Biology subjects

Darbar, S.

Publications and source records attributed to Darbar, S..

6 recordsLinked to original sources

bioRxiv2021

Redox Buffering Capacity of Nanomaterials as an Index of ROS-based Therapeutics and Toxicity: A Preclinical Animal Study

Precise control of intracellular redox status, i.e., maintenance of physiological level of reactive oxygen species (ROS) for mediating normal cellular functions (oxidative eustress) while evading the excess ROS stress (distress) is central to the concept of redox medicine. In this regard, engineered nanoparticles with unique ROS generation, transition, or depletion functions have the potential to be the choice of redox therapeutics. However, it is always challenging to estimate whether ROS-induced intracellular events are beneficial or deleterious to the cell. Here, we propose the concept of redox buffering capacity as a therapeutic index of engineered nanomaterials. As a steady redox state is maintained for normal functioning cells, we hypothesize that the ability of a nanomaterial to preserve this homeostatic condition will dictate its therapeutic efficacy. Additionally, the redox buffering capacity is expected to provide information about the nanoparticle toxicity. Here, using citrate functionalized trimanganese tetroxide nanoparticles (C-Mn3O4 NPs) as a model nanosystem we explored its redox buffering capacity in erythrocytes. Furthermore, we went on to study the chronic toxic effect (if any) of this nanomaterial in animal model in order to co-relate with the experimentally estimated redox buffering capacity. This study could function as a framework for assessing the capability of a nanomaterial as redox medicine (whether maintains eustress or damages by creating distress), thus orienting its application and safety for clinical use.

pharmacology and toxicology↗

bioRxiv2021

Redox Nanomedicine Cures Chronic Kidney Disease (CKD) by Mitochondrial Reconditioning

Targeting reactive oxygen species (ROS) while maintaining cellular redox signaling is crucial in the development of redox medicine for the therapeutic benefit as the origin of several prevailing diseases including chronic kidney disease (CKD) is linked to ROS imbalance and associated mitochondrial dysfunction. Here, we have shown that an indigenously developed nanomedicine comprising of Mn3O4 nanoparticles duly functionalized by biocompatible ligand citrate (C-Mn3O4 NPs) can maintain cellular redox balance in an animal model. We developed a cisplatin-induced CKD model in C57BL/6j mice where severe mitochondrial dysfunction resulting in oxidative distress lead to the pathogenesis. Four weeks of treatment with C-Mn3O4 NPs restored renal function, preserved normal kidney architecture, ameliorated overexpression of pro-inflammatory cytokines, and arrested glomerulosclerosis and interstitial fibrosis in CKD mice. A detailed study involving human embryonic kidney (HEK 293) cells and isolated mitochondria from experimental animals revealed that the molecular mechanism behind the pharmacological action of the nanomedicine involves protection of structural and functional integrity of mitochondria from oxidative damage, the subsequent reduction in intracellular ROS, and maintenance of cellular redox homeostasis. To the best of our knowledge, such studies that efficiently treated a multifaceted disease like CKD using a biocompatible redox nanomedicine are sparse in the literature. Successful clinical translation of this nanomedicine may open a new avenue in redox-mediated therapeutics of several other diseases (e.g., diabetic nephropathy, neurodegeneration, and cardiovascular disease) where oxidative distress plays a central role in pathogenesis.

pharmacology and toxicology↗

bioRxiv2021

Development of Tribo-Electroceutical Fabrics for Potential Application in Self-sanitizing Personal Protective Equipment (PPE)

Attachment of microbial bodies including coronavirus on the surface of personal protective equipment (PPE) is found to be potential threat of spreading infection. Here, we report the development of a novel tribo-electroceutical fabric (TECF) consisting of commonly available materials namely Nylon, and Silicone Rubber (SR) for the fabrication of protective gloves on Nitrile platform, as a model wearable PPE. A small triboelectric device (2 cm x 2 cm) consisting of SR and Nylon on Nitrile can generate more than 20 volt transient or 41 {micro}W output power, which is capable of charging a capacitor up to 65 V in only [~]50 sec. The novelty of the present work relies on the TECF led anti-microbial activity through the generation of an electric current in saline water. The fabrication of TECF based functional prototype gloves can generate hypochlorite ions through the formation of electrolysed water upon rubbing them with saline water. Further a computational modelling has been employed to reveal the optimum structure and mechanistic pathway of anti-microbial hypochlorite generation. Detailed anti-microbial assays have been performed to establish effectiveness of such TECF based gloves to reduce the risk from life threatening pathogen spreading. The present work provides the rationale to consider the studied TECF, or other material with comparable properties, as material of choice for the development of self-sanitizing PPE in the fight against microbial infections including COVID-19.

microbiology↗

bioRxiv2021

Nanoceutical Fabric Prevents COVID-19 Spread through Expelled Respiratory Droplets: A Combined Computational, Spectroscopic and Anti-microbial Study

Centers for Disease Control and Prevention (CDC) warns the use of one-way valves or vents in free masks for potential threat of spreading COVID-19 through expelled respiratory droplets. Here, we have developed a nanoceutical cotton fabric duly sensitized with non-toxic zinc oxide nanomaterial for potential use as membrane filter in the one way valve for the ease of breathing without the threat of COVID-19 spreading. A detailed computational study revealed that zinc oxide nanoflowers (ZnO NF) with almost two-dimensional petals trap SARS-CoV-2 spike proteins, responsible to attach to ACE-2 receptors in human lung epithelial cells. The study also confirm significant denaturation of the spike proteins on the ZnO surface, revealing removal of virus upon efficient trapping. Following the computational study, we have synthesized ZnO NF on cotton matrix using hydrothermal assisted strategy. Electron microscopic, steady-state and picosecond resolved spectroscopic studies confirm attachment of ZnO NF to the cotton (i.e., cellulose) matrix at atomic level to develop the nanoceutical fabric. A detailed antimicrobial assay using Pseudomonas aeruginosa bacteria (model SARS-CoV-2 mimic) reveals excellent anti-microbial efficiency of the developed nanoceutical fabric. To our understanding the novel nanoceutical fabric used in one-way valve of a face mask would be the choice to assure breathing comfort along with source control of COVID-19 infection. The developed nanosensitized cloth can also be used as antibacterial/anti CoV-2 washable dress material in general. GRAPHICAL ABSTRACT O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY A novel nanoceutical cotton fabric duly sensitized with non-toxic zinc oxide nanoflower can potentially be used as membrane filter in the one way valve of face mask to assure breathing comfort along with source control of COVID-19 infection. The nanoceutical fabric denatures the SARS-CoV-2 spike protein and makes the microorganism ineffective.

microbiology↗

bioRxiv2021

A Nanoceutical Agent for Chemoprevention of Bilirubin Encephalopathy

BackgroundTargeted degradation of bilirubin in vivo may enable safer and more effective approach to manage incipient bilirubin encephalopathy consequent to severe neonatal hyperbilirubinemia (SNH). This report builds on the use of a spinel structured mixed-valence transition metal oxide (trimanganese tetroxide) nanoparticle duly functionalized with biocompatible ligand citrate (C-Mn3O4 NP) having the ability to degrade bilirubin without photo-activation. MethodThe efficiency of C-Mn3O4 NP in in vivo degradation of serum bilirubin and amelioration of severe bilirubin encephalopathy and associated neurobehavioral changes was evaluated in C57BL/6j animal model of SNH. ResultsOral single dose (0.25 mg kg-1 body weight) of the NPs efficiently reduced serum bilirubin levels (both conjugated and unconjugated) in study mice. It prevents bilirubin-induced neurotoxicity with reduction of SNH as observed by neurobehavioral and movement studies of SNH-mice. Pharmacokinetic data suggests intestinal reabsorption of the NPs and explain sustainable action. Biodistribution, pharmacokinetics, and biocompatibility of the NPs were tested during sub-chronic exposure. ConclusionThus, we report preliminary studies that explore an affordable chemoprevention mechanism to acutely prevent or minimize bilirubin neurotoxicity in newborn infants. IMPACT STATEMENTO_LIDespite several attempts, no pharmaco-therapeutics are available for the treatment of severe neonatal hyperbilirubinemia (SNH) and associated neurotoxicity. C_LIO_LIOur newly developed nanodrug, citrate functionalized Mn3O4 nanoparticles (C-Mn3O4 NPs), can efficiently ameliorate SNH and associated neurotoxicity as investigated in preclinical rodent model. C_LIO_LIChemoprevention effect of the nanodrug is found to be safe and sustainable. C_LIO_LIIf successfully translated into clinical trials, C-Mn3O4 NPs could become the first drug to treat SNH. C_LI

pharmacology and toxicology↗

bioRxiv2020

Incorporation of a Biocompatible Nanozyme in Cellular Antioxidant Enzyme Cascade Reverses Huntington's Like Disorder in Preclinical Model

The potentiality of nano-enzymes in therapeutic use has directed contemporary research to develop a substitute for natural enzymes, which are suffering from several disadvantages including low stability, high cost, and difficulty in storage. However, inherent toxicity, inefficiency in the physiological milieu, and incompatibility to function in cellular enzyme networks limit the therapeutic use of nanozymes in living systems. Here, we have shown that citrate functionalized manganese-based biocompatible nanoscale material (C-Mn3O4 NP) efficiently mimics glutathione peroxidase enzyme in the physiological milieu and easily incorporates into the cellular multienzyme cascade for H2O2 scavenging. A detailed computational study reveals the mechanism of the nanozyme action. We further established the in vivo therapeutic efficacy of C-Mn3O4 nanozyme in a preclinical animal model of Huntingtons disease, a prevalent progressive neurodegenerative disorder, which has no effective medication till date. SUMMARYAlthough, nano-enzymes have shown lots of promises in the management of several diseases, two major concerns limit their clinical translation. Apart from the inherent toxicity of the constituent materials (e.g., cerium, vanadium, gold, etc.), activities of contemporary nanozymes are often inhibited in physiological milieu. Furthermore, most of them are incapable of incorporation into the cellular metabolic networks for functioning in tandem and parallel with natural enzymes, a major criteria for potential therapeutics. Here, we have shown that citrate-functionalized spherical Mn3O4 nanoparticles can efficiently mimic glutathione peroxidase (GPX) enzyme without the limitations of contemporary nanozymes, and effectively manage neurodegenerative Huntingtons disease in preclinical animal model. The choice of the material in the nanozyme lies on the fact that Mn is an essential micronutrient for mammals, and the stabilizing ligand citrate helps the nanoparticles to cross the blood-brain-barrier to reach brain. We have shown that the nanozyme can easily be incorporated in cellular antioxidant enzyme cascade. The specificity and efficacy of the nanozyme in the cascade was significantly higher compared to other reported nanozymes. We have justified our experimental findings with a detailed computational study. Understanding the mode of operation and management of Huntingtons disease in preclinical animal trial using a biocompatible (non-toxic) nanozyme as a part of the metabolic network may uncover a new paradigm in nanozyme based therapeutic strategy.

pharmacology and toxicology↗