can damage DNA, lipids, and proteins if OS is not controlled. To avoid oxidative damage, antioxidant systems are activated. In the present review, we focus on the basic concepts of OS, highlighting the production of reactive oxygen and nitrogen species (RONS) derived from internal and external sources and the last elimination. Moreover, we include the cellular antioxidant system regulation and their ability to decrease OS. External antioxidants are also proposed as alternatives to ameliorate OS. Finally, we review diseases involving OS and their mechanisms.
The potential protective effect of the dietary antioxidant curcumin (120 mg/Kg/day for 6 days) against the renal injury induced by maleate was evaluated. Tubular proteinuria and oxidative stress were induced by a single injection of maleate (400 mg/kg) in rats. Maleate-induced renal injury included increase in renal vascular resistance and in the urinary excretion of total protein, glucose, sodium, neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl β-D-glucosaminidase (NAG), upregulation of kidney injury molecule (KIM)-1, decrease in renal blood flow and claudin-2 expression besides of necrosis and apoptosis of tubular cells on 24 h. Oxidative stress was determined by measuring the oxidation of lipids and proteins and diminution in renal Nrf2 levels. Studies were also conducted in renal epithelial LLC-PK1 cells and in mitochondria isolated from kidneys of all the experimental groups. Maleate induced cell damage and reactive oxygen species (ROS) production in LLC-PK1 cells in culture. In addition, maleate treatment reduced oxygen consumption in ADP-stimulated mitochondria and diminished respiratory control index when using malate/glutamate as substrate. The activities of both complex I and aconitase were also diminished. All the above-described alterations were prevented by curcumin. It is concluded that curcumin is able to attenuate in vivo maleate-induced nephropathy and in vitro cell damage. The in vivo protection was associated to the prevention of oxidative stress and preservation of mitochondrial oxygen consumption and activity of respiratory complex I, and the in vitro protection was associated to the prevention of ROS production.
Intrastriatal injection of quinolinic acid (QUIN) to rodents reproduces some biochemical, morphological, and behavioral characteristics of Huntington's disease. NAD(P)H oxidase is an enzymatic complex that catalyzes superoxide anion (O(2).(-)) production from O(2) and NADPH. The present study evaluated the role of NAD(P)H oxidase in the striatal damage induced by QUIN (240 nmol/microl) in adult male Wistar rats by means of apocynin (APO; 5 mg/kg i.p.), a specific NAD(P)H oxidase inhibitor. Rats were given APO 30 min before and 1 hr after QUIN injection or only 30 min after QUIN injection. NAD(P)H oxidase activity was measured in striatal homogenates by O2(*)(-) production. QUIN infusion to rats significantly increased striatal NAD(P)H oxidase activity (2 hr postlesion), whereas APO treatments decreased the QUIN-induced enzyme activity (2 hr postlesion), lipid peroxidation (3 hr postlesion), circling behavior (6 days postlesion), and histological damage (7 days postlesion). The addition of NADH to striatal homogenates increased NAD(P)H oxidase activity in striata from QUIN-treated animals but not from sham rats. Interestingly, O2(*)(-) production in QUIN-lesioned striata was unaffected by the addition of substrates for intramitochondrial O2(*)(-) production, xanthine oxidase and nitric oxide synthase, suggesting that NAD(P)H oxidase may be the main source of O2(*)(-) in QUIN-treated rats. Moreover, the administration of MK-801 to rats as a pretreatment resulted in a complete prevention of the QUIN-induced NAD(P)H activation, suggesting that this toxic event is completely dependent on N-methyl-D-aspartate receptor overactivation. Our results also suggest that NAD(P)H oxidase is involved in the pathogenic events linked to excitotoxic/prooxidant conditions.
Severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2) causes coronavirus disease 2019 (COVID‐19), characterised by high levels of inflammation and oxidative stress (OS). Oxidative stress induces oxidative damage to lipids, proteins, and DNA, causing tissue damage. Both inflammation and OS contribute to multi‐organ failure in severe cases. Magnesium (Mg 2+ ) regulates many processes, including antioxidant and anti‐inflammatory responses, as well as the proper functioning of other micronutrients such as vitamin D. In addition, Mg 2+ participates as a second signalling messenger in the activation of T cells. Therefore, Mg 2+ deficiency can cause immunodeficiency, exaggerated acute inflammatory response, decreased antioxidant response, and OS. Supplementation with Mg 2+ has an anti‐inflammatory response by reducing the levels of nuclear factor kappa B (NF‐κB), interleukin (IL) ‐6, and tumor necrosis factor alpha. Furthermore, Mg 2+ supplementation improves mitochondrial function and increases the antioxidant glutathione (GSH) content, reducing OS. Therefore, Mg 2+ supplementation is a potential way to reduce inflammation and OS, strengthening the immune system to manage COVID‐19. This narrative review will address Mg 2+ deficiency associated with a worse disease prognosis, Mg 2+ supplementation as a potent antioxidant and anti‐inflammatory therapy during and after COVID‐19 disease, and suggest that randomised controlled trials are indicated.
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