Regulation of Tissue Inflammation by 12-Lipoxygenases

Lipoxygenases (LOXs) are lipid metabolizing enzymes that catalyze the di-oxygenation of polyunsaturated fatty acids to generate active eicosanoid products. 12-lipoxygenases (12-LOXs) primarily oxygenate the 12th carbon of its substrates. Many studies have demonstrated that 12-LOXs and their eicosanoid metabolite 12-hydroxyeicosatetraenoate (12-HETE), have significant pathological implications in inflammatory diseases. Increased level of 12-LOX activity promotes stress (both oxidative and endoplasmic reticulum)-mediated inflammation, leading to damage in these tissues. 12-LOXs are also associated with enhanced cellular migration of immune cells—a characteristic of several metabolic and autoimmune disorders. Genetic depletion or pharmacological inhibition of the enzyme in animal models of various diseases has shown to be protective against disease development and/or progression in animal models in the setting of diabetes, pulmonary, cardiovascular, and metabolic disease, suggesting a translational potential of targeting the enzyme for the treatment of several disorders. In this article, we review the role of 12-LOXs in the pathogenesis of several diseases in which chronic inflammation plays an underlying role.

Deletion of Alox15 improves kidney dysfunction and inhibits fibrosis by increased PGD2 in the kidney

Background Lipid-metabolizing enzymes and their metabolites affect inflammation and fibrosis, but their roles in chronic kidney disease (CKD) have not been completely understood. Methods To clarify their role in CKD, we measured the mRNA levels of major lipid-metabolizing enzymes in 5/6 nephrectomized (Nx) kidneys of C57BL/6 J mice. Mediator lipidomics was performed to reveal lipid profiles of CKD kidneys. Results In 5/6 Nx kidneys, both mRNA and protein levels of Alox15 were higher when compared with those in sham kidneys. With respect to in situ hybridization, the mRNA level of Alox15 was higher in renal tubules of 5/6 Nx kidneys. To examine the role of Alox15 in CKD pathogenesis, we performed 5/6 Nx on Alox15−/− mice. Alox15−/− CKD mice exhibited better renal functions than wild-type mice. Interstitial fibrosis was also inhibited in Alox15−/− CKD mice. Mediator lipidomics revealed that Alox15−/− CKD mouse kidneys had significantly higher levels of PGD2 than the control. To investigate the effects of PGD2 on renal fibrosis, we administered PGD2 to TGF-β1-stimulated NRK-52E cells and HK-2 cells, which lead to a dose-dependent suppression of type I collagen and αSMA in both cell lines. Conclusion Increased PGD2 in Alox15−/− CKD mouse kidneys could inhibit fibrosis, thereby resulting in CKD improvement. Thus, Alox15 inhibition and PGD2 administration may be novel therapeutic targets for CKD.

Dillenia indica fruit extract suppressed diet-induced obesity in rat by down-regulating the mRNA level of proadipogenic transcription factors and lipid metabolizing enzymes

Background: Dillenia indica (Family: Dilleniaceae) is an antioxidant-rich edible fruit-bearing medicinal plant. The fruit of this plant (known as elephant apple) has many uses in traditional medicine. Objective: By considering its antioxidant content and ameliorating effects this study was aimed to evaluate the antiadipogenic effects of D. indica fruit extract (DIFE) in high-fat diet (HFD) fed obese rats. Methods: Male Wistar rats were fed with a standard diet (SD), or high-fat diet (HFD), or HFD with 100 mg/kg or 200 mg/kg or 400 mg/kg DIFE for 8 weeks. The fruit extract was given orally by feeding gavage. The body weight, liver weight, visceral fat weight, plasma lipids, and oxidative stress-related parameters were measured. The mRNA level of different adipogenesis related transcription factors, lipogenic and lipolytic enzymes was also evaluated. Results: Consumption of DIFE daily (400 mg/kg) for 8 weeks resulted in a significant reduction of high-fat diet-induced body weight, liver weight, visceral fat weight, total cholesterol, and LDL-cholesterol level. High-fat diet-mediated elevation of oxidative stress markers was also lowered, with a parallel augmentation of the activities of antioxidant enzymes, due to 400 mg/kg DIFE feeding. DIFE also down-regulated the mRNA level of important pro-adipogenic factors like PPARγ, LXRα, and SREBP1c which consequently down-regulated the transcript levels of lipogenic enzymes: ACC, FAS, HMHCR, and DGAT. The transcript level of lipolytic enzyme, HSL was also down-regulated in 400 mg/kg DIFE-fed rats. Conclusion: These findings indicate that the antioxidant-rich ethanolic extract of D. indica fruit can down-regulate the gene expression of pro-adipogenic transcription factors and lipid metabolizing enzymes and thus can suppress dietinduced obesity in Wistar rat.

Hypoglycemic and antihyperlipidemic effect of aqueous leaves extract of Ficus Religiosa in alloxan induced diabetic rats

Background: Medicinal plants provide valuable therapeutic agents,with less adverse effects. A number of indigenous plants were claimed to be useful in the treatment of diabetes mellitus based on folk medicine. The purpose of this study was to examine the hypoglycemic and antihyperglycemic effect of aqueous leaves extract of F. religiosa in alloxan diabetes albino rats.Aims and Objectives: Therefore, the present thesis aim is in evaluating whether the hyperglycemic condition is related with hyperlipidemia and both these conditions could be controlled by indigenous preparations.Materials and Methods: The aqueous leaves extracts of Ficus religiosa (250 mg/kg) were administered orally for 21 days, in alloxan induced diabetic rats on Glucose, Lipid profile, Lipoproteins and Lipid metabolizing enzymes.Result: The aqueous leaves extract of F. religiosa induced signifi cant improvement in glucose, serum lipids, lipoproteins concentration and lipid metabolizing enzymes activity (Lipase, HMG CoA reductase and LCAT).Conclusion: The present study indicates that the extract of Ficus religiosa exhibits lipid lowering, maintaining lipoproteins concentration and improve the activities of lipid metabolizing enzymes in hyperglycemic rats, by initiating the release of insulin. This study confi rm the possible role of indigenous medicinal plants in the treatment of Diabetes.Asian Journal of Medical Sciences Vol.8(2) 2017 50-55