Melatonin prevents dexamethasone‐induced testicular oxidative stress and germ cell apoptosis in golden hamster,Mesocricetus auratus

This study investigated the protective effect of melatonin on dexamethasone (Dex), an extensively used anti‐inflammatory and immunosuppressive synthetic glucocorticoid, induced testicular oxidative stress and germ cell apoptosis in golden hamster. Hamsters were randomly divided into four groups (n = 7): group I – control; group II – melatonin treated (10 mg kg^?1 day^?1); group III – Dex treated (7 mg kg^?1 day^?1) and group IV – combination of Dex and melatonin. All the injections were administered intraperitoneally for seven consecutive days. The histopathological changes, specific biochemical markers, including antioxidative enzymes, plasma melatonin level and the markers for germ cell apoptosis were evaluated. Dex administration decreased antioxidant enzyme activities (SOD, CAT, GSH‐P_X), plasma melatonin level and melatonin receptor (MT1) expression with a concomitant increase in lipid peroxidation (TBARS) and altered testicular histopathology which might culminate into increased germ cell apoptosis as evident from increased Bax/Bcl‐2 ratio and caspase‐3 expression. However, melatonin pre‐treatment enhanced enzyme activities for SOD, CAT, GSH‐P_X with a simultaneous decrease in Bax/Bcl‐2 ratio and caspase‐3 expression. Our findings clearly suggest that melatonin improved defence against Dex‐induced testicular oxidative stress and prevented germ cell apoptosis, suggesting a novel combination therapeutic approach for management of male reproductive health.     

Identification of 5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine as novel orally bioavailable and metabolically stable antimalarial compound for further exploration

Malaria continues to be a significant public health problem threatened by the emergence and spread of resistance to artemisinin-based combination therapies and marked half a million deaths in 2016. A new imidazopyridine chemotype has been envisaged through scaffold-hopping approach combined with docking studies for putative-binding interactions with Plasmodium falciparum phosphatidylinositol-4-kinase (PfPI4K) target. The docking results steered to the synthesis of compound 1 [5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine] followed by the in vitro screening for antiplasmodial activity and ADME-PK studies. Combined with potent antimalarial activity of compound 1 (Pf3D7 IC₅₀ = 29 nM) with meager in vitro intrinsic clearance, moderate plasma-protein binding, and acceptable permeability, compound 1 displayed sustained exposure and high oral bioavailability in mice and can thus have the potential as next generation PI4K inhibitor for in vivo studies.     

Successful switch (tOPV to bOPV) in India: Tribute to a resilient health system

In accordance with the end game strategies for polio eradication a synchronized switch plan from tOPV to bOPV was implemented globally in 2016. The National Committee for Polio Eradication (NCCPE) validated the switch activities in India. An expert group of 104 academics conducted field visits in 25 states and 2 Union territories for independent verification (after an initial round of verification by the National Polio Surveillance Project [NPSP]). The objectives were to validate withdrawal and disposal of tOPV by screening cold chain points in public and private sector health facilities in both rural and urban areas; additionally, availability of bOPV and IPV was also documented. 34 filled tOPV and 5 empty vials were detected inside cold chain equipment and 17 outside. The disposal mechanism was found to be reasonably adequate. The key strategies -- ‘throttling’ of vaccine supplies well ahead of the switch date while preventing stock outs at various immunization points, simultaneously working with the regulators to delicense the tOPV on the switch date and helping manufacturers to calibrate vaccine production according to national timelines, and strong and persistent advocacy with professional associations to align with national bOPV and IPV policy facilitated successful accomplishment of the switch process. Effective implementation of the switch strategy in India also bears testimony to the resilience of the health system operating under diverse and heterogeneous governance.     

Changes in 32P-Labelling of Platelet Phospholipids in Response to ADP

Summary . Suspensions of washed platelets from rabbits were labelled in vitro with ³²PO₄, washed, and then stimulated with ADP. Thirty seconds after the addition of ADP or of a control solution, samples of the suspension were subjected to lipid extraction. The phospholipid classes were isolated by thin layer chromatography. The results of phosphate estimation on the isolated phospholipids were in agreement with the previously described amounts of diphosphatidylinositol (DPI) and triphosphatidylinositol (TPI) in human platelets. In both ADP-treated and control plateletes the label in phospholipid was mainly in phosphatidic acid (PA), phosphatidylinositol (MPI), DPI and TPI. Thirty seconds after the addition of ADP there was an increase in labelling of PA, DPI and TPI but the amounts of PA, DPI and TPI in platelets did not change. The results indicate that ADP probably induces an increase in turnover of the phosphate moieties of these phospholipids. The changes observed represent changes in the metabolism of the phospholipids of the platelet membrane which may be important in the mechanism of platelet aggregation.     

Stabilization of two conformers via intra- or inter-molecular hydrogen bonds in a dinuclear vanadium(v) complex with a pendant Schiff base: theoretical insight

A dinuclear vanadium(v) complex, (μ-O)₂[V(O)(L)]₂, [where HL = 2-methoxy-6-((2-(2-hydroxyethylamino)ethylimino)methyl)phenol] has been synthesized and characterized by spectral and elemental analysis. A single crystal X-ray diffraction study confirms it structure. Two different conformations, stabilized via either intra- or inter-dinuclear hydrogen bonding interactions, co-exist in the solid-state structure. The energies of these intra- or inter-dinuclear hydrogen bonding interactions have been estimated by Density functional theory (DFT) calculations. A ‘Non-covalent interaction’ (NCI) plot has also been used to characterize these interactions.

Two different hydrogen bonded conformers coexist in a synthesized dinuclear oxovanadium(v) Schiff base. Density functional theory (DFT) calculations were utilized to calculate the energies involved in two different conformers.     

The Salmonella virulence protein SifA is a G protein antagonist

Salmonella's success at proliferating intracellularly and causing disease depends on the translocation of a major virulence protein, SifA, into the host cell. SifA recruits membranes enriched in lysosome associated membrane protein 1 (LAMP1) and is needed for growth of Salmonella induced filaments (Sifs) and the Salmonella containing vacuole (SCV). It directly binds a host protein called SKIP (SifA and kinesin interacting protein) which is critical for membrane stability and motor dynamics at the SCV. SifA also contains a WxxxE motif, predictive of G protein mimicry in bacterial effectors, but whether and how it mimics the action of a host G protein is not known. We show that SKIP's pleckstrin homology domain, which directly binds SifA, also binds to the late endosomal GTPase Rab9. Knockdown studies suggest that both SKIP and Rab9 function to maintain peripheral LAMP1 distribution in cells. The Rab9:SKIP interaction is GTP-dependent and is inhibited by SifA binding to the SKIP pleckstrin homology domain, suggesting that SifA may be a Rab9 antagonist. SifA:SKIP binding is significantly tighter than Rab9:SKIP binding and may thus allow SifA to bring SKIP to the SCV via SKIP's Rab9-binding site. Rab9 can measurably reverse SifA-dependent LAMP1 recruitment and the perinuclear location of the SCV in cells. Importantly, binding to SKIP requires SifA residues W197 and E201 of the conserved WxxxE signature sequence, leading to the speculation that bacterial G protein mimicry may result in G protein antagonism.