Phagocytic cells internalize ZnO particles by FcγII/III-receptor pathway

The present study investigates the process of internalization for bulk ZnO particles in macrophages, and further elucidates the underlying mechanism. Since macrophages are active phagocytes and phagocytosis is a size dependent phenomenon, therefore we hypothesized that bulk ZnO may internalize into macrophages by phagocytic pathways. Interestingly, the phagocytic activity got enhanced in bulk ZnO treated macrophages. Moreover, the bulk ZnO treated macrophages internalized via FcγR-II/III, complement and scavenger–receptor pathways. To confirm the specificity of phagocytic pathway, the uptake was also analyzed in splenocytes where phagocytic (monocytes) and non-phagocytic cells (lymphocytes) are present. It was observed that no significant uptake of bulk ZnO in case of lymphocytes whereas significant uptake in monocytes. Henceforth, our quest for uptake mechanisms also revealed that severe plasma membrane extensions (pseudopodia), FcγR clustering over the surface of macrophages and activation of FcγR signaling were the key players for bulk ZnO uptake; whereas clathrin or caveolae mediated endocytic pathways contributed less. Uptake of these particles was further strengthened by the ZnO-induced activation of the Src-kinase p-Lyn, phospho-tyrosine kinases Syk (spleen tyrosine kinase), p-PLC-γ and PI3K (phosphatidylinositol 3-kinase). Our findings illustrate that the phagocytic nature of macrophages could have led to higher uptake of bulk ZnO.     

SARS-CoV-2 and Influenza Virus Co-Infection Cases Identified through ILI/SARI Sentinel Surveillance: A Pan-India Report

SARS-CoV-2/influenza virus co-infection studies have focused on hospitalized patients who usually had grave sequelae. Here, we report SARS-CoV-2/influenza virus co-infection cases from both community and hospital settings reported through integrated ILI/SARI (Influenza Like Illness/Severe Acute Respiratory Infection) sentinel surveillance established by the Indian Council of Medical Research. We describe the disease progression and outcomes in these cases. Out of 13,467 samples tested from 4 July 2021–31 January 2022, only 5 (0.04%) were of SARS-CoV-2/influenza virus co-infection from 3 different sites in distinct geographic regions. Of these, three patients with extremes of age required hospital admission, but none required ICU admission or mechanical ventilation. No mortality was reported. The other two co-infection cases from community settings were managed at home. This is the first report on SARS-CoV-2/Influenza virus co-infection from community as well as hospital settings in India and shows that influenza viruses are circulating in the community even during COVID-19. The results emphasize the need for continuous surveillance for multiple respiratory pathogens for effective public health management of ILI/SARI cases in line with the WHO (World Health Organization) recommendations.     

Exploring the therapeutic mechanisms of Cassia glauca in diabetes mellitus through network pharmacology,molecular docking and molecular dynamics

Cassia glauca is reported as anti-diabetic medicinal plant and is also used as an ethnomedicine. However, its mode of action as an anti-diabetic agent has not been clearly elucidated. Hence, the present study investigated the probable mechanism of action of C. glauca to manage diabetes mellitus via network pharmacology and molecular docking and simulations studies. The reported bioactives from C. glauca were retrieved from an open-source database, i.e. ChEBI, and their targets were predicted using SwissTargetPrediction. The proteins involved in the pathogenesis of diabetes were identified from the therapeutic target database. The targets involved in diabetes were enriched in STRING, and the pathways involved in diabetes were identified concerning the KEGG. Cytoscape was used to construct the network among bioactives, proteins, and probably regulated pathways, which were analyzed based on edge count. Similarly, molecular docking was performed using the Glide module of the Schrodinger suite against majorly targeted proteins with their respective ligands. Additionally, the drug-likeness score and ADMET profile of the individual bioactives were predicted using MolSoft and admetSAR2.0 respectively. The stability of these complexes were further studied via molecular dynamics simulations and binding energy calculations. Twenty-three bio-actives were retrieved from the ChEBI database in which cassiarin B was predicted to modulate the highest number of proteins involved in diabetes mellitus. Similarly, GO analysis identified the PI3K-Akt signaling pathway to be primarily regulated by modulating the highest number of gene. Likewise, aldose reductase (AKR1B1) was majorly targeted via the bioactives of C. glauca. Similarly, docking study revealed methyl-3,5-di-O-caffeoylquinate (docking score −9.209) to possess the highest binding affinity with AKR1B1. Additionally, drug-likeness prediction identified cassiaoccidentalin B to possess the highest drug-likeness score, i.e. 0.84. The molecular dynamics simulations and the MMGBSA indicate high stability and greater binding energy for the methyl-3,5-di-O-caffeoylquinate (ΔG_bind = −40.33 ± 6.69 kcal mol⁻¹) with AKR1B1, thus complementing results from other experiments. The study identified cassiarin B, cassiaoccidentalin B, and cinnamtannin A2 as lead hits for the anti-diabetic activity of C. glauca. Further, the PI3K-Akt and AKR1B1 were traced as majorly modulated pathway and target, respectively.

Cassia glauca is reported for anti-diabetic action and is also used as an ethnomedicine.     

QSAR based therapeutic management of <Emphasis Type="Italic">M. tuberculosis</Emphasis>

Mycobacterium tuberculosis is responsible for severe mortality and morbidity worldwide but, under-developed and developing countries are more prone to infection. In search of effective and wide-spectrum anti-tubercular agents, interdisciplinary approaches are being explored. Of the several approaches used, computer based quantitative structure activity relationship (QSAR) have gained momentum. Structure-based drug design and discovery implies a combined knowledge of accurate prediction of ligand poses with the good prediction and interpretation of statistically validated models derived from the 3D-QSAR approach. The validated models are generally used to screen a small combinatorial library of potential synthetic candidates to identify hits which further subjected to docking to filter out compounds as novel potential emerging drug molecules to address multidrug-resistant tuberculosis. Several newer models are integrated to QSAR methods which include different types of chemical and biological data, and simultaneous prediction of pharmacological activities including toxicities and/or other safety profiles to get new compounds with desired activity. In the process, several newer molecules have been identified which are now being assessed for their clinical efficacy. Present review deals with the advances made in the field highlighting overall future prospects of the development of anti-tuberculosis drugs.     

Buccal Mucosa Exfoliative Cell Prussian Blue Stain Co-Relates with Iron Overload in β-Thalassemia Major Patients

Thalassemics require regular blood transfusion therapy leading to iron overload in the body tissues, which is a major cause of morbidity and mortality in these patients. We hereby attempted to measure this iron overload by means of exfoliative cytology, a non-invasive and inexpensive technique. The aims and objectives of our study were: 1. To detect iron overload by oral exfoliative cytology using Perl’s Prussian blue stain in β-thalassemia major patients. 2. To correlate staining positivity with serum ferritin levels. Smears were obtained from buccal mucosa of 50 β-thalassemia major patients (who had taken more than 12 transfusions) and 25 healthy subjects of the same age group as controls. Smears were stained with Perl’s Prussian blue. Blood samples were taken from the study group for estimation of serum ferritin levels. Grading criteria were defined for assessing the Prussian blue positivity. Perl’s positivity was observed in 49 out of 50 of thalassemic patients (98%). 1 patient had Grade 0, 7 patients had Grade I, 5 had Grade II, 12 had Grade III, 14 had Grade IV while 11 patients had Grade V positivity. Spearman Rank’s Correlation Co-efficient was 0.38, signifying a weak positive correlation between positivity of buccal smears for Perl’s Prussian blue staining and respective serum ferritin levels. Perl’s Prussian blue staining of exfoliated cells from buccal mucosa can be used to assess iron overload in β-thalassemia major patients, as a screening as well as diagnostic tool. With the grading system we can give a semi-quantitative assessment of the same.     

Modified combined disc test (mCDT): a novel,labor-saving and 4 times cheaper method to differentiate Class A,B and D carbapenemase-producing Klebsiella species

Carbapenemase-producing organisms have been an immense public health problem in recent years. Combined disc test (CDT) is a simple and widely used phenotypic method for carbapenemase detection, especially in developing countries. This study evaluates the performance of modified combined disc test (mCDT), a novel and 4 times cheaper method than CDT. In total, 572 (15.5%) Klebsiella spp. including 81 (14.2%) carbapenemase producers were isolated from 3993 clinical samples. Both mCDT and CDT showed similar sensitivity, specificity, positive predictive value, and negative predictive value for the differentiation of Class A, B, and D carbapenemase-producing Klebsiella spp.