Pyridoxamine protects proteins from damage by hypohalous acids in vitro and in vivo

Madu, Hartman; Avance, Josh; Chetyrkin, Sergei V.; Darris, Carl; Rose, Kristie L.; Sánchez, Otto A.; Hudson, Billy G.; Voziyan, Paul A.

doi:10.1016/j.freeradbiomed.2015.07.001

Cited by 10 publications

(13 citation statements)

References 29 publications

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“…Mechanism of PM action in AKI also appears to involve amelioration of renal oxidative stress, as indicated by a dosedependent reduction in the ratio of renal isofuran/F2-isoprostane lipid peroxidation products, the key marker of tissue oxidative stress (21,37). This mechanism of action is consistent with previous structural and functional studies of PM in vitro and in vivo (33,59).…”

Section: Discussionsupporting

confidence: 87%

“…Pyridoxamine (PM) is a structural analog of pyridoxal phosphate (vitamin B 6 ) that can interfere with oxidative stress via a number of different mechanisms (33,59). These include: scavenging of RCS, including products of lipid peroxidation; detoxification of hypohalous acids; and sequestration of catalytic transition metal ions such as copper and iron, which are essential in the production of toxic ROS and RCS (58).…”

mentioning

confidence: 99%

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Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury

Skrypnyk

Voziyan

Yang

et al. 2016

American Journal of Physiology-Renal Physiology

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Acute kidney injury (AKI) is a common and independent risk factor for death and chronic kidney disease (CKD). Despite promising preclinical data, there is no evidence that antioxidants reduce the severity of injury, increase recovery, or prevent CKD in patients with AKI. Pyridoxamine (PM) is a structural analog of vitamin B6 that interferes with oxidative macromolecular damage via a number of different mechanisms and is in a phase 3 clinical efficacy trial to delay CKD progression in patients with diabetic kidney disease. Because oxidative stress is implicated as one of the main drivers of renal injury after AKI, the ability of PM to interfere with multiple aspects of oxidative damage may be favorable for AKI treatment. In these studies we therefore evaluated PM treatment in a mouse model of AKI. Pretreatment with PM caused a dose-dependent reduction in acute tubular injury, long-term postinjury fibrosis, as well as improved functional recovery after ischemia-reperfusion AKI (IR-AKI). This was associated with a dose-dependent reduction in the oxidative stress marker isofuran-to-F2-isoprostane ratio, indicating that PM reduces renal oxidative damage post-AKI. PM also reduced postinjury fibrosis when administered 24 h after the initiating injury, but this was not associated with improvement in functional recovery after IR-AKI. This is the first report showing that treatment with PM reduces short- and long-term injury, fibrosis, and renal functional recovery after IR-AKI. These preclinical findings suggest that PM, which has a favorable clinical safety profile, holds therapeutic promise for AKI and, most importantly, for prevention of adverse long-term outcomes after AKI.

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Section: Discussionsupporting

confidence: 87%

mentioning

confidence: 99%

Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury

Skrypnyk

Voziyan

Yang

et al. 2016

American Journal of Physiology-Renal Physiology

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“…In addition, the oxidation of HDL may also be alternatively mediated by MPO-derived hypochlorous acid (HOCl). Both 2-HOBA and PPM are electron rich molecules, which may readily react with HOCl [51]. Importantly, in vivo administration of reactive dicarbonyl scavengers to Ldlr −/− mice consuming a western diet, which increases oxidative stress, enhanced PON1 activity and HDL cholesterol efflux capacity (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Reactive Dicarbonyl Scavenging Effectively Reduces MPO-Mediated Oxidation of HDL and Restores PON1 Activity

et al. 2020

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Atheroprotective functions of high-density lipoproteins (HDL) are related to the activity of HDL-associated enzymes such as paraoxonase 1 (PON1). We examined the impact of inhibition of myeloperoxidase (MPO)-mediated HDL oxidation by PON1 on HDL malondialdehyde (MDA) content and HDL function. In the presence of PON1, crosslinking of apoAI in response to MPO-mediated oxidation of HDL was abolished, and MDA-HDL adduct levels were decreased. PON1 prevented the impaired cholesterol efflux capacity of MPO-oxidized HDL from Apoe−/− macrophages. Direct modification of HDL with MDA increased apoAI crosslinking and reduced the cholesterol efflux capacity. MDA modification of HDL reduced its anti-inflammatory function compared to native HDL. MDA-HDL also had impaired ability to increase PON1 activity. Importantly, HDL from subjects with familial hypercholesterolemia (FH-HDL) versus controls had increased MDA-apoAI adducts, and PON1 activity was also impaired in FH. Consistently, FH-HDL induced a pro-inflammatory response in Apoe−/− macrophages and had an impaired ability to promote cholesterol efflux. Interestingly, reactive dicarbonyl scavengers, including 2-hydroxybenzylamine (2-HOBA) and pentyl-pyridoxamine (PPM), effectively abolished MPO-mediated apoAI crosslinking, MDA adduct formation, and improved cholesterol efflux capacity. Treatment of hypercholesterolemic mice with reactive dicarbonyl scavengers reduced MDA-HDL adduct formation and increased HDL cholesterol efflux capacity, supporting the therapeutic potential of reactive carbonyl scavenging for improving HDL function.

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“…Among these biomolecules, B 6 -vitamers deserve special recognition since they have been shown to exert protection against chlorination stress as assessed using in vivo disease models, an effect attributed to formation of stabilized chloramine derivatives (110). Likewise, imidazole-derivatives (e.g.…”

Section: Endogenous Phytochemical and Synthetic Hocl-antagonists: Ant...mentioning

confidence: 99%

“…Nephrotoxity and urogenital tract dysfunction are established pathological outcomes of chlorination stress. Among other pathologies, acute kidney injury, glomerulonephritis, diabetic nephropathy, and bladder cancer have been associated with exposure to pathological chlorination stress (110,(162)(163)(164)(165)(166).…”

Section: Human Target Organs Of Environmental Chlorination Stressmentioning

confidence: 99%

Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer

2022

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A multitude of extrinsic environmental factors (referred to in their entirety as the ‘skin exposome’) impact structure and function of skin and its corresponding cellular components. The complex (i.e. additive, antagonistic, or synergistic) interactions between multiple extrinsic (exposome) and intrinsic (biological) factors are important determinants of skin health outcomes. Here, we review the role of hypochlorous acid (HOCl) as an emerging component of the skin exposome serving molecular functions as an innate immune factor, environmental toxicant, and topical chemopreventive agent targeting solar UV-induced skin cancer. HOCl [and its corresponding anion (OCl-; hypochlorite)], a weak halogen-based acid and powerful oxidant, serves two seemingly unrelated molecular roles: (i) as an innate immune factor [acting as a myeloperoxidase (MPO)-derived microbicidal factor] and (ii) as a chemical disinfectant used in freshwater processing on a global scale, both in the context of drinking water safety and recreational freshwater use. Physicochemical properties (including redox potential and photon absorptivity) determine chemical reactivity of HOCl towards select biochemical targets [i.e. proteins (e.g. IKK, GRP78, HSA, Keap1/NRF2), lipids, and nucleic acids], essential to its role in innate immunity, antimicrobial disinfection, and therapeutic anti-inflammatory use. Recent studies have explored the interaction between solar UV and HOCl-related environmental co-exposures identifying a heretofore unrecognized photo-chemopreventive activity of topical HOCl and chlorination stress that blocks tumorigenic inflammatory progression in UV-induced high-risk SKH-1 mouse skin, a finding with potential implications for the prevention of human nonmelanoma skin photocarcinogenesis.

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Pyridoxamine protects proteins from damage by hypohalous acids in vitro and in vivo

Cited by 10 publications

References 29 publications

Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury

Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury

Reactive Dicarbonyl Scavenging Effectively Reduces MPO-Mediated Oxidation of HDL and Restores PON1 Activity

Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer

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