1,4-Diaryl-substituted triazoles as cyclooxygenase-2 inhibitors: Synthesis,biological evaluation and molecular modeling studies

A novel group of 1,4-diaryl-substituted triazoles was designed and synthesized by introducing the cyclooxygenase-2 (COX-2) pharmacophore SO₂NH₂ attached to one aryl ring and various substituents (H, F, Cl, CH₃ or OCH₃) attached to the other aryl ring. The effects of size and flexibility of the compounds upon COX-1/COX-2 inhibitory potency and selectivity was studied by increasing the size of an alkyl linker chain [(–CH₂)_n, where n = 0, 1, 2]. In vitro COX-1/COX-2 inhibition studies showed that all compounds (14–18, 21–25 and 28–32) are more potent inhibitors of COX-2 isozyme (IC₅₀ = 0.17–28.0 μM range) compared to COX-1 isozyme (IC₅₀ = 21.0 to >100 μM range). Within the group of 1,4 diaryl-substituted triazoles, 4-{2-[4-(4-chloro-phenyl)-[1,2,3]triazol-1-yl]-ethyl}-benzenesulfonamide (compound 30) displayed highest COX-2 inhibitory potency and selectivity (COX-1: IC₅₀ = >100 μM, COX-2: IC₅₀ = 0.17 μM, SI >588). Molecular docking studies using the catalytic site of COX-1 and COX-2, respectively, provided complementary theoretical support for the obtained experimental biological structure–activity relationship data. Results of molecular docking studies revealed that COX-2 pharmacophore SO₂NH₂ in compound 30 is positioned in the secondary pocket of COX-2 active site; with the nitrogen atom of the SO₂NH₂ group being hydrogen bonded to Q192 (N?OC = 2.85 Å), and one of the oxygen atoms of SO₂NH₂ group forming a hydrogen bond to H90 (SO?N = 2.38 Å).     

Systematic Dissection of the Metabolic-Apoptotic Interface in AML Reveals Heme Biosynthesis to Be a Regulator of Drug Sensitivity

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Affinity purification and characterization of a seed lectin from Crotalaria medicaginea

Purification of lectin from the seeds of Crotalaria medicaginea Lamk by affinity chromatography on asialofetuin-linked amino activated silica, yielded a single band on non-denatured PAGE at pH 4.5 and 8.3 and, a single peak on HPLC size exclusion and cation exchange columns. The molecular mass of the native C. medicaginea lectin was determined to be 125 kDa by gel filtration. In SDS-PAGE, the lectin migrated as a single band of M(r) 31.6 kDa under reducing and nonreducing conditions, indicating that it is a tetramer of apparently identical subunits. It agglutinated red blood cells (RBCs) from rabbit and human ABO blood groups. It also reacted with RBCs from rat, sheep, goat and guinea pig but after desialylation with neuraminidase. The hemagglutination activity of the lectin was inhibited by D-galactose and its derivatives. Amino acid analysis showed that lectin was rich in aspartic and glutamic acid and, did not contain sulphur containing amino acids. The lectin is a glycoprotein having 1.41% of neutral sugars. It is labile at temperature above 60 degrees C. It needs divalent cations for its activity, as a loss of activity was observed on removal of Ca2+ and Mn2+. Denaturing agents like urea, thiourea and guanidine-HCl have no effect on its activity.     

Gastrointestinal parasites of the chimpanzee population introduced onto Rubondo Island National Park,Tanzania

The release of any species into a novel environment can evoke transmission of parasites that do not normally parasitize the host as well as potentially introducing new parasites into the environment. Species introductions potentially incur such risks, yet little is currently known about the parasite fauna of introduced primate species over the long term. We describe the results of long‐term monitoring of the intestinal parasite fauna of an unprovisioned, reproducing population of chimpanzees introduced 40 years earlier (1966–1969) onto Rubondo Island in Lake Victoria, Tanzania, a non‐native habitat for chimpanzees. Two parasitological surveys (March 1997–October 1998 and October 2002–December 2005) identified Entamoeba spp. including E. coli, Iodamoeba buetschlii, Troglodytella abrassarti, Chilomastix mesnili, Trichuris sp., Anatrichosoma sp., Strongyloides spp., Strongylida fam. gen. sp., Enterobius anthropopitheci, Subulura sp., Ascarididae gen. sp., and Protospirura muricola. The parasite fauna of the Rubondo chimpanzees is similar to wild chimpanzees living in their natural habitats, but Rubondo chimpanzees have a lower prevalence of strongylids (9%, 3.8%) and a higher prevalence of E. anthropopitheci (8.6%, 17.9%) than reported elsewhere. Species prevalence was similar between our two surveys, with the exception of Strongyloides spp. being higher in the first survey. None of these species are considered to pose a serious health risk to chimpanzees, but continued monitoring of the population and surveys of the parasitic fauna of the two coinhabitant primate species and other animals, natural reservoir hosts of some of the same parasites, is important to better understand the dynamics of host–parasite ecology and potential long‐term implications for chimpanzees introduced into a new habitat. Am. J. Primatol. 72:307–316, 2010. © 2009 Wiley‐Liss, Inc.     

Design,synthesis and evaluations of acridone derivatives using Candida albicans—Search for MDR modulators led to the identification of an anti-candidiasis agent

In order to search for MDR modulators, rationally designed acridone derivatives were investigated for their effect on influx or efflux of Rhodamine6G (R6G) in CAI4 cells. Results of these investigations indicate that in presence of compound 12, inhibition of growth of CAI4 cells and also an increased influx/efflux of R6G in CAI4 cells have been observed. This seems to be occurring due to the cell wall rupturing of Candida albicans. Compound 12 may be a suitable candidate for candidiasis therapy.     

HPLC method with fluorescence detection for the quantitative determination of flaxseed lignans

We report a rapid and simple HPLC method with fluorescence detection for the quantification of the major flaxseed lignan, secoisolarisiresinol diglucoside (SDG) and its major metabolites. The method is specific for SDG, secoisolarisiresinol (SECO), enterodiol (ED) and entrolactone (EL) in rat serum. The assay procedure involves chromatographic separation using a Waters Symmetry C₁₈ reversed-phase column (4.6 mm × 150 mm, 5 μm) and mobile phase gradient conditions consisting of acetonitrile (0.1% formic acid) and water (0.1% formic acid). SDG extraction from serum requires the use of Centrifuge filters while SECO, ED and EL are extracted with diethyl ether. The organic layer is evaporated and reconstituted in 100 μL of mobile phase and 50 μL of reconstituted sample or filtrate is injected onto the column. Total run time is 25 min. Calibration curves are linear (r² ≥ 0.997) from 0.05 to 10 μg/mL for SDG and EL and 0.01–10 μg/mL for SECO and ED. Precision and accuracy are within USFDA specified limits. The stability of all lignans is established in auto-injector, bench-top, freeze–thaw and long-term stability at −80 °C for 30 days. The method's reasonable sensitivity and reliance on more widely available HPLC technology should allow for its straightforward application to pharmacokinetic evaluations of lignans in animal model systems such as the rat.     

Hydrolytic activities of anaerobic fungi from wild blue bull (Boselaphus tragocamelus)

The anaerobic fungi play an active role in the plant fibre degradation by producing a wide array of potential hydrolytic enzymes in the rumen. In present study, 12 anaerobic fungal strains were isolated from the faecal samples of wild blue bull, and identified as species of Piromyces, Anaeromyces, Orpinomyces and Neocallimastix based on their morphological characteristics. Isolate WNG-12 (Piromyces sp.), showed maximum filter paper cellulase (23 mIU ml(-1)) and xylanase (127 mIU ml(-1)) activity, while WNG-5 (Piromyces sp.) showed maximum carboxymethyl cellulase activity (231 mIU ml(-1)). Based on the results obtained, it can be stated that Piromyces sp. WNG-12 may be a promising isolate in utilizing fibre rich diets in the rumen as evidenced by the production of hydrolytic enzymes in vitro.     

Tetramethylpyrazine Attenuates Cognitive Impairment Via Suppressing Oxidative Stress,Neuroinflammation, and Apoptosis in Type 2 Diabetic Rats

Cognitive dysfunction is an important complication observed in type 2 diabetes mellitus (T2DM) patients. Tetramethylpyrazine (TMP) is known to exhibit anti-diabetic and neuroprotective properties. Therefore, the present study aimed to investigate the possible therapeutic effects of TMP against type 2 diabetes-associated cognitive impairment in rats. High-fat diet (HFD) followed by a low dose of streptozotocin (35 mg/kg) was used to induce diabetes in Sprague–Dawley rats. TMP (20, 40, and 80 mg/kg) and Pioglitazone (10 mg/kg) were administered for 4 weeks. The Morris water maze (MWM) and novel objective recognition task (NOR) tests were used to assess memory function. Fasting blood glucose (FBG), lipid profile, HOMA-IR, glycosylated hemoglobin (HbA1c), and glucose tolerance were measured. Acetylcholinesterase (AChE) and choline acetytransferase (ChAT) activity, acetylcholine (ACh) levels, oxidative stress, apoptotic (Bcl-2, Bax, caspase-3), and inflammatory markers (TNF-α, IL-1β, and NF-kβ) were assessed. BDNF, p-AKT, and p-CREB levels were also measured. In the present work, we observed that treatment of diabetic rats with TMP alleviated learning and memory deficits, improved insulin sensitivity, and attenuated hyperglycemia and dyslipidemia. Furthermore, treatment with TMP increased BDNF, p-Akt, and p-CREB levels, normalized cholinergic dysfunction, and suppressed oxidative, inflammatory, and apoptotic markers in the hippocampus. Collectively, our results suggest that the TMP may be an effective neuroprotective agent in alleviating type 2 diabetes-associated cognitive deficits.

     

In vitro fibrolytic potential of anaerobic rumen fungi from ruminants and non-ruminant herbivores

In the present study, anaerobic fungi were isolated from different ruminants and non-ruminants; i.e., cattle, buffalo, sheep, goats, wild bluebulls, elephants, deer, and zebras; and were identified as Anaeromyces, Orpinomyces, Caecomyces, Piromyces, and Neocallimastix sp., based on their morphological characteristics. These isolates possessed significant in vitro hydrolytic enzyme activities; however, an isolate of Caecomyces sp. from elephant was found to exhibit maximum activity, i.e., filter paper cellulase (Fpase; 21.4 mIU/ml), carboxymethyl cellulose (CMCase; 15.1 mIU/ml), cellobiase (37.4 mIU/ml), and xylanase (26.0 mIU/ml). Besides, this isolate also showed the significantly highest ability to digest plant cell-wall contents in vitro. The in vitro dry matter digestibility increased from 45.1 to 48.9% after 48 h of incubation, and the plant cell-wall contents, in terms of neutral detergent fiber and acid detergent fiber, decreased from 64.2 to 61.3% and from 31.3 to 29.6%, respectively. These results indicate that such fibrolytic ruminal fungal strains are prevalent in wild herbivores such as elephants, as well as in other ruminants and non-ruminants, and could be exploited as microbial feed additives for improved nutrition and productivity in domesticated ruminants.