The combined treatment of insulin and naringin improves bone properties in rats with type 1 diabetes mellitus.

We have studied the effects of individual and combined treatment of insulin (I) and naringin (NAR) on the bone structure and biomechanical properties of femurs from streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were divided into five groups: (1) controls, (2) STZ-induced diabetic rats, (3) STZ-induced diabetic rats treated with I, (4) STZ-induced diabetic rats treated with NAR, and (5) STZ-induced diabetic rats treated with I + NAR. Bone mineral density (BMD), bone histomorphometry, biomechanical testing, and bone biomarker expressions were accomplished in femur of all animals, as well as serum biochemical analyses. The combined treatment of I + NAR increased the body weight and the femur BMD from STZ-induced diabetic rats. The bone biomechanical properties and the bone morphology of the femurs from STZ-induced diabetic rats were also improved by the combined treatment. The increased number of osteoclasts in STZ-induced diabetic rats was partially prevented by I, NAR, or I + NAR. NAR or I + NAR completely blocked the decrease in the number of osteocalcin (+) cells in the femur from STZ-induced diabetic rats. RUNX family transcription factor 2 immunostaining was much lower in STZ-induced diabetic rats than in control animals; the combination of I + NAR totally blocked this effect. The combined treatment not only ameliorated bone quality and function, but also normalized the variables related to glucose metabolism. Therefore, the combination of I + NAR might be a better therapeutic strategy than the individual I or NAR administration to reduce bone complications in diabetic patients.

Pharmacoinformatics studies of coenzyme Q10 and potassium polyacrylate on angiotensin-converting enzyme associated with hypertension.

Coenzyme Q10's (CoQ10) favorable impact on cardiovascular diseases risk factors like hypertension and atherosclerosis is linked to the antioxidant action of CoQ10 in these conditions. This study showed the possible effects of CoQ10, potassium polyacrylate (PCK), and valsartan, a reference drug, on the angiotensin-converting enzyme (ACE), a crucial component of the renin-angiotensin system. The Glide tool on Maestro 11.1 was used to calculate the respective binding affinity and binding energy of these compounds towards ACE. The Schrödinger suite was used to run molecular dynamic simulations for 100 ns. The pkCSM tool was used to forecast the pharmacokinetic characteristics and toxicological effects. The SwissADME server was used to estimate the drug-like properties of these compounds. Based on their corresponding scoring values and the negative values of the binding free energies, molecular docking analysis of CoQ10 and PCK revealed that both exhibited favorable binding affinities towards the ACE, with CoQ10 having the highest binding scores. The results showed that both CoQ10 and PCK and the reference drug, valsartan, have some amino acids in common (at the pocket site of ACE) as the key residues for binding to ACE. Both CoQ10 and PCK demonstrated drug-like qualities and were not harmful, according to the predicted pharmacokinetics and toxicology studies. The results of this study suggest that because of its inhibitory interactions with ACE, CoQ10 in particular could be useful in regulating and reducing hypertension.Communicated by Ramaswamy H. Sarma.

Naringin prevents bone damage in the experimental metabolic syndrome induced by a fructose-rich diet.

We analyzed the effect of naringin (NAR), a flavonoid from citric fruits, on bone quality and biomechanical properties, as well as the redox state of bone marrow in rats fed a fructose-rich diet (FRD), an experimental model to mimic human metabolic syndrome. NAR blocked the increase in the number of osteoclasts and adipocytes and the decrease in the number of osteocytes and osteocalcin (+) cells caused by FRD. Trabecular number was significantly higher in the FRD+NAR group. FRD induced a decrease in the femoral trabecular and cortical bone mineral density, which was blocked by NAR. The fracture and ultimate loads were also decreased in the FRD and FRD+NAR groups. NAR increased the number of nodes to terminal trabecula, the number of nodes to node trabecula, the number of nodes, and the number of nodes with 2 terminals and decreased the Dist (mean size of branches) value. FRD decreased bone marrow catalase activity, an effect that was prevented by NAR. In conclusion, FRD has detrimental effects on the long bones, which are associated with oxidative stress in the bone marrow. Most of these changes are prevented by NAR through its antioxidant properties and promotion of bone formation. Novelty: Fructose-rich diets have detrimental effects on long bones, which are associated with oxidative stress in the bone marrow. Most of these changes are prevented by naringin through its antioxidant properties and promotion of bone formation.

Lithocholic acid: a new emergent protector of intestinal calcium absorption under oxidant conditions.

LCA and 1,25(OH)2D3 are vitamin D receptor ligands with different binding affinity. The secosteroid stimulates intestinal Ca2+ absorption. Whether LCA alters this process remains unknown. The aim of our work was to determine the effect of LCA on intestinal Ca2+ absorption in the absence or presence of NaDOC, bile acid that inhibits the cation transport. The data show that LCA by itself did not alter intestinal Ca2+ absorption, but prevented the inhibitory effect of NaDOC. The concomitant administration of LCA avoided the reduction of intestinal alkaline phosphatase activity caused by NaDOC. In addition, LCA blocked a decrease caused by NaDOC on gene and protein expression of molecules involved in the transcellular pathway of intestinal Ca2+ absorption. The oxidative stress and apoptosis triggered by NaDOC were abrogated by LCA co-treatment. In conclusion, LCA placed in the intestinal lumen protects intestinal Ca2+ absorption against the inhibitory effects caused by NaDOC. LCA avoids the reduction of the transcellular Ca2+ movement, apparently by blocking the oxidative stress and apoptosis triggered by NaDOC, normalizing the gene and protein expression of molecules involved in Ca2+ movement. Therefore, LCA might become a possible treatment to improve intestinal calcium absorption under oxidant conditions.

Ursodeoxycholic and deoxycholic acids: Differential effects on intestinal Ca(2+) uptake, apoptosis and autophagy of rat intestine.

The aim of this work was to study the effect of sodium deoxycholate (NaDOC) and ursodeoxycholic acid (UDCA) on Ca(2+) uptake by enterocytes and the underlying mechanisms. Rats were divided into four groups: a) controls, b) treated with NaDOC, c) treated with UDCA d) treated with NaDOC and UDCA. Ca(2+) uptake was studied in enterocytes with different degrees of maturation. Apoptosis, autophagy and NO content and iNOS protein expression were evaluated. NaDOC decreased and UDCA increased Ca(2+) uptake only in mature enterocytes. The enhancement of protein expression of Fas, FasL, caspase-8 and caspase-3 activity by NaDOC indicates triggering of the apoptotic extrinsic pathway, which was blocked by UDCA. NO content and iNOS protein expression were enhanced by NaDOC, and avoided by UDCA. The increment of acidic vesicular organelles and LC3 II produced by NaDOC was also prevented by UDCA. In conclusion, the inhibitory effects of NaDOC on intestinal Ca(2+) absorption occur by decreasing the Ca(2+) uptake by mature enterocytes. NaDOC triggers apoptosis and autophagy, in part as a result of nitrosative stress. In contrast, UDCA increases the Ca(2+) uptake by mature enterocytes, and in combination with NaDOC acts as an antiapoptotic and antiautophagic agent normalizing the transcellular Ca(2+) pathway.

Sodium deoxycholate inhibits chick duodenal calcium absorption through oxidative stress and apoptosis.

High concentrations of sodium deoxycholate (NaDOC) produce toxic effects. This study explores the effect of a single high concentration of NaDOC on the intestinal Ca(2+) absorption and the underlying mechanisms. Chicks were divided into two groups: 1) controls and 2) treated with different concentrations of NaDOC in the duodenal loop for variable times. Intestinal Ca(2+) absorption was measured as well as the gene and protein expressions of molecules involved in the Ca(2+) transcellular pathway. NaDOC inhibited the intestinal Ca(2+) absorption, which was concentration dependent. Ca(2+)-ATPase mRNA decreased by the bile salt and the same occurred with the protein expression of Ca(2+)-ATPase, calbindin D(28k) and Na(+)/Ca(2+) exchanger. NaDOC produced oxidative stress as judged by ROS generation, mitochondrial swelling and glutathione depletion. Furthermore, the antioxidant quercetin blocked the inhibitory effect of NaDOC on the intestinal Ca(2+) absorption. Apoptosis was also triggered by the bile salt, as indicated by the TUNEL staining and the cytochrome c release from the mitochondria. As a compensatory mechanism, enzyme activities of the antioxidant system were all increased. In conclusion, a single high concentration of NaDOC inhibits intestinal Ca(2+) absorption through downregulation of proteins involved in the transcellular pathway, as a consequence of oxidative stress and mitochondria mediated apoptosis.

Minireview on regulation of intestinal calcium absorption. Emphasis on molecular mechanisms of transcellular pathway.

An overview of current information on the mechanisms by which intestinal calcium absorption occurs is described in this article. Both paracellular and transcellular pathways are analyzed. Special emphasis focuses on molecules participating in the latter pathway, such as TRPV5 and TRPV6 channels, located in the apical region of the enterocytes, CB(9k) and CB(28k), presumably involved in the cation movement from the apical to the basolateral pole of the cell, and PMCA(1b) and Na(+)/Ca(2+) exchanger, proteins that extrude Ca(2+) from the cells. Current concepts on the relative importance of paracellular and transcellular calcium transport and the vitamin D dependence of each pathway are referred and analyzed showing the contrasting views on this issue. More detailed information is given regarding the stimulatory effect of vitamin D on intestinal Ca(2+) absorption either in animal models or in the human intestine. The possible mechanisms triggered by hormones such as PTH, calcitonin, estrogen, thyroid hormone, glucocorticoids and different nutritional factors on intestinal calcium absorption are also reviewed. Finally, the influence of physiological conditions such as growth, pregnancy, lactation and aging on intestinal calcium absorption are discussed.

Efectos del alendronato oral, la hormonoterapia de reeplazo y la conbinacion de ambos sobre la masa osea en mujeres posmenopausicas: informe preliminar de um estudio comparativo / Effects on bone mass of oral alendronate, hormone replacement therapy and combined regimesns in post-menopausal women: p

Se informa el análisis comparativo preliminar de los efectos sobre la densidad mineral ósea de la terapia con alendronato, la hormonoterapia de reemplazo (HTR) y la asociación de ambas el primer año de tratamiento continuo. Se incluyeron en un estudio prospectivo y abierto mujeres posmenopáusicas de hasta 70 años de edad, con osteopenia de columna lumbar y/o de cuello de fémur (DMO menor que -1 DE del adulto joven) determinada por absorciometría de rayos X dual (DEXA). Noventa y seis pacientes fueron incluidas al azar en uno de los 4 grupos terapéuticos: Grupo I (n:19): hormonoterapia de reemplazo (HTR) con 17 beta estradiol 50 Mug/día por vía transdermal y medroxiprogesterona 2,5 mg/día por vía oral; Grupo II (n:42): alendronato 10 mg/día por vía oral; Grupo III (n:15): HTR + alendronato 10 mg/día y Grupo IV (n:20): HTR + alendronato 5 mg/día. Los resultados ajustados a los 12 meses de tratamiento, evidenciaron un aumento promedio significativo de la densidad mineral ósea (DMO) vertebral de 3,6 por ciento; 4,1 por ciento; 6,5 por ciento y 3,1 por ciento en los grupo I a IV respectivamente con respecto a la basal (p < 0,01), sin diferencias significativas entre los grupos. El porcentaje de pacientes respondedoras en columna lumbar en cada grupo fue del 68,8 por ciento; 92 por ciento; 90 por ciento y 83 por ciento, respectivamente. Los incrementos promedio sobre la DMO del cuello de fémur (CF) respecto a la basal no superaron la variación del método de determinación. El porcentaje de respondedoras sobre el CF en cada grupo fue de 58,8 por ciento; 60 por ciento; 62,5 por ciento y 45,5 por ciento, respectivamente. La disminución en los marcadores bioquímicos de metabolismo óseo, especialmente de la piridinolina urinaria y la osteocalcina indicaron la tendencia a la inhibición del metabolismo óseo, que fue más constante en el grupo III. Se concluye que, si bien todos los grupos favorecieron el balance óseo positivo, los resultados más favorables fueron observados con el tratamiento combinado con alendronato 10 mg y HTR (grupo III) sugiriendo el beneficio potencial de esta asociación.

Efectos del alendronato oral, la hormonoterapia de reeplazo y la conbinacion de ambos sobre la masa osea en mujeres posmenopausicas: informe preliminar de um estudio comparativo / Effects on bone mass of oral alendronate, hormone replacement therapy and combined regimesns in post-menopausal women: p

Se informa el análisis comparativo preliminar de los efectos sobre la densidad mineral ósea de la terapia con alendronato, la hormonoterapia de reemplazo (HTR) y la asociación de ambas el primer año de tratamiento continuo. Se incluyeron en un estudio prospectivo y abierto mujeres posmenopáusicas de hasta 70 años de edad, con osteopenia de columna lumbar y/o de cuello de fémur (DMO menor que -1 DE del adulto joven) determinada por absorciometría de rayos X dual (DEXA). Noventa y seis pacientes fueron incluidas al azar en uno de los 4 grupos terapéuticos: Grupo I (n:19): hormonoterapia de reemplazo (HTR) con 17 beta estradiol 50 Mug/día por vía transdermal y medroxiprogesterona 2,5 mg/día por vía oral; Grupo II (n:42): alendronato 10 mg/día por vía oral; Grupo III (n:15): HTR + alendronato 10 mg/día y Grupo IV (n:20): HTR + alendronato 5 mg/día. Los resultados ajustados a los 12 meses de tratamiento, evidenciaron un aumento promedio significativo de la densidad mineral ósea (DMO) vertebral de 3,6 por ciento; 4,1 por ciento; 6,5 por ciento y 3,1 por ciento en los grupo I a IV respectivamente con respecto a la basal (p < 0,01), sin diferencias significativas entre los grupos. El porcentaje de pacientes respondedoras en columna lumbar en cada grupo fue del 68,8 por ciento; 92 por ciento; 90 por ciento y 83 por ciento, respectivamente. Los incrementos promedio sobre la DMO del cuello de fémur (CF) respecto a la basal no superaron la variación del método de determinación. El porcentaje de respondedoras sobre el CF en cada grupo fue de 58,8 por ciento; 60 por ciento; 62,5 por ciento y 45,5 por ciento, respectivamente. La disminución en los marcadores bioquímicos de metabolismo óseo, especialmente de la piridinolina urinaria y la osteocalcina indicaron la tendencia a la inhibición del metabolismo óseo, que fue más constante en el grupo III. Se concluye que, si bien todos los grupos favorecieron el balance óseo positivo, los resultados más favorables fueron observados con el tratamiento combinado con alendronato 10 mg y HTR (grupo III) sugiriendo el beneficio potencial de esta asociación. (AU)