Over the last decade, there is accumulating evidence for a role of reactive oxygen metabolites in the pathogenesis of a variety of renal diseases, including gentamicin, glycerol, cisplatin, and cyclosporine A models of toxic acute renal failure. Gentamicin has been shown both in in vitro and in vivo studies to enhance the generation of reactive oxygen metabolites. Iron is important in models of tissue injury, presumably because it is capable of catalyzing free-radical formation. Gentamicin has been shown to cause release of iron from renal cortical mitochondria. Scavengers of reactive oxygen metabolites as well as iron chelators provide protection in gentamicin-induced nephrotoxicity. In glycerol-induced acute renal failure, an animal model of rhabdomyolysis, there is enhanced generation of hydrogen peroxide, and scavengers of reactive oxygen metabolites and iron chelators provide protection. Although the dogma is that the myoglobin is the source of iron, recent studies suggest that cytochrome P450 may be an important source of iron in this model. In addition, there are marked alterations in antioxidant defenses, such as glutathione, as well as changes in heme oxygenase. Several recent in vitro and in vivo studies indicate an important role of reactive oxygen metabolites in cisplatin-induced nephrotoxicity. Thus, catalytic iron is increased both in vitro and in vivo by cisplatin, and iron chelators as well as hydroxyl radical scavengers have been shown to be protective. Recent studies indicate that cytochrome P450 may also be an important source of the catalytic iron in cisplatin nephrotoxicity. Cyclosporine A has been shown to enhance generation of hydrogen peroxide in vitro and enhance lipid peroxidation in vitro and in vivo. Antioxidants have been shown to be protective in cyclosporine A nephrotoxicity. This collective body of evidence suggests an important role for reactive oxygen metabolites in toxic acute renal failure and may provide therapeutic opportunities of preventing or treating acute renal failure in humans.

https://www.ajkd.org/article/S0272-6386(97)90212-2/pdf

Oxidant mechanisms in toxic acute renal failure

Hydrogen peroxide (H2O2) is suspected to be involved in numerous brain pathologies such as neurodegenerative diseases or in acute injury such as ischemia or trauma. In this study, we examined the ability of pyruvate to improve the survival of cultured striatal neurons exposed for 30 min to H2O2, as estimated 24 hr later by the 3-[4,5-dimethylthiazol-2-yl]−2,5-diphenyltetrazoliumbromide assay. Pyruvate strongly protected neurons against both H2O2 added to the external medium and H2O2 endogenously produced through the redox cycling of the experimental quinone menadione. The neuroprotective effect of pyruvate appeared to result rather from the ability of α-ketoacids to undergo nonenzymatic decarboxylation in the presence of H2O2 than from an improvement of energy metabolism. Indeed, several other α-ketoacids, including α-ketobutyrate, which is not an energy substrate, reproduced the neuroprotective effect of pyruvate. In contrast, lactate, a neuronal energy substrate, did not protect neurons from H2O2. Optimal neuroprotection was achieved with relatively low concentrations of pyruvate (≤1 mm), whereas at high concentration (10 mm) pyruvate was ineffective. This paradox could result from the cytosolic acidification induced by the cotransport of pyruvate and protons into neurons. Indeed, cytosolic acidification both enhanced the H2O2-induced neurotoxicity and decreased the rate of pyruvate decarboxylation by H2O2. Together, these results indicate that pyruvate efficiently protects neurons against both exogenous and endogenous H2O2. Its low toxicity and its capacity to cross the blood–brain barrier open a new therapeutic perspective in brain pathologies in which H2O2is involved.

https://www.jneurosci.org/content/jneuro/17/23/9060.full.pdf

Pyruvate Protects Neurons against Hydrogen Peroxide-Induced Toxicity

The widespread existence of unhealed wounds, ulcers, and burns has a great impact on public health and economy. Many interventions, including new medications and technologies, are being used to help achieve significant wound healing and to eliminate infections. Therefore, to find an intervention that has both therapeutic effect on the healing process and the ability to kill microbes is of great value. Honey is a natural product that has been recently introduced in modern medical practice. Honey's antibacterial properties and its effects on wound healing have been thoroughly investigated. Laboratory studies and clinical trials have shown that honey is an effective broad-spectrum antibacterial agent. This paper reviews data that support the effectiveness of natural honey in wound healing and its ability to sterilize infected wounds. Studies on the therapeutic effects of honey collected in different geographical areas on skin wounds, skin and gastric ulcers, and burns are reviewed and mechanisms of action are discussed. (Ulcers and burns are included as an example of challenging wounds.) The data show that the wound healing properties of honey include stimulation of tissue growth, enhanced epithelialization, and minimized scar formation. These effects are ascribed to honey's acidity, hydrogen peroxide content, osmotic effect, nutritional and antioxidant contents, stimulation of immunity, and to unidentified compounds. Prostaglandins and nitric oxide play a major role in inflammation, microbial killing, and the healing process. Honey was found to lower prostaglandin levels and elevate nitric oxide end products. These properties might help to explain some biological and therapeutic properties of honey, particularly as an antibacterial agent or wound healer. The data presented here demonstrate that honeys from different geographical areas have considerable therapeutic effects on chronic wounds, ulcers, and burns. The results encourage the use of honey in clinical practice as a natural and safe wound healer.

/pdf/honey-for-wound-healing-ulcers-and-burns-data-supporting-its-vdf3rxscca.pdf

Honey for wound healing, ulcers, and burns; data supporting its use in clinical practice.

Induction of heme oxygenase in toxic renal injury: A protective role in cisplatin nephrotoxicity in the rat

The effectiveness of honey as a therapeutic agent has been unequivocally demonstrated in the literature reviewed in Part 1 of this article published in 1999, but the biochemical explanation of these effects is more hypothetical. However, a rational explanation can be seen when one looks at the scientific literature outside that on honey. Some of the components of honey are substances known to have physiological actions that would explain many of its therapeutic effects. In addition, research on honey has shown directly that it has physiological actions that would give therapeutic effects.

https://researchcommons.waikato.ac.nz/bitstream/handle/10289/2060/why%20honey%20is%20effective%202.pdf?sequence=1&isAllowed=y

Why honey is effective as a medicine. 2. The scientific explanation of its effects

Hydrogen peroxide (H2O2) contributes to renal cellular injury. alpha-Keto acids nonenzymatically reduce H2O2 to water while undergoing decarboxylation at the 1-carbon (1-C) position. We examined, in vitro and in vivo, the protective role of sodium pyruvate in H2O2-induced renal injury. Pyruvate effectively scavenged H2O2 in vitro, and suppressed H2O2-induced renal lipid peroxidation. Injury to LLC-PK1 cells induced by hydrogen peroxide was attenuated by pyruvate to an extent comparable to that seen with catalase. Studies utilizing [1-14C]pyruvate further demonstrated 1-C decarboxylation concurrent with cytoprotection by pyruvate from H2O2-induced injury. Pyruvate was also protective in vivo. Infusion of pyruvate before and during the intrarenal infusion of H2O2 attenuated H2O2-induced proteinuria. Systemic administration of pyruvate was also protective in the glycerol model of acute renal failure, a model also characterized by increased generation of H2O2. These findings indicate that pyruvate, a ubiquitous alpha-keto acid, scavenges H2O2 and protects renal tissue in vitro and in vivo from H2O2-mediated injury. These data suggest a potential therapeutic role for pyruvate in diseases in which increased generation of H2O2 is incriminated in renal damage.

/pdf/hydrogen-peroxide-induced-renal-injury-a-protective-role-for-v0j77js4kq.pdf

Edward C. Clark

Papers

Hydrogen peroxide-induced renal injury. A protective role for pyruvate in vitro and in vivo.