Mechanism of butyrate binding to histone deacetylase[HDAC] correlation with chemopreventive effects and ligand selectivity

Sodium butyrate [SB] is a natural cytodifferentiating and cancer preventive agent. These actions are largely triggered by inhibition of the HDAC enzyme, thereby inducing hyperacetylation/ transcription of certain genes. Unlike the prototype HDAC inhibitor, trichostatin-A [TSA], SB offers higher selectivity on cancer cells, with a lower affinity to HDAC. The mechanisms underlying these distinct biological profiles for SB remain undefined. We currently propose for, and attempt to identify differences in the binding of SB and TSA to the HDAC binding pocket. The lowest energy conformer of SB was prepositioned on TSA binding site of HDAC. Following minimization of the best-docked S8-HDAC complex, binding profiles, conformational changes and energy calculations have been derived. TSA elicited 4 hydrogen bonds with 3 key enzyme pocket residues [His131, His132 and Tyr297; bidentated]. SB missed a hydrogen bond with Tyr297 and caused more disruption of the pocket amino acid residues His131, His132 [RMS deviation value difference of up to 0.40 A]. Besides, a looser binding to the pivotal zinc atom of HDAC was evident with SB [1 vs. 2 bonds in case of TSA]. Likewise, SB was far loosely packed in the HDAC's binding tunnel as compared to TSA. Moreover, energy computations indicated that SB had a lower binding affinity than that of TSA [-27.8 vs. -66.3 Kcal/mol]. Detailed binding differences for both ligands are described. These studies demonstrate that SB binding to HDAC confers unique catalytic, conformational and computational characteristics consistent with a lower binding affinity to HDAC and a higher selectivity on cancer cells than TSA. These newly defined binding properties of SB can further state a framework strategy for the rational development of SB-like anticancer drugs with enhanced biological and safety profiles

Direct brow lift surgery as a primary procedure for correction of severe upper eyelid dermatochalisis

Dermatochalisis is a quiet common condition affecting elderly people and leading to remarkable visual and cosmetic disabilities. Traditionally those patients were treated with blepharoplasty and most of them achieve satisfactory results. But in some severe cases a brow lift surgery should be considered to correct the problem. To evaluate direct brow lift surgery as a primary procedure for correction of sever upper eyelid dermatochalisis. Seven patients [6 females and 1 male] with a mean age 71.1 years complaining of severe bilateral dermatochalisis were included in the study, one of them had a previous unsatisfactory blepharoplasty surgery in one eye. All of the patients underwent a direct brow lift surgery to correct their problem. The results were very satisfactory with a mean postoperative marginal reflex distance [MRD] 2.9 mm and a mean difference between the two eyelids less than 0.5 mm in all cases. Brow ptosis should be suspected in elderly people complaining of upper eyelid dermatochalisis and a brow lift surgery should be considered as the primary management procedure

Effect of deoxycholic acid, polycarbophil or both on the relative hyperglycemia of rectal insulin suppositories containing sodium salicylate in diabetic rabbits

The effect of insulin [50 u] suppositories containing sodium salicylate [50 mg] without and with 50 mg of either polycarbophil, deoxycholic acid or 50 mg of each on plasma glucose levels of hyperglycemic rabbits was studied. The hypoglycemia of these formulations was determined relative to that produced after s.c. injection of insulin suspension and were 45.6%, 46.7%, 48.2% and 39.5% respectively. Insulin suppositories containing sodium salicylate were effective in reducing plasma glucose levels which steadily decreased and reached 66% of the initial values by the 3rd h.the addition of polycarbophil to insulin suppositories containing sodium salicylate induced faster and higher rate of insulin absorption as indicated by the shorter Tmax and higher Cmax. addition of deoxycholic acid increased non significantly the Tmax MRT, AUC0-7 h of that of insulin suppositories containing sodium salicylate. The incorporation of both polycarbophil and deoxycholic acid in insulin suppositories containing sodium salicylate is not recommended as these additives reduced the Cmax and AUC0-7 h. accordingly, insulin suppositories containing sodium salicylate with and without the addition of polycarbophil or deoxycholic acid may be considered as a good alternative to insulin injection

Toward the mechanism of valproate teratogenesis: structural basis and interactions with agents that alter folate metabolism

The hypothesis that valproate-induced neural tube defects [NTDs] may be due to interference with folate metabolic pathways was investigated by studying the possible interactions of valproate and a number of agents that modulate folate metabolism. Valproate [VPA]-induced exencephaly [an anterior NTDs] in NMRI mice was used as an animal model. A single dose of valproic acid sodium salt [300 - 500 mg/kg, s.c.] on day 8 of gestation produced a dose related increase in exencephaly rate, embryolethality, and fetal weight retardation. Supplementation with vitamin B[6]+B[12] without and with folinic acid, serine with folinic acid, and carnitine was found to reduce valproate- induced exencephaly rate. Vitamin B[6]+B[12] and methionine reduced VPA-induced fetal weight retardation and embryotoxicity, respectively. The protection was not complete and was not always dose related, and in case of carnitine, higher doses were devoid of such effects and even increased valproate-induced exencephaly. On the other hand, coadministration of valproate with low [threshold] doses of methotrexate, trimethoprim, nitrous oxide and ethanol was found to increase the incidence of exencephaly rate. Embryotoxicity was also increased as a result of such combinations except with trimethoprim. The observed effects were not due to altered valproate toxicokinetics in case of methotrexate and trimethoprim but was probably due to decreased valproate elimination by ethanol and advise against the use of these agents in valproate-treated epileptics during pregnancy. The previous results support the view that valproate-induced NTDs may be mediated via an interaction with folate metabolism. Study of the structural-activity relationships of several valproate analogues revealed a strict structural requirement for high teratogenic potency. In contrast, the anticonvulsant activity and neurotoxicity showed broader structural specificity. Furthermore, the R- and S-enantiomers of 2-n-propyl-4-pentenoic acid and 2-n-propyl-4-pentynoic acid showed different teratogenic activity [S-enantiomers were more teratogenic than R-enantiomers] in contrast to anticonvulsant potency in the absence of pharmacokinetic differences. These findings opens the possibility for development of novel antiepileptic agents with low teratogenic potency

LCAT activity, APO A1 and HDL-C in staging patients with hepatosplenic bilharziasis

The aim of this study was to assess the lipids and lipoproteins abnormalities as indicators of hepatic dysfunction in hepatosplenic bilharziasis. Patients with different clinical stages of hepatosplenic affection were involved in this study. 15 patients were in the hepatic phase [stage I], 25 in the phase of shrunken liver and splenomegaly [stage III] and 30 patients were in the terminal phase of shrunken liver and ascites [stage IV]. 25 healthy subjects were carefully selected as a control group. In addition to the routine liver function tests, serum total, free and esterified cholesterol, triglycerides, low and high density lipoproteins-cholesterol, apolipoprotein Al levels and lecithin cholesterol acyl transferase [LCAT] activity were estimated. From the present study, unlike the routine liver function tests, direct assessment of LCAT activity or indirect assessment of this activity by measuring apolipoprotein Al and/or HDL-C are sensitive markers of hepatic affection from the early stages of hepatosplenic bilharziasis. They also reflect the degree of hepatic affection as the disease progress

Mutagenic potentials of certain herbal extracts in mutant strains of salmonella typhimurium

Damage to DNA appears to be the major cause of most cancer and genetic birth defects and may contribute to aging heart diseases. The genetical damage can be caused by many substances used in medicine, industry, pest control and food preservatives. The present study investigated the mutagenic potentials of certain medicinal plants commonly used in traditional medicine, using five mutant strains of salmonella typhimurium/mammalian microsome in-vitro test [Ames test]. The histidine-dependent strains [TA 98, TA 100, TA 1535, TA 1537, and TA 1538] were used to detect DNA frame shifts and base-pair substitutions, which were recommended for preliminary screening of potential mutagens and carcinogens. Three different concentrations of each extract were used in the presence and absence of activated rat liver microsomal enzymes [S9 mix] to detect whether they produce direct or indirect genotoxic activity. Positive controls using diagnostic mutagens were also used to confirm the reversion properties and specificity of each strain and efficacy of the S9 mix. The results showed that extracts of the 16 herbs investigated did not induce mutations in the Salmonella mammalian microsome general mutagenicity test of Ames in concentrations up to 10 mg/plate

Mechanism of caffeine-induced corticosterone release in pregnant mice

The pituitary-adrenal axis of day 14 pregnancy was suppressed by parenteral administration of dexamethasone [0.4 mg/mouse, -20 h], pentobarbital [80 mg/kg, -0.75 h], pentobarbital [20 mg/kg, -0.75 h], intraperitoneally [100 mg/kg, 0 h] and plasma corticosterone and caffeine levels were determined 1.5 hours later. Plasma corticosterone of suppressed control animals was significantly decreased than that of unsuppressed controls at day 14 of gestation. Caffeine administration produced no change in plasma corticosterone level of 3 out of 7 animals and slightly increased the steroid level of the other 4 suppressed mice. In unsuppressed animals, however, a marked increase in plasma corticosterone level was observed. The low plasma corticosterone level in caffeine treated suppressed mice, compared with that of unsuppressed ones, indicated the high corticosterone level, and may indicate that the high corticosterone level induced by caffeine administration during pregnancy in mice could be mediated through release of adrenocorticotrophic hormone from the anterior pituitary gl and and not due to direct stimulation of the adrenal cortex