Molecular Engineering of Ultrabright Biomimetic NanoGhost for Site-Selective Tumor Imaging and Biodistribution.

Optically active ultrabright imaging agents are shown to delineate tumor location with deep tissue visualization in pre noclinical tumor models. NanoGhosts (NGs) particles are reconstructed from the cell membrane and integrated with organic fluorophores to attain ultra-brightness for solid tumor imaging. Moreover, the integration of amphiphilic and lipophilic molecules reveals structural characteristics of NGs (≈70 nm), which also alter their brightness.

Molecular Mechanisms of Cell Death in Leishmania donovani Induced by Selected Steroidal Alkaloids.

We have earlier reported novel anti-leishmanial molecules, veratramine and hupehenine, targeting dephospho-coenzyme A kinase of the parasite. In our current investigation, we assessed the efficacy of these two steroidal alkaloids, veratramine and hupehenine, in combating the parasite. Contrary to expectations, our study did not detect the typical signs of apoptosis such as mitochondrial membrane potential loss and phosphatidylserine externalization.

A squalene oil emulsified MPL-A and anti-CD200/CD300a antibodies adjuvanted whole-killed Leishmania vaccine provides durable immunity against L. donovani parasites.

Antigenic inefficacy to induce robust immune responses and durable memory are major causes of constantly failing prophylactic approaches in leishmaniasis. Here, we determine the potential of a standardized whole-killed Leishmania vaccine (Leishvacc) adjuvanted with anti-CD200 and anti-CD300a antibodies, either alone or with monophosphoryl lipid A (MPL-SE) emulsified in squalene oil, in restoring the compromised antigen presenting abilities of dendritic cells (DCs), effector properties of CD4T cells and providing protection against Leishmania donovani parasites. In animals vaccinated with antibodies adjuvanted vaccines, either alone or with MPL-SE, the antigen presenting abilities of CD11c DCs against Leishmania antigens, measured in terms of CD80, CD86, MHC-I, and MHC-II surface receptors and intracellular IL-12 were found enhanced than non-adjuvanted vaccine.

Identification of novel anti-leishmanials targeting glutathione synthetase of the parasite: a drug repurposing approach.

Drug repurposing has emerged as an effective strategy against infectious diseases such as visceral leishmaniasis. Here, we evaluated four FDA-approved drugs-valrubicin, ciclesonide, deflazacort, and telithromycin-for their anti-leishmanial activity on Leishmania donovani parasites, especially their ability to target the enzyme glutathione synthetase (LdGS), which enables parasite survival under oxidative stress in host macrophages. Valrubicin and ciclesonide exhibited superior inhibitory effects compared to deflazacort and telithromycin, inhibiting the promastigotes at very low concentrations, with IC values of 1.

Biochemical and biophysical characterization of Leishmania donovani citrate synthase.

Citrate synthase is a crucial enzyme in the TCA cycle and represents a potential therapeutic target. However, knowledge about this enzyme in Leishmania parasites remains limited. In this study, we have successfully cloned, expressed, and purified citrate synthase from Leishmania donovani (LdCS) using a bacterial system, and characterized it through various biophysical and biochemical methods.

Leishmania antigens activated CD4 T cells expressing CD200R receptors are the prime IL-10 producing phenotype and an important determinant of visceral leishmaniasis pathogenesis.

The excessive production of IL-10, an anti-inflammatory cytokine, by Leishmania antigen-activated T cells is supposed to be a key player in the onset and progression of visceral leishmaniasis (VL). The IL-10-producing sources in VL remain unidentified and uncharacterized. In this study, we reveal that antigen-activated CD4 T cells, i.

Dual-target drugs against Leishmania donovani for potential novel therapeutics.

Antioxidant defense mechanisms are important for a parasite to overcome oxidative stress and survive within host macrophage cells. Mitochondrial iron superoxide dismutase A (FeSODA) and trypanothione reductase (TR) are critical enzymes in the antioxidant defense mechanism of Leishmania donovani. FeSODA is responsible for neutralizing reactive oxygen species in mitochondria, while TR is responsible for reducing trypanothione, the molecules that help the parasite fight oxidative stress in Leishmania.

Repurposing the in-house generated Alzheimer's disease targeting molecules through computational and preliminary in-vitro studies for the management of SARS-coronavirus-2.

Covid-19 was declared a world pandemic. Recent studies demonstrated that Covid-19 impairs CNS activity by crossing the blood-brain barrier and ensuing cognitive impairment. In this study, we have utilized Covid-19 main protease (Mpro) as a biological target to repurpose our previously reported multifunctional compounds targeting Alzheimer's disease.

Novel chemical scaffold as potential drug against Leishmania donovani: Integrated computational and experimental approaches.

In this study, we have screened a large number of Food and Drug Administration-approved compounds for novel anti-leishmanial molecules targeting the citrate synthase enzyme of the parasite. Based on their docking and molecular dynamic simulation statistics, five compounds were selected. These compounds followed Lipinski's rule of five.

Structure-based drug designing against using docking and molecular dynamics simulation studies: exploring glutathione synthetase as a drug target.

In the pursuit of developing novel anti-leishmanial agents, we conducted an extensive computational study to screen inhibitors from the FDA-approved ZINC database against glutathione synthetase. The three-dimensional structure of glutathione synthetase was constructed by homology modeling, using the crystallographic structure of glutathione synthetase as a template. Subsequently, molecular docking studies were carried out for a large number of compounds using AutoDock Vina.

Periodic orbits in deterministic discrete-time evolutionary game dynamics: An information-theoretic perspective.

Even though the existence of nonconvergent evolution of the states of populations in ecological and evolutionary contexts is an undeniable fact, insightful game-theoretic interpretations of such outcomes are scarce in the literature of evolutionary game theory. As a proof-of-concept, we tap into the information-theoretic concept of relative entropy in order to construct a game-theoretic interpretation for periodic orbits in a wide class of deterministic discrete-time evolutionary game dynamics, primarily investigating the two-player two-strategy case. Effectively, we present a consistent generalization of the evolutionarily stable strategy-the cornerstone of the evolutionary game theory-and aptly term the generalized concept "information stable orbit.

Drug Encapsulated Lipid-Polymeric Nanohybrid as a Chemo-therapeutic Platform of Cancer.

The focus of this research is to design a bioengineered drug delivery vehicle that is efficient in anti-cancer drug delivery in a controlled manner. The experimental work focuses on constructing a methotrexate-loaded nano lipid polymer system (MTX-NLPHS) that can transport methotrexate (MTX) in MCF-7 cell lines in a controlled manner through endocytosis via phosphatidylcholine. In this experiment, MTX is embedded with polylactic-co-glycolic acid (PLGA) in phosphatidylcholine, which acts as a liposomal framework for regulated drug delivery.

Integrated computational and experimental approach for novel anti-leishmanial molecules by targeting Dephospho-coenzyme A kinase.

Coenzyme A acts as a necessary cofactor for many enzymes and is a part of many biochemical processes. One of the critical enzymes involved in Coenzyme A synthesis is Dephospho-coenzyme A-kinase (DPCK). In this study, we have used integrated computational and experimental approaches for promising inhibitors of DPCK using the natural products available in the ZINC database for anti-leishmanial drug development.

Krebs cycle enzymes for targeted therapeutics and immunotherapy for anti-leishmanial drug development using: Pathways, potential targets, and future perspectives.

Leishmaniasis is a parasitic and neglected tropical disease which majorly impacts poor and developing nations. One of the significant factors that impacts the severity of the pathological condition includes the socioeconomic background of the affected region. The rise of drug-resistant Leishmania is a serious concern for the effectiveness of the present treatment.

Gene Alterations Induced by Glutamine (Q) Encoding CAG Repeats Associated with Neurodegeneration.

Several studies have been reported linking the role of polyglutamine (polyQ) disease-associated proteins with altered gene regulation induced by an unstable trinucleotide (CAG) repeat. Owing to their dynamic nature of expansion, these DNA repeats form secondary structures interfering with the normal cellular mechanisms like replication and transcription and, thereby, have become the underlying cause of numerous neurodegenerative disorders involving mental retardation and/or muscular or neuronal degeneration. Despite the widespread expression of the disease-causing protein, specific subsets of neurons are susceptible to specific patterns of inheritance and clinical symptoms.

Perspectives on evolutionary and functional importance of intrinsically disordered proteins.

Structural biology of proteins emphasises that proteins ought to have an ordered structure to perform their biological role optimally. The over-reliance on the ordered structure of proteins is now slowly shifting towards a more comprehensive discussion platform. Intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) are gaining momentum in protein structural biology as we update ourselves with evolutionary traits and functional importance in various organisms.

Ligand conjugated lipid-based nanocarriers for cancer theranostics.

Cancer is one of the major health-related issues affecting the population worldwide and subsequently accounts for the second-largest death. Genetic and epigenetic modifications in oncogenes or tumor suppressor genes affect the regulatory systems that lead to the initiation and progression of cancer. Conventional methods, including chemotherapy/radiotherapy/appropriate combinational therapy and surgery, are being widely used for theranostics of cancer patients.

Targeting two potential sites of SARS-CoV-2 main protease through computational drug repurposing.

Before the rise of SARS-CoV-2, emergence of different coronaviruses such as SARS-CoV and MERS-CoV has been reported that indicates possibility of the future novel pathogen from the coronavirus family at a pandemic level. In this context, explicit studies on identifying inhibitors focused on the coronavirus life cycle, are immensely important. The main protease is critical for the life cycle of coronaviruses.

Beclin1-mediated interplay between autophagy and apoptosis: New understanding.

The definition for autophagy holds a 'single' meaning as a conserved cellular process that constitutes a recycling pathway for damaged organelles and long-lived proteins to maintain nutrient homeostasis and mediate quality control within the cell. But this process of autophagy may behave ambiguously depending on the physiological stress as the stress progresses in the cellular microenvironment; the 'single' meaning of the autophagy changes from the 'cytoplasmic turnover process' to 'tumor suppressive' and a farther extent, 'tumor promoter' process. In a tumorigenic state, the chemotherapy-mediated resistance and intolerance due to upregulated autophagy in cancer cells have become a significant concern.

Synthesis and characterization of zinc derivatized 3, 5-dihydroxy 4', 7-dimethoxyflavone and its anti leishmaniasis activity against Leishmania donovani.

This study reports the synthesis and characterization of zinc derivatized 3,5-dihydroxy 4', 7- dimethoxyflavone (DHDM-Zn) compound for the development of new antileishmanial agents. The interaction studies of DHDM with zinc were carried out by UV spectra and fluorescence spectra analysis. Characterization of the complex was further accomplished by multi-spectroscopic techniques such as FTIR, Raman, HRMS, NMR, FESEM-EDX.

Potential alternatives to current cholinesterase inhibitors: an drug repurposing approach.

Acetylcholinesterase/Butyrylcholinesterase inhibitors are considered an effective method for treating Alzheimer's disease (AD). In this current work, we have computationally analyzed 11 new small molecule drugs used in various neurological diseases and Donepezil, a known inhibitor of acetylcholinesterase, as a positive control. We investigated these drugs for possible fundamental interactions with acetylcholinesterase and butyrylcholinesterase as both are critical in the pathophysiology of Alzheimer's disease.

Identification of high affinity and low molecular alternatives of boceprevir against SARS-CoV-2 main protease: A virtual screening approach.

SARS-CoV-2 has posed global challenge for healthcare due to COVID-19. The main protease (M) of this virus is considered as a major target for drug development efforts. In this work, we have used virtual screening approach with molecular dynamics simulations to identify high affinity and low molecular weight alternatives of boceprevir, a repurposed drug currently being evaluated against M.

Microsecond MD Simulation and Multiple-Conformation Virtual Screening to Identify Potential Anti-COVID-19 Inhibitors Against SARS-CoV-2 Main Protease.

The recent pandemic outbreak of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), raised global health and economic concerns. Phylogenetically, SARS-CoV-2 is closely related to SARS-CoV, and both encode the enzyme main protease (M/3CL), which can be a potential target inhibiting viral replication. Through this work, we have compiled the structural aspects of M conformational changes, with molecular modeling and 1-μs MD simulations.

Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: an effort toward drug repurposing to combat COVID-19.

The importance of the main protease (M) enzyme of SARS-CoV-2 in the digestion of viral polyproteins introduces M as an attractive drug target for antiviral drug design. This study aims to carry out the molecular docking, molecular dynamics studies, and prediction of ADMET properties of selected potential antiviral molecules. The study provides an insight into biomolecular interactions to understand the inhibitory mechanism and the spatial orientation of the tested ligands and further, identification of key amino acid residues within the substrate-binding pocket that can be applied for structure-based drug design.