(S)-N-{3-[1-cyclopropyl-1-(2,4-difluoro-phenyl)-ethyl]-1H-indol-7-yl}-methanesulfonamide: a potent, nonsteroidal, functional antagonist of the mineralocorticoid receptor

A novel, potent series of indole analogs were recently developed as MR antagonists, culminating in 14. This compound represents the first MR antagonist in this class of molecules, exhibiting picomolar binding affinity and in vivo blood pressure lowering at pharmaceutically relevant doses.     

Chlorotrifluoroethylidenes: an efficient and convenient approach to their synthesis

A convenient one step synthesis of chlorotrifluoroalkyl olefins starting from aldehydes was developed. The stable reagent 2-((1-chloro-2,2,2-trifluoroethyl)sulfonyl)benzothiazole was prepared from readily available benzothiazole-2-thiol and halothane. This method comprises using stable 2-((1-chloro-2,2,2-trifluoroethyl)sulfonyl)benzothiazole according to the Julia procedure and presents new opportunities for the synthesis of trifluoroalkylidene derivatives.

A convenient one step synthesis of chlorotrifluoroalkyl olefins starting from aldehydes was developed.     

Multiresistant Uropathogenic Escherichia coli from a Region in India Where Urinary Tract Infections Are Endemic: Genotypic and Phenotypic Characteristics of Sequence Type 131 Isolates of the CTX-M-15 Extended-Spectrum-β-Lactamase-Producing Lineage

Escherichia coli sequence type 131 (O25b:H4), associated with the CTX-M-15 extended-spectrum beta-lactamases (ESBLs) and linked predominantly to the community-onset antimicrobial-resistant infections, has globally emerged as a public health concern. However, scant attention is given to the understanding of the molecular epidemiology of these strains in high-burden countries such as India. Of the 100 clinical E. coli isolates obtained by us from a setting where urinary tract infections are endemic, 16 ST131 E. coli isolates were identified by multilocus sequence typing (MLST). Further, genotyping and phenotyping methods were employed to characterize their virulence and drug resistance patterns. All the 16 ST131 isolates harbored the CTX-M-15 gene, and half of them also carried TEM-1; 11 of these were positive for bla_OXA groups 1 and 12 for aac(6′)-Ib-cr. At least 12 isolates were refractory to four non-beta-lactam antibiotics: ciprofloxacin, gentamicin, sulfamethoxazole-trimethoprim, and tetracycline. Nine isolates carried the class 1 integron. Plasmid analysis indicated a large pool of up to six plasmids per strain with a mean of approximately three plasmids. Conjugation and PCR-based replicon typing (PBRT) revealed that the spread of resistance was associated with the FIA incompatibility group of plasmids. Pulsed-field gel electrophoresis (PFGE) and genotyping of the virulence genes showed a low level of diversity among these strains. The association of ESBL-encoding plasmid with virulence was demonstrated in transconjugants by serum assay. None of the 16 ST131 ESBL-producing E. coli strains were known to synthesize carbapenemase enzymes. In conclusion, our study reports a snapshot of the highly virulent/multiresistant clone ST131 of uropathogenic E. coli from India. This study suggests that the ST131 genotypes from this region are clonally evolved and are strongly associated with the CTX-M-15 enzyme, carry a high antibiotic resistance background, and have emerged as an important cause of community-acquired urinary tract infections.     

Subtype B and subtype C HIV type 1 recombinants in the northeastern state of Manipur, India

The predominant HIV-1 strain circulating in India is subtype C. However, subtype A and B strains of HIV-1 have also been reported in India. In 1999, the first A/C recombinant strain was reported from Pune in India. Intravenous drug users (IVDUs) from the northeastern region of India have a high HIV-1 seroprevalence. Studies carried out in intravenous drug users in the northeastern region of India have shown that HIV-1 subtype C is the predominant strain infecting IVDUs. Fourteen blood samples were collected from HIV-1-infected individuals from the northeastern region of India and screened by env and gag heteroduplex mobility assays (HMA). Where the env and gag HMA results from a sample yielded different subtypes, sequencing of env and gag PCR products was carried out to confirm the presence of HIV-1 recombinants. Of the 14 samples subtyped, nine samples belonged HIV-1 subtype C (gag C/env C), one to HIV-1 subtype B (gag B/env B), and the remaining were B/C recombinants (gag C/env B). This is the first report of HIV-1 B/C recombinants from India.     

Exo1: a new chemical inhibitor of the exocytic pathway

A phenotypic screen was used to search for drug-like molecules that can interfere with specific steps in membrane traffic. 2-(4-Fluorobenzoylamino)-benzoic acid methyl ester (Exo1), identified in this screen, induces a rapid collapse of the Golgi to the endoplasmic reticulum, thus acutely inhibiting the traffic emanating from the endoplasmic reticulum. Like Brefeldin A (BFA), Exo1 induces the rapid release of ADP-ribosylation factor (ARF) 1 from Golgi membranes but has less effect on the organization of the trans-Golgi network. Our data indicate that Exo1 acts by a different mechanism from BFA. Unlike BFA, Exo1 does not induce the ADP-ribosylation of CtBP/Bars50 and does not interfere with the activity of guanine nucleotide exchange factors specific for Golgi-based ARFs. Thus, Exo1 allows the fatty acid exchange activity of Bars50 to be distinguished from ARF1 activity in the control of Golgi tubulation.     

Which Parameters Affect Biofilm Removal with Acoustic Cavitation? A Review

Bacterial biofilms are a cause of contamination in a wide range of medical and biological areas. Ultrasound is a mechanical energy that can remove these biofilms using cavitation and acoustic streaming, which generate shear forces to disrupt biofilm from a surface. The aim of this narrative review is to investigate the literature on the mechanical removal of biofilm using acoustic cavitation to identify the different operating parameters affecting its removal using this method. The properties of the liquid and the properties of the ultrasound have a large impact on the type of cavitation generated. These include gas content, temperature, surface tension, frequency of ultrasound and acoustic pressure. For many of these parameters, more research is required to understand their mechanisms in the area of ultrasonic biofilm removal, and further research will help to optimise this method for effective removal of biofilms from different surfaces.     

In vitro isolation and identification of human immunodeficiency virus (HIV) variants with reduced sensitivity to C-2 symmetrical inhibitors of HIV type 1 protease.

Protease inhibitors are another class of compounds for treatment of human immunodeficiency virus (HIV)-caused disease. The emergence of resistance to the current anti-HIV drugs makes the determination of potential resistance to protease inhibitors imperative. Here we describe the isolation of an HIV type 1 (HIV-1) resistant to an HIV-protease inhibitor. Serial passage of HIV-1 (strain RF) in the presence of the inhibitor, [2-pyridylacetylisoleucylphenylalanyl-psi (CHOH)]2 (P9941), failed to yield a stock of virus with a resistance phenotype. However, variants of the virus with 6- to 8-fold reduced sensitivity to P9941 were selected by using a combination of plaque assay and endpoint titration. Genetic analysis and computer modeling of the variant proteases revealed a single change in the codon for amino acid 82 (Val-->Ala), which resulted in a protease with lower affinity and reduced sensitivity to this inhibitor and certain, but not all, related inhibitors.     

Effect of ethanolic extract of seeds of Linum usitatissimum (Linn.) in hyperglycaemia associated ROS production in PBMNCs and pancreatic tissue of alloxan induced diabetic rats

ObjectiveTo evaluate the effect of ethanolic extract of seeds of Linum usitatissimum (EELU) in hyperglycemia associated reactive oxygen species (ROS) production in peripheral blood mononuclear cells (PBMNCs) and pancreatic antioxidant enzymes in alloxan induced diabetic rat.MethodsDiabetes was induced in male Wistar rats by alloxan (120 mg/kg, i.p.). After acute and subacute treatment serum glucose was determined. Oral glucose tolerance test (OGTT) was performed in EELU pretreated animals. ROS production in PBMNCs and pancreatic antioxidant enzymes were measured in alloxan induced diabetic rat.ResultsOur results showed that, treatment of EELU (200 and 400 mg/kg) significantly reduced serum glucose level in acute and subacute study. The antihyperglycaemic effects of EELU showed onset at 4th h (P<0.001) and peak effect at 6th h (P<0.001). The effect was sustained until 24th h with 400 mg/kg. In subacute study, significant antihyperglycaemic effect was observed from 14th day (P<0.001) onwards. In EELU treated rat the body weight was significantly (P<0.001) increased as compared to diabetic group on 21st day onwards. In OGTT, increased glucose utilization was observed. Treatment of EELU 400 mg/kg showed significant reversal in pancreatic GSH (P<0.01) and SOD (P<0.05) indicating antioxidant nature of EELU. Flow cytometric estimation of total ROS production in PBMNCs in diabetic rats was significantly increased (P<0.001), whereas EELU treatment showed significant (P<0.001) decrease in PBMNCs ROS.ConclusionsIt is concluded from the investigation that EELU showed antihyperglycaemic effect mediated through inhibition of ROS level in PBMNCs and preservation of endogenous antioxidant enzymes in pancreatic tissue in alloxan induced diabetic rat.