Browsing by Subject "Resveratrol"
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Item Effect of pentacyclic triterpenes found in Perilla frutescens alone or in combination with resveratrol on skin tumor promotion by 12-o-tetra-decanoylphorbol-13-acetate(2015-08) Cho, Jiyoon; DiGiovanni, John; Vasquez, Karen M; Mills, Edward M; Slaga, Thomas J; Siegel, Dionicio RA series of pentacyclic triterpenes found in P. frutescens, including ursolic acid (UA), oleanolic acid (OA), augustic acid (AA), corosolic acid (CA), 3-epi-corosolic acid (3-epiCA), maslinic acid (MA), and 3-epi-maslinic acid (3-epiMA) were evaluated for their effects on skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). UA was also evaluated in a combination with resveratrol (Res) for possible combinatorial chemopreventive activity. All triterpene compounds significantly inhibited skin tumor promotion by TPA. MA and 3-epiCA, were significantly more effective than UA at inhibiting tumor development. Topical pretreatment with all of these compounds significantly inhibited epidermal proliferation induced by TPA, however, CA, 3-epiCA and MA were more effective than UA. All compounds reduced skin inflammation and inflammatory gene expression induced by TPA, however, 3-epiCA and MA were identified to be more effective than UA. Finally, the ability of these compounds to alter epidermal signaling pathways associated with skin tumor promotion by TPA was also evaluated. The greater ability of 3-epiCA and MA to inhibit skin tumor promotion was associated with greater reduction of Cox-2 and Twist1 proteins and inhibition of activation of IGF-1R, Stat3 and Src. The effect of combining UA + Res for combinatorial inhibitory effects on skin tumor promotion were also examined. The combination of UA + Res produced a greater inhibition of TPA-induced epidermal hyperproliferation, epidermal inflammatory signaling, and inflammatory gene expression when compared to UA or Res alone. Furthermore, NF-kB, Egr-1, and AP-1 DNA binding activities following TPA treatment were dramatically decreased by the combination of UA + Res. Treatment with UA + Res during skin tumor promotion by TPA produced greater inhibition of tumor multiplicity and tumor size than with either agent alone. Collectively, the current data demonstrate that UA and related triterpenes as well as the combination of UA + Res inhibited skin tumor promotion by TPA via effects on multiple cellular and biochemical/molecular mechanisms associated with this process similar to calorie restriction. Of the tritperpenes tested, 3-epiCA and MA were the most active. Furthermore, the favorable anti-tumor promoting effects of combining UA + Res suggest that phytochemical combination therapy may be a more efficacious strategy for cancer chemoprevention.Item The influence of obesity and lipid metabolism on thymic function(2011-05) Gulvady, Apeksha Ashok; Ciolino, Henry P.; Jolly, Christopher A.; Sanders, Bob G.; Kline, Kimberly; Richie, Ellen R.; Maynard, Jennifer A.Approximately two-thirds of US adults are overweight or obese, and obesity is also becoming more prevalent in children and adolescents. Similar to adults, obese children are at a higher risk of developing health problems due in part to dysfunctional immune surveillance. Obesity has been shown reduce the generation of new T-cells by accelerating thymic aging in an adult mouse. This study therefore aimed at determining whether similar diet induced obesity (DIO) changes can be induced in a young mouse. Comparisons made between lean and DIO C57Bl/6 mice showed a significant increase in thymic weight, decrease in thymic cellularity and thymic output, and impaired T-cell development at the double negative stage. We associate these alterations with changes in thymic architecture and accumulation of lipid droplets within the thymic cortex and medulla of the obese mice. The above observations indicate that DIO can induce fat accumulation and reduce thymic function at a young age. Resveratrol, a natural polyphenolic compound, was then used to regulate fat metabolism in an attempt to reduce these DIO changes we observed. Resveratrol induces fat oxidation via 5' adenosine monophosphate-activated protein kinase (AMPK), and its reciprocal regulation of glycerol-3-phosphate acyltransferase-1 (GPAT-1) and carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting enzymes required for glycerophospholipid biosynthesis and oxidation, respectively. Through resveratrol feeding, we were able to prevent the effects of DIO on thymic architecture and thymic T-cell proliferation. This was achieved by manipulating AMPK into inhibiting GPAT-1 and enhancing CPT-1 activity. Since the expression of GPAT-1 was upregulated in the obese mice, we investigated whether deleting GPAT-1 altogether might prevent the thymic involution, by inhibiting synthesis of glycerophospholipids and triacylglycerol. Instead, we found that GPAT-1 deletion slowed thymic growth and reduced cellularity in young mice, which we associated with impaired thymic T-cell function and development, suggesting that the deleterious effects of GPAT-1 deficiency may be due to perturbations in thymic T-cell activation and signaling. These data provide a novel link between lipid metabolism and T-cell development, and identify the use of the naturally-occurring resveratrol to reduce lipid accumulation within the involution-prone thymus, thus providing a useful approach to preventing a decline in thymic function in childhood.Item OXIDATIVE STRESS AND RENAL AT1R FUNCTION DURING HYPERTENSION(2012-04-19) Javkhedkar, Apurva; Lokhandwala, Mustafa F.; Banday, Anees A.; Marwaha, Aditi; Tam, Vincent; Vaziri, Nosratola D.Angiotensin (Ang) II via renal Ang II type 1 receptors (AT1R) modulates proximal tubular Na/K-ATPase such that, low concentrations of Ang II stimulates Na/K-ATPase whereas at high concentrations the stimulatory effect is lost. Studies show that oxidative stress can impair Ang II-induced Na/K-ATPase regulation and can contribute to hypertension. In the present study we first determined whether renal oxidative stress precedes development of hypertension in SHR. We found that at 3-4 weeks of age, SHR are normotensive and do not exhibit proximal tubular oxidative stress. Also, renal AT1R protein expression and Ang II-induced Na/K-ATPase stimulation was similar in SHR and WKY rats. Next we determined if antioxidant treatment at an early age can prevent renal oxidative stress and alleviate increase in blood pressure in SHR. We found that in adult SHR, there was high blood pressure, increased renal oxidative stress and decreased proximal tubular Nrf-2 activation as well as antioxidant activity compared to WKY rats. In WKY rats Ang II exerted a biphasic effect on Na/K-ATPase whereas in SHR, there was loss of biphasic effect such that Ang II produced stimulation at both high and low concentrations. In presence of nitric oxide (NO) synthase (NOS) inhibitor, L-NAME, Ang II (high concentration) produced stimulation of Na/K-ATPase in WKY rats. Ang II via AT1R caused NO iv production in WKY rats but not in SHR. Ang II caused enhanced activation of NADPH oxidase and L-arginine dependent NOS mediated superoxide production in proximal tubules of SHR. NADPH oxidase inhibitor DPI prevented Ang II-induced L-arginine dependent superoxide production and normalized NO production in SHR. There was increased renal NF kappaB activation, Giα protein expression and AT1R-G protein-coupling in SHR compared to WKY rats. Antioxidant resveratrol decreased blood pressure, increased Nrf-2 mediated antioxidant enzymes, reduced oxidative stress, normalized NOS coupling and restored Ang II-induced NO production as well as biphasic effect on Na/K-ATPase. Resveratrol treatment in SHR decreased Giα protein expression and normalized AT1R-G protein-coupling. Together these results demonstrate mechanism by which renal oxidative stress contributes to hypertension in SHR.