Browsing by Author "Rai, Geeta"
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Publication A novel formulation with potential for improving osteoarthritis mediated through COX2 and MMP9 receptors(Inderscience Publishers, 2021) Jain, Mohit M.; Rai, GeetaOsteoarthritis is a most common form of arthritis, affecting the synovial joints and characterised by loss of cartilage. Current treatment mostly includes non-steroidal anti-inflammatory drugs which have limited advantage and high associated cytotoxicity. In this study, we evaluated a formulation joint joy containing ingredients from natural sources like Withania somnifera, Curcumin-C3-complex along with Glucosamine and Chondroitin Sulphate, in-silico for mechanism involved in improvement of osteoarthritis. We conducted molecular docking and ADMET analysis of these compounds on COX-2R- and MMP-9- receptors, which are implicated in inflammation and joint degradation and are also key therapeutic targets for drugs against joint degradation. Binding free energy was calculated and information on hydrogen bonds, interacting residues and drug-likeness properties were generated. Molecular docking and pharmacokinetics analysis showed docking scores of joint joy ingredients comparable to that of reference drug celecoxib, suggesting that the formulation has the potential to improve the joint pain and inflammation of osteoarthritis patients. Copyright � 2021 Inderscience Enterprises Ltd.Publication Exploration of Neuroprotective Properties of a Naturally Inspired Multifunctional Molecule (F24) against Oxidative Stress and Amyloid ? Induced Neurotoxicity in Alzheimer�s Disease Models(American Chemical Society, 2022) Singh, Yash Pal; Kumar, Navneet; Priya, Khushbu; Chauhan, Brijesh Singh; Shankar, Gauri; Kumar, Saroj; Singh, Gireesh Kumar; Srikrishna, Saripella; Garg, Prabha; Singh, Gourav; Rai, Geeta; Modi, GyanThe pathological hallmarks of Alzheimer�s disease (AD) are manifested as an increase in the level of oxidative stress and aggregation of the amyloid-? protein. In vitro, in vivo, and in silico experiments were designed and carried out with multifunctional cholinergic inhibitor, F24 (EJMC-7a) to explore its neuroprotective effects in AD models. The neuroprotection ability of F24 was tested in SH-SY5Y cells, a widely used neuronal cell line. The pretreatment and subsequent co-treatment of SH-SY5Y cells with different doses of F24 was effective in rescuing the cells from H2O2 induced neurotoxicity. F24 treated cells were found to be effective in the reduction of cellular reactive oxygen species, DNA damage, and A?1�42 induced neurotoxicity, which validated its neuroprotective effectiveness. F24 exhibited efficacy in an in vivo Drosophila model by rescuing eye phenotypes from degeneration caused by A? toxicity. Further, computational studies were carried out to monitor the interaction between F24 and A?1�42 aggregates. The computational studies corroborated our in vitro and in vivo studies suggesting A?1�42 aggregation modulation ability of F24. The brain entry ability of F24 was studied in the parallel artificial membrane permeability assay. Finally, F24 was tested at doses of 1 and 2.5 mg/kg in the Morris water maze AD model. The neuroprotective properties shown by F24 strongly suggest that multifunctional features of this molecule provide symptomatic relief and act as a disease-modifying agent in the treatment of AD. The results from our experiments strongly indicated that natural template-based F24 could serve as a lead molecule for further investigation to explore multifunctional therapeutic agents for AD management. � 2021 American Chemical SocietyPublication Genetic Association in Lower Limb Swelling(Springer Nature, 2022) Rai, Geeta; Priya, Khushbu; Das, DoliLeg swelling or edema involves a wide spectrum of causes and symptoms. They can be diagnosed by classifying them on the basis of different parameters like duration of disease-swelling is acute or chronic, the distribution of swelling-whether it involves one leg (unilateral), both the legs (bilateral), or either of them (unilateral or bilateral), and the associated symptoms such as dyspnea, pain, thickening of skin, and pigmentation. Systemic diseases such as heart failure, liver disease, thyroid disorder and local conditions such as pelvic tumors, infection, trauma, and venous thrombosis are the different diagnosis associated with the risk of lower limb edema. There is robust conditional evidence which implicates genetics in the etiology and pathology of this disease. With the inadequate knowledge of the biological pathways concerned with the pathogenesis of venous disease, it is difficult to devise erudite candidate gene hypothesis-directed studies. Hence, the study of associated genes and proteins should be considered to help enhance the current understanding of the inheritance of disease, and also, they can serve as good candidates for follow-up functional studies and be significant as potential drug targets. The knowledge of genetics and genomics associated with a condition would help physicians in the treatment of the progressive disease. � The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022.Publication Green Synthesis of Silver Nanoparticles Using Musa balbisiana and Their Cytotoxic Effect on HL-60 and SiHa Cancer Cells Through Clathrin-Mediated Endocytosis(Springer, 2022) Priya, Khushbu; Das, Doli; Singh, Sakshi; Rai, GeetaWe report herein a one-step, biomimetic synthesis of silver nanoparticles (AgNPs) from Musa balbisiana leaf extract having a cytotoxic effect on SiHa and HL-60 cancer cell lines without affecting non-cancerous, healthy peripheral blood mononuclear cells (PBMCs). The EDX analysis of AgNP dispersion, with a peak of 3.2�keV, confirmed the presence of elemental silver with a weight percentage of 54.57%. As is revealed from both SEM and TEM, monodispersed AgNPs were spherical in morphology with a diameter ranging from 11.28 to 87.53�nm with an average size of 12�nm. The diffraction pattern revealed polycrystalline AgNPs with FCC crystal structure. We report increased cytotoxicity accompanied with characteristic morphological change in HL-60 and SiHa, significant reduction in proliferation, increased reactive oxygen species (ROS) generation, and decreased mitochondrial membrane potential (MMP) following AgNP treatment at various doses. No such detrimental cellular impact of AgNPs was observed on healthy PBMCs. Fluorescence microscopy tracked coumarin-loaded AgNP accumulation in lysosomes as well as the nucleus, suggesting that both lysosome and nucleus served as cellular targets of AgNPs. AgNPs were internalized through passive and active pathways and that energy-dependent, clathrin-mediated endocytosis was involved in the trafficking of AgNPs. Our in silico docking studies confirm the binding of AgNPs to adaptor protein 2 on the ?2 subunit facilitating clathrin-mediated endocytosis. Graphical abstract: [Figure not available: see fulltext.]. � 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Publication Immunogenetic perspective of inflammatory disorders(Elsevier, 2022) Rai, Geeta; Thacker, Hiral; Das, Doli; Priya, KhushbuUnderstanding of the genetic basis underlying inflammatory disorders has progressed in recent years. Contribution of proinflammatory cytokines, human leukocyte antigen (HLA), and non-HLA polymorphisms in the pathogenesis of several autoimmune and immune-mediated inflammatory disorder is critical. HLA plays a central role in disease pathology. Harmful stimuli triggering the signaling mechanisms including nuclear factor-kappa B pathway, Janus kinase-signal transducer and activator of transcription pathway, and mitogen-activated protein kinase pathway results in the release of inflammatory mediators. From acute to chronic inflammation, the etiology of various inflammatory disorders is poorly understood. Inflammatory disorder such as COVID 19 is a devastating havoc to the world. As we reach the end of 2020, >1 million people have succumbed to death worldwide. Disease-manifesting clinical features include mild to severe pneumonia, loss of respiratory function progressing to acute respiratory distress syndrome with occasional multiorgan failure. Cytokine storm, decreased T cell count, and insufficient immune response are conducive issues to COVID 19 pandemic. Varied immune responses to the same antigen across different individuals determine the genetic perspective of disease susceptibility. Through genome-wide association studies, next-generation sequencing and other genetic techniques, several genetic risk loci associated with various inflammatory diseases such as inflammatory bowel disease, psoriasis, sclerosis, and systemic lupus erythematosus (SLE) have been identified. Dysregulated inflammatory pathways, gene mutation, or elevated cytokine level may lead to the disease progression. However, the production of autoantibodies against the nuclear antigens is a hallmark of diseases like SLE and rheumatoid arthritis. Moreover, environmental factors like smoking also increase the risk of inflammatory disorders. Understanding the functional aspects of casual genetic factors underlying the disease pathogenesis greatly facilitates the ability to identify the therapeutic targets relevant to disease. The current chapter deals with the idea of genetic perspective associated with various inflammatory disorders and their potential therapeutic targets along with the factors contributing to disease susceptibility. � 2022 Elsevier Inc. All rights reserved.Publication Innate Immune Mechanism of Neutrophil Extracellular Trap Formation is Impaired in at-Risk Term Low Birth Weight Newborns(Taylor and Francis Ltd., 2023) Das, Doli; Singh, Vikas V.; Chauhan, Sudhir K.; Rai, Richa; Kumar, Ashok; Jain, Madhu; Rai, GeetaLow birth weight (LBW) is a leading cause of newborn�s mortality however the underlying defects in cellular immunity and immune mechanisms leading to severe neonatal infections in term LBW (tLBW) newborns are not well understood. Neutrophil extracellular traps (NETs), or NETosis, is an innate immune defense mechanism of neutrophils involved in trapping and killing of microbes. The efficiency of NET formation in cord blood derived neutrophils of tLBW and normal birth weight (NBW) newborns in the presence of toll like receptor (TLR) agonist inductions was evaluated. The NET formation was observed to be substantially impaired in tLBW newborns along with NET proteins expression, extracellular deoxyribonucleic acid (DNA) release and reactive oxygen species generation. The placental tissues from tLBW newborns delivery also showed minimal NETosis. These findings suggest impaired NET formation to be an important factor underlying the deficient immune status of tLBW newborns making them susceptible to life- threatening infections. � 2023 Taylor & Francis Group, LLC.Publication Pongamol from the seeds of Tephrosia purpurea exert anti-cancer activity against cervical cancer cell line(National Institute of Science Communication and Policy Research, 2023) Kumari, Snehal; Chaudhary, Neha; Priya, Khushbu; Rai, Geeta; Gautam, Dev Nath Singh; Singh, Narendra KumarTephrosia purpurea belongs to the family Fabaceae, is used for the treatment of inflammation, diabetes, cancer, chronic fever, boils, gingivitis etc. In the present study, three compounds (TP-1, TP-3 and TP-5) were isolated from ethyl acetate extract of the seeds of T. purpurea (EETP). Quantity of TP-3 (6.05%) in EETP was determined by HPLC. In-vitro anti-cancer activity of EETP and isolated compound TP-3 on SiHa cells as well as PBMCs (peripheral blood mononuclear cells) were evaluated by MTT (3-(4,5-di methyl thiazol-2-yl)-2,5-di phenyl tetrazolium bromide) assay. On the basis of spectroscopic analysis and physical properties, structure of isolated compounds TP-1, TP-3 and TP-5 were characterized as teclenone, pongamol and ?-sitosterol respectively. Isolated compound TP-3 showed cytotoxicity against SiHa cells with the IC50 33.06 �gmL-1. TP-3 showed significant cytotoxicity at the concentration range from 20-50 �gmL-1 as compared to control. Maximum cytotoxicity (72.75%) was observed at the concentration of 50 �gmL-1. TP-3 showed non-significant cytotoxicity against PBMCs cells at all the concentrations except at 50 �gmL-1 (cytotoxicity 24.19%). EETP showed significant cytotoxicity (IC50 value 113.63 �gmL-1) against SiHa cells at the concentration range from 75-150 �gmL-1 as compared to control. Maximum cytotoxicity (75.34%) was observed at the concentration of 150 �gmL-1. � 2023, National Institute of Science Communication and Policy Research. All rights reserved.Publication Structural Insights into the IL12:IL12 Receptor Complex Assembly by Molecular Modeling, Docking, and Molecular Dynamics Simulation(Bentham Science Publishers, 2022) Singh, Sakshi; Rai, GeetaBackground: Interleukin-12 receptor (IL12R) is a type I cytokine receptor that can promote hematopoiesis and regulate innate and adaptive immunity. It binds with the IL12 ligand, which activates the IL-12 signaling pathway that triggers hematopoietic progenitor cell proliferation and differentiation process. The structure of IL12:IL12R complex is not known. Objective: The present work describes a de novo computational method for rational protein designing to elucidate the structure of IL12:IL12R complex. Methods: Homology modeling, docking, and MD simulation methods were used to design mimics of the interaction of IL12 and IL12R. Results: 3D structure prediction and validation confirm the accurate structure of IL12R protein that contains immunoglobin domain, fibronectin type three domain, cytokine-binding domain, and WSXWS motif. Molecular docking and MD simulation revealed that IL12R bound tightly with IL12 ligand at their interface. The estimated binding energy of the docked complex was-26.7 kcal/mol, and the interface area was 281.4 �2. Hotspot prediction suggested that ARG34, SER58, GLU61, CYS62, LEU63, SER73, ASP142, GLN146, LYS168, THR169 ARG181, ARG183, ARG189, and TYR193 residues in IL12 ligand interacted with SER175, ALA176, CYS177, PRO178, ALA179, ALA180, GLU181, GLU182, ALA192, VAL193, HIS194, ARG208, TYR246, GLN289, ASP290, ARG291, TYR292, TYR293 and SER294 residues in IL12 receptor. Conclusion: The results of the study provides a simulated molecular structure of IL12:IL12R complex that could offer a promising target complex to substantiate IL12 based drug-designing approaches. � 2022 Bentham Science Publishers.
