Enantioselectivity in some physiological and pathophysiological roles of hydroxyeicosatetraenoic acids.

The phenomenon of chirality has been shown to greatly impact drug activities and effects. Different enantiomers may exhibit different effects in a certain biological condition or disease state. Cytochrome P450 (CYP) enzymes metabolize arachidonic acid (AA) into a large variety of metabolites with a wide range of activities. Hydroxylation of AA by CYP hydroxylases produces hydroxyeicosatetraenoic acids (HETEs), which are classified into mid-chain (5, 8, 9, 11, 12, and 15-HETE), subterminal (16-, 17-, 18- and 19-HETE) and terminal (20-HETE) HETEs. Except for 20-HETE, these metabolites exist as a racemic mixture of R and S enantiomers in the physiological system. The two enantiomers could have different degrees of activity or sometimes opposing effects. In this review article, we aimed to discuss the role of mid-chain and subterminal HETEs in different organs, importantly the heart and the kidneys. Moreover, we summarized their effects in some conditions such as neutrophil migration, inflammation, angiogenesis, and tumorigenesis, with a focus on the reported enantiospecific effects. We also reported some studies using genetically modified models to investigate the roles of HETEs in different conditions.

Physiological and pathophysiological roles of hepoxilins and their analogs.

The metabolism of arachidonic acid (AA) occurs via different pathways leading to the production of a great number of metabolites with a wide range of biological effects. Hepoxilins (HXs) are physiologically active AA metabolites produced through the lipoxygenase pathway. Since their discovery, several researchers have investigated their biological effects. They were proven to have pro-inflammatory, anti-apoptotic, and skin-protective effects. HXs also contribute to the processes of neutrophil activation and migration and inflammatory hyperalgesia. The major limitation to their effects is that they are highly labile and are metabolized into less active compounds which led to the synthesis of stable HXs analogs called proprietary bioactive therapeutics (PBTs). Although PBTs were synthesized to further study the effect of HXs, they showed different effects than natural HXs under some conditions. PBTs were proven to have anti-inflammatory and anti-cancer effects and were found to be potent antagonists of the thromboxane receptor. In this review article, we aimed to provide an overview of some physiological and pathophysiological effects of hepoxilins and their analogs on the skin, platelet, blood vessel, neutrophil, and cell survival.

Upregulation of PPAR-γ mediates the renoprotective effect of omega-3 PUFA and ferulic acid in gentamicin-intoxicated rats.

Ferulic acid (FrA) is a natural product containing phenolic compounds. ω-3 PUFA is the major constituent of fish oil. The aim of this study was to investigate the renoprotective role of FrA and FO in gentamicin (GM)-induced nephrotoxicity in rats. Forty four male rats were divided equally into 4 groups: Control group, GM group, FrA + GM group and FO + GM group. Each of the treated groups was injected with GM (40 mg/kg) i.p. for 9 consecutive days. FrA (100 mg/kg) and FO (5 mL/kg) were given to rats orally daily for 10 days prior to GM and then concomitantly with GM for additional 9 days. Kidney function was assessed by serum BUN and creatinine, urinary albumin excretion and N-acetyl-beta-D-glucosaminidase (NAG) activity and histopathological examination. The anti-inflammatory property was evaluated by measuring renal resolvin E1 and gene expression of PPAR-γ. The antioxidant activity was indicated by renal catalase (CAT) activity. GM-induced nephrotoxicity was evidenced by the renal histopathological changes along with increased renal indices. Prior and concomitant treatment with FrA or FO ameliorated nephrotoxic effect of GM as indicated by the significant decrease of serum BUN and creatinine, urinary albumin excretion and urinary NAG activity. Both treatments significantly enhanced CAT activity and gene expression of PPAR-γ. Resolvin E1 was significantly elevated in FO but not in FrA group. FrA and FO proved anti-inflammatory and renoprotective effects, which could be through their PPAR-γ agonist activity. Because FrA and FO are natural products, they could provide a safe intervention strategy in cases of exposure to nephrotoxins.