Triazoloquinoxalines-based DNA intercalators-Topo II inhibitors: design,synthesis, docking,ADMET and anti-proliferative evaluations

Sixteen [1, 2, 4]triazolo[4,3-a]quinoxalines as DNA intercalators-Topo II inhibitors have been prepared and their anticancer actions evaluated towards three cancer cell lines. The new compounds affected on high percentage of MCF-7. Derivatives 7e, 7c and 7b exhibited the highest anticancer activities. Their activities were higher than that of doxorubicin. Molecular docking studies showed that the HBA present in the chromophore, the substituted distal phenyl moiety and the extended linkers enable our derivatives to act as DNA binders. Also, the pyrazoline moiety formed six H-bonds and improved affinities with DNA active site. Finally, 7e, 7c and 7b exhibited the highest DNA affinities and act as traditional intercalators of DNA. The most active derivatives 7e, 7c, 7b, 7g and 6e were subjected to evaluate their Topo II inhibition and DNA binding actions. Derivative 7e exhibited the highest binding affinity. It intercalates DNA at IC₅₀ = 29.06 µM. Moreover, compound 7e potently intercalates DNA at an IC₅₀ value of 31.24 µM. Finally, compound 7e demonstrated the most potent Topo II inhibitor at a value of 0.890 µM. Compound 7c exhibited an equipotent IC₅₀ value (0.940 µM) to that of doxorubicin. Furthermore, derivatives 7b, 7c, 7e and 7g displayed a high ADMET profile.     

Pre-mating plasma prolactin profile affects California doe rabbit reproductive performance

Ovulation failure was associated with a reduction in pre-mating concentrations of oestradiol-17β and prolactin (PRL). The present study aimed to evaluate whether pre-mating PRL levels have a role in the reproductive efficiency of doe rabbits. A total of 78 multiparous California does (2nd parity) were divided, according to plasma pre-mating PRL, into five categories, >20–25, >25–30, >30–35, >35–40, and >40–45 ng/ml. Does in all categories were naturally mated and kindled, then their reproductive measurements and progesterone (P4) levels were determined. Results show that pre-mating PRL averaged 23.60 ± 0.78, 28.00 ± 0.83, 33.46 ± 0.43, 38.17 ± 0.49 and 41.98 ± 0.68 ng/ml in five categories (p < 0.05), respectively, representing the highest distribution (38.5%) in the 3rd-category. Live body weight of doe rabbits, at mating, pregnancy, and parturition increased (p < 0.05) with increasing pre-mating PRL level. The number of services, litter size, and pregnancy rate increased (p < 0.05) by increasing PRL levels. Reproductive traits and P4 level at mid-pregnancy of does, and the average weight of kits at birth increased (p < 0.05) by increasing PRL levels. The pre-mating PRL profile is important for the identification of reproductive performance in doe rabbits.     

Tricarboxylic Acid Cycle and One-Carbon Metabolism Pathways Are Important in Edwardsiella ictaluri Virulence

Edwardsiella ictaluri is a Gram-negative facultative intracellular pathogen causing enteric septicemia of channel catfish (ESC). The disease causes considerable economic losses in the commercial catfish industry in the United States. Although antibiotics are used as feed additive, vaccination is a better alternative for prevention of the disease. Here we report the development and characterization of novel live attenuated E. ictaluri mutants. To accomplish this, several tricarboxylic acid cycle (sdhC, mdh, and frdA) and one-carbon metabolism genes (gcvP and glyA) were deleted in wild type E. ictaluri strain 93-146 by allelic exchange. Following bioluminescence tagging of the E. ictaluri ΔsdhC, Δmdh, ΔfrdA, ΔgcvP, and ΔglyA mutants, their dissemination, attenuation, and vaccine efficacy were determined in catfish fingerlings by in vivo imaging technology. Immunogenicity of each mutant was also determined in catfish fingerlings. Results indicated that all of the E. ictaluri mutants were attenuated significantly in catfish compared to the parent strain as evidenced by 2,265-fold average reduction in bioluminescence signal from all the mutants at 144 h post-infection. Catfish immunized with the E. ictaluri ΔsdhC, Δmdh, ΔfrdA, and ΔglyA mutants had 100% relative percent survival (RPS), while E. ictaluri ΔgcvP vaccinated catfish had 31.23% RPS after re-challenge with the wild type E. ictaluri.     

Atenolol Induced HDL-C Change in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study

We sought to identify novel pharmacogenomic markers for HDL-C response to atenolol in participants with mild to moderate hypertension. We genotyped 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study on the Illumina HumanCVD Beadchip. During PEAR, participants were randomized to receive atenolol or hydrochlorothiazide. Blood pressure and cholesterol levels were evaluated at baseline and after treatment. This study focused on participants treated with atenolol monotherapy. Association with atenolol induced HDL-C change was evaluated in 232 whites and 152 African Americans using linear regression. No SNPs achieved a Bonferroni corrected P-value. However, we identified 13 regions with consistent association across whites and African Americans. The most interesting of these regions were seven with prior associations with HDL-C, other metabolic traits, or functional implications in the lipid pathway: GALNT2, FTO, ABCB1, LRP5, STARD3NL, ESR1, and LIPC. Examples are rs2144300 in GALNT2 in whites (P=2.29x10^-4, β=-1.85 mg/dL) and rs12595985 in FTO in African Americans (P=2.90x10^-4, β=4.52 mg/dL), both with consistent regional association (P<0.05) in the other race group. Additionally, baseline GALNT2 expression differed by rs2144300 genotype in whites (P=0.0279). In conclusion, we identified multiple gene regions associated with atenolol induced HDL-C change that were consistent across race groups, several with functional implications or prior associations with HDL-C.     

Immunization against GnRH in the male camel (Camelus dromedarius): Effects on sexual behavior, testicular volume, semen characteristics and serum testosterone concentrations

The effect of immunization against gonadotrophin releasing hormone (GnRH) on sexual behavior, total scrotal size, semen characteristics and serum concentrations of testosterone, was evaluated for 24 wks in sexually mature camels (Camelus dromedarius). Eight bull camels were randomly divided into a treatment and control group. Four male camels were immunized using 2 mg GnRH - tandem-dimer conjugated to ovalbumin, (Pepscan Systems, the Netherlands) administered subcutaneously, 4 wks apart. Control male camels received the same amount of saline solution. Significant decline in serum testosterone level was observed in three immunized camels out of four, whereas one camel showed no effect. The testosterone levels reached to <1.0 ng/mL serum by week 4 after booster injection and remained suppressed through the course of the study. The total testicular volume was not affected until the end of the experiment. In treated animals, the sexual behavior negatively affected after the booster injection. Anti-GnRH vaccine had a seriously detrimental effect on the acrosin amidase activity and normal acrosome percentages in treated male camels. It is concluded that the vaccine was effective in reducing serum testosterone levels and libido, and it had a serious harmful effect on the acrosin amidase activity and percentages of spermatozoa with normal acrosome. The immunogen did not affect the total testicular volume.     

The Effect of Lead Acetate Toxicity on Experimental Male Albino Rat

The toxic effect of Pb ion (lead acetate) was investigated using male albino rats, which was ingested at 1/20, 1/40, and 1/60 sublethal doses. Relative to normal control, the ingestion of Pb²⁺ induced significant stimulation in ALT and AST activity. In addition, total soluble protein and albumin contents of plasma were decreased, while the content of globulin was changed by the Pb²⁺ treatments. The cholinesterase activity was inhibited, but the activities of alkaline and acid phosphates as well as lactate dehydrogenase were stimulated as a result of lead acetate intoxication. These observations were gradually paralleled across the experiment dose of the three doses of intoxicated Pb²⁺. In the case of blood picture, Pb²⁺ ingestion significantly reduced the contents of hemoglobin and RBC count of intoxicated rat’s blood, while the plasma levels of T3 and T4 and blood WBC count were insignificantly decreased or unchanged. All results of the present study showed that the Pb²⁺ ingestion was more effective in the case of the high dose (1/20 LD₅₀) than that of the low dose (1/60 LD₅₀) ingestion relative to the normal healthy control. The results of the present work advice the need to avoid exposure of humans to the lead compound to avoid injurious hazard risk.     

Antidiabetic activity of phenolic compounds from Pecan bark in streptozotocin-induced diabetic rats

The n-butanol fraction (BF) of bark of Pecan tree, Carya illinoinensis (Wangenh) K. Koch (Juglandaceae) afforded two new flavonol methyl ether: caryatin-3′ sulfate (6) and caryatin-3′ methyl ether-7-O-β-d-glucoside (7) while five known phenolics (1–5) were isolated from its ethyl acetate fraction (EAF). The structures of isolated compounds were established based on 1D and 2D NMR spectroscopy. The isolated compounds were investigated for their hypoglycaemic, antioxidant as well as the aldose reductase (AR) inhibitory effect in lenses of streptozocin diabetic rats. All the isolated compounds showed significant hypoglycaemic and antioxidant activities, except 5 and 6. A marked AR-inhibitory effect was identified for compounds 2, 3 and 7.     

Genetic network analysis between Apis mellifera subspecies based on mtDNA argues the purity of specimens from North Africa,the Levant and Saudi Arabia

ObjectivesThis study aimed to analyze the genetic relationships between honey bee subspecies using reference specimens and recently collected specimens from different parts of the world. The purity of these specimens was discussed in light of the obtained results.MethodsThe genetic networks were constructed between 21 subspecies of honey bees, Apis mellifera L.: 9 in Africa, 7 in Europe and 5 in Asia. The analysis was performed using the mtDNA of these subspecies and the Population Analysis with Reticulate Trees software. Some subspecies were represented by more than two specimens based on the available online sequences.Results and conclusionsThe subspecies A. m. sahariensis from Africa showed unique characteristics and is genetically isolated than all other studied bee subspecies. Specimens collected from Saudi Arabia showed genetic relatedness to A. m. jemenitica, A. m. lamarckii, and some European subspecies, suggesting high degree of hybridization. The close genetic relationship between the Egyptian bees, A. m. lamarckii, and the Syrian bees, A. m. syriaca, were emphasized. The overall genetic network showed the presence of three distinct branches in relation to geographical locations. The high accurateness of the used analysis was confirmed by previous phylogenetic studies as well as the genetic relationships between hybrid bees of A. m. capensis and A. m. scutellata. The genetic networks showed the presence of bee subspecies from Africa in all branches including Europe and Asia. The study suggests the impurity of some specimens mostly due to the hybridization between subspecies. Specific recommendations for future conservation efforts of bees were presented in light of this study.     

Nature-inspired male contraceptive and spermicidal products

Phytochemistry Reviews - The use of hazardous female contraceptives is still the first choice in family planning programs. Moreover, all the drugs examined to be used as infertility inducers in...