RESUMEN
Glucocorticoid-induced osteoporosis (GIO) complicates the clinical management of patients subjected to long-term glucocorticoid use. This study explored the effects of genistein on bone loss in a randomized double-blind alendronate-controlled trial in postmenopausal women with GIO. 200 postmenopausal women (taking at least 5 mg of prednisone equivalents) since 3 months, or more, and expected to continue for at least other 12 months, were randomized to receive genistein (54 mg/day daily) or alendronate (70 mg once a week) for 24 months. Both groups received also Calcium and Vitamin D3 supplementation. Median bone mineral density (BMD) at the antero-posterior lumbar spine significantly increased from 0.75 g/cm2 at baseline to 0.77 g/cm2 at 1 year and 0.79 g/cm2 at 2 years in alendronate-treated patients and from 0.77 g/cm2 at baseline to 0.79 g/cm2 at 12 months and to 0.80 g/cm2 at 24 months in genistein recipients. No difference was observed between the two treatments. Median BMD at the femoral neck increased from 0.67 g/cm2 at baseline to 0.68 g/cm2 at 1 year and 0.69 g/cm2 at 2 years in alendronate-treated patients and from 0.68 g/cm2 at baseline to 0.70 g/cm2 at 12 months and to 0.71 g/cm2 at 24 months in genistein recipients. No difference was observed between alendronate and genistein groups in BMD. Regarding bone markers genistein and alendronate statistically decreased c-terminal telopeptide, while osteocalcin, bone-ALP, and sclerostin showed greater changes in genistein treated patients. This randomized clinical trial suggests that genistein aglycone represents an additional therapeutic option for patients with GIO.
Asunto(s)
Conservadores de la Densidad Ósea , Osteoporosis Posmenopáusica , Osteoporosis , Humanos , Femenino , Alendronato/uso terapéutico , Glucocorticoides/farmacología , Genisteína/farmacología , Genisteína/uso terapéutico , Conservadores de la Densidad Ósea/farmacología , Conservadores de la Densidad Ósea/uso terapéutico , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológico , Densidad Ósea , Osteoporosis Posmenopáusica/inducido químicamente , Osteoporosis Posmenopáusica/tratamiento farmacológico , Método Doble CiegoRESUMEN
Polydeoxyribonucleotide (PDRN) is an agonist of the A2A adenosine receptor derived from salmon trout sperm. Selenium (Se) is a trace element normally present in the diet. We aimed to investigate the long-term role of PDRN and Se, alone or in association, after ischemia-reperfusion (I/R) in rats. The animals underwent 1 h testicular ischemia followed by 30 days of reperfusion or a sham I/R and were treated with PDRN or Se alone or in association for 30 days. I/R significantly increased hypoxia-inducible factor 1-α (HIF-1α) in Leydig cells, malondialdehyde (MDA), phosphorylated extracellular signal-regulated kinases 1/2 (pErk 1/2), and apoptosis decreased testis weight, glutathione (GSH), testosterone, nuclear factor erythroid 2-related factor 2 (Nrf2), induced testicular structural changes, and eliminated HIF-1α spermatozoa positivity. The treatment with either PDRN or Se significantly decreased MDA, apoptosis, and HIF-1α positivity of Leydig cells, increased testis weight, GSH, testosterone, and Nrf2, and improved the structural organization of the testes. PDRN and Se association showed a higher protective effect on all biochemical, structural, and immunohistochemical parameters. Our data suggest that HIF-1α could play important roles in late testis I/R and that this transcriptional factor could be modulated by PDRN and Se association, which, together with surgery, could be considered a tool to improve varicocele-induced damages.
Asunto(s)
Daño por Reperfusión , Selenio , Ratas , Masculino , Animales , Polidesoxirribonucleótidos/farmacología , Factor 2 Relacionado con NF-E2/análisis , Selenio/farmacología , Selenio/análisis , Ratas Sprague-Dawley , Semen , Testículo , Isquemia , Daño por Reperfusión/tratamiento farmacológico , Subunidad alfa del Factor 1 Inducible por Hipoxia/análisis , Reperfusión , Testosterona/análisisRESUMEN
Chronic glucocorticoid (GC) therapy is the most common cause of iatrogenic osteoporosis and represents an important risk factor for osteoporosis and bone fractures. New therapeutic approaches are required in order to treat osteoporosis and reduce the side effects related to the use of anti-osteoporotic drugs. In this context, previous studies reported the efficacy of some isoflavones and carotenoids, such as lycopene and genistein, on the reduction of the risk of fracture related to osteoporosis. The aim of this study was to investigate the effects of a combined oral treatment, consisting of genistein and lycopene, in an experimental model of glucocorticoid-induced osteoporosis (GIO). GIO was induced by subcutaneous injection of methylprednisolone (MP, 30 mg/kg) for 60 days, whereas the control group (Sham) received saline solution only. Following induction, MP animals randomly were assigned to receive alendronate, genistein, lycopene, or the association of genistein and lycopene or saline solution for additional 60 days together with MP. Femurs obtained from the Sham group were used for osteoblasts extraction; they were then incubated with dexamethasone (DEX) for 24 h to be then treated with lycopene or genistein or the association of lycopene and genistein for an additional 24 h. Treatments with lycopene and genistein restored the impaired mineralization of cells observed following DEX treatment and stimulated osteoblast differentiation by increasing the depressed expression of bALP and RUNX2 (p < 0.0001). Wnt5a, ß-catenin, and Nrf-2 expression were significantly increased following genistein and lycopene treatment (p < 0.0001), thus confirming their antioxidant activity as well as their ability in stimulating osteoblast function, mostly when genistein and lycopene were used in association. The combined treatment of genistein and lycopene improved the bone damage induced by glucocorticoids and significantly restored the normal architecture of bones as well as adequate interconnectivity of bone trabeculae, thus increasing bone mineral density parameters. The obtained data demonstrated that genistein and lycopene but in particular their association might prevent GC's adverse effects, thus stimulating bone formation and reducing bone resorption, improving bone structure and microarchitecture, through different molecular pathways, such as the Wnt/ß-catenin and the Nrf-2 signaling.
Asunto(s)
Glucocorticoides , Osteoporosis , Animales , Alendronato/farmacología , Antioxidantes/metabolismo , beta Catenina/metabolismo , Densidad Ósea , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Dexametasona/farmacología , Suplementos Dietéticos , Genisteína/farmacología , Glucocorticoides/farmacología , Licopeno/farmacología , Metilprednisolona/efectos adversos , Osteoblastos , Osteogénesis , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológicoRESUMEN
Previous studies have demonstrated that, in addition to inducing structural changes in thyroid follicles, cadmium (Cd) increased the number of C cells. We examined the effects of myo-inositol (MI), seleno-L-methionine (Se), MI + Se, and resveratrol on C cells of mice exposed to cadmium chloride (Cd Cl2), as no data are currently available on the possible protective effects of these molecules. In contrast, we have previously shown this protective effect against CdCl2 on the thyroid follicles of mice. Ninety-eight C57 BL/6J adult male mice were divided into 14 groups of seven mice each: (i) 0.9% NaCl (vehicle; 1 ml/kg/day i.p.); (ii) Se (0.2 mg/kg/day per os); (iii) Se (0.4 mg/kg/day per os); (iv) MI (360 mg/kg/day per os); (v) Se (0.2 mg/kg/day) + MI; (vi) Se (0.4 mg/kg/day) + MI; (vii) resveratrol (20 mg/kg); (viii) CdCl2 (2 mg/kg/day i.p.) + vehicle; (ix) CdCl2 + Se (0.2 mg/kg/day); (x) CdCl2 + Se (0.4 mg/kg/day); (xi) CdCl2 + MI; (xii) CdCl2 + Se (0.2 mg/kg/day) + MI; (xiii) CdCl2 + Se (0.4 mg/kg/day) + MI; (xiv) CdCl2 + resveratrol (20 mg/kg). After 14 days, thyroids were processed for histological, immunohistochemical, and morphometric evaluation. Compared to vehicle, Cd significantly decreased follicle mean diameter, increased CT-positive cells number, area and cytoplasmic density, and caused the disappearance of TUNEL-positive C cells, namely, the disappearance of C cells undergoing apoptosis. Se at either 0.2 or 0.4 mg/kg/day failed to significantly increase follicular mean diameter, mildly decreased CT-positive cells number, area and cytoplasmic density, and was ineffective on TUNEL-positive C cells. Instead, MI alone increased significantly follicular mean diameter and TUNEL-positive cells number, and decreased significantly CT-positive cells number, area and cytoplasmic density. MI + Se 0.2 mg/kg/day or MI + Se 0.4 mg/kg/day administration improved all five indices more markedly. Indeed, follicular mean diameter and TUNEL-positive cells number increased significantly, while CT-positive cells number, area and cytoplasmic density decreased significantly. Thus, all five indices overlapped those observed in vehicle-treated mice. Resveratrol improved significantly all the considered parameters, with a magnitude comparable to that of MI alone. In conclusion, the association Myo + Se is effective in protecting the mouse thyroid from the Cd-induced hyperplasia and hypertrophy of C cells. This benefit adds to that exerted by Myo + Se on thyrocytes and testis.
Asunto(s)
Cadmio/farmacología , Inositol/farmacología , Selenio/farmacología , Glándula Tiroides/efectos de los fármacos , Animales , Tamaño de la Célula/efectos de los fármacos , Bocio/inducido químicamente , Bocio/patología , Hiperplasia/inducido químicamente , Hipertrofia/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL , Tamaño de los Órganos/efectos de los fármacos , Células Epiteliales Tiroideas/citología , Células Epiteliales Tiroideas/efectos de los fármacos , Glándula Tiroides/citología , Glándula Tiroides/patologíaRESUMEN
Cadmium (Cd) damages the thyroid gland. We evaluated the effects of myo-inositol (MI), seleno-L-methionine (Se) or their combination on the thyroids of mice simultaneously administered with Cd chloride (CdCl2). Eighty-four male mice were divided into 12 groups (seven mice each). Six groups (controls) were treated with 0.9% NaCl (vehicle), Se (0.2 mg/kg/day), Se (0.4 mg/kg/day), MI (360 mg/kg/day), MI+Se (0.2 mg/kg) and MI+Se (0.4 mg/kg). The other six groups were treated with CdCl2 (2 mg/kg), CdCl2+MI, CdCl2+Se (0.2 mg/kg), CdCl2+Se (0.4 mg/kg), CdCl2+MI+Se (0.2 mg/kg) and CdCl2+MI+Se (0.4 mg/kg). An additional group of CdCl2-challenged animals (n= 7) was treated with resveratrol (20 mg/kg), an effective and potent antioxidant. All treatments lasted 14 days. After sacrifice, the thyroids were evaluated histologically and immunohistochemically. CdCl2 reduced the follicular area, increased the epithelial height, stroma, and cells expressing monocyte chemoattractant protein-1 (MCP-1) and C-X-C motif chemokine 10 (CXCL10). CdCl2+Se at 0.2/0.4 mg/kg insignificantly reversed the follicular and stromal structure, and significantly decreased the number of MCP-1 and CXCL10-positive cells. CdCl2+MI significantly reversed the thyroid structure and further decreased the number of MCP-1 and CXCL10-positive cells. CdCl2+MI+Se, at both doses, brought all indices to those of CdCl2-untreated mice. MI, particularly in association with Se, defends mice from Cd-induced damage. The efficacy of this combination was greater than that of resveratrol, at least when using the follicular structure as a read-out for a comparison. We suggest that the use of these nutraceuticals, more specifically the combination of MI plus SE, can protect the thyroid of Cd-exposed subjects.
Asunto(s)
Cloruro de Cadmio/toxicidad , Suplementos Dietéticos , Inositol/administración & dosificación , Inositol/farmacología , Selenio/administración & dosificación , Selenio/farmacología , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/metabolismo , Animales , Antioxidantes , Quimiocina CCL2/metabolismo , Quimiocina CXCL10/metabolismo , Inmunohistoquímica , Masculino , Ratones Endogámicos C57BL , Resveratrol/administración & dosificación , Resveratrol/farmacología , Glándula Tiroides/patologíaRESUMEN
Varicocele is one of the main causes of infertility in men. Oxidative stress and consequently apoptosis activation contribute to varicocele pathogenesis, worsening its prognosis. Natural products, such as lycopene, showed antioxidant and anti-inflammatory effects in several experimental models, also in testes. In this study we investigated lycopene effects in an experimental model of varicocele. Male rats (n = 14) underwent sham operations and were administered with vehicle (n = 7) or with lycopene (n = 7; 1 mg/kg i.p., daily). Another group of animals (n = 14) underwent surgical varicocele. After 28 days, the sham and 7 varicocele animals were euthanized, and both operated and contralateral testes were weighted and processed. The remaining rats were treated with lycopene (1 mg/kg i.p., daily) for 30 days. Varicocele rats showed reduced testosterone levels, testes weight, Bcl-2 mRNA expression, changes in testes structure and increased malondialdehyde levels and BAX gene expression. TUNEL (Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling) assay showed an increased number of apoptotic cells. Treatment with lycopene significantly increased testosterone levels, testes weight, and Bcl-2 mRNA expression, improved tubular structure and decreased malondialdehyde levels, BAX mRNA expression and TUNEL-positive cells. The present results show that lycopene exerts beneficial effects in testes, and suggest that supplementation with the tomato-derived carotenoid might be considered a novel nutraceutical strategy for the treatment of varicocele and male infertility.
Asunto(s)
Suplementos Dietéticos , Infertilidad Masculina/tratamiento farmacológico , Licopeno/farmacología , Varicocele/tratamiento farmacológico , Animales , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Carotenoides/farmacología , Etiquetado Corte-Fin in Situ , Masculino , Malondialdehído/sangre , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Sprague-Dawley , Testículo/efectos de los fármacos , Testosterona/sangre , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
The antibiotic doxorubicin is often used as an anti-neoplastic drug; however, many patients showed very unpleasant side-effects. Previous studies have demonstrated that dietary substances such as Aloe arborescens, Annona muricata, Morinda citrifolia, Beta rubra, Scutellaria baicalensis, and Vaccinium myrtillus may have anti-oxidant, anti-proliferative, and anti-inflammatory effects. The purpose of this study was to investigate the protective effects of a mixture of these components in an experimental model of doxorubicin toxicity. Rats (n = 30) received doxorubicin (5 mg/kg/day) for 4 weeks and were randomized to receive the dietary mixture 2 hours following the first doxorubicin injection and until the end of the experiment. Animals were killed following 4 weeks, and blood, liver, and heart were collected for further analysis. The dietary supplement improved the depressed body weight and food consumption induced by DOX. In addition, the nutraceutical mixture reduced oxidative stress, ameliorated the morphological score, and preserved liver and heart structure, demonstrating a protective effect. These data show for the first time that the mixture of Aloe arborescens, Annona muricata, Morinda citrifolia, Beta rubra, Scutellaria baicalensis, and Vaccinium myrtillus may be useful to reduce the side effects following treatment with doxorubicin, and might ameliorate the quality of life of patients following chemotherapy.
Asunto(s)
Antibióticos Antineoplásicos/toxicidad , Cardiotoxicidad/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Suplementos Dietéticos , Doxorrubicina/toxicidad , Extractos Vegetales/farmacología , Aloe/química , Animales , Annona/química , Cardiotoxicidad/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Masculino , Morinda/química , Extractos Vegetales/administración & dosificación , Ratas , Ratas Sprague-Dawley , Scutellaria baicalensis/química , Vaccinium myrtillus/químicaRESUMEN
Cadmium (Cd) induces functional and morphological changes in kidney. Therefore, the effects of a natural nutraceutical antioxidant, myo-inositol (MI), were evaluated in mice kidneys after Cd challenge. Twenty-eight C57 BL/6â¯J mice were divided into these groups: 0.9% NaCl; MI (360â¯mg/kg/day); CdCl2 (2â¯mg/kg/day) plus vehicle; CdCl2 (2â¯mg/kg/day) plus MI (360â¯mg/kg/day). After 14 days, kidneys were processed for structural, biochemical and morphometric evaluation. Treatment with CdCl2 increased urea nitrogen and creatinine in serum and augmented tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) expression. Furthermore, monocyte chemoattractant protein-1 (MCP-1), kidney injury molecule-1 (KIM-1) and myo-inositol oxygenase (MIOX) immunoreactivity, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells number were significantly higher than control and MI groups. Glutathione (GSH) content and glutathione peroxidase (GPx) activity were reduced and structural changes were evident. The treatment with MI significantly lowered urea nitrogen and creatinine levels, TNF-α and iNOS expression, MCP-1, KIM-1 and MIOX immunoreactivity and TUNEL positive cells number, increased GSH content and GPx activity and preserved kidney morphology. A protection of MI against Cd-induced damages in mice kidney was demonstrated, suggesting a strong antioxidant role of this nutraceutical against environmental Cd harmful effects on kidney lesions.
Asunto(s)
Cloruro de Cadmio/toxicidad , Suplementos Dietéticos , Inositol/farmacología , Riñón/efectos de los fármacos , Animales , Antioxidantes/administración & dosificación , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo II/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
HIV-infected patients show high risk of fracture. The aims of our study were to determine the prevalence of vertebral fractures (VFs) and their associations with vitamin D in HIV patients. 100 patients with HIV infection and 100 healthy age- and sex-matched controls were studied. Bone mineral density was measured by quantitative ultrasound at the non-dominant heel. Serum osteocalcin and C-terminal telopeptide of collagen type 1 served as bone turnover markers. Bone ultrasound measurements were significantly lower in patients compared with controls (Stiffness Index (SI): 80.58 ± 19.95% vs. 93.80 ± 7.10%, respectively, p < 0.001). VFs were found in 16 patients and in 2 controls. HIV patients with vertebral fractures showed lower stiffness index (SI) (70.75 ± 10.63 vs. 83.36 ± 16.19, respectively, p = 0.045) and lower vitamin D levels (16.20 ± 5.62 vs. 28.14 ± 11.94, respectively, p < 0.02). The majority of VFs (87.5%) were observed in HIV-infected patients with vitamin D insufficiency, and regression analysis showed that vitamin D insufficiency was significantly associated with vertebral fractures (OR 9.15; 95% CI 0.18-0.52, p < 0.04). VFs and are a frequent occurrence in HIV-infected patients and may be associated with vitamin D insufficiency.
Asunto(s)
Fracturas Óseas/sangre , Fracturas Óseas/complicaciones , Infecciones por VIH/sangre , Infecciones por VIH/complicaciones , Vitamina D/sangre , Adulto , Calcio/sangre , Calcio/orina , Estudios de Casos y Controles , Femenino , Fracturas Óseas/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Fósforo/sangre , Fósforo/orina , Factores de RiesgoRESUMEN
Genistein, a soy-derived isoflavone, may improve cardiovascular risk profile in postmenopausal women with metabolic syndrome (MetS), but few literature data on its cardiac effects in humans are available. The aim of this sub-study of a randomized double-blind case-control study was to analyze the effect on cardiac function of one-year genistein dietary supplementation in 22 post-menopausal patients with MetS. Participants received 54 mg/day of genistein (n = 11) or placebo (n = 11) in combination with a Mediterranean-style diet and regular exercise. Left ventricular (LV) systolic function was assessed as the primary endpoint, according to conventional and strain-echocardiography measurements. Also, left atrial (LA) morphofunctional indices were investigated at baseline and at the final visit. Results were expressed as median with interquartile range (IQ). A significant improvement of LV ejection fraction (20.3 (IQ 12.5) vs. -1.67 (IQ 24.8); p = 0.040)), and LA area fractional change (11.1 (IQ 22.6) vs. 2.8 (9.5); p = 0.034)) were observed in genistein patients compared to the controls, following 12 months of treatment. In addition, body surface area indexed LA systolic volume and peak LA longitudinal strain significantly changed from basal to the end of the study in genistein-treated patients. One-year supplementation with 54 mg/day of pure genistein improved both LV ejection fraction and LA remodeling and function in postmenopausal women with MetS.
Asunto(s)
Suplementos Dietéticos , Genisteína/farmacología , Corazón/efectos de los fármacos , Síndrome Metabólico , Posmenopausia , Método Doble Ciego , Femenino , Corazón/fisiología , Humanos , Persona de Mediana EdadRESUMEN
Genistein has a preventive role against bone mass loss during menopause. However, experimental data in animal models of osteoporosis suggest an anti-osteoporotic potential for this isoflavone. We performed a post-hoc analysis of a previously published trial investigating the effects of genistein in postmenopausal women with low bone mineral density. The parent study was a randomized, double-blind, placebo-controlled trial involving postmenopausal women with a femoral neck (FN) density <0.795 g/cm². A cohort of the enrolled women was, in fact, identified at the baseline as osteoporotic (n = 121) on the basis of their T-score and analyzed thereafter for the 24 months' treatment with either 1000 mg of calcium and 800 IU vitamin D3 (placebo; n = 59); or calcium, vitamin D3, and Genistein aglycone (54 mg/day; genistein; n = 62). According to the femoral neck T-scores, 31.3% of the genistein and 30.9% of the placebo recipients were osteoporotic at baseline. In the placebo and genistein groups, the 10-year hip fracture probability risk assessed by Fracture Risk Assessment tool (FRAX) was 4.1 ± 1.9 (SD) and 4.2 ± 2.1 (SD), respectively. Mean bone mineral density (BMD) at the femoral neck increased from 0.62 g/cm² at baseline to 0.68 g/cm² at 1 year and 0.70 g/cm² at 2 years in genistein recipients, and decreased from 0.61 g/cm² at baseline to 0.60 g/cm² at 1 year and 0.57 g/cm² at 2 years in placebo recipients. At the end of the study only 18 postmenopausal women had osteoporosis in the genistein group with a prevalence of 12%, whereas in the placebo group the number of postmenopausal women with osteoporosis was unchanged, after 24 months. This post-hoc analysis is a proof-of concept study suggesting that genistein may be useful not only in postmenopausal osteopenia but also in osteoporosis. However, this proof-of concept study needs to be confirmed by a large, well designed, and appropriately focused randomized clinical trial in a population at high risk of fractures.
Asunto(s)
Genisteína/uso terapéutico , Osteoporosis Posmenopáusica/tratamiento farmacológico , Posmenopausia , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea , Calcio de la Dieta/uso terapéutico , Colecalciferol/uso terapéutico , Método Doble Ciego , Femenino , Cuello Femoral , Fracturas de Cadera/epidemiología , Fracturas de Cadera/prevención & control , Humanos , Fitoestrógenos , Placebos , Riesgo , Medición de RiesgoRESUMEN
Benign prostatic hyperplasia (BPH) treatment includes the apoptosis machinery modulation through the direct inhibition of caspase cascade. We previously demonstrated that Serenoa repens (Ser) with lycopene (Ly) and selenium (Se) reawakened apoptosis by reducing survivin and neuronal apoptosis inhibitory protein (NAIP) levels in rats. The aim of this study was to evaluate the effectiveness of Ser-Se-Ly association on survivin and NAIP expression in BPH patients. Ninety patients with lower urinary tract symptoms (LUTS) due to clinical BPH were included in this randomized, double-blind, placebo-controlled trial. Participants were randomly assigned to receive placebo (Group BPH + placebo, n = 45) or Ser-Se-Ly association (Group BPH + Ser-Se-Ly; n = 45) for 3 months. At time 0, all patients underwent prostatic biopsies. After 3 months of treatment, they underwent prostatic re-biopsy and specimens were collected for molecular, morphological, and immunohistochemical analysis. After 3 months, survivin and NAIP were significantly decreased, while caspase-3 was significantly increased in BPH patients treated with Ser-Se-Ly when compared with the other group. In BPH patients treated with Ser-Se-Ly for 3 months, the glandular epithelium was formed by a single layer of cuboidal cells. PSA showed high immunoexpression in all BPH patients and a focal positivity in Ser-Se-Ly treated patients after 3 months. Evident prostate specific membrane antigen (PSMA) immunoexpression was shown in all BPH patients, while no positivity was present after Ser-Se-Ly administration. Ser-Se-Ly proved to be effective in promoting apoptosis in BPH patients.
Asunto(s)
Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteína Inhibidora de la Apoptosis Neuronal/metabolismo , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patología , Anciano , Antígenos de Superficie/genética , Antígenos de Superficie/metabolismo , Apoptosis/efectos de los fármacos , Biomarcadores , Carotenoides/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Glutamato Carboxipeptidasa II/genética , Glutamato Carboxipeptidasa II/metabolismo , Humanos , Inmunohistoquímica , Proteínas Inhibidoras de la Apoptosis/genética , Licopeno , Masculino , Persona de Mediana Edad , Proteína Inhibidora de la Apoptosis Neuronal/genética , Extractos Vegetales/farmacología , Hiperplasia Prostática/etiología , Hiperplasia Prostática/prevención & control , Selenio/farmacología , Compuestos de Selenio/farmacología , Serenoa/química , SurvivinRESUMEN
BAY 11-7082 antagonizes I-κB kinase-ß preventing nuclear translocation of nuclear factor-κB (NF-κB); it also inhibits NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation. NF-κB is involved in psoriasis, whereas the role of NLRP3 is controversial. We investigated BAY 11-7082 effects in an experimental model of psoriasis-like dermatitis. Psoriasis-like lesions were induced by a topical application of imiquimod (IMQ) cream (62.5 mg/day) on the shaved back skin of C57BL/6 and NLRP3 knockout (KO) mice for 7 consecutive days. Sham psoriasis animals were challenged with Vaseline cream. Sham and IMQ animals were randomized to receive BAY 11-7082 (20 mg/kg/i.p.) or its vehicle (100 µl/i.p of 0.9% NaCl). Skin of IMQ animals developed erythema, scales, thickening and epidermal acanthosis. IMQ skin samples showed increased expression of pNF-κB and NLRP3 activation. BAY 11-7082 blunted epidermal thickness, acanthosis and inflammatory infiltrate. BAY 11-7082 reduced pNF-κB, NLRP3, tumour necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1ß expression, blunted the phosphorylation of signal transducer and activators of transcription 3 (STAT3) and decreased IL-23 levels. In addition, BAY 11-7082 reawakened the apoptotic machinery. NLRP3 KO animals showed a reduced total histological score but persistent mild acanthosis, dermal thickness and expression of pNF-κB and pSTAT3, following IMQ application. Our data suggest that BAY 11-7082 might represent an interesting approach for the management of psoriasis-like dermatitis depending on the dual inhibition of NF-κB and NLRP3.
Asunto(s)
Fármacos Dermatológicos/uso terapéutico , Inflamasomas/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Nitrilos/uso terapéutico , Psoriasis/prevención & control , Sulfonas/uso terapéutico , Aminoquinolinas , Animales , Apoptosis/efectos de los fármacos , Citocinas/antagonistas & inhibidores , Citocinas/genética , Fármacos Dermatológicos/farmacología , Erupciones por Medicamentos/metabolismo , Erupciones por Medicamentos/patología , Erupciones por Medicamentos/prevención & control , Evaluación Preclínica de Medicamentos/métodos , Imiquimod , Inflamasomas/fisiología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/fisiología , Proteína con Dominio Pirina 3 de la Familia NLR/deficiencia , Proteína con Dominio Pirina 3 de la Familia NLR/fisiología , Nitrilos/farmacología , Psoriasis/inducido químicamente , Psoriasis/metabolismo , Psoriasis/patología , ARN Mensajero/genética , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/fisiología , Sulfonas/farmacologíaRESUMEN
During menopause, an increased prevalence of metabolic syndrome (MetS) and central obesity seems to increase hot flashes (HFs). Visfatin is an inflammatory adipokine secreted by visceral fat. We investigated visfatin levels and its relationship with hot flash number and BMI, in postmenopausal women with MetS. We also evaluated the effect of genistein, an isoflavone effective in reducing HFs, on visfatin levels and HFs after 1 year of treatment. This was a randomized, double-blind, placebo-controlled trial. Postmenopausal women with MetS were randomly assigned to receive placebo (n = 60) or 54 mg genistein (n = 60), daily for 1 year. As main outcome measures, hot flashes number and circulating visfatin levels were evaluated. Visfatin significantly correlated with BMI and HFs number in women with MetS at basal. After 6 and 12 months, our results indicate a strong correlation and a significant effect of genistein in reducing both HFs and visfatin in women with MetS. The present study suggests that visfatin plays a role in the vasomotor symptoms, at least in postmenopausal women with metabolic syndrome. Genistein may reduce HFs decreasing the circulating levels of this inflammatory adipokine.
Asunto(s)
Genisteína/uso terapéutico , Sofocos/sangre , Síndrome Metabólico/sangre , Nicotinamida Fosforribosiltransferasa/sangre , Fitoestrógenos/uso terapéutico , Posmenopausia/sangre , Anciano , Índice de Masa Corporal , Método Doble Ciego , Femenino , Sofocos/tratamiento farmacológico , Humanos , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Benign prostatic hyperplasia (BPH) is a chronic condition common in older men that can result in bothersome lower urinary tract symptoms. The molecular mechanisms and networks underlying the development and the progression of the disease are still far from being fully understood. BPH results from smooth muscle cell and epithelial cell proliferation, primarily within the transition zone of the prostate. Apoptosis and inflammation play important roles in the control of cell growth and in the maintenance of tissue homeostasis. Disturbances in molecular mechanisms of apoptosis machinery have been linked to BPH. Increased levels of the glycoprotein Dickkopf-related protein 3 in BPH cause an inhibition of the apoptosis machinery through a reduction in B cell lymphoma (Bcl)-2 associated X protein (Bax) expression. Inhibitors of apoptosis proteins influence cell death by direct inhibition of caspases and modulation of the transcription factor nuclear factor-κB. Current pharmacotherapy targets either the static component of BPH, including finasteride and dutasteride, or the dynamic component of BPH, including α-adrenoceptor antagonists such as tamsulosin and alfuzosin. Both these classes of drugs significantly interfere with the apoptosis machinery. Furthermore, phytotherapic supplements and new drugs may also modulate several molecular steps of apoptosis.
Asunto(s)
Apoptosis/efectos de los fármacos , Sistema Endocrino/metabolismo , Hiperplasia Prostática/tratamiento farmacológico , Hiperplasia Prostática/metabolismo , Dutasterida/uso terapéutico , Sistema Endocrino/efectos de los fármacos , Finasterida/uso terapéutico , Humanos , Masculino , Quinazolinas/uso terapéutico , Sulfonamidas/uso terapéutico , Tamsulosina , Agentes Urológicos/uso terapéuticoRESUMEN
Noncovalent proteasome inhibitors introduce an alternative mechanism of inhibition to that of covalent inhibitors, e.g. carfilzomib, used in cancer therapy. A multistep hierarchical structure-based virtual screening (SBVS) of the 65,375 NCI lead-like compound library led to the identification of two compounds (9 and 28) which noncovalently inhibited the chymotrypsin-like (ChT-L) activity (Ki = 2.18 and 2.12 µM, respectively) with little or no effects on the other two major proteasome proteolytic activities, trypsin-like (T-L) and post-glutamyl peptide hydrolase (PGPH) activities. A subsequent hierarchical similarity search over the full NCI database with the most active tripeptide-based inhibitor 9 resulted in the discovery of the ß5/ß6-specific tripeptide derivative 38 that noncovalently binds the ChT-L site (Ki = 0.42 µM). The solution structure of 9 and 38 was solved by (1)H NMR spectroscopy and the binding mode of the inhibitors was elucidated by docking experiments using the yeast 20S proteasome. Compound 38 (IC50 = 26.7 µM) is slightly more potent than 9 (IC50 = 34.3 µM) at inhibiting survival of dexamethasone-resistant (MM.1R) human multiple myeloma cells. The identified ligand thus provides valuable insights for the future structure-based design of subtype-specific proteasome inhibitors.
Asunto(s)
Quimotripsina/metabolismo , Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/farmacología , Línea Celular Tumoral , Proliferación Celular , Evaluación Preclínica de Medicamentos , Humanos , Simulación del Acoplamiento Molecular , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/metabolismo , Conformación Proteica , Proteolisis/efectos de los fármacos , Relación Estructura-Actividad , Especificidad por Sustrato , Interfaz Usuario-ComputadorRESUMEN
Flavonoids, from Scutellaria baicalensis (Chinese skullcap) and Acacia catechu (black catechu), have been shown to exert a variety of therapeutic effects, including anti-inflammatory, antiviral, antibacterial, and anticancer activities. Flavocoxid is a mixed extract containing baicalin and catechin and it acts as a dual balanced inhibitor of cyclooxygenase-1 (COX-1) and COX-2 peroxidase enzyme activities with a significant inhibition of 5-lipoxygenase (5-LOX) enzyme activity in vitro. Flavocoxid downregulates gene or protein expression of several inflammatory markers and exerts also strong antioxidant activity in several experimental models. Controlled clinical trials and a postmarketing study have clearly shown that flavocoxid is as effective as naproxen in managing the signs and symptoms of osteoarthritis of the knee and it has better upper gastrointestinal, renal, and respiratory safety profile than naproxen. Flavocoxid may therefore provide a potential therapeutic approach to the treatment of chronic inflammatory conditions.
Asunto(s)
Catequina/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Acacia/química , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Araquidonato 5-Lipooxigenasa/metabolismo , Combinación de Medicamentos , Humanos , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Scutellaria baicalensis/químicaRESUMEN
BACKGROUND: The apoptosis machinery is a promising target against benign prostatic hyperplasia (BPH). Inhibitors of apoptosis proteins (IAPs) modulate apoptosis by direct inhibition of caspases. Serenoa Repens (SeR) may be combined with other natural compounds such as Lycopene (Ly) and Selenium (Se) to maximize its therapeutic activity in BPH. We investigated the effects of SeR, Se and Ly, alone or in association, on the expression of four IAPs, cIAP-1, cIAP-2, NAIP and survivin in rats with experimental testosterone-dependent BPH. Moreover, caspase-3, interleukin-6 (IL-6) and prostate specific membrane antigen (PSMA) have been evaluated.Rats were administered, daily, with testosterone propionate (3 mg/kg/sc) or its vehicle for 14 days. Testosterone injected animals (BPH) were randomized to receive vehicle, SeR (25 mg/kg/sc), Se (3 mg/kg/sc), Ly (1 mg/kg/sc) or the SeR-Se-Ly association for 14 days. Animals were sacrificed and prostate removed for analysis. RESULTS: BPH animals treated with vehicle showed unchanged expression of cIAP-1 and cIAP-2 and increased expression of NAIP, survivin, caspase-3, IL-6 and PSMA levels when compared with sham animals. Immunofluorescence studies confirmed the enhanced expression of NAIP and survivin with a characteristic pattern of cellular localization. SeR-Se-Ly association showed the highest efficacy in reawakening apoptosis; additionally, this therapeutic cocktail significantly reduced IL-6 and PSMA levels. The administration of SeR, Se and Ly significantly blunted prostate overweight and growth; moreover, the SeR-Se-Ly association was most effective in reducing prostate enlargement and growth by 43.3% in treated animals. CONCLUSIONS: The results indicate that IAPs may represent interesting targets for drug therapy of BPH.
Asunto(s)
Apoptosis/efectos de los fármacos , Carotenoides/administración & dosificación , Proteínas Inhibidoras de la Apoptosis/administración & dosificación , Hiperplasia Prostática/tratamiento farmacológico , Animales , Proteínas Reguladoras de la Apoptosis/biosíntesis , Carotenoides/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Licopeno , Masculino , Fitoterapia , Hiperplasia Prostática/patología , Ratas , Serenoa/químicaRESUMEN
BACKGROUND: Previous data have suggested that genistein could exert beneficial effects on endothelial function and on predictors of cardiovascular risk in healthy postmenopausal women. In a randomized clinical trial, we studied the effects of genistein on endothelial function in postmenopausal women with metabolic syndrome (MS). METHODS: Twenty postmenopausal women with MS, according to modified NCEP-ATP III criteria were randomly assigned to receive placebo or genistein (54 mg/day) for 6 months, along with a Mediterranean-style diet. Postmenopausal women without MS (n = 15), served as controls. The primary goal was the assessment of endothelial function by flow-mediated vasodilation (FMD) of brachial artery; moreover, time-to-peak dilation in the FMD response has been evaluated. Secondary outcomes were fasting glucose, fasting insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, visfatin, adiponectin and homocysteine blood levels. Data on adverse events were also recorded. RESULTS: After 6 months of treatment, FMD at 50s and peak FMD significantly increased in genistein recipients compared with placebo. Moreover, genistein significantly decreased the blood levels of total cholesterol, triglycerides, homocysteine and visfatin compared with placebo, while blood adiponectin levels were increased. Genistein recipients neither experienced more side-adverse effects than placebo nor discontinued the study. CONCLUSIONS: Six months of treatment with genistein effectively improves brachial artery flow-mediated vasodilation in postmenopausal women with metabolic syndrome.
Asunto(s)
Endotelio Vascular/fisiología , Genisteína/uso terapéutico , Síndrome Metabólico/tratamiento farmacológico , Fitoestrógenos/uso terapéutico , Posmenopausia/efectos de los fármacos , Índice Tobillo Braquial , Endotelio Vascular/efectos de los fármacos , Femenino , Humanos , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Proyectos Piloto , Resultado del Tratamiento , Vasodilatación/efectos de los fármacosRESUMEN
OBJECTIVE: To evaluate the efficacy of Profluss® on prostatic chronic inflammation (PCI). MATERIALS AND METHODS: We prospectively enrolled 168 subjects affected by LUTS due to bladder outlet obstruction submitted to 12 cores prostatic biopsy for suspected prostate cancer + 2 cores collected for PCI valuation. First group consisted of 108 subjects, with histological diagnosis of PCI associated with BPH and high grade PIN and/or ASAP, randomly assigned to 1:1 ratio to daily Profluss® (group I) for 6 months or to control group (group Ic). Second group consisted of 60 subjects, with histological diagnosis of BPH, randomly assigned to 1:1 ratio to daily Profluss® + a-blockers treatment (group II) for 3 months or to control group (group IIc). After 6 months first group underwent 24 cores prostatic re-biopsy + 2 cores for PCI while after 3 months second group underwent two-cores prostatic for PCI. Specimens were evaluated for changes in inflammation parameters and for density of T-cells (CD3, CD8), B-cells (CD20) and macrophages (CD68). RESULTS: At follow-up there were statistical significant reductions of extension and grading of flogosis, mean values of CD20, CD3, CD68 and mean PSA value in group I compared to Ic, while extension and grading of flogosis in group II were inferior to IIc but not statistical significant. A statistically significant reduction in the density of CD20, CD3, CD68, CD8 was demonstrated in group II in respect to control IIc. CONCLUSIONS: Serenoa repens+Selenium+Lycopene may have an anti-inflammatory activity that could be of interest in the treatment of PCI in BPH and/or PIN/ASAP patients.