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Articles by B Singh
Total Records ( 2 ) for B Singh
  S. M Mense , B Singh , F Remotti , X Liu and H. K. Bhat

The mechanisms underlying the pathogenesis of estrogen-induced breast carcinogenesis remain unclear. The present study investigated the roles of estrogen metabolism and oxidative stress in estrogen-mediated mammary carcinogenesis in vivo. Female August Copenhagen Irish (ACI) rats were treated with 17β-estradiol (E2), the antioxidant vitamin C, the estrogen metabolic inhibitor -naphthoflavone (ANF), or cotreated with E2 + vitamin C or E2 + ANF for up to 8 months. E2 (3 mg) was administered as an subcutaneous implant, ANF was given via diet (0.2%) and vitamin C (1%) was added to drinking water. At necropsy, breast tumor incidence in the E2, E2 + vitamin C and E2 + ANF groups was 82, 29 and 0%, respectively. Vitamin C and ANF attenuated E2-induced alterations in oxidative stress markers in breast tissue, including 8-iso-prostane F2 formation and changes in the activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase. Quantification of 2-hydroxyestradiol (2-OHE2) and 4-hydroxyestradiol (4-OHE2) formation in breast tissue confirmed that ANF inhibited 4-hydroxylation of E2 and decreased formation of the highly carcinogenic 4-OHE2. These results demonstrate that antioxidant vitamin C reduces the incidence of estrogen-induced mammary tumors, increases tumor latency and decreases oxidative stress in vivo. Further, our data indicate that ANF completely abrogates breast cancer development in ACI rats. The present study is the first to demonstrate the inhibition of breast carcinogenesis by antioxidant vitamin C or the estrogen metabolic inhibitor ANF in an animal model of estrogen-induced mammary carcinogenesis. Taken together, these results suggest that E2 metabolism and oxidant stress are critically involved in estrogen-induced breast carcinogenesis.

  A Kerem , J Yin , S. M Kaestle , J Hoffmann , A. M Schoene , B Singh , H Kuppe , M. M Borst and W. M. Kuebler

Rationale: Congestive heart failure (CHF) frequently results in remodeling and increased tone of pulmonary resistance vessels. This adaptive response, which aggravates pulmonary hypertension and thus, promotes right ventricular failure, has been attributed to lung endothelial dysfunction.

Objective: We applied real-time fluorescence imaging to identify endothelial dysfunction and underlying molecular mechanisms in an experimental model of CHF induced by supracoronary aortic banding in rats.

Methods and Results: Endothelial dysfunction was evident in lungs of CHF rats as impaired endothelium-dependent vasodilation and lack of endothelial NO synthesis in response to mechanical stress, acetylcholine, or histamine. This effect was not attributable to downregulation of endothelial NO synthase. Imaging of the cytosolic Ca2+ concentration ([Ca2+]i) revealed a singular impairment of endothelial [Ca2+]i homeostasis and signaling characterized by a lack of [Ca2+]i oscillations and deficient or attenuated [Ca2+]i responses to mechanical stress, histamine, acetylcholine, or thapsigargin. Reconstitution of a [Ca2+]i signal by ionophore treatment restored endothelial NO production, but lack of endothelial responsiveness was not primarily attributable to downregulation of Ca2+ influx channels in CHF. Rather, we identified a massive remodeling of the endothelial cytoskeleton in the form of an increased expression of β-actin and F-actin formation which contributed critically to endothelial dysfunction in CHF because cytoskeletal disruption by cytochalasin D largely reconstituted endothelial [Ca2+]i signaling and NO production.

Conclusions: Our findings characterize a unique scenario of endothelial dysfunction in CHF that is caused by a singular impairment of [Ca2+]i signaling, and identify cytoskeletal reorganization as a major regulator of endothelial signaling and function.

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