Recent Cutting-Edge Designing Strategies for Mtb-DHFR Inhibitors as Antitubercular Agents.

Tuberculosis (TB) is an obstinate and infectious disease requiring a relatively longer treatment duration than other bacterial infections. The current treatment regime is prolonged and cumbersome, with adverse effects, often leading to nonadherence. The upsurge in TB's multidrug-resistant and extensively drug-resistant strains with evolved resistance to existing drugs has compounded the problems.

Arabidopsis cell suspension culture and RNA sequencing reveal regulatory networks underlying plant-programmed cell death.

Programmed cell death (PCD) facilitates selective, genetically controlled elimination of redundant, damaged, or infected cells. In plants, PCD is often an essential component of normal development and can mediate responses to abiotic and biotic stress stimuli. However, studying the transcriptional regulation of PCD is hindered by difficulties in sampling small groups of dying cells that are often buried within the bulk of living plant tissue.

Comparative evaluation of changes in salivary flow rate, pH, and levels in children undergoing fixed and removable space maintainer therapy.

Background: Placement of intraoral appliances such as space maintainers (SMs) may be associated with the alteration of microbial and nonmicrobial parameters of saliva which may lead to the initiation of incipient caries.

Aim: The aim of this study was to compare and evaluate the changes in salivary flow rate, pH, and Streptococcus mutans levels in children undergoing fixed and removable SM therapy.

Materials And Methods: The study participants comprised 40 children aged 4-10 years divided into two groups of 20 each.

Central retinal vein occlusion post-COVID-19 vaccination.

Coronavirus disease 2019 (COVID-19) is known to cause thromboembolic episodes apart from acute respiratory distress syndrome (ARDS). With large vaccine drives all across the world, there are a few case reports on post-vaccine thrombotic events seen with the AZD1222, ChAdO × 1 vaccine. Here, we present two cases of central retinal vein occlusion presenting immediately after receiving the second dose of the Covishield vaccine.

Accidental Cannulation of Persistent Left Superior Vena Cava in a Case of Absent Right Internal Jugular Vein: A Case Report on the Role of Ultrasonography and X-Ray.

Persistent left superior vena cava is a rare vascular anatomical variant. Although ultrasonography has facilitated the process of central venous catheterization, it cannot be used to locate the tip of a catheter. Postprocedure chest X-ray is desirable for locating the course and tip of the catheter.

Orbital apex osteodural fistula--An unusual surgical access.

Dural arteriovenous fistulas (DAVFs) are fistulas connecting the branches of dural arteries to dural veins or a venous sinus. Osteodural fistulas are a rare subset of this group of diseases. We wish to report a rare case of an osteodural arteriovenous fistula at the foot of the superior ophthalmic vein (SOV), treatment of which required an unusual surgical approach via the orbit and SOV.

Efficacy and safety of a flaxseed hull extract in the symptomatic management of benign prostatic hyperplasia: a parallel, randomized, double-blind, placebo-controlled, pilot study.

This exploratory study was designed to assess the effectiveness of a lignan-rich extract of flaxseed hulls (LinumLife EXTRA(®)) in alleviating symptoms in subjects with benign prostatic hyperplasia (BPH) compared with placebo. Two dosages of extract were compared against placebo in a double-blinded, randomized, parallel, multicenter study. Newly diagnosed cases of BPH in patients aged 45-75 years with an American Urological Association Symptom Index (AUASI) score of ≥13 were included.

Development of real-time RT-PCR for detection of human metapneumovirus and genetic analysis of circulating strains (2009-2011) in Pune, India.

Human metapneumovirus (HMPV) is an important respiratory virus implicated in respiratory infections. The purpose of this study was to develop a one-step real-time RT-PCR assay that can detect all four lineages of HMPV and to identify the HMPV lineages circulating in Pune, India. Conserved regions of the nucleoprotein gene were used to design real-time primers and a probe.

Assessment of population-based HIV RNA levels in a rural east African setting using a fingerprick-based blood collection method.

Background: Population-based human immunodeficiency virus type 1 (HIV-1) RNA levels (viral load [VL]) are proposed metrics for antiretroviral therapy (ART) program effectiveness. We estimated population-based HIV RNA levels using a fingerprick-based approach in a rural Ugandan community implementing rapid ART scale-up.

Methods: A fingerprick-based HIV RNA measurement technique was validated against standard phlebotomy.

Evaluation of a multi-herb supplement for erectile dysfunction: a randomized double-blind, placebo-controlled study.

Background: Evidence is lacking for multi-ingredient herbal supplements claiming therapeutic effect in sexual dysfunction in men. We examined the safety and efficacy of VigRX Plus (VXP) - a proprietary polyherbal preparation for improving male sexual function, in a double blind, randomized placebo-controlled, parallel groups, multi-centre study.

Methods: 78 men aged 25-50 years of age; suffering from mild to moderate erectile dysfunction (ED), participated in this study.

Increased plasma membrane cholesterol in cystic fibrosis cells correlates with CFTR genotype and depends on de novo cholesterol synthesis.

Background: Previous observations demonstrate that Cftr-null cells and tissues exhibit alterations in cholesterol processing including perinuclear cholesterol accumulation, increased de novo synthesis, and an increase in plasma membrane cholesterol accessibility compared to wild type controls. The hypothesis of this study is that membrane cholesterol accessibility correlates with CFTR genotype and is in part influenced by de novo cholesterol synthesis.

Methods: Electrochemical detection of cholesterol at the plasma membrane is achieved with capillary microelectrodes with a modified platinum coil that accepts covalent attachment of cholesterol oxidase.

Nanomolar potency pyrimido-pyrrolo-quinoxalinedione CFTR inhibitor reduces cyst size in a polycystic kidney disease model.

Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel are predicted to slow cyst enlargement in polycystic kidney disease and reduce intestinal fluid loss in secretory diarrheas. Screening of approximately 110000 small synthetic and natural compounds for inhibition of halide influx in CFTR-expressing epithelial cells yielded a new class of pyrimido-pyrrolo-quinoxalinedione (PPQ) CFTR inhibitors. Testing of 347 analogues established structure-activity relationships.

Thiazolidinone CFTR inhibitors with improved water solubility identified by structure-activity analysis.

The thiazolidinone 3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone (CFTR(inh)-172) inhibits cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel conductance with submicromolar affinity and blocks cholera toxin-induced intestinal fluid secretion. Fifty-eight CFTR(inh)-172 analogs were synthesized to identify CFTR inhibitors with improved water solubility, exploring modifications in its two phenyl rings, thiazolidinone core, and core-phenyl connectors. Greatest CFTR inhibition potency was found for 3-CF(3) and polar group-substituted-phenyl rings, and a thiazolidinone core.

Nanomolar CFTR inhibition by pore-occluding divalent polyethylene glycol-malonic acid hydrazides.

Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel have potential application as antisecretory therapy in cholera. We synthesized mono- and divalent CFTR inhibitors consisting of a malonic acid hydrazide (MalH) coupled via a disulfonic stilbene linker to polyethylene glycols (PEGs; 0.2-100 kDa).

Small-molecule CFTR inhibitors slow cyst growth in polycystic kidney disease.

Cyst expansion in polycystic kidney disease (PKD) involves progressive fluid accumulation, which is believed to require chloride transport by the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Herein is reported that small-molecule CFTR inhibitors of the thiazolidinone and glycine hydrazide classes slow cyst expansion in in vitro and in vivo models of PKD. More than 30 CFTR inhibitor analogs were screened in an MDCK cell model, and near-complete suppression of cyst growth was found by tetrazolo-CFTR(inh)-172, a tetrazolo-derived thiazolidinone, and Ph-GlyH-101, a phenyl-derived glycine hydrazide, without an effect on cell proliferation.

Evidence for direct CFTR inhibition by CFTR(inh)-172 based on Arg347 mutagenesis.

CFTR (cystic fibrosis transmembrane conductance regulator) is an epithelial Cl- channel inhibited with high affinity and selectivity by the thiazolidinone compound CFTR(inh)-172. In the present study, we provide evidence that CFTR(inh)-172 acts directly on the CFTR. We introduced mutations in amino acid residues of the sixth transmembrane helix of the CFTR protein, a domain that has an important role in the formation of the channel pore.

Alpha-aminoazaheterocyclic-methylglyoxal adducts do not inhibit cystic fibrosis transmembrane conductance regulator chloride channel activity.

Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel have potential applications in the therapy of secretory diarrheas and polycystic kidney disease. In a recent study, several highly polar alpha-aminoazaheterocyclic-methylglyoxal adducts were reported to reversibly inhibit CFTR chloride channel activity with IC50 values in the low picomolar range (J Pharmacol Exp Ther 322:1023-1035, 2007), more than 10,000-fold better than that of thiazolidinone and glycine hydrazide CFTR inhibitors previously identified by high-throughput screening. In this study, we resynthesized and evaluated the alpha-aminoazaheterocyclic-methylglyoxal adducts reported to have high CFTR inhibition potency (compounds 5, 7, and 8).

Comparative transport efficiencies of urea analogues through urea transporter UT-B.

Expression of urea transporter UT-B confers high urea permeability to mammalian erythrocytes. Erythrocyte membranes also permeate various urea analogues, suggesting common transport pathways for urea and structurally similar solutes. In this study, we examined UT-B-facilitated passage of urea analogues and other neutral small solutes by comparing transport properties of wildtype to UT-B-deficient mouse erythrocytes.

Lectin conjugates as potent, nonabsorbable CFTR inhibitors for reducing intestinal fluid secretion in cholera.

Background & Aims: Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel are predicted to prevent intestinal fluid secretion in cholera. We previously discovered low- affinity glycine hydrazide (GlyH) CFTR inhibitors that block CFTR at its external pore. The goal of this study was to develop potent CFTR inhibitors that are minimally absorbed and washed out of the intestinal lumen for application as antisecretory agents in cholera.

Small molecules with antimicrobial activity against E. coli and P. aeruginosa identified by high-throughput screening.

Background And Purpose: New antimicrobials are needed because of the emergence of organisms that are resistant to available antimicrobials. The purpose of this study was to evaluate a high-throughput screening approach to identify antibacterials against two common disease-causing bacteria, and to determine the frequency, novelty, and potency of compounds with antibacterial activity.

Experimental Approach: A high-throughput, turbidometric assay of bacterial growth in a 96-well plate format was used to screen a diverse collection of 150,000 small molecules for antibacterial activity against E.

Luminally active, nonabsorbable CFTR inhibitors as potential therapy to reduce intestinal fluid loss in cholera.

Enterotoxin-mediated secretory diarrheas such as cholera involve chloride secretion by enterocytes into the intestinal lumen by the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. We previously identified glycine hydrazide CFTR blockers that by electrophysiological studies appeared to block the CFTR anion pore at its lumen-facing surface. Here, we synthesize highly water-soluble, nonabsorbable malondihydrazides by coupling 2,4-disulfobenzaldehyde, 4-sulfophenylisothiocyante, and polyethylene glycol (PEG) moieties to 2-naphthalenylamino-[(3,5-dibromo-2,4-dihydroxyphenyl) methylene] propanedioic acid dihydrazide, and aminoacethydrazides by coupling PEG to [(N-2-naphthalenyl)-2-(2-hydroxyethyl)]-glycine-2-[(3,5-dibromo-2,4-dihydroxyphenyl) methylene] hydrazide.