Catalytic, Antifungal, and Antiproliferative Activity Studies of a New Family of Mononuclear [VIVO]/[VVO2] Complexes.

Ligands derived from 2-(1-phenylhydrazinyl)pyridine and salicylaldehyde (HL1), 3-methoxysalicylaldehyde (HL2), 5-bromosalicylaldehyde (HL3), and 3,5-di-tert-butylsalicylaldehyde (HL4) react with [VIVO(acac)2] in MeOH followed by aerial oxidation to give [VVO2(L1)] (1), [VVO2(L2)] (2), [VVO2(L3)] (3), and [VVO2(L4)] (4). Complex [VIVO(acac)(L1)] (5) is also isolable from [VIVO(acac)2] and HL1 in dry MeOH. Structures of all complexes were confirmed by single-crystal X-ray and spectroscopic studies. They efficiently catalyze benzyl alcohol and its derivatives' oxidation in the presence of H2O2 to their corresponding aldehydes. Under optimized reaction conditions using 1 as a catalyst precursor, conversion of benzyl alcohol follows the order: 4 (93%) > 2 (90%) > 1 (86%) > 3 (84%) ≈ 5 (84%). These complexes were also evaluated for antifungal and antiproliferative activities. Complex 3 with MIC50 = 16 µg/mL, 4 with MIC50 = 12 µg/mL, and 5 with MIC50 = 16 µg/mL are efficient toward planktonic cells of Candida albicans and Candida tropicalis. On Michigan cancer foundation-7 (MCF-7) cells, they show comparable cytotoxic effects and exhibit IC50 in the 27.3-33.5 µg/mL range, and among these, 4 exhibits the highest cytotoxicity. A similar study on human embryonic kidney cells (HEK293) confirms their less toxicity at lower concentrations (4 to 16 µg/mL) compared to MCF-7.

Exploring the Immunomodulatory Aspect of Mesenchymal Stem Cells for Treatment of Severe Coronavirus Disease 19.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is an enveloped, positive sense, single stranded RNA (+ssRNA) virus, belonging to the genus Betacoronavirus and family Coronaviridae. It is primarily transmitted from infected persons to healthy ones through inhalation of virus-laden respiratory droplets. After an average incubation period of 2-14 days, the majority of infected individuals remain asymptomatic and/or mildly symptomatic, whereas the remaining individuals manifest a myriad of clinical symptoms, including fever, sore throat, dry cough, fatigue, chest pain, and breathlessness. SARS-CoV-2 exploits the angiotensin converting enzyme 2 (ACE-2) receptor for cellular invasion, and lungs are amongst the most adversely affected organs in the body. Thereupon, immune responses are elicited, which may devolve into a cytokine storm characterized by enhanced secretion of multitude of inflammatory cytokines/chemokines and growth factors, such as interleukin (IL)-2, IL-6, IL-7, IL-8, IL-9, tumor necrosis factor alpha (TNF-α), granulocyte colony-stimulating factor (GCSF), basic fibroblast growth factor 2 (bFGF2), monocyte chemotactic protein-1 (MCP1), interferon-inducible protein 10 (IP10), macrophage inflammatory protein 1A (MIP1A), platelet-derived growth factor subunit B (PDGFB), and vascular endothelial factor (VEGF)-A. The systemic persistence of inflammatory molecules causes widespread histological injury, leading to functional deterioration of the infected organ(s). Although multiple treatment modalities with varying effectiveness are being employed, nevertheless, there is no curative COVID-19 therapy available to date. In this regard, one plausible supportive therapeutic modality may involve administration of mesenchymal stem cells (MSCs) and/or MSC-derived bioactive factors-based secretome to critically ill COVID-19 patients with the intention of accomplishing better clinical outcome owing to their empirically established beneficial effects. MSCs are well established adult stem cells (ASCs) with respect to their immunomodulatory, anti-inflammatory, anti-oxidative, anti-apoptotic, pro-angiogenic, and pro-regenerative properties. The immunomodulatory capabilities of MSCs are not constitutive but rather are highly dependent on a holistic niche. Following intravenous infusion, MSCs are known to undergo considerable histological trapping in the lungs and, therefore, become well positioned to directly engage with lung infiltrating immune cells, and thereby mitigate excessive inflammation and reverse/regenerate damaged alveolar epithelial cells and associated tissue post SARS-CoV-2 infection. Considering the myriad of abovementioned biologically beneficial properties and emerging translational insights, MSCs may be used as potential supportive therapy to counteract cytokine storms and reduce disease severity, thereby facilitating speedy recovery and health restoration.

Insights into COVID-19 Vaccine Development Based on Immunogenic Structural Proteins of SARS-CoV-2, Host Immune Responses, and Herd Immunity.

The first quarter of the 21st century has remarkably been characterized by a multitude of challenges confronting human society as a whole in terms of several outbreaks of infectious viral diseases, such as the 2003 severe acute respiratory syndrome (SARS), China; the 2009 influenza H1N1, Mexico; the 2012 Middle East respiratory syndrome (MERS), Saudi Arabia; and the ongoing coronavirus disease 19 (COVID-19), China. COVID-19, caused by SARS-CoV-2, reportedly broke out in December 2019, Wuhan, the capital of China's Hubei province, and continues unabated, leading to considerable devastation and death worldwide. The most common target organ of SARS-CoV-2 is the lungs, especially the bronchial and alveolar epithelial cells, culminating in acute respiratory distress syndrome (ARDS) in severe patients. Nevertheless, other tissues and organs are also known to be critically affected following infection, thereby complicating the overall aetiology and prognosis. Excluding H1N1, the SARS-CoV (also referred as SARS-CoV-1), MERS, and SARS-CoV-2 are collectively referred to as coronaviruses, and taxonomically placed under the realm Riboviria, order Nidovirales, suborder Cornidovirineae, family Coronaviridae, subfamily Orthocoronavirinae, genus Betacoronavirus, and subgenus Sarbecovirus. As of 23 September 2021, the ongoing SARS-CoV-2 pandemic has globally resulted in around 229 million and 4.7 million reported infections and deaths, respectively, apart from causing huge psychosomatic debilitation, academic loss, and deep economic recession. Such an unprecedented pandemic has compelled researchers, especially epidemiologists and immunologists, to search for SARS-CoV-2-associated potential immunogenic molecules to develop a vaccine as an immediate prophylactic measure. Amongst multiple structural and non-structural proteins, the homotrimeric spike (S) glycoprotein has been empirically found as the most suitable candidate for vaccine development owing to its immense immunogenic potential, which makes it capable of eliciting both humoral and cell-mediated immune responses. As a consequence, it has become possible to design appropriate, safe, and effective vaccines, apart from related therapeutic agents, to reduce both morbidity and mortality. As of 23 September 2021, four vaccines, namely, Comirnaty, COVID-19 vaccine Janssen, Spikevax, and Vaxzevria, have received the European Medicines Agency's (EMA) approval, and around thirty are under the phase three clinical trial with emergency authorization by the vaccine-developing country-specific National Regulatory Authority (NRA). In addition, 100-150 vaccines are under various phases of pre-clinical and clinical trials. The mainstay of global vaccination is to introduce herd immunity, which would protect the majority of the population, including immunocompromised individuals, from infection and disease. Here, we primarily discuss category-wise vaccine development, their respective advantages and disadvantages, associated efficiency and potential safety aspects, antigenicity of SARS-CoV-2 structural proteins and immune responses to them along with the emergence of SARS-CoV-2 VOC, and the urgent need of achieving herd immunity to contain the pandemic.

Host Cell and SARS-CoV-2-Associated Molecular Structures and Factors as Potential Therapeutic Targets.

Coronavirus disease 19 (COVID-19) is caused by an enveloped, positive-sense, single-stranded RNA virus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the realm Riboviria, order Nidovirales, family Coronaviridae, genus Betacoronavirus and the species Severe acute respiratory syndrome-related coronavirus. This viral disease is characterized by a myriad of varying symptoms, such as pyrexia, cough, hemoptysis, dyspnoea, diarrhea, muscle soreness, dysosmia, lymphopenia and dysgeusia amongst others. The virus mainly infects humans, various other mammals, avian species and some other companion livestock. SARS-CoV-2 cellular entry is primarily accomplished by molecular interaction between the virus's spike (S) protein and the host cell surface receptor, angiotensin-converting enzyme 2 (ACE2), although other host cell-associated receptors/factors, such as neuropilin 1 (NRP-1) and neuropilin 2 (NRP-2), C-type lectin receptors (CLRs), as well as proteases such as TMPRSS2 (transmembrane serine protease 2) and furin, might also play a crucial role in infection, tropism, pathogenesis and clinical outcome. Furthermore, several structural and non-structural proteins of the virus themselves are very critical in determining the clinical outcome following infection. Considering such critical role(s) of the abovementioned host cell receptors, associated proteases/factors and virus structural/non-structural proteins (NSPs), it may be quite prudent to therapeutically target them through a multipronged clinical regimen to combat the disease.

Molecular docking, DFT analysis, and dynamics simulation of natural bioactive compounds targeting ACE2 and TMPRSS2 dual binding sites of spike protein of SARS CoV-2.

The scientific community is continuously working to discover drug candidates against potential targets of SARS-CoV-2, but effective treatment has not been discovered yet. The virus enters the host cell through molecular interaction with its enzymatic receptors i.e., ACE2 and TMPRSS2, which, if, synergistically blocked can lead to the development of novel drug candidates. In this study, 1503 natural bioactive compounds were screened by HTVS, followed by SP and XP docking using Schrodinger Maestro software. Bio-0357 (protozide) and Bio-597 (chrysin) were selected for dynamics simulation based on synergistic binding affinity on S1 (docking score -9.642 and -8.78 kcal/mol) and S2 domains (-5.83 and -5.3 kcal/mol), and the RMSD, RMSF and Rg analyses showed stable interaction. The DFT analysis showed that the adsorption of protozide/chrysin, the band gap of protozide/chrysin-F/G reduced significantly. From SERS, results, it can be concluded that QDs nanocluster will act as a sensor for the detection of drugs. The docking study showed Bio-0357 and Bio-0597 bind to both S1 and S2 domains through stable molecular interactions, which can lead to the discovery of new drug candidates to prevent the entry of SARS-CoV-2. This in-silico study may be helpful to researchers for further in vitro experimental validation and development of new therapy for COVID-19.

Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19.

Coronavirus belongs to the family of Coronaviridae, comprising single-stranded, positive-sense RNA genome (+ ssRNA) of around 26 to 32 kilobases, and has been known to cause infection to a myriad of mammalian hosts, such as humans, cats, bats, civets, dogs, and camels with varied consequences in terms of death and debilitation. Strikingly, novel coronavirus (2019-nCoV), later renamed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and found to be the causative agent of coronavirus disease-19 (COVID-19), shows 88% of sequence identity with bat-SL-CoVZC45 and bat-SL-CoVZXC21, 79% with SARS-CoV and 50% with MERS-CoV, respectively. Despite key amino acid residual variability, there is an incredible structural similarity between the receptor binding domain (RBD) of spike protein (S) of SARS-CoV-2 and SARS-CoV. During infection, spike protein of SARS-CoV-2 compared to SARS-CoV displays 10-20 times greater affinity for its cognate host cell receptor, angiotensin-converting enzyme 2 (ACE2), leading proteolytic cleavage of S protein by transmembrane protease serine 2 (TMPRSS2). Following cellular entry, the ORF-1a and ORF-1ab, located downstream to 5' end of + ssRNA genome, undergo translation, thereby forming two large polyproteins, pp1a and pp1ab. These polyproteins, following protease-induced cleavage and molecular assembly, form functional viral RNA polymerase, also referred to as replicase. Thereafter, uninterrupted orchestrated replication-transcription molecular events lead to the synthesis of multiple nested sets of subgenomic mRNAs (sgRNAs), which are finally translated to several structural and accessory proteins participating in structure formation and various molecular functions of virus, respectively. These multiple structural proteins assemble and encapsulate genomic RNA (gRNA), resulting in numerous viral progenies, which eventually exit the host cell, and spread infection to rest of the body. In this review, we primarily focus on genomic organization, structural and non-structural protein components, and potential prospective molecular targets for development of therapeutic drugs, convalescent plasm therapy, and a myriad of potential vaccines to tackle SARS-CoV-2 infection.

Acquaintance and Approach in the Direction of Tobacco Cessation Among Dental Practitioners-A Systematic Review.

BACKGROUND: Nowadays, tobacco consumption has become one of the major public health problems and is the leading cause of escapable illness and death. A significant role is played by dental professionals in the identification of smokers; they are, thus, in a better position to offer preventive care. The aim of the present study was to systemically review the knowledge and attitude of dental practitioners toward tobacco cessation. METHODS: A literature search was performed in PubMed Central and Cochrane Library, Medline-PubMed, Embase, Google Scholar up to 2018 to identify appropriate studies. Full-text original research articles of the cross-sectional design were only included in the study. Our target was to systemically review the knowledge and attitude of dental practitioners toward tobacco cessation. RESULTS: The present review included a total of nine articles (studies) that fulfilled the eligibility criteria. Two articles which were hand searched and one article which was obtained through contact with experts were included. The results of the review revealed that the dental practitioners in most of the included studies lack satisfactory knowledge and were unaware of existing referral pathways to specialist smoking cessation services. At the same time, most of the dentists have a positive attitude toward tobacco cessation. CONCLUSIONS: Dental professionals are aware of their obligations toward smoking cessation counseling for patients but certain barriers including lack of time, confidence, and training prevent them from practicing the same in their daily routine. The dental professionals should obtain appropriate training and attain knowledge along with quantifiable skills for the prevention and cessation of tobacco use.

Assessment of knowledge and attitude regarding management of patients with substance usage in dental clinics in Modinagar- A cross-sectional study.

INTRODUCTION: The consequences of oral issues among drug users necessitate the implementation of a comprehensive dental care program. Integrated oral health-care services should be programmed for the management of drug addiction as a multi-organ disease needs a multi-disciplinary approach. AIM: The aim of the present study was to assess the knowledge and attitude regarding the management of patients with substance usage at a dental clinic. METHODOLOGY: A cross-sectional study was conducted among 208 dentists working as clinicians. A self-structured 27-item questionnaire consisting of questions related to the management of patients with substance usage at a dental clinic was distributed to them. Data were analyzed using Statistical Package for Social Sciences (SPSS) 20.0 (SPSS Inc., Chicago, IL, USA) and descriptive and analytical tests, including mean, standard deviation, and Chi-square test were used. P < 0.05 was considered statistically significant. RESULTS: Majority of the dentist irrespective of qualification were unaware of the modalities regarding the management of the patients with substance usage at the dental clinic. Most dental clinicians were having a positive attitude regarding such patients and agreed that abuser should be identified and managed in dental settings. CONCLUSION: Educating dental graduates and postgraduates about the oral implications of substance usage and making it a part of the dental curriculum may help us deal with the global issues of substance usage. The dental setting is recognized increasingly as an untapped venue for the delivery of medical screenings, given the long-term nature and frequent contacts associated with the patient-dentist relationship.