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1.
Mol Neurobiol ; 2024 May 03.
Article in English | MEDLINE | ID: mdl-38702566

ABSTRACT

Although the world is acquitting from the throes of COVID-19 and returning to the regularity of life, its effects on physical and mental health are prominently evident in the post-pandemic era. The pandemic subjected us to inadequate sleep and physical activities, stress, irregular eating patterns, and work hours beyond the regular rest-activity cycle. Thus, perturbing the synchrony of the regular circadian clock functions led to chronic psychiatric and neurological disorders and poor immunological response in several COVID-19 survivors. Understanding the links between the host immune system and viral replication machinery from a clock-infection biology perspective promises novel avenues of intervention. Behavioral improvements in our daily lifestyle can reduce the severity and expedite the convalescent stage of COVID-19 by maintaining consistent eating, sleep, and physical activity schedules. Including dietary supplements and nutraceuticals with prophylactic value aids in combating COVID-19, as their deficiency can lead to a higher risk of infection, vulnerability, and severity of COVID-19. Thus, besides developing therapeutic measures, perpetual healthy practices could also contribute to combating the upcoming pandemics. This review highlights the impact of the COVID-19 pandemic on biological rhythms, sleep-wake cycles, physical activities, and eating patterns and how those disruptions possibly contribute to the response, severity, and outcome of SARS-CoV-2 infection.

2.
Sci Rep ; 12(1): 17038, 2022 10 11.
Article in English | MEDLINE | ID: mdl-36220880

ABSTRACT

The vaccination drive against COVID-19 worldwide was quite successful. However, the second wave of infections was even more disastrous. There was a rapid increase in reinfections and human deaths due to the appearance of new SARS-CoV-2 variants. The viral genome mutations in the variants were acquired while passing through different human hosts that could escape antibodies in convalescent or vaccinated individuals. The treatment was based on oxygen supplements and supportive protocols due to the lack of a specific drug. In this study, we identified three lead inhibitors of arylated coumarin derivatives 4,6,8-tri(naphthalen-2-yl)-2H-chromen-2-one (NF1), 8-(4-hydroxyphenyl)-4,6-di(naphthalen-2-yl)-2H-chromen-2-one (NF12) and 8-(4-hydroxyphenyl)-3,6-di(naphthalen-2-yl)-2H-chromen-2-one (NF-13) that showed higher binding affinity towards the junction of SARS-CoV-2 spike glycoprotein (S-protein) and human angiotensin-converting enzyme 2 (ACE2) receptor. Using molecular docking analysis, we identified the putative binding sites of these potent inhibitors. Notably, molecular dynamics (MD) simulation and MM-PBSA studies confirmed that these inhibitors have the potential ability to bind Spike-protein/ACE2 protein complex with minimal energy. Further, the two major concerns are an adaptive mutation of spike proteins- N501Y and D614G which displayed strong affinity towards NF-13 in docking analysis. Additionally, in vitro and in vivo studies are required to confirm the above findings and develop the inhibitors as potential drugs against SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 Drug Treatment , Coumarins/pharmacology , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Oxygen , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Protein Domains , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
3.
Gene ; 768: 145313, 2021 Feb 05.
Article in English | MEDLINE | ID: mdl-33220345

ABSTRACT

The whole world is still suffering substantially from the coronavirus disease 2019 (COVID-19) outbreak. Several protein-based molecules that are associated with the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which are essential for its functionality, survival, and pathogenesis have been identified and are considered as potential therapeutic targets. These protein-based molecules are either structural/non-structural components of SARS-CoV-2 or host factors, which play a crucial role in this infection. Developing drug molecules against these essential functional molecules to hinder their regular functioning and associated physiological pathways could be promising for successful clinical management of this novel coronavirus infection. The review aims to highlight the functional molecules that play crucial roles in SARS-CoV-2 pathogenesis. We have emphasized how these potential druggable targets could be beneficial in tackling the COVID-19 crisis.


Subject(s)
Antiviral Agents/pharmacology , Host-Pathogen Interactions/drug effects , SARS-CoV-2/physiology , SARS-CoV-2/pathogenicity , COVID-19/transmission , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Humans , Methyltransferases/chemistry , Methyltransferases/metabolism , Molecular Targeted Therapy , RNA Helicases/chemistry , RNA Helicases/metabolism , RNA, Viral/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Viral Structural Proteins/metabolism , Virulence , Virus Replication/drug effects , COVID-19 Drug Treatment
4.
Article in English | MEDLINE | ID: mdl-32957898

ABSTRACT

There is close interdependence between cell survival, cell senescence, events of the cell cycle, apoptosis, malignancy development, and tumor responses to cancer treatment. Intensive studies and elaborate researches have been conducted on the functional aspects of oncogenes, tumor suppressor genes, apoptotic genes, and members guiding cell cycle regulation. These disquisitions have put forward the existence of a highly organized response pathway termed as a DNA-damage response network. The pathways detecting DNA damage and signaling are intensively linked to the events of cell-cycle arrest, cell proliferation, apoptosis, and cell senescence. DNA damage responses are complex systems that incorporate specific "sensor" and "transducer" proteins, for assessment of damage and signal transmission, respectively. These signals are thereafter relayed upon various "effector" proteins involved in different cellular pathways. It may include those governing cell-cycle checkpoints, participating in DNA repair, cell senescence, and apoptosis. This review discusses the role of the tumour suppressor gene, oncogenes, cell cycle checkpoint regulators during DNA damage response and regulation.


Subject(s)
Cell Cycle Checkpoints/genetics , Cell Proliferation/genetics , DNA Repair/genetics , Animals , DNA Damage/genetics , Gene Regulatory Networks/physiology , Humans , Signal Transduction/genetics
5.
J Biomol Struct Dyn ; 39(16): 6306-6316, 2021 Oct.
Article in English | MEDLINE | ID: mdl-32698689

ABSTRACT

Spike glycoprotein, a class I fusion protein harboring the surface of SARS-CoV-2 (SARS-CoV-2S), plays a seminal role in the viral infection starting from recognition of the host cell surface receptor, attachment to the fusion of the viral envelope with the host cells. Spike glycoprotein engages host Angiotensin-converting enzyme 2 (ACE2) receptors for entry into host cells, where the receptor recognition and attachment of spike glycoprotein to the ACE2 receptors is a prerequisite step and key determinant of the host cell and tissue tropism. Binding of spike glycoprotein to the ACE2 receptor triggers a cascade of structural transitions, including transition from a metastable pre-fusion to a post-fusion form, thereby allowing membrane fusion and internalization of the virus. From ancient times people have relied on naturally occurring substances like phytochemicals to fight against diseases and infection. Among these phytochemicals, flavonoids and non-flavonoids have been the active sources of different anti-microbial agents. We performed molecular docking studies using 10 potential naturally occurring compounds (flavonoids/non-flavonoids) against the SARS-CoV-2 spike protein and compared their affinity with an FDA approved repurposed drug hydroxychloroquine (HCQ). Further, our molecular dynamics (MD) simulation and energy landscape studies with fisetin, quercetin, and kamferol revealed that these molecules bind with the hACE2-S complex with low binding free energy. The study provided an indication that these molecules might have the potential to perturb the binding of hACE2-S complex. In addition, ADME analysis also suggested that these molecules consist of drug-likeness property, which may be further explored as anti-SARS-CoV-2 agents. Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Drug Development , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Phytochemicals , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
6.
J Biomol Struct Dyn ; 39(15): 5768-5778, 2021 Sep.
Article in English | MEDLINE | ID: mdl-32684109

ABSTRACT

The entire human population over the globe is currently facing appalling conditions due to the spread of infection from coronavirus disease-2019 (COVID-19). The spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present on the surface of the virion mediates the virus entry into the host cells and therefore is targeted by several scientific groups as a novel drug target site. The spike glycoprotein binds to the human angiotensin-converting enzyme-2 (hACE2) cell surface receptor abundantly expressed in lung tissues, and this binding phenomenon is a primary determinant of cell tropism and pathogenesis. The binding and internalization of the virus is the primary and most crucial step in the process of infection, and therefore the molecules targeting the inhibition of this process certainly hold a significant therapeutic value. Thus, we systematically applied the computational techniques to identify the plausible inhibitor from a chosen set of well characterized diaryl pyrimidine analogues which may disrupt interfacial interaction of spike glycoprotein (S) at the surface of hACE2. Using molecular docking, molecular dynamics (MD) simulation and binding free energy calculation, we have identified AP-NP (2-(2-amino-5-(naphthalen-2-yl)pyrimidin-4-yl)phenol), AP-3-OMe-Ph (2-(2-amino-5-(3-methoxyphenyl)pyrimidin-4-yl)phenol) and AP-4-Me-Ph (2-(2-amino-5-(p-tolyl) pyrimidin-4-yl)phenol) from a group of diaryl pyrimidine derivatives which appears to bind at the interface of the hACE2-S complex with low binding free energy. Thus, pyrimidine derivative AP-NP may be explored as an effective inhibitor for hACE2-S complex. Furthermore, in vitro and in vivo studies will strengthen the use of these inhibitors as suitable drug candidates against SARS-COV-2. Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , Pharmaceutical Preparations , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pyrimidines/pharmacology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
7.
Open Biol ; 10(9): 200174, 2020 09.
Article in English | MEDLINE | ID: mdl-32898468

ABSTRACT

The world is passing through a very difficult phase due to the coronavirus disease 2019 (COVID-19) pandemic, which has disrupted almost all spheres of life. Globally, according to the latest World Health Organization report (10 August 2020), COVID-19 has affected nearly 20 million lives, causing 728 013 deaths. Due to the lack of specific therapeutic drugs and vaccines, the outbreak of disease has spawned a corpus of contagious infection all over the world, day by day, without control. As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a very rapid infection rate, it is essential to develop a novel ameliorative and curative strategy as quickly as possible. Convalescent plasma (CP) therapy is a type of adaptive immunity that has already been found to be effective in confronting several infectious diseases from the last two decades. For example, CP therapy was used in the treatment of viral-induced diseases like SARS-CoV epidemics, Middle East respiratory syndrome coronavirus (MERS-CoV) pandemics, Ebola epidemics and H1N1 pandemic. In this review, we have mainly focused on the therapeutic role of CP therapy and its neutralizing effect to fight against the COVID-19 outbreak.


Subject(s)
Coronavirus Infections/therapy , Immunization, Passive , Pneumonia, Viral/therapy , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Humans , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Severity of Illness Index , COVID-19 Serotherapy
8.
Heliyon ; 6(9): e05007, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32984620

ABSTRACT

The coronavirus disease 2019 (COVID-19), the pandemic that originated in China has already spread into more than 190 countries, resulting in huge loss of human life and many more are at the stake of losing it; if not intervened with the best therapeutics to contain the disease. For that aspect, various scientific groups are continuously involved in the development of an effective line of treatment to control the novel coronavirus from spreading rapidly. Worldwide scientists are evaluating various biomolecules and synthetic inhibitors against COVID-19; where the nucleic acid-based molecules may be considered as potential drug candidates. These molecules have been proved potentially effective against SARS-CoV, which shares high sequence similarity with SARS-CoV-2. Recent advancements in nucleic acid-based therapeutics are helpful in targeted drug delivery, safely and effectively. The use of nucleic acid-based molecules also known to regulate the level of gene expression inside the target cells. This review mainly focuses on various nucleic acid-based biologically active molecules and their therapeutic potentials in developing vaccines for SARS-CoV-2.

9.
Nanomedicine ; 12(7): 1973-1985, 2016 10.
Article in English | MEDLINE | ID: mdl-27133192

ABSTRACT

Triple negative breast cancer (TNBC) is one of the most common invasive malignancies among women, associated with poor prognosis. Standard chemotherapy targets all dividing cells, resulting in dose-limiting toxicities. In this study, we demonstrated a strategy of encapsulating a hydrophobic synthetic compound, nifetepimine, having anticancer properties, in poly (lactic-co-glycolic acid) nanoparticles to increase selectivity of drug to cancerous cells with minimum toxicity towards normal cells. Nanoencapsulated nifetepimine (30-100nm) having loading and encapsulation efficiency of 7.45% and 75% respectively, was successfully internalized inside TNBC cells upon sustained release resulting in apoptosis. An in vivo bio-distribution study indicated that nanonifetepimine selectively accumulated into breast tumor sites of mice, primarily due to prolonged blood circulation time and binding of nifetepimine to epidermal growth factor receptor that remains overexpressed in most of the TNBC tumors. Moreover, we observed significant reduction in breast tumor volume with improved survival implying high tumor targetability of nanonifetepimine.


Subject(s)
Antineoplastic Agents/administration & dosage , Pyrimidinones/administration & dosage , Triple Negative Breast Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Breast , Cell Line, Tumor , Female , Humans , Mice , Nanoparticles , Pyrimidinones/pharmacology , Tissue Distribution
10.
Biomed Res Int ; 2015: 320941, 2015.
Article in English | MEDLINE | ID: mdl-25866775

ABSTRACT

Brain tumors are one of the most formidable diseases of mankind. They have only a fair to poor prognosis and high relapse rate. One of the major causes of extreme difficulty in brain tumor treatment is the presence of blood brain barrier (BBB). BBB comprises different molecular components and transport systems, which in turn create efflux machinery or hindrance for the entry of several drugs in brain. Thus, along with the conventional techniques, successful modification of drug delivery and novel therapeutic strategies are needed to overcome this obstacle for treatment of brain tumors. In this review, we have elucidated some critical insights into the composition and function of BBB and along with it we have discussed the effective methods for delivery of drugs to the brain and therapeutic strategies overcoming the barrier.


Subject(s)
Antineoplastic Agents , Blood-Brain Barrier , Brain Neoplasms , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Biological Transport, Active/drug effects , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/pathology , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Humans
11.
Inflamm Res ; 62(3): 259-73, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23229721

ABSTRACT

OBJECTIVE AND DESIGN: To determine alternate therapeutic measures to combat Staphylococcus aureus induced arthritis. Thus, azithromycin was combined with riboflavin, which may combat the ROS production and inflammation. METHODS: An in vivo model of S. aureus infection-induced arthritis was set up by infecting mice with 5 × 106 bacterial cell/mouse. S. aureus was administered intravenously. Azithromycin and riboflavin was injected intraperitoneally at a single dose of 100 and 20 mg/kg body, respectively. The mice were sacrificed at 3, 9, 15 days post infection (dpi). TNF-α, IFN-γ, IL-6 and IL-10 from serum and SOD, catalase and reduced glutathione concentration were observed in hepatic, cardiac, renal and splenic tissue. RESULTS: CFU was found very prominent in spleen and joints and reduced in blood at 3 and 9 dpi. However, treatment with azithromycin and riboflavin completely eradicated the bacteria from blood and spleen. TNF-α, IFN-γ, IL-6, and MCP-1 were induced due to infection which were downregulated by treatment with azithromycin and riboflavin. Infected mice were also found to have altered antioxidant status, measured in terms of reduced glutathione and anti-oxidant enzymes such as SOD and catalase. CONCLUSION: These changes were found to be ameliorated when the animals were co-treated with azithromycin and riboflavin.


Subject(s)
Arthritis, Infectious/drug therapy , Azithromycin/therapeutic use , Cytokines/metabolism , Free Radicals/metabolism , Riboflavin/therapeutic use , Severity of Illness Index , Staphylococcal Infections/drug therapy , Animals , Anti-Bacterial Agents/therapeutic use , Antioxidants/therapeutic use , Arthritis, Infectious/microbiology , Arthritis, Infectious/mortality , Disease Models, Animal , Drug Therapy, Combination , Male , Mice , Reactive Oxygen Species/metabolism , Staphylococcal Infections/complications , Staphylococcal Infections/mortality , Staphylococcus aureus , Survival Rate , Treatment Outcome
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