esculetin and kaempferol

Chronic allograft damage, defined by interstitial fibrosis and tubular atrophy (IF/TA), is a leading cause of allograft failure. Few effective therapeutic options are available to prevent the progression of IF/TA. We applied a meta-analysis approach on IF/TA molecular datasets in Gene Expression Omnibus to identify a robust 85-gene signature, which was used for computational drug repurposing analysis. Among the top ranked compounds predicted to be therapeutic for IF/TA were azathioprine, a drug to prevent acute rejection in renal transplantation, and kaempferol and esculetin, two drugs not previously described to have efficacy for IF/TA. We experimentally validated the anti-fibrosis effects of kaempferol and esculetin using renal tubular cells in vitro and in vivo in a mouse Unilateral Ureteric Obstruction (UUO) model. Kaempferol significantly attenuated TGF-β1-mediated profibrotic pathways in vitro and in vivo, while esculetin significantly inhibited Wnt/β-catenin pathway in vitro and in vivo. Histology confirmed significantly abrogated fibrosis by kaempferol and esculetin in vivo. We developed an integrative computational framework to identify kaempferol and esculetin as putatively novel therapies for IF/TA and provided experimental evidence for their therapeutic activities in vitro and in vivo using preclinical models. The findings suggest that both drugs might serve as therapeutic options for IF/TA.

Topics: Allografts; Animals; Cell Line; Computational Biology; Disease Models, Animal; Drug Discovery; Fibrosis; Graft Rejection; Humans; Informatics; Kaempferols; Kidney; Kidney Diseases; Kidney Transplantation; Male; Mice, Inbred BALB C; Signal Transduction; Umbelliferones

Two currently available edible oils-olive and canola-and two oil blends of plant origin having different n-3/n-6 polyunsaturated fatty acid (PUFA) ratios were evaluated for their ability to modify vascular dysfunction in the spontaneously hypertensive rat (SHR). Synthetic diets supplemented with test oils (5% w/w) were fed for 12 weeks, and segments of thoracic aorta used to assess vascular function. Vessels from the SHR displayed a spontaneous constrictor response after the inhibition of endothelial cell nitric oxide (NO) with N(omega)-nitro-L-arginine (NOLA). Dietary alpha -linoleate enrichment led to a reduction (P<0.05) in this abnormality with a dietary n-3/n-6 PUFA ratio of 1.0 (blend-1) yielding the best outcome. Relaxation to acetylcholine (ACh) was unaffected by dietary lipid supplementation. NOLA treated rings also displayed contractions to ACh that were abolished by indomethacin, thromboxane antagonists SQ29548, picotamide and flavonoids kaempferol and quercetin. In contrast, alpha-tocopherol, rutin and the lipoxygenase inhibitor esculetin resulted in only partial (30-55%) inhibition, and were ineffective against the NOLA-induced contraction suggesting the operation of different biochemical mechanisms in mediating the spontaneous and Ach-induced contractions. Results implicate plant-based oils and antioxidants as potential modulators of vascular function.

Topics: Acetylcholine; alpha-Tocopherol; Animals; Antioxidants; Aorta; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Agents; Diet; Dose-Response Relationship, Drug; Endothelium, Vascular; Fatty Acids, Unsaturated; Flavonoids; Hydrazines; Hypertension; Indomethacin; Kaempferols; Lipid Metabolism; Nitric Oxide; Phthalic Acids; Plant Oils; Platelet Aggregation Inhibitors; Quercetin; Rats; Rats, Inbred SHR; Rutin; Umbelliferones

The anti-inflammatory activity of three benzo-pyrones with prevalent lipooxigenase-inhibitory activity was studied using the Croton oil ear test in mice, in comparison with nordihydroguaieretic acid (NDGA) and indomethacin. Kaempferol, quercetin and NDGA possess a strong and prolonged anti-inflammatory effect, whereas the action of indomethacin appears relevant, but not long-lasting. In contrast the anti-inflammatory activity of esculetin is rather weak, but persistent.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Croton Oil; Cyclooxygenase Inhibitors; Edema; Flavonoids; Granulocytes; Indomethacin; Kaempferols; Lipoxygenase Inhibitors; Male; Masoprocol; Mice; Mice, Inbred Strains; Quercetin; Umbelliferones