Orcinol derivative compound with antioxidant properties protects Langerhans islets against streptozotocin damage.

OBJECTIVE: To design and synthesize an orcinol derivative compound, 3-formyl-2,4-dihydroxy-5,6-dimethyl sodium benzoate (A4), as an antioxidant molecule and to test its effects on oxidative stress in an in-vitro model of apoptosis of pancreatic rat beta cells induced by streptozotocin (STZ). METHODS: Scavenger properties of A4 were assessed using its capacity to capture the DPPH radical in vitro. Antiapoptotic properties of A4 were analysed by electron microscopy and TUNEL assay in rat pancreatic islets in a streptozotocin model. KEY FINDINGS: The results show that A4 displays antioxidant activity in in-vitro assays and induced a significant reduction in STZ-induced beta cell apoptosis and low ultrastructural damage to cellular organelles in the rat pancreatic islets as evidenced by electronic microscopy, this effect could be attributed to its antioxidant activity in a similar manner than resveratrol. CONCLUSION: The overall results indicate that the new orcinol derivative molecule displays both antioxidant and antiapoptotic effects and protect pancreatic beta cells against STZ damage.

Biological evaluation of androstene derivatives.

The effect of several new dihydroepiandrosterone ester derivatives A2-A6 was demonstrated using female cycling mice, which were synchronized for estrus with luteinizing hormone-releasing hormone (LHRH) and injected with the steroids. The binding to the progesterone receptor (PR), was obtained from the cytosol of uteri from adult estrogen-primed rabbits. A1 binds to the PR and inhibited the ovulation in cycling mice stimulated with LHRH. The activity of the endometrium and mammary glands in these mice was markedly reduced as compared to the control. A2, A4, and A5 were not active; nevertheless, A3 binds to the PR with high affinity. However, this steroid did not produce any effect as compared to that observed for the control in the endometrial and mammary glands. A6 binds to the PR with the highest affinity and induces a synergistic activity with progesterone in these tissues. Furthermore, A6 inhibited the ovulation in the same manner as A1. These results suggested that A1 and A6 are blocking the gonadotropin secretion. A1 inhibited the conversion of progesterone to 5α-progesterone. As a result of this, a blockage of the ductal and alveolar epithelial cell proliferation in the mammary and endometrial glands, which depends on 5α-progesterone, was also observed.

Efficacy of an MFGM-enriched complementary food in diarrhea, anemia, and micronutrient status in infants.

OBJECTIVE: The aim of the present study was to evaluate the efficacy of a milkfat globule membrane (MFGM)-enriched protein fraction in a complementary food, on diarrhea, anemia, and micronutrient status. SUBJECTS AND METHODS: A randomized, double-blind controlled design to study 550 infants, 6 to 11 months old, who received daily for 6 months a complementary food (40 g/day) with the protein source being either the MFGM protein fraction or skim milk proteins (control). Health and nutritional status of infants were examined monthly in the outpatient clinic; product intake, food patterns, and diarrhea morbidity were assessed by home visits twice per week. Hemoglobin and micronutrient status were measured at 0 and 6 months of intervention. Results are presented as the entire group and as 6 to 8 and 9 to 11 months subgroups. RESULTS: A total of 499 infants completed the study. Global prevalence of diarrhea was 3.84% and 4.37% in the MFGM group and control group, respectively (P < 0.05). Consumption of the MFGM protein fraction reduced episodes of bloody diarrhea (odds ratio 0.54; 95% confidence interval 0.31-0.93, P = 0.025) adjusting for anemia and potable water facilities as covariates. There were no differences between groups in anemia, serum ferritin, zinc, or folate. CONCLUSIONS: Addition of an MFGM-enriched protein fraction to complementary food had beneficial effects on diarrhea in infants and may thus help to improve the health of vulnerable populations.

Molecular interactions of progesterone derivatives with 5 alpha-reductase types 1 and 2 and androgen receptors.

The aim of this study was to ascertain the inhibitory effect of several progesterone derivatives for 5 alpha-reductase types 1 and 2 isozymes and to determine the binding to the androgen receptor. The 3,20-dioxopregna-4-ene-17 alpha-yl acetate 4 containing an acetoxy group in C-17 and steroid 17 alpha-hydroxypregn-4-ene-3,20-dione 5 having a hydroxyl group in the same position inhibited both isozymes. On the other hand, 17 alpha-hydroxy-4,5-epoxypregnan-3,20-dione 6 with an epoxy function at C-4, inhibited only the type 1 enzyme. Steroid 4-chloro-17 alpha-hydroxypregn-4-ene-3,20-dione 7a and 4-bromo-17 alpha-hydroxypregn-4-ene-3,20-dione 7b having the C-4 conjugated system and a chlorine or a bromine atom at C-4 respectively, inhibited both types of 5 alpha-reductase. These results indicate that an increase in the electronegativity of ring A produces a major inhibitory activity for 5 alpha-reductase type 1; however this increase was not observed for type 2 enzyme. When the free hydroxyl group of 7a or 7b was esterified, compounds 3,20-dioxo-4-chloropregn-4-ene-17 alpha yl-4-ethylbenzoate 8a and 3,20-dioxo-4-bromopregn-4-ene-17 alpha yl-4-ethylbenzoate 8b were obtained; these steroids inhibited only the 5 alpha-reductase type 2 enzyme. Finasteride and steroids 4, 5, 7b, 8a showed a comparable in vivo pharmacological activity, however the IC(50) values of these compounds were higher as compared to that of finasteride. These results indicated also that steroids 4, 5, 7a, and 7b bind to the androgen receptor whereas compounds 6, 8a and 8b failed to do so. The overall data from this study showed that steroids 5 and 7b bind to the AR and decreased of the growth of prostate and seminal vesicles. Moreover, 4 decreased also the growth of seminal vesicles.

Novel C-6 substituted and unsubstituted pregnane derivatives as 5alpha-reductase inhibitors and their effect on hamster flank organs diameter size.

The present study is addressed to ascertain the inhibitory effect of several progesterone derivatives having a chlorine substituent at C-6 (12a-12d), 15 with a bromine substituent at C-6 and 14a-14d, without any halogen atom at C-6 all having an ester side chain at C-17 (benzoate ester bearing a Cl, F and a Br atom at C-4 position of the phenyl ring) on the 5alpha-reductase enzyme activity present in human prostate. In addition, it was also of interest to investigate the pharmacological effect on hamster flank organs diameter size. In order to study the structure-activity relationships of steroids 12a-12d, 14a-14d and 15 we determined the concentration of these steroids that inhibited 50% of the activity of human prostate 5alpha-reductase enzyme (IC(50)), as well as the in vivo effect of these compounds in the hamster flank organs diameter size. We also ascertained, the capacity of these steroids to bind to the androgen receptors present in the rat prostate cytosol using labeled mibolerone (MIB) for monitoring the binding to the androgen receptor. The results from this study indicated that compounds 12a-12d (having a chlorine substituent at C-6), 14a-14d (lacking a halogen atom at C-6), 13 and 15 (having a bromine atom at C-6) showed an increased antiandrogenic effect (lower value for the diameter of the flank organs) as compared to the flank organs from testosterone-treated hamsters. On the other hand, the series of compounds containing a chlorine substituent at C-6 compounds (12a-12d) showed a higher antiandrogenic activity as compared to the compounds lacking a halogen atom at C-6 (14a, 14b and 14d). Although compounds 13 and 15 decreased the flank organs diameter size, however, this increase was not statistically significant as compared to that of the commercially available product finasteride. The steroidal derivatives 13, 14a-14d (lacking the chlorine substituent at C-6) and 15 (having a bromine atom at C-6) exhibited a higher 5alpha-reductase inhibitory activity (lower IC(50) values) as compared to the series of compounds 12a-12d having the halogen substituent at C-6. Finasteride reduced the diameter size of the flank organs. The effect of this steroid and compounds 12a-12d, 13, 14a-14d and 15 on hamster flank organs can be explained by the fact that these steroids did not bind to the androgens receptor, which indicates that its mechanism of action is an inhibiting for the 5alpha-reductase activity. This enzyme is present in the hamster flank organs and was inhibited by the novel steroids in the human prostate homogenates.

Molecular interactions of new pregnenedione derivatives.

The in vitro inhibitory activity of five new progesterone derivatives: 17alpha-hydroxy-16beta-methylpregna-1,4,6-triene-3,20-dione 1; 16beta-methyl-17alpha-toluoyloxypregna-1,4,6-triene-3,20-dione 2; 17alpha-hydroxy-6-methylenepregn-4-ene-3,20-dione 3; 6-methylene-17alpha-toluoyloxypregn-4ene-3,20-dione 4 and 17alpha-(p-bromobenzoyloxy)-6-methylenepregn-4-ene-3,20-dione 5 was determined. These compounds were evaluated as 5alpha-reductase inhibitors as well as antagonists for the androgen receptor. Compounds 1, 2, 3, 4 and 5 showed the following inhibitory activity for the 5alpha-reductase enzyme with IC(50) values of: 1 (1.65 microM), 2 (10 microM), 3 (19 nM), 4 (100 nM) and 5 (100 nM). The results of this study also showed the effect of increasing concentrations of the novel steroids upon [(3)H]dihydrotestosterone binding to androgen receptors from male hamster prostate. The K(i) values for compounds 1, 2, 3, 4, 5 and dihydrotestosterone showed the following order of affinity for the androgen receptor: 4>5>dihydrotestosterone>2>3>1. The overall data indicated that all synthesized compounds 1, 2, 3, 4 and 5 are inhibitors of the 5alpha-reductase enzyme present in the hamster prostate. In addition compounds 1, 2, 3, 4 and 5 also presented an affinity for the androgen receptor.