Life Sciences

<p>Shiv Nadar University is a comprehensive, multidisciplinary, research-focused, and student-centric University offering a full range of academic programs at the undergraduate, postgraduate and doctoral level. With state-of-the-art infrastructure, the University comprises of academic wings, sophisticated labs, international standard sports facilities, amphitheaters, auditorium, conference rooms and smart classrooms. The University&rsquo;s goal is to become internationally recognized for the quality of its research and creative endeavors and their applicability to improving quality of life, generating new insights and expanding the boundaries of human knowledge creativity. Committed to excellence in teaching, research and service, the University aims to serve the higher education needs of India and the world beyond.</p>

Shiv Nadar University

<p>Resistance to antimicrobial agents in Gram-positive bacteria has become a major concern in the last decade. Recently, nanoparticles (NP) have emerged as a potential solution to antibiotic resistance. We synthesized three reduced graphene oxide (rGO) nanoparticles, namely rGO, rGO-S, and rGO-S/Se, and characterized them using X-ray diffraction (PXRD), Raman analysis, and thermo-gravimetric analysis. Transmission electron microscopy confirmed spherical shape nanometer size S and S/Se NPs on the rGO surface. Antibacterial properties of all three nanomaterials were probed against Gram-positive pathogens Staphylococcus aureus and Enterococcus faecalis, using turbidometeric and CFU assays. Among the synthesized nanomaterials, rGO-S/Se exhibited relatively strong an-tibacterial activity against both Gram-positive microorganism tested in a concentration dependent manner (growth inhibition &gt;90% at 200 µg/mL). Atomic force microscopy of rGO-S/Se treated cells displayed morphological aberrations. Our studies also revealed that rGO composite NPs are able to deposit on the bacterial cell surface, resulting in membrane perturbation and oxidative stress. Taken together, our results suggest a possible three-pronged approach of bacterial cytotoxicity by these graphene-based materials. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.</p>

World University root node

Chemistry

(SoNS) School of Natural Sciences

Fulltext

Nanomaterials

Synthesis and Characterization of Sulfur and Sulfur-Selenium Nanoparticles Loaded on Reduced Graphene Oxide and Their Antibacterial Activity against Gram-Positive Pathogens

Owing to the inherent complications in membrane distillation (MD) operations, it has become a challenge to acknowledge swiftly and appropriately to safeguard the quality of effluent, particularly when the processing cost is a prominent concern. Membrane wetting in MD operations is a major concern during long-term performance. In this study, machine learning (ML) methodologies were utilized to overcome the limitations of conventional mechanistic modeling. ML applications have never been explored to investigate how operational factors, such as water flux and salt flux, are affected during long-term MD performance. Furthermore, time-dependent factors were neglected, making it difficult to analyze the relationship between effluent quality and operational factors. Therefore, this study demonstrates a novel ML-based framework designed to enhance the performance of MD. The ML-based framework consists of an autoregressive integrated moving average (ARIMA) and utilizes a unique pathway to explain the impact of time series among operational factors. The accuracy of forecasting has been explored by utilizing 180 h (180 datasets), that was further used and divided into training (165 datasets) and test datasets (15 datasets). Eventually, the ARIMA model demonstrated a highly precise relationship order between the model and experimental data, which can be further used to forecast membrane performance in terms of wetting and fouling. The selected ARIMA model (3,2,1) appears to be an adequate model for water and salt flux data which has been effectively used to capture the course of permeate water and salt flux by producing the smallest forecast RMSE. The RMSE values were observed to be 0.22 and 0.05 for water and salt flux respectively, which can better predict long time series with high frequency. These frameworks can be applied for the early prediction of membrane wetting if ample high-resolution data are available. © 2022 The Institution of Chemical Engineers

Process Safety and Environmental Protection

Exploration of time series model for predictive evaluation of long-term performance of membrane distillation desalination

Constant emergence of drug-resistant Plasmodium falciparum warrants urgent need for effective and inexpensive drugs. Herein, phthalimide (Pht) analogs possessing the bioactive scaffolds, benzimidazole and 1,2,3-triazole, were evaluated for in vitro and in vivo anti-plasmodial activity without any apparent hemolysis, or cytotoxicity. Analogs 4(a-e) inhibited the growth of 3D7 and RKL-9 strains at submicromolar concentrations. Defects were observed during parasite egress from or invasion of the red blood cells. Mitochondrial membrane depolarization was measured as one of the causes of cell death. Phts 4(a-e) in combination with artemisinin exhibited two-to three-fold increased efficacy. Biophysical and biochemical analysis suggest that Pht analogs mediate plasmodial growth inhibition by interacting with tubulin protein of the parasite. Lastly, Phts 4(a-e) significantly decreased parasitemia and extended host survival in murine model Plasmodium berghei ANKA infection. Combined, the data indicate that Pht analogs should be further explored, which could offer novel value to the antimalarial drug development pipeline. © 2022

European Journal of Medicinal Chemistry

Designing and development of phthalimides as potent anti-tubulin hybrid molecules against malaria

Ornamental aquaculture is an economically important industry with many enthusiasts worldwide. Much of the supply for the industry is provided by individuals and businesses in tropical countries because many ornamental species originated in the tropics. But Czechia, a temperate region in Central Europe, is an exception. Czech suppliers have significantly influenced the global freshwater ornamental aquaculture market for decades. Here we present and discuss the history of ornamental aquaculture in Czechia considering its geopolitical background, social status and history, pet-trade trends, overlapping to research activities, public education, and related risks and threads. We list the most traded and exported species, and list species that rarely reproduce in captivity, but that are successfully bred for commercial purposes by Czech producers globally, we introduce the term “Czech aquarium phenomenon” to describe the substantial economic and scientific importance of Czechia in ornamental aquaculture. Given that the diversity and volume of species traded are vast, we suggest the importance of this phenomenon for consideration to key stakeholders who design aquaculture policies, including the management of invasive alien species and ex-situ conservation programs for endangered species. © 2022

Aquaculture

Ornamental aquaculture significantly affected by the “Czech aquarium phenomenon”

The increased resistance of human malaria parasite Plasmodium falciparum (Pf) to currently used drugs necessities the development of novel anti-malarials. Here, we examine the potential of erythritol, a sugar substitute for therapeutic intervention. Erythritol is a permeant of Plasmodium falciparum aquaglyceroporin (PfAQP) which is a multifunctional channel responsible for maintaining hydro-homeostasis. We show that erythritol effectively inhibited growth and progression of asexual blood stage malaria parasite, and effect invasion and egress processes. It also inhibited the liver stage (sporozoites) and transmission stage parasite (gametocytes) development. Interestingly, erythritol inhibited in vivo growth of malaria parasite in mouse experimental model. It was more effective in inhibiting parasite growth both in vivo and in vitro when tested together with a known anti-malarial ‘artesunate’. Additionally, erythritol showed cytokine-modulating effect which suggests its direct effect on the host immune system. Ammonia detection assay demonstrated that erythritol uptake effects the amount of ammonia release across the parasite. Our functional complementation assays suggest that PfAQP expression in yeast mutant restores its growth in hyperosmotic conditions but showed reduced growth in the presence of erythritol. Osmotic lysis assay suggests that erythritol creates osmotic stress for killing the parasite. Overall, our data bestow erythritol as a promising lead compound with an attractive antimalarial profile and could possibly be combined with known drugs without losing its efficacy. We propose the use of erythritol based sweet candies for protection against malaria specially in children living in the endemic area. © 2022 Elsevier Inc.

Biochemical Pharmacology

‘Erythritol’, a safe natural sweetener exhibits multi-stage anti-malarial activity by permeating into Plasmodium falciparum through aquaglyceroporin channel

The artemisinin resistance has posed a serious threat against malaria elimination lately. Past few years have seen important development of several peroxide based medicinal compounds and their derivatives such as trioxanes and tetraoxanes. Here, we report a rapid, one-pot method for synthesizing a new series of N-sulfonylpiperidine dispiro-1,2,4,5-tetraoxane analogs with diverse substitution on the tetraoxane ring i.e., various substituted alkyl and aryl sulfonyl chlorides, as well as cyclic, acyclic and aryl substituted ketones. All the synthesized tetraoxanes were characterized by spectroscopic (1H NMR,13C NMR), and spectrometric (High-resolution mass spectrometry) techniques and quantify by High Performance Liquid Chromatography (HPLC) analysis. The structure of compound 19 was confirmed by single crystal XRD. From the overall preliminary in vitro data, analogs 14, 16, 19, 20, 24, 41, and 44 exhibited potential IC50 values in the nanomolar range between 4.7 ± 0.3 to 12.9 ± 1.1 nM against P. falciparum (Pf3D7) strains of human malaria parasite. Furthermore, these selective analogs were evaluated in vivo for their antimalarial potential against P. berghei and results revealed that analogue 24 rapidly kills the infected cell at asexual erythrocytic stage, with activity comparable to positive control chloroquine. © 2022 Elsevier Masson SAS

N-sulfonylpiperidinedispiro-1,2,4,5-tetraoxanes exhibit potent in vitro antiplasmodial activity and in vivo efficacy in mice infected with P. berghei ANKA

Gallbladder cancer (GBC) is an aggressive and difficult to treat biliary tract carcinoma with a poor survival rate. The aim of this study was to design a peptide-based multi-epitope vaccine construct against GBC using immunoinformatics approaches. Three proteins implicated in the progression of GBC were selected for B and T cell epitope prediction and the designing of the potential vaccine construct. Seven CTL, four HTL and six Bcell epitopes along with a suitable adjuvant were selected and connected using linkers for designing the vaccine construct. The secondary and tertiary models of the designed vaccine were generated and satisfactorily validated. A Ramachandran plot of the final 3D model showed more than 90% of the residues in allowed regions and only 0.4% in disallowed regions. The binding affinity of a vaccine construct with TLR 2, 3 and 4 receptors was assessed through molecular docking and simulation. The average numbers of hydrogen bonds for vaccine-TLR 2, 3 and 4 complexes in the simulation were 15.36, 16.45, and 11.98, respectively, and remained consistent over a 100 ns simulation period, which is critical for their function. The results of this study provide a strong basis for further evaluation through in vitro/in vivo experimental validation of the safety and efficacy of the designed vaccine construct. © 2022 by the authors.

Vaccines

Designing of Peptide Based Multi-Epitope Vaccine Construct against Gallbladder Cancer Using Immunoinformatics and Computational Approaches

The development and growth of a normal prostate gland, as well as its physiological functions, are regulated by the actions of androgens through androgen receptor (AR) signaling which drives multiple cellular processes including transcription, cellular proliferation, and apoptosis in prostate cells. Post-translational regulation of AR plays a vital role in directing its cellular activities via modulating its stability, nuclear localization, and transcriptional activity. Among various post-translational modifications (PTMs), acetylation is an essential PTM recognized in AR and is governed by the regulated actions of acetyltransferases and deacetyltransferases. Acetylation of AR has been identified as a critical step for its activation and depending on the site of acetylation, the intracellular dynamics and activity of the AR can be modulated. Various acetyltransferases such as CBP, p300, PCAF, TIP60, and ARD1 that are known to acetylate AR, may directly coactivate the AR transcriptional function or help to recruit additional coactivators to functionally regulate the transcriptional activity of the AR. Aberrant expression of acetyltransferases and their deregulated activities have been found to interfere with AR signaling and play a key role in development and progression of prostatic diseases, including prostate cancer (PCa). In this review, we summarized recent research advances aimed at understanding the role of various lysine acetyltransferases (KATs) in the regulation of AR activity at the level of post-translational modifications in normal prostate physiology, as well as in development and progression of PCa. Considering the critical importance of KATs in modulating AR activity in physiological and patho-physiological context, we further discussed the potential of targeting these enzymes as a therapeutic option to treat AR-related pathology in combination with hormonal therapy. Copyright © 2022 Jaiswal, Agarwal and Gupta.

Frontiers in Endocrinology

Lysine Acetyltransferases and Their Role in AR Signaling and Prostate Cancer

Phosphorylation and other post-translational modifications of red blood cell (RBC) proteins govern membrane function and have a role in the invasion of RBCs by the malaria parasite, Plasmodium falciparum. Furthermore, a percentage of RBC proteins are palmitoylated, although the functional consequences are unknown. We establish dynamic palmitoylation of 118 RBC membrane proteins using click chemistry and acyl biotin exchange (ABE)-coupled LC-MS/MS and characterize their involvement in controlling membrane organization and parasite invasion. RBCs were treated with a generic palmitoylation inhibitor, 2-bromopalmitate (2-BMP), and then analyzed using ABE-coupled LC-MS/MS. Only 42 of the 118 palmitoylated proteins detected were palmitoylated in the 2-BMP-treated sample, indicating that palmitoylation is dynamically regulated. Interestingly, membrane receptors such as semaphorin 7A, CR1, and ABCB6, which are known to be involved in merozoite interaction with RBCs and parasite invasion, were found to be dynamically palmitoylated, including the blood group antigen, Kell, whose antigenic abundance was significantly reduced following 2-BMP treatment. To investigate the involvement of Kell in merozoite invasion of RBCs, a specific antibody to its extracellular domain was used. The antibody targeting Kell inhibited merozoite invasion of RBCs by 50%, implying a role of Kell, a dynamically palmitoylated potent host-derived receptor, in parasite invasion. Furthermore, a significant reduction in merozoite contact with the RBC membrane and a consequent decrease in parasite invasion following 2-BMP treatment demonstrated that palmitoylation does indeed regulate RBC susceptibility to parasite invasion. Taken together, our findings revealed the dynamic palmitoylome of RBC membrane proteins and its role in P. falciparum invasion. © 2022 American Chemical Society.

ACS Infectious Diseases

Dynamic Palmitoylation of Red Cell Membrane Proteins Governs Susceptibility to Invasion by the Malaria Parasite, Plasmodium falciparum

Visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL) affect most of the poor populations worldwide. The current treatment modalities include liposomal formulation or deoxycholate salt of amphotericin B, which has been associated with various complications and severe side effects. Encouraged from the recent marked antimalarial effects from plant-derived glycosides, in this study, we have exploited a green chemistry-based approach to chemically synthesize a library of diverse glycoside derivatives (Gly1–12) and evaluated their inhibitory efficacy against the AG83 strain of Leishmania donovani. Among the synthesized glycosides, the in vitro inhibitory activity of Glycoside-2 (Gly2) (1.13 µM IC50 value) on L. donovani promastigote demonstrated maximum cytotoxicity with ~94% promastigote death as compared to amphotericin B that was taken as a positive control. The antiproliferative effect of Gly2 on promastigote encouraged us to analyze the structure–activity relationship of Gly2 with Gp63, a zinc metalloprotease that majorly localizes at the surface of the promastigote and has a role in its development and multiplication. The result demonstrated the exceptional binding affinity of Gly2 toward the catalytic domain of Gp63. These data were thereafter validated through cellular thermal shift assay in a physiologically relevant cellular environment. Mechanistically, reduced multiplication of promastigotes on treatment with Gly2 induces the destabilization of redox homeostasis in promastigotes by enhancing reactive oxygen species (ROS), coupled with depolarization of the mitochondrial membrane. Additionally, Gly2 displayed strong lethal effects on infectivity and multiplication of amastigote inside the macrophage in the amastigote–macrophage infection model in vitro as compared to amphotericin B treatment. Gp63 is also known to bestow protection against complement-mediated lysis of parasites. Interestingly, Gly2 treatment enhances the complement-mediated lysis of L. donovani promastigotes in serum physiological conditions. In addition, Gly2 was found to be equally effective against the clinical promastigote forms of PKDL strain (IC50 value of 1.97 µM); hence, it could target both VL and PKDL simultaneously. Taken together, this study reports the serendipitous discovery of Gly2 with potent antileishmanial activity and proves to be a novel chemotherapeutic prototype against VL and PKDL. Copyright © 2022 Chakrabarti, Narayana, Joshi, Garg, Garg, Ranganathan, Sagar, Pati and Singh.