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Birmingham, AL, United States

Sharma S.D.,Birmingham Veteran Affairs Medical Center | Katiyar S.K.,Birmingham Veteran Affairs Medical Center | Katiyar S.K.,University of Alabama at Birmingham
Pharmaceutical Research | Year: 2010

Purpose: The purpose of this study was to determine the chemopreventive mechanism of dietary grape seed proanthocyanidins (GSPs) against ultraviolet (UV) radiation-induced skin tumor development in mice. Methods: Six-to-seven-week-old SKH-1 hairless mice were subjected to photocarcinogenesis protocol, and exposed to UVB radiation (180 mJ/cm2) three times/week for 24 weeks. Mice were fed a standard AIN76A control diet with or without supplementation with grape seed proanthocyanidins (GSPs; 0.2% or 0.5%, w/w). At the termination of the experiment, mice were sacrificed, and skin and skin tumor samples were harvested and subjected to the analysis of biomarkers related to inflammation using immunostaining, western blot analysis, ELISA and real-time PCR. Results: Dietary GSPs inhibited UVB-induced infiltration of proinflammatory leukocytes and the levels of myeloperoxidase, cyclooxygenase-2 (COX-2), prostaglandin (PG) E2, cyclin D1 and proliferating cell nuclear antigen (PCNA) in the skin and skin tumors compared to non-GSPs-treated UVB irradiated mouse skin and skin tumors. GSPs also significantly inhibited the levels of proinflammatory cytokines, tumor necrosis factor-α (P<0.01), IL-1β (P<0.001) and IL-6 (P<0.001), in UVB-exposed skin and skin tumors. Conclusion: The results from this study clearly suggest that dietary GSPs inhibit photocarcinogenesis in mice through the inhibition of UVB-induced inflammation and mediators of inflammation in mouse skin. © 2010 Springer Science+Business Media, LLC.

Barnes J.,University of Alabama at Birmingham | Dell'Italia L.J.,Birmingham Veteran Affairs Medical Center | Dell'Italia L.J.,University of Alabama at Birmingham
American Journal of the Medical Sciences | Year: 2014

Mitral regurgitation and other conditions marked by a pure isolated volume overload (VO) of the heart result in a progressive form of eccentric left ventricular remodeling and dysfunction. As opposed to the more extensively studied pressure overload, there are no approved medical therapies because an understanding of the underlying pathological mechanisms at work in VO is lacking. Over the past 20 years, our laboratory has identified multiple key biological functions involved in the pathological remodeling in VO. Specifically, we have noted perturbed matrix homeostasis, detrimental adrenergic signaling, increased intracellular reactive oxygen species and an intense inflammatory response that implicates mast cells and their product chymase, which seems to cause extensive remodeling both inside and outside the cardiomyocyte. How these multiple pathways intersect over the course of VO and their response to various single and combined interventions are now the subject of intense investigation. © 2014 Lippincott Williams and Wilkins.

Ahmed M.I.,University of Alabama at Birmingham | Gladden J.D.,University of Alabama at Birmingham | Litovsky S.H.,University of Alabama at Birmingham | Lloyd S.G.,University of Alabama at Birmingham | And 7 more authors.
Journal of the American College of Cardiology | Year: 2010

Objectives: This study assessed myocardial damage in patients with chronic isolated mitral regurgitation (MR) and left ventricular ejection fraction (LVEF) >60%. Background: Typically, MR patients have decreased LVEF after mitral valve (MV) repair despite normal pre-operative LVEF. Methods: Twenty-seven patients with isolated MR had left ventricular (LV) biopsies taken at time of MV repair. Magnetic resonance imaging with tissue tagging was performed in 40 normal subjects and in MR patients before and 6 months after MV repair. Results: LVEF (66 ± 5% to 54 ± 9%, p < 0.0001) and LV end-diastolic volume index (108 ± 28 ml/m2 to 78 ± 24 ml/m2, p < 0.0001) decreased, whereas left ventricular end-systolic (LVES) volume index was 60% above normal pre- and post-MV repair (p < 0.05). The LV circumferential and longitudinal strain rates decreased below normal following MV repair (6.38 ± 1.38 vs. 5.11 ± 1.28, p = 0.0009, and 7.51 ± 2.58 vs. 5.31 ± 1.61, percentage of R to R interval, p < 0.0001), as LVES stress/LVES volume index ratio was depressed at baseline and following MV repair versus normal subjects (0.25 ± 0.10 and 0.28 ± 0.05 vs. 0.33 ± 0.12, p < 0.01). LV biopsies demonstrated cardiomyocyte myofibrillar degeneration versus normal subjects (p = 0.035). Immunostaining and immunoblotting demonstrated increased xanthine oxidase in MR versus normal subjects (p < 0.05). Lipofuscin deposition was increased in cardiomyocytes of MR versus normal subjects (0.62 ± 0.20 vs. 0.33 ± 0.11, percentage of area: p < 0.01). Conclusions: Decreased LV strain rates and LVES wall stress/LVES volume index following MV repair indicate contractile dysfunction, despite pre-surgical LVEF >60%. Increased oxidative stress could cause myofibrillar degeneration and lipofuscin accumulation resulting in LV contractile dysfunction in MR. © 2010 American College of Cardiology Foundation.

Vaid M.,University of Alabama at Birmingham | Sharma S.D.,University of Alabama at Birmingham | Katiyar S.K.,University of Alabama at Birmingham | Katiyar S.K.,Birmingham Veteran Affairs Medical Center
Cancer Prevention Research | Year: 2010

Dietary grape seed proanthocyanidins (GSP) inhibit photocarcinogenesis in mice; however, the molecular mechanisms underlying this effect have not been fully elucidated. As ultraviolet B (UVB)-induced DNA damage in the form of cyclobutane pyrimidine dimers (CPDs) has been implicated in skin cancer risk, we studied whether dietary GSPs enhance repair of UVB-induced DNA damage and, if so, what is the potential mechanism? Supplementation of GSPs (0.5%, w/w) with AIN76A control diet significantly reduced the levels of CPD + cells in UVB-exposed mouse skin; however, GSPs did not significantly reduce UVB-induced CPD + cells in the skin of interleukin-12p40 (IL-12) knockout (KO) mice, suggesting that IL-12 is required for the repair of CPDs by GSPs. Using IL-12 KO mice and their wild-type counterparts and standard photocarcinogenesis protocol, we found that supplementation of control diet with GSPs (0.5%, w/w) significantly reduced UVB-induced skin tumor development in wild-type mice, which was associated with the elevated mRNA levels of nucleotide excision repair genes, such as XPA, XPC, DDB2, and RPA1; however, this effect of GSPs was less pronounced in IL-12 KO mice. Cytostaining analysis revealed that GSPs repaired UV-induced CPD + cells in xeroderma pigmentosum complementation group A (XPA)-proficient fibroblasts from a healthy individual but did not repair in XPA-deficient fibroblasts from XPA patients. Furthermore, GSPs enhance nuclear translocation of XPA and enhanced its interactions with other DNA repair protein ERCC1. Together, our findings reveal that prevention of photocarcinogenesis by GSPs is mediated through enhanced DNA repair in epidermal cells by IL-12- and XPA-dependent mechanisms. ©2010 AACR.

Vaid M.,University of Alabama at Birmingham | Sharma S.D.,University of Alabama at Birmingham | Katiyar S.K.,University of Alabama at Birmingham | Katiyar S.K.,Birmingham Veteran Affairs Medical Center
Carcinogenesis | Year: 2010

To develop newer and more effective chemopreventive agents for skin cancer, we assessed the effect of honokiol, a phytochemical from the Magnolia plant, on ultraviolet (UV) radiation-induced skin tumorigenesis using the SKH-1 hairless mouse model. Topical treatment of mice with honokiol in a hydrophilic cream-based topical formulation before or after UVB (180 mJ/cm2) irradiation resulted in a significant protection against photocarcinogenesis in terms of tumor multiplicity (28-60%, P < 0.05 to <0.001) and tumor volume per tumor-bearing mouse (33-80%, P < 0.05 to 0.001, n = 20). Honokiol also inhibited and delayed the malignant progression of papillomas to carcinomas. To investigate the in vivo molecular targets of honokiol efficacy, tumors and tumoruninvolved skin samples from the tumor-bearing mice were analyzed for inflammatory mediators, cell cycle regulators and survival signals using immunostaining, western blotting and enzyme-linked immunosorbent assay. Treatment with honokiol significantly inhibited UVB-induced expression of cyclooxygenase-2, prostaglandin E2 (P < 0.001), proliferating cell nuclear antigen and proinflammatory cytokines, such as tumor necrosis factor-α (P < 0.001), interleukin (IL)-1β (P < 0.01) and IL-6 (P < 0.001) in the skin as well as in skin tumors. Western blot analysis revealed that honokiol: (i) inhibited the levels of cyclins D1, D2 and E and associated cyclin-dependent kinases (CDKs)2, CDK4 and CDK6, (ii) upregulated Cip/p21 and Kip/p27 and (iii) inhibited the levels of phosphatidylinositol 3-kinase and the phosphorylation of Akt at Ser473 in UVB-induced skin tumors. Together, our results indicate that honokiol holds promise for the prevention of UVB-induced skin cancer by targeting inflammatory mediators, cell cycle regulators and cell survival signals in UVB-exposed skin. © The Author 2010. Published by Oxford University Press. All rights reserved.

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