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Visceral Leishmaniasis or Kala-Azar is one of the most severe and deadly neglected tropical disease caused by the Leishmania parasite. A few number of vaccines are going through different phases in clinical trial but failing of these vaccines in successive phase trial or less efficacy, urge to develop highly immunogenic and cost-effective treatment to get rid of deadly VL. This study focuses on the development of more potent vaccine candidate against VL. The recombinant vaccine candidate LeiSp was expressed in Pichia pastoris, followed by purification and characterization. The purified protein was also tested for any post-translation modification, which favors being a potent immunogenic candidate. Further, the expression modulation of different pro-inflammatory and anti-inflammatory cytokines was evaluated in THP1 cell lines. A significant upregulation in the expression of pro-inflammatory cytokines while no significant changes were observed in the expression of anti-inflammatory cytokines. The impact of recombinant vaccine protein candidates in infected conditions were determined. Here, upon treatment with chimeric vaccine protein candidate, we observed a considerable recovery in the expression level of pro-inflammatory cytokines, which were downregulated upon infection alone. In addition to this, we found a significant decrease in the expression of anti-inflammatory cytokines, which were upregulated during infection alone. We further validated our findings in infected hPBMCs and observed similar expression modulation of pro-inflammatory and anti-inflammatory cytokines with and without treatment. Thus, the present study indicates that the chimeric LeiSp protein which was designed using bioinformatics approaches shows a potential inductive efficacy for pro-inflammatory cytokines in Leishmania-infected cells., Competing Interests: Declaration of competing interest The authors have declared no competing interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Malaria deaths occur primarily due to complicated malaria associated with the sequestration of Plasmodium falciparum-infected erythrocyte (PfIE) in the capillary microvasculature. This study aims to design peptide ligand conjugates (PLCs) for treating complicated malaria using various in silico techniques. The PLC includes a natural ligand for the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1): expressed explicitly on the surface of PfIE, and a highly immunogenic peptide derived from the commonly used peptide vaccines in malaria-endemic countries. The ligand is predicted to prevent the sequestration of PfIE, and the peptide is predicted to eliminate PfIE from circulation by the pre-existing vaccine-induced immunity., Main Methods: The epitope identification from the vaccines and the analysis of physicochemical properties, antigenicity, allergenicity, and toxicity were performed using SVMTriP, ProtParam, VaxiJen, AllerTop, and ToxinPred servers, respectively. The high throughput virtual screening (HTVS) and drug-like properties analysis of natural compound ligands were carried out by Schrodinger-2021 software. The molecular dynamics simulations were performed through the WebGro server., Key Findings: HTVS revealed three bioactive natural ligands for PfEMP1 from (NPASS) database. Three super immunogenic peptides were identified from malaria-endemic countries' commonly used peptide vaccines. Finally, Nine PLCs were designed with different combinations of peptides and ligands with the suitable non-cleavable triazole linker., Significance: Antimalarials have been losing efficacy in a time when malaria deaths in 2020 significantly increased than in 2019. In this scenario, further research on the designed PLCs may offer some innovative immune therapeutics for complicated malaria with minimum possibilities of drug resistance., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Oxidation of the anti-tumour agent [Pt{(p-BrC 6 F 4 )NCH 2 CH 2 NEt 2 }Cl(py)], 1 (py = pyridine) with hydrogen peroxide under a variety of conditions yields a range of organoenamineamidoplatinum(II) compounds [Pt{(p-BrC 6 F 4 )NCH=C(X)NEt 2 }Cl(py)] (X = H, Cl, Br) as well as species with shared occupancy involving H, Cl and Br. Thus, oxidation of the -CH 2 -CH 2 - backbone (dehydrogenation) occurs, often accompanied by substitution. Oxidation of 1 with H 2 O 2 in acetone yielded 1:1 co-crystallized [Pt{(p-BrC 6 F 4 )NCH=CHNEt 2 }Cl(py)], 1H and [Pt{(p-BrC 6 F 4 )NCH=C(Cl)NEt 2 }Cl(py)], 1Cl. The former was obtained pure in low yield from the oxidation of 1 with (NH 4 ) 2 [Ce(NO 3 ) 6 ] in acetone, and the latter was obtained from 1 and H 2 O 2 in CH 2 Cl 2 at near reflux. From the latter reaction under vigorous refluxing [Pt{(p-BrC 6 F 4 )NCH=C(Br)NEt 2 }Cl(py)], 1Br was isolated. In refluxing acetonitrile, oxidation of 1 with H 2 O 2 yielded [Pt{(p-BrC 6 F 4 )NCH=C(H 0 . 25 Br 0.75 )NEt 2 }Cl(py)], 1H 0.25 Br 0.75 , in which the alkene is mainly substituted by Br in a dual occupancy. Treatment of 1 with H 2 O 2 and tetrabutylammonium hydroxide in acetone at room temperature formed [Pt{(p-HC 6 F 4 )NCH 2 CH 2 NEt 2 }Cl(py)], 2. Oxidation of [Pt{(p-HC 6 F 4 )NCH 2 CH 2 NEt 2 }Br(py)], 3 with H 2 O 2 in boiling acetonitrile gave the ligand oxidation product [Pt{(p-HC 6 F 4 )NCH=C(Br)NEt 2 }Br(py)], 3Br. All major products were identified by X-ray crystallography as well as by 1 H and 19 F NMR spectra. In cases of mixed crystals or dual occupancy compounds, the 19 F and 1 H NMR spectra showed dissociation into the components in the solution in the same proportions as in isolated crystalline material., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The present-day world is severely suffering from the recently emerged SARS-CoV-2. The lack of prescribed drugs for the deadly virus has stressed the likely need to identify novel inhibitors to alleviate and stop the pandemic. In the present high throughput virtual screening study, we used in silico techniques like receptor-ligand docking, Molecular dynamic (MD), and ADME properties to screen natural compounds. It has been documented that many natural compounds display antiviral activities, including anti-SARS-CoV effect. The present study deals with compounds of Natural Product Activity and Species Source (NPASS) database with known biological activity that probably impedes the activity of six essential enzymes of the virus. Promising drug-like compounds were identified, demonstrating better docking score and binding energy for each druggable targets. After an extensive screening analysis, three novel multi-target natural compounds were predicted to subdue the activity of three/more major drug targets simultaneously. Concerning the utility of natural compounds in the formulation of many therapies, we propose these compounds as excellent lead candidates for the development of therapeutic drugs against SARS-CoV-2., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Visceral leishmaniasis (VL) has been declared as one of the most severely neglected tropical diseases by the World Health Organization report 2017. Cumulative incidences of treatment failure and drug resistance, demanding a potential treatment and preventive strategy for VL. In this study, we have devised a multi-epitope vaccine by targeting sandfly saliva and parasite-derived membrane and secretory antigens. We have predicted the immunogenic B-cell, HTL, and CTL epitopes from all the selected protein sequences. The epitopes were then linked to the spacer sequences for providing stability and flexibility, and the construct was linked with a synthetic TLR-4 agonist namely RS09 as an adjuvant. The 3D structure of vaccine was modelled, refined and validated by generating a Ramachandran plot. Later, molecular docking was performed between the TLR-4 receptor and vaccine. The obtained docked complex was then checked for their stability by performing MD simulation. The immune dynamics simulation was done to check the probable immune response generated when the host will be exposed to the vaccine candidate. This novel vaccine strategy will provide functional and mechanistic evidence on parasite and vector-derived epitopes that could activate B- and T-cells and potentially elicit a long-lasting memory cell response., Competing Interests: Declaration of competing interest The authors have declared no competing interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Indoline framework is often perpended as a privileged heterocycle present in medicinally valuable compounds of natural and synthetic origin. This review article presents the rational approaches/strategies employed for the design of anticancer indolines along with the structure activity relationship and mechanistic insights revealed in the in-vitro and in-vivo assays. The chemist has always been fascinated towards the indoline ring for the construction of antitumor scaffolds owing to its versatility as evidenced by its existence in scaffolds inducing antiproliferative effects via diverse mechanisms. To the delight of medicinal chemist, the applicability of indoline has also been expanded towards the design of dual inhibitors (multitargeting anticancer agents) as well as PROTACS. Overall, it can be concluded that indoline moiety is a magic bullet and the scaffolds containing this ring are foraying towards detailed preclinical and clinical stage investigations by leaps and bounds., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: In a developing country like India with intermediate level of prevalence of hepatitis B, most of the patients remain undiagnosed as they are asymptomatic. The purpose of the study was to diagnose asymptomatic HBsAg positive patients from the general population and evaluate further the potential clinical implications of IDAHS., Methods: Asymptomatic subjects with unknown HBV status were screened free of cost for hepatitis-B surface antigen. Those who tested positive for HBsAg were further tested to identify those who were potential candidates for anti-viral therapy. To explore the relevance of our screening we assessed potential implications of HBsAg detection., Results: A total of 30,836 patients were screened in medical camps over the period of 7 years. Out of these 704 (2.3%) subjects were found to be positive for HBsAg. Distress of being diagnosed with HBV was expressed by 649 (92%) of the positive subjects. High cost of further testing and antiviral therapy, leading to inability to pursue further management was elicited in 510 (72%) of the positive subjects. HBV DNA was detected in 349 (59%) out of 592 subjects, out of which 236 (67%) had high viral load., Conclusion: Incidental detection of asymptomatic HBsAg positive subjects was seen in 2.3% of subjects. One third of these patients had an actively replicating virus and required antiviral therapy. Financial support was required in 72% of the subjects for further HBV management. Detecting HBsAg in asymptomatic person in an endemic community has considerable health and psycho-economic impact on the individual.

The southern house vector, Culex quinquefasciatus is the paramount cause of Japanese encephalitis, West Nile fever and Lymphatic Filariasis, which is globally affecting the worldwide population. Many attempts were made by researchers with different perceptions to discover regimen against these aforementioned ailments but the output was not that effectual. Consequently, there is an imminent need to develop very effective and potential treatment against these perilous diseases. Employing immunoinformatic approaches, we have designed the multi-epitope subunit vaccine by exploring salivary proteins of Culex quinquefasciatus, which possess both antigenic and potent immunogenic behaviour. The immunogenic epitopes from the immune cells (B-cell, CTL, and HTL) were predicted and linked together with the help of linkers. Apart from this, at the N-terminal of the construct, an adjuvant was added in order to enhance the immunogenicity of the vaccine. The physiological parameters, antigenicity and allergenicity were also evaluated for the designed vaccine construct. Molecular docking between ligand (vaccine construct) and TLR-4 receptor was performed. Molecular dynamics simulation of the docked complex was performed to identify the stability, patterns, macromolecules interactions and their behaviour. Finally, to ensure the translation and gene expression efficiency of designed construct, insilico restriction cloning was executed into suitable expression vector pET28a., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Tuberculosis is a menacing disease caused eminently to the people inhabiting the tropical and sub-tropical nations. A holistic approach is required to generate T and B memory cells to effectuate a long-term exemption from the pulmonary tuberculosis. In this study, immunoinformatic approaches were used to design a multi-epitope-based subunit vaccine for pulmonary tuberculosis which may improve human immune system. The various B-cell, T H cell and T C cell binding epitopes were predicted for selected 2 membrane and 12 secretory proteins of Mycobacterium tuberculosis. The final vaccine construct was assembled by merging the predicted epitope sequences and an adjuvant at the N-terminal of the construct. Furthermore, the physiochemical characterization was done to check the molecular weight, aliphatic index, theoretical PI, hydropathicity and thermostable nature of the designed vaccine. The construct was a potential antigen while wasn't allergenic in nature. Tertiary modeling was performed, by filtering them a refined model was chosen and was docked with TLR-4 (immune receptor). Molecular docking and dynamic simulation was performed and the microscopic interaction between the vaccine construct (ligand) and TLR-4 receptor complex was verified. In silico cloning was used to fortify the expression and translation efficiency of the vaccine within an expression vector., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cancer cells are exposed to various intrinsic and extrinsic factors that disrupt protein homeostasis, producing endoplasmic reticulum (ER) stress. To cope with these situations, cancer cells evoke a highly conserved adaptive mechanism called the unfolded protein response (UPR) to restore the ER homeostasis. Recently, several pharmacological agents have been found to exhibit anti-tumor activity by targeting the UPR components. The development of potent and specific compounds that target the UPR components has not only shed light on the regulation of the UPR in cancer cells, but also brought the field closer to clinical drug candidates. Here we present an overview of the milestones in the field of UPR biology in cancer with a focus on new strategies for pharmacological inhibition., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The bulk oxidative electrolysis of a 2mM solution of trans-[Pt II {(p-HC 6 F 4 )NCH 2 CH 2 NEt 2 }Cl(py)] in highly non-coordinating dichloromethane (0.05M [Bu 4 N][B(C 6 F 5 )]) media leads to the formation of about 14% of the Pt III species trans-[Pt III {(p-HC 6 F 4 )NCH 2 CH 2 NEt 2 }Cl(py)] + . The EPR spectrum of this electro-synthesized formally Pt III species shows Pt-hyperfine coupling with g x ~g y >g z ~g e , and is broadly consistent with the simple crystal field theory prediction for 5d 7 Pt III in an elongated tetragonal environment where the unpaired electron is in a 5d(z 2 ) orbital. The crystal field calculations lead to an estimate of the 5d(z 2 ) character of around 37% and indicate partial delocalization of the unpaired electron onto the orbitals of the surrounding ligands. Transient cyclic voltammetric and steady-state microelectrode studies in the same media as used for bulk electrolysis exhibit a chemically reversible one electron oxidation process under their shorter time scale conditions. Analysis of X-ray diffraction data obtained from a single crystal of trans-[Pt II {(p-HC 6 F 4 )NCH 2 CH 2 NEt 2 }Cl(py)] shows the square planar geometry of the ligands around the Pt metal center and the 'W' arrangement of the ethyl groups on the ligand is explained in terms of agostic interactions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Magnetic resonance spectroscopy (MRS) is an established tool for in-vivo evaluation of the biochemical basis of human diseases. On one hand, such lucid depiction of 'live biochemistry' helps one to decipher the true nature of the pathology while on the other hand one can track the response to therapy at sub-cellular level. Brain tumors have been an area of continuous interrogation and instigation for mankind. Evaluation of these lesions by MRS plays a crucial role in the two aspects of disease management described above., Scope of Review: Presented is an overview of the window provided by MRS into the biochemical aspects of brain tumors. We systematically visit each metabolite deciphered by MRS and discuss the role of deconvoluting the biochemical aspects of pathologies (here in context of brain tumors) in the disease management cycle. We further try to unify a radiologist's perspective of disease with that of a biochemist to prove the point that preclinical work is the mother of the treatment we provide at bedside as clinicians. Furthermore, an integrated approach by various scientific experts help resolve a query encountered in everyday practice., Major Conclusions: MR spectroscopy is an integral tool for evaluation and systematic follow-up of brain tumors. A deeper understanding of this technology by a biochemist would help in a swift and more logical development of the technique while a close collaboration with radiologist would enable definitive application of the same., General Significance: The review aims at inciting closer ties between the two specialists enabling a deeper understanding of this valuable technology.

The 2-azaadenine antibiotic is known to be a potent cytotoxic nucleoside analog. Evaluation of the interaction energy of this molecule with nucleic acid bases and base pairs has been performed using a quantum-mechanical perturbation technique. Both in-plane and stacking energies have been computed. These energy values along with their sites of association have been compared with the standard energy values and spatial positions for the nucleic acid bases during transcription. The results have been examined in the light of their biological significance.

The incorporation model of Sanyal et al. has been used to understand the biological activity of the cytostatic compound 3-deazauridine. The interaction energies of various types of binding pattern of the enterant molecule with nucleic acid fragments have been computed. The energy values and the sites of association of the analogous base, obtained by optimization of energy values as well as the sites of association of nucleic acid bases during the transcription process have been compared. The specificity of the binding of the interacting molecule has been discussed, along with the inhibitory effect of 3-deazauridine. They are in agreement with the experimentally observed evidence.

A molecular model for the role of nucleoside or nucleotide analogs in drug action has been developed. This model, an extension of our earlier model has been employed to examine the possibility of incorporation of the formycin class of antibiotics (formycin, formycin B and oxoformycin B) in the growing RNA chain. Interaction energy of the analogous bases has been computed for the entire available space inside the deep groove of the DNA double helix. The values of the interaction energy thus computed along with the location of the sites of possible association are compared with the recommended configuration for RNA during transcription. It has been found that only formycin which structurally and energy-wise fulfils the requirement of the model, can successfully replace adenosine during transcription. Results are in agreement with experimental findings.

The possible incorporation of 8-azaguanine during transcription has been examined in the light of the model of transcription developed earlier by Sanyal et al. Electrostatic energy of interaction has been calculated for the nucleoside analogue (8-azaguanine) base for the entire space inside the deep groove of the DNA double helix. The interaction energy values and the location of the possible sites of association are compared with the recommended configurations of RNA transcription. It is concluded that 8-azaguanine is capable of replacing guanine during transcription. These conclusions are in general agreement with the experimental results.