Synthesis,structure–activity relationship and molecular docking of 3-oxoaurones and 3-thioaurones as acetylcholinesterase and butyrylcholinesterase inhibitors

The present study describes efficient and facile syntheses of varyingly substituted 3-thioaurones from the corresponding 3-oxoaurones using Lawesson’s reagent and phosphorous pentasulfide. In comparison, the latter methodology was proved more convenient, giving higher yields and required short and simple methodology. The structures of synthetic compounds were unambiguously elucidated by IR, MS and NMR spectroscopy. All synthetic compounds were screened for their inhibitory potential against in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Molecular docking studies were also performed in order to examine their binding interactions with AChE and BChE human proteins. Both studies revealed that some of these compounds were found to be good inhibitors against AChE and BChE.     

Syntheses and anti-depressant activity of 5-amino-1, 3, 4-thiadiazole-2-thiol imines and thiobenzyl derivatives

A number of new imine derivatives of 5-amino-1, 3, 4-thiadiazole-2-thiol have been synthesized, and their anti-depressant activity was tested using imipramine as reference drug. Two compounds namely 5-{[1-(4-chlorophenyl)-3-(4-methoxy-phenyl)prop-2-en-1-ylidene]-amino}-5-benzylthio-1, 3,4 -thiadiazole 4i(b) and 5-{[1-(4-chlorophenyl)-3-(4-dimethyl-aminophenyl)-prop-2-en-1-ylidene]amino}-5-benzylthio-1,3,4-thiadiazole 4i(c) have shown significant anti-depressant activity, which decreased immobility time by 77.99% and 76.26% compared to the standard imipramine (82%). All the compounds in the series have passed neurotoxicity tests.     

Operculina turpethum attenuates N-nitrosodimethylamine induced toxic liver injury and clastogenicity in rats

The root extract of Operculina turpethum (OTE) has been used as an anti-inflammatory, purgative, and hepato-protective agent. N-Nitrosodimethylamine (NDMA) is a potent hepatotoxin that induces fibrosis of the liver. In the present study, we examined the therapeutic effects of OTE root extract against NDMA-induced hepatotoxicity and clastogenicity in rats. Hepatic fibrosis was induced in adult male albino rats through serial intraperitoneal administrations of NDMA at a concentration of 10 mg/kg body weight on three consecutive days of each week over a period of three weeks. A group of rats received OTE orally in doses of 75, 150 and 200 mg/kg body weight at 5 h after the administration of NDMA. The controls and treated animals were sacrificed on days-7, 14 and 21 after the start of the administration of NDMA. The progression of hepatic fibrosis as well as the amelioration effect of OTE was evaluated through histopathologically as well as by immunohistochemical staining for the activation of hepatic stellate cells. Alterations in serum and liver biochemical parameters and LDH isoenzymes were also studied. Serial administration of NDMA resulted in well formed fibrosis in the liver and induction of micronuclei in the bone marrow cells. Staining of α-SMA demonstrated activated stellate cells from day-7 onwards which was dramatically increased on day-21. An elevation of micronuclei count, liver function enzymes, serum hydroxyproline levels and LDH isoenzymes 4 and 5 were also observed. All these changes were remarkably reduced in OTE administered animals and fibrogenesis was completely absent. Our results suggest that OTE has hepatoprotective and anti-clastogenic effects against NDMA-induced hepatic fibrosis. Therefore OTE may be used as a hepatoprotective agent against various liver diseases including toxic liver injury.     

Molecular cloning of fungal xylanases: an overview

Xylanases have received great attention in the development of environment-friendly technologies in the paper and pulp industry. Their use could greatly improve the overall lignocellulosic materials for the generation of liquid fuels and chemicals. Fungi are widely used as xylanase producers and are generally considered as more potent producers of xylanases than bacteria and yeasts. Large-scale production of xylanases is facilitated with the advent of genetic engineering. Recent breakthroughs in genomics have helped to overcome the problems such as limited enzyme availability, substrate scope, and operational stability. Genes encoding xylanases have been cloned in homologous and heterologous hosts with the objectives of overproducing the enzyme and altering its properties to suit commercial applications. Owing to the industrial importance of xylanases, a significant number of studies are reported on cloning and expression of the enzymes during the last few years. We, therefore, have reviewed recent knowledge regarding cloning of fungal xylanase genes into various hosts for heterologous production. This will bring an insight into the current status of cloning and expression of the fungal xylanases for industrial applications.     

Synthesis of 6-deoxy-6-chloro and 6-deoxy-6-bromo derivatives of scleroglucan as intermediates for conjugation with methotrexate and other carboxylate containing compounds

Polysaccharides are widely used as carriers in the field of drug delivery. We present a methodology to obtain water soluble drug-conjugates based on scleroglucan. Selective C-6 halogenation gives access to C-6 esters; conjugates between methotrexate and scleroglucan are described, potentially useful for antitumour therapy or in rheumatoid arthritis treatment.     

Microbial modification of host long-distance dispersal capacity

Background  

Dispersal plays a key role in shaping biological and ecological processes such as the distribution of spatially-structured populations or the pace and scale of invasion. Here we have studied the relationship between long-distance dispersal behaviour of a pest-controlling money spider,Erigone atra, and the distribution of maternally acquired endosymbionts within the wider meta-population. This spider persists in heterogeneous environments because of its ability to recolonise areas through active long-distance airborne dispersal using silk as a sail, in a process termed 'ballooning'.     

Massive Fluid Requirements and an Unusual BUN/Creatinine Ratio for Pre-Renal Failure in Patients with Cholera

Background

Cholera is an important infectious cause of secretory diarrhea. The primary symptom of infection is the sudden onset of watery diarrhea with subsequent volume depletion causing renal insufficiency. The objective of this research is to study the level of dehydration at presentation and subsequent fluid management in patients with cholera.

Methods

This study was conducted on 191 patients of Cholera admitted at a tertiary care hospital in Karachi, Pakistan during the period of 5 years. Medical charts were evaluated retrospectively for initial hydration status, baseline lab investigations on admission and discharge and fluid therapy given to all the patients while their stay in the hospital and the data was analyzed on SPSS 15.0.

Results

Out of the 191 patients, 83(43%) were males and 108 (57%) were females with mean age of 42.3 years (SD±18.34). The average duration of symptoms was 3.75 days (SD±2.04). Of 191 patients, 175 (92.1%) presented with dehydration, 80 (42.3%) were given Ringer''s Lactate (R/L) + Normal Saline (N/S), 45 (24%) patients were given R/L + N/S + Oral Rehydration Therapy (ORS), 27 (14.3%) of the patients were kept on R/L only and remaining were given various combinations of R/L, N/S, ORS and Dextrose Saline (D/S). On admission mean Blood Urea Nitrogen (BUN) was 24.54 (SD±16.6), mean creatinine was 2.47 (SD±2.35) and mean BUN/Creatinine ratio was 11.63 (SD±5.7).

Conclusion

Aggressive fluid rehydration remains the cornerstone of management of cholera. Instead of presenting with a classical BUN/Creatinine ratio of >20∶1, patients with pre-renal failure in cholera may present with a BUN/Creatinine ratio of <15∶1.     

Insilico Structural 3D Modelling of Novel Cry1Ib9 and Cry3A Toxins from Local Isolates of Bacillus thuringiensis

Three-dimensional (3D) models for the 79.2 kDa activated Cry1Ib9 and 77.4 kDa activated Cry3A δ-endotoxins from Bacillus thuringiensis (Bt) native isolates that are specifically toxic to Coleopteran insect pests were constructed by utilizing homology modeling online tool. Evidences presented here, based on the identification of structural equivalent residues of Cry1Ib9 and Cry3A toxin through homology modelling indicate that, they share a common Bt toxin tridimensional structure. The main differences observed in Cry1I9 domain I at positions α2b (S56-I60), α4 (F78-l93) and additionally β0 (Q10-L12), α8a (T280-V282) were observed, in domain II at positions α9b (P333-L339), β6(T390-Q393), β7(V398-W404), β8 (V418-W425), β9 (E453-N454), β10 (S470-I479) where as in domain III the changes were observed at positions β19 (R601-F607), β20 (609-L613), β21 (S618-F627) and α11a (K655-F664), α13, α14 components present at downstream sites, where as in Cry3A main differences observed in domain I is at the position of α4 (P105-I152), α5 (Q163-A185), β1A(E190-L192), α6 (F193-Y217), Domain II is not consevered and main variations were observed at β2 (E292-L295), β3(V299-L308), β4(I340-F347), β5(D356-P368), β6(I375-T377), β7(V389-F394), β8(K398-N405), β9(Y416-Y427), β10 (T436-Y439), β12(G476-H495), β12A (M503-I504) where as in domain III main variations observed at positions of β18 (P583-I593), β19(F604-S610), β20(P611-L615), β21(N619-G626). Cry1Ib9 and Cry3A contain the most variable regions in the loops of domain II, which determine the specificity of these toxins. These are the first models of Coleopteran-active protein from native isolates of Bt and its importance can be perceived since members of this group of toxins are potentially important candidates for coleoptera insect pest control programs.     

Mitochondrial DNA diversity in Francolinus pondicerianus interpositus (grey francolin, Galliformes) from Pakistan

Francolinus pondicerianus interpositus (grey francolin, Galliformes) is the only francolin present in the Suleiman Range (central Pakistan), one of the poorest and least developed areas in Pakistan. As a game bird, the francolin is an important income source for the region, but no demographic data are available. Therefore, the aim of this work was to study the polymorphism pattern of the Control Region gene (mitochondrial DNA, mtDNA), in order to obtain some initial information about genetic diversity, possible structure and demographic dynamics in this population. In 29 individuals captured in four sampling areas in the western and the eastern Suleiman Range, we detected nine polymorphic sites in a 511 bp fragment of the mtDNA Control Region gene, resulting in seven haplotypes. Haplotype (h = 0.818 ± 0.032) and nucleotide diversity (π % = 0.308 ± 0.210) values suggested a large population size and a low divergence among the haplotypes. AMOVA (Φ(ST) = 0.005; P = 0.352) did not detect any significant differences among the western and eastern populations; therefore, specimens of both sampled areas could be considered as drawn from a single population. The observed distribution of pairwise mismatches was bimodal, revealing significant departure from a growing-decreasing population model (P = 0.030); these results would point to a demographic equilibrium. Tribal control of hunting might provide an explanation for this situation, but future overhunting would threaten the survival of this population.     

A molecular evaluation of dengue virus pathogenesis and its latest vaccine strategies

More than one third of the world’s population living in tropical and subtropical areas of the world is at risk of dengue infections and as many as 100 million people are yearly infected. This disease has reemerged during the past 20 years in the form of an epidemic. Dengue is caused by one of four related serotypes of dengue virus and often leads to severe forms of the disease, resulting commonly from secondary infections. Dengue virus is a mosquito borne virus, belongs to the family Flaviviridae and consists of a single stranded positive sense RNA genome. Like other RNA viruses it escapes defense mechanisms and neutralization attempts by mutations, which make it more resistant and adaptable to its environment. Antiviral strategies and vaccine development is thus impaired and hence to date there is no licensed vaccine available for dengue virus. Here we discuss various efforts made towards the identification of potential vaccine targets for dengue as well as various strategies employed by research groups/pharmaceutical companies towards the development of a successful dengue vaccine.