Selection of Efficient Inhibitors for Caspas-9 according to Structure-Based Pharmacophore Screening Strategy and Molecular Dynamics Simulations

Caspases are enzymes which are the main pathways for apoptosis. Any irregulation in their functions causes increase or decrease in cell death, which result in autoimmune disease or cancer, respectively. In this study, structure-based pharmacophore drug discovery method as a virtual screening was used to discover selective inhibitors for caspase-9. This enzyme is an initiator caspase that is the main pathway in Alzheimer’s disease. A pharmacophore model was developed by investigating essential interactions among the reported potent inhibitors employing a docking analysis methodology. Applying pharmacophore virtual screening, nine compounds from both National Cancer Institute (NCI), and ZINC databases were filtered as potent inhibitors of caspase-9. The efficiency of the discovered compounds was further investigated by docking studies.HIGHLIGHTS•Caspase-9 is an important enzyme for apoptosis and its activity is pivotal in cell death.•A computational design of small molecular inhibitors for caspase-9 performed by structure-based pharmacophore model.•9 compounds from both National Cancer Institute (NCI) and ZINC databases were discovered as potent inhibitors

Adding wheat to a pre-partum diet of Holstein cows favours post-partum protein utilization and benefits calcium status

This study evaluated the effects of replacing corn with wheat on the lactation performance, ruminal fermentation, plasma metabolites and hormonal profiles of multiparous Holstein cows. Thirty-four multiparous cows were divided into two equal groups, based on parity, body condition score, and bodyweight. The basal diet was supplemented with 186 g/kg corn or wheat, and was offered from day -28 (±7) relative to the date of expected calving. After calving, all cows received the same diet for four weeks (day +28). The wheat diets increased (P <0.05) the body condition score in the peri-parturient period and caused greater changes in dry matter intake and bodyweight post-partum, with no differences in energy balance compared with the corn diets. Further, the wheat increased (P <0.05) the concentration of propionate in the rumen, thus reducing the ratio of acetate to propionate, and produced (P <0.05) more milk and milk protein, but had reduced levels of urea nitrogen in the milk and serum. Similarly, the wheat diets increased (P <0.05) the plasma concentrations of albumin and glucose, and reduced (P <0.05) triglycerides with no effect (P >0.10) post partum on insulin, cortisol, β-hydroxybutyric acid and aspartate aminotransferase. The replacement of corn with wheat increased (P <0.05) plasma calcium and reduced non-esterified fatty acids around calving (day 0±1) and post-partum (days 0 to +28), and reduced urinary pH during the last week relative to the date of expected calving.Keywords: calving, energy balance, grain source, peri-parturient perio

Assessment of salivary and serum antioxidant status in patients with recurrent aphthous stomatitis

Objective: The aim of this study was to determine the possible association of oxidant/antioxidant status and recurrent aphthous stomatitis (RAS). Study design: The study consis ted of thirty-one patients with RAS and thirty-two healthy controls from whom saliva and blood samples were collected. Superoxide dismutase (SOD), glutathione peroxidase (GSHPx) and catalase (CAT) were measured in erythrocytes and total antioxidant status (TAS) was measured in plasma and saliva. Results: Erythrocyte SOD activity was significantly lower in RAS patients in comparison to healthy controls (P=0.012). No significant differences were found in erythrocyte GSHPx, CAT activities, and salivary and plasma TAS between RAS patients and control subjects (p>0.1). Conclusion: Changes in SOD activity may be important in the inflammatory reactions observed in RAS, but other tested defense systems such as CAT and GSHPx do not seem to play a primary role in the aetiopathogenesis of RAS. Moreover, the antioxidant system in saliva and plasma is not as affected as in erythrocytes in RAS patients, and therefore it may not be considered an appropriate indicator of the body?s total antioxidant status

Benzylidene Barbituric Acid Derivatives Shown Anticonvulsant Activity on Pentylenetetrazole-Induced Seizures in Mice: Involvement of Nitric Oxide Pathway

ABSTRACT Background: Barbituric acid derivatives have long been used as central nervous system (CNS) suppressants, such as sedatives, hypnotics and anticonvulsants. In addition, previous studies have implicated the involvement of nitric oxide (NO) in the anticonvulsive effects of barbiturates in CNS. Therefore, the purpose of this study was to figure out the effects of a novel class of barbituric acid derivatives on pentylenetetrazole (PTZ)-induced seizures in male mice. Methods: Thirteen synthesized barbituric acid derivatives (a-m) and phenobarbital were administered intraperitoneally (i.p.) 30 min before induction of seizures by PTZ administration. The mechanisms of PTZ-induced seizures in the mice was evaluated using a non-selective nitric oxide synthase (NOS) inhibitor, selective inducible NOS (iNOS) inhibitor, a selective neuronal NOS (nNOS) inhibitor, and NO substrate. Results: Administration of most of the above mentioned derivatives significantly increased the seizures threshold (P<0.001). The most potent derivative (compound a), was chosen in order to investigate the mechanism of action involving in anticonvulsant activity. Administration of a non-selective NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) and a selective nNOS inhibitor, 7-nitroindazole (7-NI) reversed anticonvulsant activity of compound a. However, injection of the nitric oxide precursor, L-arginine (L-Arg) and a selective iNOS inhibitor, aminoguanidine (AG), did not change anticonvulsant activity of the mentioned compound. Conclusion: These results indicated that the NO system, specifically nNOS may contribute to the anticonvulsant activity of benzylidene barbituric acid derivative a. Therefore, this compound is a good candidate in order to designing new anticonvulsant medication

Mesoporous silica nanoparticles functionalized with folic acid/methionine for active targeted delivery of docetaxel

Abstract: Mesoporous silica nanoparticles (MSNs) are known as carriers with high loading capacity and large functionalizable surface area for target-directed delivery. In this study, a series of docetaxel-loaded folic acid- or methionine-functionalized mesoporous silica nanoparticles (DTX/MSN-FA or DTX/MSN-Met) with large pores and amine groups at inner pore surface properties were prepared. The results showed that the MSNs were successfully synthesized, having good pay load and pH-sensitive drug release kinetics. The cellular investigation on MCF-7 cells showed better performance of cytotoxicity and cell apoptosis and an increase in cellular uptake of targeted nanoparticles. In vivo fluorescent imaging on healthy BALB/c mice proved that bare MSN-NH2 are mostly accumulated in the liver but MSN-FA or MSN-Met are more concentrated in the kidney. Importantly, ex vivo fluorescent images of tumor-induced BALB/c mice organs revealed the ability of MSN-FA to reach the tumor tissues. In conclusion, DTX/MSNs exhibited a good anticancer activity and enhanced the possibility of targeted drug delivery for breast cancer

Growth Performance, Eating Behavior, Digestibility, Blood Metabolites, and Carcass Traits in Growing-Finishing Fat-Tailed Lambs Fed Different Levels of Dietary Neutral Detergent Fiber with High Rumen Undegradable Protein

This study was conducted to investigate the effect of decreasing concentrations of dietary neutral detergent fiber (NDF) at high rumen undegradable protein (RUP) on performance, digestibility, chewing activity, blood attributes, and carcass characteristics in 32 weaned male Afshari lambs (90 days of age; 26 kg initial body weight; BW). Dietary metabolic energy (ME) was increased from 10.6–11.5 and 11.8 MJ/kg dry matter (DM) by replacing alfalfa hay with grain to achieve NDF concentrations of 270, 245, and 220 g/kg DM, respectively, at 66.6 g/kg DM of RUP. The control (CON) diet contained 10.9 MJ/kg ME, 270 g/kg NDF and 59.6 g/kg RUP on DM basis. Rations containedsimilar concentrations of crude protein (CP, 160 g/kg DM). Lambs were slaughtered after a 56-d feeding period. The increase in dietary RUP had no effect on BW and average daily gain (ADG) but tended to decrease apparent digestibility of CP and DM, significantlydecreasedplasma urea concentration, and increased carcass CP content. Other body or carcass characteristics were unchanged. Decreasing dietary fiber at high RUP did not result in adverse effects on BW, ADG, body length, withers height, apparent digestibility of DM and CP, and BFT, but decreased DM intake (1539 vs. 1706 g/d) and feed conversion ratio (FCR; 4.33 vs. 5.39) compared with CON. Gradual reduction in NDF and physically effective NDF did not affecteating, ruminating or chewing times. Plasma glucose concentration was greater for NDF220 than for the three other treatments (p = 0.015).Slaughtering traits were not affected by dietary treatment except for hot carcass weight, which increased in NDF220 and NDF245 compared with NDF270 (p = 0.021). The concentration of meat CP increased in NDF270 versus CON (167 vs. 152 g/kg). Quadratic effects occurred for meat ether extract concentration (highest in NDF220) and fat-tail weight (highest in NDF245). In conclusion, the results showed that increasing the proportion of RUP within dietary CP improves carcass protein accretion. Decreasing dietary NDF to 220 g/kg DM at high RUP does not impair eating behavior and improves FCR in 3-month-old fat-tailed lambs

Determination of buprenorphine in raw material and pharmaceutical products using ion-pair formation

A simple and sensitive extractive spectrophotometric method has been described for the determination of buprenorphine either in raw material or in pharmaceutical formulations. The developed method is based on the formation of a colored ion-pair complex (1 : 1 drug/dye) of buprenorphine and bromocresol green (BCG) in buffer pH 3 and extracting in chloroform. The extracted complex shows absorbance maxima at 415 nm. Beer's law is obeyed in the concentration range of 1.32-100.81 μg mL−1 . The proposed method has been applied successfully for the determination of drug in commercial sublingual tablets and injectable dosage form. No significant interference was observed from the excipients commonly used as pharmaceutical aids with the assay procedure

Extractive Spectrophotometric Method for the Determination of Tropicamide

Two simple, rapid, and extractive spectrophotometric methods were developed for the determination of tropicamide (TPC). These methods are based on the formation of ionpair complexes between the basic nitrogen of the drug with bromocresol purple (BCP) and methyl orange (MO) in acidic buffer solution. The formed complexes were extracted with chloroform and measured at 408 and 427 nm using BCP and MO, respectively. Beer's law was obeyed in the range 1.0–16 μg ml–1 with correlation coefficient (n=6) ≥0.9991. The molar absorpitivity, Sandell sensitivity, detection, and quantification limits were also calculated. The composition of the ion pairs was found 1:1 by Job's method. The proposed methods have been applied successfully for the analysis of TPC in pure and in its eye drops

Nutritional value of raw soybeans, extruded soybeans, roasted soybeans and tallow as fat sources in early lactating dairy cows

Thirty multiparous Holstein cows (29.8 ± 4.01days in milk; 671.6 ± 31.47 kg of body weight) were used in a completely randomized design to compare nutritional value of four fat sources including tallow, raw soybeans, extruded soybeans and roasted soybeans for 8 weeks. Experimental diets were a control containing 27.4 % alfalfa silage, 22.5% corn silage, and 50.1% concentrate, and four diets with either tallow, raw soybean, extruded soybean, or roasted soybean added to provide 1.93% supplemental fat. Dry matter and NEL intakes were similar among treatments, while cows fed fat diets had significantly (P<0.05) high NEL intakes when compared to control with no fat. Supplemental fat, whether tallow or full fat soybeans increased milk production (1.89-2.45 kg/d; P<0.01) and FCM production (1.05-2.79; P<0.01). Milk fat yield and percentage of cows fed fat-supplemented diets were significantly (P<0.01 and P<0.05 respectively) higher than control. Between fat-supplemented diets, roasted soybean caused highest milk fat yield and extruded soybean caused lowest milk fat yield. There was no significant effect of supplemental fat on the milk protein and lactose content and yield. Feed efficiency of fat-supplemented diets was significantly (P<0.01) higher than control. Body weight, body weight change and BCS (body condition score) of cows, as well as energy balance and energy efficiency were similar between treatments. In conclusion, while there was no significant effect of fat sources on production response of cows, fat originating from heat-treated soybean help to minimize imported RUP (rumen undegradable protein) sources level as fish meal in comparison with tallow and raw soybean oil. In the Current study, there was no statistical significance among nutritional values of oil from extruded soybeans and roasted soybeans