Decreased In Vitro Artemisinin Sensitivity of Plasmodium falciparum across India.

Artemisinin-based combination therapy (ACT) has been used to treat uncomplicated Plasmodium falciparum infections in India since 2004. Since 2008, a decrease in artemisinin effectiveness has been seen throughout the Greater Mekong Subregion. The geographic proximity and ecological similarities of northeastern India to Southeast Asia may differentially affect the long-term management and sustainability of ACT in India. In order to collect baseline data on variations in ACT sensitivity in Indian parasites, 12 P. falciparum isolates from northeast India and 10 isolates from southwest India were studied in vitro Ring-stage survival assay (RSA) showed reduced sensitivity to dihydroartemisinin in 50% of the samples collected in northeast India in 2014 and 2015. Two of the 10 assayed samples from the southwest region of India from as far back as 2012 also showed decreased sensitivity to artemisinin. In both these regions, kelch gene sequences were not predictive of reduced artemisinin sensitivity, as measured by RSA. The present data justify future investments in integrated approaches involving clinical follow-up studies, in vitro survival assays, and molecular markers for tracking potential changes in the effectiveness of artemisinin against P. falciparum throughout India.

Circulatory heavy metals (cadmium, lead, mercury, and chromium) inversely correlate with plasma GST activity and GSH level in COPD patients and impair NOX4/Nrf2/GCLC/GST signaling pathway in cultured monocytes.

This study aims to examine the hypothesis that circulatory heavy metals may be associated with lung function decline and lower plasma GST activity and GSH level in COPD patients via activating monocytes mediated by impairing the NOX4/Nrf2/GCLC/GST signaling pathway. Results showed that the blood levels of heavy metals (cadmium, lead, mercury, and chromium) were significantly higher in COPD patients of coal mine site compared to the healthy controls. The levels of heavy metals in COPD patients were significantly and negatively correlated with lung function, GST activity, and GSH level. Using flowcytometry, fluorescence spectroscopy, and immunoblotting studies we have further demonstrated that treatment with individual heavy metals dose-dependently increased the NOX4 protein expression, intracellular ROS production, and decreased the Nrf2, GCLC, and GST protein expression, GST activity, and GSH level in THP-1 monocytes. None of the treatment caused any change in cell viability compared to control. In conclusion, this study suggests that circulatory heavy metals in COPD patients of coal mine site weakened the lung function, decreased the plasma GST activity and GSH level via impairing the NOX4/Nrf2/GCLC/GST signaling pathway in monocytes, which may cause monocyte activation and initiate the COPD pathophysiology.

In vitro adaptability of Plasmodium falciparum to different fresh serum alternatives.

To reduce the dependency on fresh AB+ serum in continuous culture of Plasmodium falciparum, a comparative study was undertaken to assess the in vitro adaptability of P. falciparum to media supplemented with fresh AB+ serum from whole blood, AB+ plasma, serum derived from AB+ plasma, AB+ human serum from Sigma, Albumax II, fetal bovine serum and new born calf serum, independently and in different combinations. Combinations were used to analyze whether two different substitutes demonstrate any synergistic effect on the growth of the parasites. Our findings exhibited that the combination of fresh human serum and Albumax II showed good growth pattern in comparison to that of fresh serum and can thereby be instrumental in reducing the role of fresh human serum in continuous parasite maintenance. Culture maintained with Albumax II with or without hypoxanthine showed average growth.

Antimalarial silver and gold nanoparticles: Green synthesis, characterization and in vitro study.

In the present study, we are reporting antimalarial potential of silver (AgNPs) and gold (AuNPs) nanoparticles synthesized by leaf and bark extract of Syzygium jambos (L.) Alston (Myrtaceae). AuNPs and AgNPs obtained by both the extracts were characterized using UV-vis spectroscopy, zeta potential, transmission electron microscopy (TEM), X-ray diffraction (XRD), and Fourier Transform Infrared spectroscopy (FTIR). NMR and FTIR spectra indicate that the saccharides and phenolics present in the S. jambos extracts were the major contributors responsible for the synthesis and stabilization of NPs. NPs were also synthesized by chemical methods and were compared for their antiplasmodial potential against chloroquine sensitive (3D7) and resistant (Dd2) strain of Plasmodium falciparum by using 24h schizont maturation assay. AgNPs synthesized by both the extracts showed higher antiplasmodial activity than the rest. Further, NPs synthesized by S. jambos extracts have shown insignificant cytotoxicity against human cervical cancer cell line (HeLa) and rat skeletal muscle cell line (L6), which proved their biocompatibility.

Design, in silico and in vitro evaluation of curcumin analogues against Plasmodium falciparum.

The polyphenolic compound curcumin has been reported for its antimalarial properties in various scientific studies. Plasmodium falciparum ATP6, the parasite orthologue of mammalian sarcoplasmic Ca2+ ATPase (SERCA) has been identified as a key molecular target of both artemisinin and curcumin. The work was thereby undertaken to study the anti-malarial properties of two different series of curcumin analogues based on their docking interactions with PfATP6 and correlating the results with their anti-malarial activity. The compounds were designed retaining similar functional groups as that of the parent curcumin nucleus while incorporating changes in the carbon chain length, unsaturated groups and the number of ketone groups. The compounds (1E, 4E)-1,5-bis(4-methylphenyl)penta-1,4-dien-3-one (CD-9), (1E, 4E)-1,5-bis(4-methoxyphenyl)penta-1,4-dien-3-one (CD-8) and (E)-1,3-bis(4-hydroxylphenyl)prop-2-en-1-one (CD-1) showed IC50 values of 1.642 µM, 1.764 µM and 2.59 µM in 3D7 strain and 3.039 µM, 7.40 µM and 11.3 µM in RKL-2 strain respectively. Detailed structure-activity relationship studies of the compounds showed that CD-9 and CD-8 had a common hydrophobic interaction with the residue Leu268 of the PfATP6 protein and has been postulated through our study to be the reason for their antimalarial activity as seen after corroborating the results with the in vitro study. The study provided valuable insight about the ligand-protein interaction of the various functional groups of curcumin and its analogues against the PfATP6 protein and their importance in imparting antimalarial action.

Molecular docking, synthesis and in vitro antimalarial evaluation of certain novel curcumin analogues

ABSTRACT The receptor protein PfATP6 has been identified as the common target of artemisinin and curcumin. The work was initiated to assess the antimalarial activity of six curcumin derivatives based on their binding affinities and correlating the in silico docking outcome with in vitro antimalarial screening results. A ligand library of thirty two Knoevenagel condensates of curcumin were designed and docked against PfATP6 protein and six compounds with the best binding scores were synthesized and screened for their antimalarial activity against the sensitive 3D7 strain of Plasmodium falciparum. ADME/Tox, pharmacokinetic and pharmacodynamic profiles of the designed compounds were analyzed and reported. 4-FB was found to have similar binding energy to the standard artemisinin (-6.75 and -6.73 respectively) while 4-MB, 3-HB, 2-HB, B, 4-NB displayed better binding energy than curcumin (-5.95, -5.89, -5.68, -5.35, -5.29 and -5.25 respectively). At a dose of 50 µg/mL all the six compounds showed 100% schizont inhibition while at 5µg/ml, five showed more than 75% inhibition and better results than curcumin. 4-FB showed the best activity with 97.8% schizonticidal activity. The in vitro results superimpose the results obtained from the in silico study thereby encouraging development of promising curcumin leads in the battle against malaria.

Synthesis, antimalarial activity and molecular docking of hybrid 4-aminoquinoline-1,3,5-triazine derivatives.

A series of novel hybrid 4-aminoquinoline 1,3,5-triazine derivatives was synthesized in a five-steps reaction and evaluated for their in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (RKL-2) strains of Plasmodium falciparum. Entire synthetic derivatives showed higher antimalarial activity on the sensitive strain while two compounds, viz., 9a and 9c displayed good activity against both the strains of P. falciparum. The observed activity was further substantiated by docking study on both wild and qradruple mutant type P. falciparum dihydrofolate reductase-thymidylate synthase (pf-DHFR-TS).

Role of environmental pollutants in liver physiology: special references to peoples living in the oil drilling sites of Assam.

The populations residing near polluted sites are more prone to various types of diseases. The important causes of air pollution are the suspended particulate matter, respirable suspended particulate matter, sulfur dioxide and nitrogen dioxide. As limited information is available enumerating the effect of these pollutants on liver physiology of the population living near the polluted sites; in the present study, we tried to investigate their effect on liver of the population residing near the oil drilling sites since birth. In this study, a randomly selected 105 subjects (46 subjects from oil drilling site and 61 subjects from control site) aged above 30 years were taken under consideration. The particulate matter as well as the gaseous pollutants, sulfur dioxide and nitrogen dioxide, were analyzed through a respirable dust sampler. The level of alkaline phosphatase, alanine transaminase and aspartate transaminase enzymes in serum were measured by spectrophotometer. The generalized regression model studies suggests a higher concentration of respirable suspended particulate matter, suspended particulate matter and nitrogen dioxide lowers the alkaline phosphatase level (p<0.0001) by 3.5 times (95% CI 3.1-3.9), 1.5 times (95% CI 1.4-1.6) and 12 times (95% CI 10.74-13.804), respectively in the exposed group. The higher concentration of respirable suspended particulate matter and nitrogen dioxide in air was associated with increase in alanine transaminase level (p<0.0001) by 0.8 times (95% CI 0.589-1.049) and by 2.8 times (95% CI 2.067-3.681) respectively in the exposed group. The increase in nitrogen dioxide level was also associated with increase in aspartate transaminase level (p<0.0001) by 2.5 times (95% CI 1.862-3.313) in the exposed group as compared to control group. Thus, the study reveals that long-term exposure to the environmental pollutants may lead to liver abnormality or injury of populations living in polluted sites.

Developing novel bacterial based bioformulation having PGPR properties for enhanced production of agricultural crops.

Plant growth promoting rhizobacteria (PGPR) are beneficial rhizobacteria which enhance plant growth as well as the productivity by a variety of mechanisms PGPR were isolated from the rhizosphere region of som plants (Machilus bombycina King) maintained at the Central Muga Eri Research and Training Institute, Lahdoigarh, Jorhat. A bacterial based bioformulation was prepared and sprayed over the experimental crops including tomato (Solanum lycopersicum), cauliflower (Brassica oleracea var botrytis), chili (Capsicum annuum) and brinjal (Solanum melongena). Biochemical analysis was done on these PGPR treated crops as well as the untreated crops. The bioformulations prepared from Bacillus cereus (MTCC 8297), Pseudomonas rhodesiae (MTCC 8299) and Pseudomonas rhodesiae (MTCC 8300) was found to be the most effective in increasing the shoot height, number of leaves, early fruiting and total biomass content of the plants after treatment.

Synthesis, Docking, In Vitro and In Vivo Antimalarial Activity of Hybrid 4-aminoquinoline-1,3,5-triazine Derivatives Against Wild and Mutant Malaria Parasites.

A new series of hybrid 4-aminoquinoline-1,3,5-triazine derivatives was synthesized by a four-step reaction. Target compounds were screened for in vitro antimalarial activity against chloroquine-sensitive (3D-7) and chloroquine-resistant (RKL-2) strains of Plasmodium falciparum. Compounds exhibited, by and large, good antimalarial activity against the resistant strain, while two of them, that is 8g and 8a, displayed higher activity against both the strains of P. falciparum. Additionally, docking study was performed on both wild (1J3I.pdb) and quadruple mutant (N51I, C59R, S108 N, I164L, 3QG2.pdb) type pf-DHFR-TS to highlight the structural features of hybrid molecules.

Role of glutathione S transferase polymorphism in COPD with special reference to peoples living in the vicinity of the open cast coal mine of Assam.

BACKGROUND: COPD may develop due to variation in the functioning of antioxidants along with smoking and environmental factors in genetically susceptible individuals. Since there are different views about the antioxidants responsible for detoxifying xenobiotic compound in the human body whose functional variation may lead to obstructive disease, this associative study has been taken up between GST gene polymorphism and COPD in populations exposed to coal dusts. METHODS: Genotypes of the 70 COPD patients and 85 non COPD patients were determined by PCR based methods followed by multiplex PCR of GSTT1 and GSTM1 genes taking albumin gene as a control. Suspended particulate analyses were determined through the Respirable Dust sampler along with the FTIR analysis of the dust samples from the glass microfiber filters. RESULTS: Dust sampling analysis reveals higher level of respirable suspended particulate matter, non respirable particulate matter, SO2 and NO2 present in air of the study site. FTIR analysis also suggests a higher concentration of organic silicone and aliphatic C-F compounds present in air of the study site and when spirometry was done, low lung function was observed among most of the subjects. GSTM1 null type was significantly associated with low lung function in smoker groups and the presence of at least one active allele (either GSTM1/GSTT1) seemed to have a protective role in the development of COPD. CONCLUSIONS: GSTM1 (null genotype) appeared to be a risk factor for lower lung function in smokers living in the vicinity of coal mines. Apart from polluted environment and genetic susceptibility, mixed coal dust exposure rich in organic silicone and aliphatic C-F compounds also appears to be a factor for the low lung function.

Antimalarial evaluation and docking studies of hybrid phenylthiazolyl-1,3,5-triazine derivatives: a novel and potential antifolate lead for Pf-DHFR-TS inhibition.

Present communication deals with the docking study of hybrid phenyl thiazolyl-1,3,5-triazine analogues (1a-36d) on three selected different binding site viz., α, ß and γ of wild type Pf-DFHR-TS. In admiration of excellent H-bond scoring, with regard to cycloguanil and to a large extent similar scoring with WR99210, compound 4a, 12b, 21c, 23c, 28d, 29d, 34d, and 35d were selected for in vitro antimalarial activity against 3D7 strain of Plasmodium falciparum. Findings from the study disclose that a significant correlation was exist between in vitro results and in silico prediction (r(2)=0.543). Furthermore, investigation of structure-activity relationships elucidate crucial structural requirement for site specific binding of ligands.