NITD-688, a pan-serotype inhibitor of the dengue virus NS4B protein, shows favorable pharmacokinetics and efficacy in preclinical animal models.

Dengue virus (DENV) is a mosquito-borne flavivirus that poses a threat to public health, yet no antiviral drug is available. We performed a high-throughput phenotypic screen using the Novartis compound library and identified candidate chemical inhibitors of DENV. This chemical series was optimized to improve properties such as anti-DENV potency and solubility.

A Cyclic Phosphoramidate Prodrug of 2'-Deoxy-2'-Fluoro-2'--Methylguanosine for the Treatment of Dengue Virus Infection.

Monophosphate prodrug analogs of 2'-deoxy-2'-fluoro-2'--methylguanosine have been reported as potent inhibitors of hepatitis C virus (HCV) RNA-dependent RNA polymerase. These prodrugs also display potent anti-dengue virus activities in cellular assays although their prodrug moieties were designed to produce high levels of triphosphate in the liver. Since peripheral blood mononuclear cells (PBMCs) are among the major targets of dengue virus, different prodrug moieties were designed to effectively deliver 2'-deoxy-2'-fluoro-2'--methylguanosine monophosphate prodrugs and their corresponding triphosphates into PBMCs after oral administration.

Beneficiary effect of ethanolic extract against high fructose diet induced abnormalities in carbohydrate and lipid metabolism in wistar rats.

The present study was proposed to elucidate the effect of gum resin elthanolic extract treatment on alterations in carbohydrate and lipid metabolisms in rats fed with high-fructose diet. Male Wistar rats were divided into four groups: two of these groups (group C and C+CM) were fed with standard pellet diet and the other two groups (group F and F+CM) were fed with high fructose (66 %) diet. suspension in 5% Tween-80 in distilled water (200 mg/kg body weight/day) was administered orally to group C+CM and group F+CM.

Discovery of 2-oxopiperazine dengue inhibitors by scaffold morphing of a phenotypic high-throughput screening hit.

A series of 2-oxopiperazine derivatives were designed from the pyrrolopiperazinone cell-based screening hit 4 as a dengue virus inhibitor. Systematic investigation of the structure-activity relationship (SAR) around the piperazinone ring led to the identification of compound (S)-29, which exhibited potent anti-dengue activity in the cell-based assay across all four dengue serotypes with EC<0.1μM.

Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design.

The discovery and optimization of non-nucleoside dengue viral RNA-dependent-RNA polymerase (RdRp) inhibitors are described. An X-ray-based fragment screen of Novartis' fragment collection resulted in the identification of a biphenyl acetic acid fragment 3, which bound in the palm subdomain of RdRp. Subsequent optimization of the fragment hit 3, relying on structure-based design, resulted in a >1000-fold improvement in potency in vitro and acquired antidengue activity against all four serotypes with low micromolar EC50 in cell-based assays.

Bioprospecting of gum kondagogu (Cochlospermum gossypium) for bioremediation of uranium (VI) from aqueous solution and synthetic nuclear power reactor effluents.

An ecofriendly green chemistry method using a natural biopolymer, Gum Kondagogu (GK) for the removal of U (VI) from aqueous, simulated nuclear effluents was studied. The adsorption characteristic of GK towards U (VI) from aqueous solution was studied at varied pH, contact time, adsorbent dose, initial U (VI) concentration and temperature using UV-Visible spectroscopy and ICP-MS. Maximum adsorption was seen at pH 4, 0.

Discovery of Dengue Virus NS4B Inhibitors.

The four serotypes of dengue virus (DENV-1 to -4) represent the most prevalent mosquito-borne viral pathogens in humans. No clinically approved vaccine or antiviral is currently available for DENV. Here we report a spiropyrazolopyridone compound that potently inhibits DENV both in vitro and in vivo.

Lead optimization of spiropyrazolopyridones: a new and potent class of dengue virus inhibitors.

Spiropyrazolopyridone 1 was identified, as a novel dengue virus (DENV) inhibitor, from a DENV serotype 2 (DENV-2) high-throughput phenotypic screen. As a general trend within this chemical class, chiral resolution of the racemate revealed that R enantiomer was significantly more potent than the S. Cell-based lead optimization of the spiropyrazolopyridones focusing on improving the physicochemical properties is described.

Detection of dihydroxycholesterols in human plasma using HPLC-ESI-MS/MS.

We report a straightforward sample preparation procedure and a direct liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method for the analysis of 7alpha,25-dihydroxycholesterol (7α25-OHC) and 7alpha,27-dihydroxycholesterol (7α27-OHC). By applying a slow protein precipitation approach using cold ethanol, we were able to detect and quantify 7α25-OHC and 7α27-OHC in a fast and reliable manner. The average concentrations from 20 healthy individuals were determined to be 0.

Activation of peripheral blood mononuclear cells by dengue virus infection depotentiates balapiravir.

In a recent clinical trial, balapiravir, a prodrug of a cytidine analog (R1479), failed to achieve efficacy (reducing viremia after treatment) in dengue patients, although the plasma trough concentration of R1479 remained above the 50% effective concentration (EC(50)). Here, we report experimental evidence to explain the discrepancy between the in vitro and in vivo results and its implication for drug development. R1479 lost its potency by 125-fold when balapiravir was used to treat primary human peripheral blood mononuclear cells (PBMCs; one of the major cells targeted for viral replication) that were preinfected with dengue virus.

Effect of Commiphora mukul gum resin on hepatic marker enzymes, lipid peroxidation and antioxidants status in pancreas and heart of streptozotocin induced diabetic rats.

Objective: To study the antioxidant efficacy of Commiphora mukul (C. mukul) gum resin ethanolic extract in streptozotocin (STZ) induced diabetic rats.

Methods: THE MALE WISTAR ALBINO RATS WERE RANDOMLY DIVIDED INTO FOUR GROUPS OF EIGHT ANIMALS EACH: Control group (C), CM-treated control group (C+CMEE), Diabetic control group (D), CM- treated diabetic group (D+CMEE).

Evaluation of the use of gel card system for assessment of direct coombs test: weighing the pros and cons.

A positive direct Coombs test (DCT) is the hallmark of diagnosis of immune hemolytic anemias. The reagent used for the test is the Antihuman globulin (AHG), which may be either 'Polyspecific' or 'Monospecific'. The advent of the Gel card systems has made the procedure and interpretation of DCT simpler.

Lack of micronuclei induction by fumonisin B(1) mycotoxin in BALB/c mice.

The genotoxic potential of fumonisin B(1) (FB(1)) in vivo in BALB/c mice (male and female) was assessed by induction of micronuclei (MN) formation in bone marrow polychromatic erythrocytes. The ratio of polychromatic erythrocytes to normochromatic erythrocytes (PCE/NCE) was also determined. Mice were injected intraperitoneally (i.

Ethanolic extract of Commiphora mukul gum resin attenuates streptozotocin-induced alterations in carbohydrate and lipid metabolism in rats.

The purpose of this study was to investigate the effects of Commiphora mukul gum resin ethanolic extract (CMEEt) administration against altered activities of key enzymes of carbohydrate metabolism, lipid metabolism and changes in glycogen content (liver and muscle) and lipids (liver and heart) in streptozotocin (STZ) induced insulin deficient diabetic Wistar albino rats. Diabetes was induced by intraperitoneal injection of STZ (55 mg/kg body wt) to male Wistar rats. The animals were divided into four groups: Control (C), control-treated (C+CM), diabetic (D) and diabetic-treated group (D+CM).

Lipoprotein distribution and serum concentrations of 7α-hydroxy-4-cholesten-3-one and bile acids: effects of monogenic disturbances in high-density lipoprotein metabolism.

BA (bile acid) formation is considered an important final step in RCT (reverse cholesterol transport). HDL (high-density lipoprotein) has been reported to transport BAs. We therefore investigated the effects of monogenic disturbances in human HDL metabolism on serum concentrations and lipoprotein distributions of the major 15 BA species and their precursor C4 (7α-hydroxy-4-cholesten-3-one).

Plasma levels of sphingosine-1-phosphate and apolipoprotein M in patients with monogenic disorders of HDL metabolism.

Background: Apolipoprotein M (apoM) has been identified as a specific sphingosine-1-phosphate (S1P) binding protein of HDL.

Objectives And Methods: To investigate the in vivo effects of disturbed apoM or HDL metabolism we quantified S1P and apoM in plasmas of wild-type, apoM-knock-out, and apoM transgenic mice as well as 50 patients with seven different monogenic disorders of HDL metabolism and their 51 unaffected relatives.

Results: Compared to wild type mice, S1P plasma levels in apoM knock-out and apoM transgenic mice were decreased by 30% and increased by 270%, respectively.

Protective effects of Phyllanthus amarus aqueous extract against renal oxidative stress in Streptozotocin -induced diabetic rats.

Aim And Objectives: In the present study, we have evaluated the antihyperglycemic, hypolipidemic and antioxidant activities of aqueous extract of Phyllanthus amarus (PAAEt) in streptozotocin (STZ)-induced diabetic rats.

Materials And Methods: PAAEt was administered at 200 mg/kg body weight/day to normal treated (NT-group) and STZ-induced diabetic treated rats (DT-group) by gavage for eight weeks. During the experimental period, blood was collected from fasted rats at 10 days intervals and plasma glucose level was estimated.

Oxysterols direct immune cell migration via EBI2.

Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2.

Plasma levels of 27-hydroxycholesterol in humans and mice with monogenic disturbances of high density lipoprotein metabolism.

Secretion of 27-hydroxycholesterol (27OHC) from macrophages is considered as an alternative to HDL-mediated reverse transport of excess cholesterol. We investigated 27OHC-concentrations in plasma of humans and mice with monogenic disorders of HDL metabolism. As compared to family controls mutations in the genes for apolipoprotein A-I, ATP binding cassette transporter (ABC) A1 and lecithin:cholesterol acylstransferase (LCAT) were associated with reduced concentrations of both HDL-cholesterol and HDL-27OHC whereas mutations in the genes for cholesterylester transfer protein (CETP), scavenger receptor type BI and hepatic lipase were associated with elevated HDL concentrations of either sterol.

Effect of various surfactants (cationic, anionic and non-ionic) on the growth of Aspergillus parasiticus (NRRL 2999) in relation to aflatoxin production.

The effect of surfactants (two cationic, one anionic and three non-ionic) at 0.001, 0.01, 0.

Antioxidant potential of aqueous extract of Phyllanthus amarus in rats.

Objective: Increased levels of oxidative stress may be implicated in the etiology of many pathological conditions. Protective antioxidant action imparted by many plant extracts and plant products make them promising therapeutic drugs for free radical induced pathologies. In this study we assessed the antioxidant potential of Phyllanthus amarus (Euphorbiaceae).

Clinical patterns and hematological spectrum in autoimmune hemolytic anemia.

Background: Autoimmune hemolytic anemia (AIHA) results from red cell destruction due to circulating autoantibodies against red cell membrane antigens. They are classified etiologically into primary and secondary AIHAs. A positive direct antiglobulin test (DAT) is the hallmark of diagnosis for AIHA.