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Alessandra Bitto
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Francesca Polito
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Bruce Burnett Section of Pharmacology, Primus Pharmaceuticals, Section of Physiology and Human Nutrition, Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica 5th Floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy

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Robert Levy Section of Pharmacology, Primus Pharmaceuticals, Section of Physiology and Human Nutrition, Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica 5th Floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy

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Vincenzo Di Stefano
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Mary Ann Armbruster Section of Pharmacology, Primus Pharmaceuticals, Section of Physiology and Human Nutrition, Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica 5th Floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy

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Herbert Marini Section of Pharmacology, Primus Pharmaceuticals, Section of Physiology and Human Nutrition, Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica 5th Floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy

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Letteria Minutoli
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Domenica Altavilla
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Francesco Squadrito
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Glucocorticoid (GC)-induced osteoporosis (GIO) is the most important secondary cause of bone loss. Clinical evidence suggests a role for genistein (GEN) aglycone in the prevention of osteoporosis. We investigated whether GEN could prevent GIO as well as the development of osteonecrosis in the femoral head using an experimental rat model. A total of 28 female Sprague–Dawley rats were used in the study. GIO and osteonecrosis were induced by daily s.c. injections of 30 mg/kg of methylprednisolone (MP; n=7). Another group of animals (MP+GEN; n=7) concomitantly received MP (30 mg/kg per s.c.) and GEN aglycone (5 mg/kg per i.p.) for 60 days. Control animals were administered daily with vehicle (VEH) or GEN (5 mg/kg per i.p.) only. At the beginning and end of the treatment, animals were examined for bone mineral density (BMD) and bone mineral content (BMC). After killing, serum was collected to determine bone-alkaline phosphatase (b-ALP), carboxy-terminal collagen crosslink (CTX) and osteoprotegerin (OPG) levels. Femurs were removed and tested for breaking strength and bone histology analyzed for structural quality of the femoral neck. GEN aglycone prevented bone loss as measured by BMD and BMC. Moreover, GEN significantly increased the bone formation markers b-ALP and OPG, reduced the bone resorption marker CTX and statistically maintained comparable strength versus the VEH only group. Finally, histological scoring revealed a protective effect of GEN on bone structure statistically comparable with the VEH control animals. Results suggest that the GEN aglycone might be a preventive treatment for GIO and complications of osteonecrosis with long-term GC treatment.

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Alessandra Bitto Section of Pharmacology, Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Torre Biologica 5th floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy
Section of Pharmacology, Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Torre Biologica 5th floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy

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Domenica Altavilla Section of Pharmacology, Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Torre Biologica 5th floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy

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Antonio Bonaiuto Section of Pharmacology, Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Torre Biologica 5th floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy

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Francesca Polito Section of Pharmacology, Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Torre Biologica 5th floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy

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Letteria Minutoli Section of Pharmacology, Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Torre Biologica 5th floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy

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Vincenzo Di Stefano Section of Pharmacology, Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Torre Biologica 5th floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy

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Daniela Giuliani Section of Pharmacology, Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Torre Biologica 5th floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy

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Salvatore Guarini Section of Pharmacology, Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Torre Biologica 5th floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy

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Vincenzo Arcoraci Section of Pharmacology, Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Torre Biologica 5th floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy

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Francesco Squadrito Section of Pharmacology, Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Torre Biologica 5th floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy

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Genistein aglycone, a soy derived isoflavone, has been demonstrated to be effective in reducing cardiovascular risk in postmenopausal women. We therefore investigated its effects in an experimental model of postmenopausal metabolic syndrome. Female spontaneously hypertensive obese rats (SHROB, n=40), a genetic model of syndrome X, and age-matched Wistar Kyoto (WKY, n=40) rats were used. A group of SHROB (n=20) and WKY (n=20) animals were ovariectomized (OVX). Four weeks after surgery all animals were randomized to receive either genistein (54 mg/human equivalent dose/day for 4 weeks), or vehicle. Body weight, food intake, systolic blood pressure (SBP), heart rate, plasma glucose, insulin resistance (HOMA-IR), total plasma cholesterol and triglycerides, and uterine weights were studied. Furthermore, we investigated acetylcholine- and sodium nitroprusside-induced relaxation of aortic rings as well as NG-L-arginine (L-NMA: 10–100 mM) induced vasoconstriction in phenylephrine-precontracted aortic segments. Liver expression of the peroxisome proliferator-activated receptor alpha (PPARA and gamma (PPARG was also assessed. OVX animals had a slight increase in SBP, body weight, insulin resistance, and plasma cholesterol. OVX-SHROB rats showed also impaired endothelial responses, blunted L-NMA induced contraction (L-NMA 100 mM, WKY=2.2±0.3 g/mg tissue; OVX-SHROB=1.1±0.4 g/mg tissue). Genistein treatment decreased SBP and plasma lipids, ameliorated endothelial dysfunction and insulin resistance, increased HDL cholesterol, and enhanced liver expression of PPARA and PPARG. Our data suggest that genistein is effective in ameliorating cardiovascular profiles in an experimental model of postmenopausal metabolic syndrome, attenuating the features of this disease. The effects of genistein are likely mediated by PPARA and PPARG receptors. This evidence would support the rationale for some pilot clinical trials using genistein in postmenopausal women affected by metabolic syndrome.

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