Using a pharmacological inhibitor of Hsp90 in cultured malarial parasite, we have previously implicated Plasmodium falciparum Hsp90 (PfHsp90) as a drug target against malaria. In this study, we have biochemically characterized PfHsp90 in terms of its ATPase activity and interaction with its inhibitor geldanamycin (GA) and evaluated its potential as a drug target in a preclinical mouse model of malaria. In addition, we have explored the potential of Hsp90 inhibitors as drugs for the treatment of Trypanosoma infection in animals. Our studies with full-length PfHsp90 showed it to have the highest ATPase activity of all known Hsp90s; its ATPase activity was 6 times higher than that of human Hsp90. Also, GA brought about more robust inhibition of PfHsp90 ATPase activity as compared with human Hsp90. Mass spectrometric analysis of PfHsp90 expressed in P. falciparum identified a site of acetylation that overlapped with Aha1 and p23 binding domain, suggesting its role in modulating Hsp90 multichaperone complex assembly. Indeed, treatment of P. falciparum cultures with a histone deacetylase inhibitor resulted in a partial dissociation of PfHsp90 complex. Furthermore, we found a well known, semisynthetic Hsp90 inhibitor, namely 17-(allylamino)-17-demethoxygeldanamycin, to be effective in attenuating parasite growth and prolonging survival in a mouse model of malaria. We also characterized GA binding to Hsp90 from another protozoan parasite, namely Trypanosoma evansi. We found 17-(allylamino)-17-demethoxygeldanamycin to potently inhibit T. evansi growth in a mouse model of trypanosomiasis. In all, our biochemical characterization, drug interaction, and animal studies supported Hsp90 as a drug target and its inhibitor as a potential drug against protozoan diseases.

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Coronavirus disease (COVID‐19) caused by the novel coronavirus (SARS‐CoV‐2) has rapidly spread across the globe affecting 213 countries or territories with greater than six million confirmed cases and about 0.37 million deaths, with World Health Organization categorizing it as a pandemic. Infected patients present with fever, cough, shortness of breath, and critical cases show acute respiratory infection and multiple organ failure. Likelihood of these severe indications is further enhanced by age as well as underlying comorbidities such as diabetes, cardiovascular, or thoracic problems, as well as due to an immunocompromised state. Currently, curative drugs or vaccines are lacking, and the standard of care is limited to symptom management. Natural products like ginger, turmeric, garlic, onion, cinnamon, lemon, neem, basil, and black pepper have been scientifically proven to have therapeutic benefits against acute respiratory tract infections including pulmonary fibrosis, diffuse alveolar damage, pneumonia, and acute respiratory distress syndrome, as well as associated septic shock, lung and kidney injury, all of which are symptoms associated with COVID‐19 infection. This review highlights the potential of these natural products to serve as home‐based, inexpensive, easily accessible, prophylactic agents against COVID‐19.

The ability of plasmonic nanoparticles (NPs) to focus the impinging electromagnetic (EM) radiation to subwavelength regimes assists in the detection of molecules at extremely low concentrations. Numerous nanomaterials have been exploited in the surface plasmon-coupled emission (SPCE) technology, presenting quintessential physicochemical insights. However, seldom attention has been paid toward utilizing the biocompatible nanotechnology for substrate nanoengineering in SPCE. In this context, we present LYCOAT-based silver (Ag) NPs synthesized via a frugal disruptive approach by exposing a simple physical mixture of Ag+ ions and LYCOAT to UV irradiation. Variations in the time of UV exposure resulted in nanofractals and nanocubes of Ag presenting unique architectures for nanophotonic applications, where the biocompatible LYCOAT functions as both reducing and capping agents under ambient conditions. Nanomaterials synthesized in this approach were studied in spacer, cavity, and extended cavity nanointerfaces in the SPCE platform for obtaining tunable plasmonic coupling. The augmented >900-fold SPCE enhancements were utilized for mobile phone-based attomolar sensing of environmentally hazardous Hg2+ ions. The simple, realistic, and eco-friendly methodology adopted here for developing nanomaterials for photonic applications opens the door for exploring such next-generation bio-inspired nanomaterials for point-of-care diagnostic applications.

SummaryElucidating mechanisms by which Ca 2+ signals are generated by monocytes is important for understanding monocyte function in health and disease. We have investigated mechanisms underlying Ca 2+ signals generated following disruption of lysosomes by exposure to the cathepsin C substrate glycyl-L-phenylalanine-b-napthylamide (GPN

Avascular necrosis of the femur head (AVNFH) is a debilitating disease caused due to the use of alcohol, steroids, following trauma or unclear (idiopathic) etiology, affecting mostly the middle aged population. Clinically AVNFH is associated with impaired blood supply to the femoral head resulting in bone necrosis and collapse. Although Homocysteine (HC) has been implicated in AVNFH, levels of homocysteine and its associated pathway metabolites have not been characterized. We demonstrate elevated levels of homocysteine and concomitantly reduced levels of vitamins B6 and B12, in plasma of AVNFH patients. AVNFH patients also had elevated blood levels of sodium and creatinine, and reduced levels of random glucose and haemoglobin. Biophysical and ultrastructural analysis of AVNFH bone revealed increased remodelling and reduced bone mineral density portrayed by increased carbonate to phosphate ratio and decreased Phosphate to amide ratio together with disrupted trabeculae, loss of osteocytes, presence of calcified marrow, and elevated expression of osteocalcin in the osteoblasts localized in necrotic regions. Taken together, our studies for the first time characterize the metabolomic, pathophysiological and morphometric changes associated with AVNFH providing insights for development of new markers and therapeutic strategies for this debilitating disorder.

Background: P2X receptors are localized both to the cell surface and within intracellular vacuoles. Mechanisms activating intracellular receptors are unclear. Results: The P2X receptor ATP binding site faces into the vacuole lumen. ATP translocation triggers P2X receptor-dependent release of calcium. Conclusion: Vacuolar P2X receptors are luminal ATP sensors releasing stored calcium in response to luminal ATP accumulation. Significance: Intracellular P2X receptors are calcium release channels.

BCZT (Ba0.85Ca0.15Zr0.1Ti0.9O3) is a recent class of lead-free ferroelectric material associated with high piezoelectric coefficient, making it suitable to inspire hydroxyapatite (HA)-BCZT ceramics for bone materials. Nano-crystalline hydroxyapatite (HA) synthesized using the hydrothermal route was characterized via FT-IR, Raman spectroscopy, X-ray powder diffraction (XRD), and Scanning Electron Microscopy (SEM). We also rationalized its formation as a function of operating conditions such as dwell time and temperature in this route. The nano-crystalline BCZT powder was synthesized via a sol-gel technique and its structural and morphological characterization were carried out using Raman Spectroscopy, XRD and Transmission Electron Microscopy (TEM). These investigations facilitated the optimization of HA-BCZT compositions and their electrical poling conditions to achieve enhanced piezoelectric effect. The composites (HA-BCZT) sintered at 1350∘C exhibited promising piezoelectric properties. We report the enhanced piezoelectric coefficient (d33) of 7±1 pC/N for 50% HA-BCZT which is significant as compared to that reported in the literature for ~98% BT (barium titanate) -HA composites. We highlight the role of Simulated Body Fluid (SBF) on the intriguing phase-change of Tricalcium Phosphate (TCP) obtained at this sintering temperature, to hydroxyapatite for its essential contribution to promote bone growth. We theoretically support the confirmed in vitro biocompatibility of these composites. Graphical abstract: Novel lead-free biocompatible piezoelectric HA-BCZT nanocrystal composites for accelerated Bone regeneration