Synthesis, Molecular Docking, and Preclinical Evaluation of a New Succinimide Derivative for Cardioprotective, Hepatoprotective and Lipid-Lowering Effects.

Cardiac and hepatotoxicities are major concerns in the development of new drugs. Better alternatives to other treatments are being sought to protect these vital organs from the toxicities of these pharmaceuticals. In this regard, a preclinical study is designed to investigate the histopathological effects of a new succinimide derivative (Comp-1) on myocardial and liver tissues, and the biochemical effects on selected cardiac biomarkers, hepatic enzymes, and lipid profiles. For this, an initially lethal/toxic dose was determined, followed by a grouping of selected albino rats into five groups (each group had n = 6). The control group received daily oral saline for 8 days. The 5-FU (5-Fluorouracil) group received oral saline daily for 8 days, added with the administration of a single dose of 5-FU (150 mg/kg I.P.) on day 5 of the study. The atenolol group received oral atenolol (20 mg/kg) for 8 days and 5-FU (150 mg/kg I.P.) on day 5 of the protocol. Similarly, two groups of rats treated with test compound (Comp-1) were administered with 5 mg/kg I.P. and 10 mg/kg I.P. for 8 days, followed by 5-FU (150 mg/kg I.P.) on day 5. Toxicity induced by 5-FU was manifested by increases in the serum creatinine kinase myocardial band (CK-MB), troponin I (cTnI) and lactate dehydrogenase (LDH), lipid profile, and selected liver enzymes, including ALP (alkaline phosphatase), ALT (alanine transaminase), AST (aspartate aminotransferase), BT (bilirubin total), and BD (direct bilirubin). These biomarkers were highly significantly decreased after the administration of the mentioned doses of the test compound (5 mg/kg and 10 mg/kg). Similarly, histological examination revealed cardiac and hepatic tissue toxicity by 5-FU. However, those toxic effects were also significantly recovered/improved after the administration of Comp-1 at the said doses. This derivative showed dose-dependent effects and was most effective at a dose of 10 mg/kg body weight. Binding energy data computed via docking simulations revealed that our compound interacts toward the human beta2-adrenergic G protein-coupled receptor (S = -7.89 kcal/mol) with a slight stronger affinity than the calcium channel T-type (S = -7.07 kcal/mol). In conclusion, the histological and biochemical results showed that the test compound (Comp-1) had prominent cardioprotective, hepatoprotective, and lipolytic effects against 5-FU-induced toxicity in the subjected animal model.

Interdental Papillary Reconstruction by Microtunnelling Technique Using Autologous Biomatrices-A Randomised Controlled Clinical Trial.

Background and objectives: The study aimed to evaluate and compare the amount of papillary gain and black triangle height reduction after intervention with a microtunnelling technique with either Connective tissue graft (CTG) or Platelet-rich fibrin (PRF) as a biomatrix at 6 months using a microsurgical approach. Materials and Methods: Twenty-six patients with interdental papillary loss were included in the study. The patients were selected randomly for the study groups with thirteen patients in each group: a control group where CTG was utilised as a matrix, and a test group where PRF was utilised as a matrix, for interdental papillary reconstruction. A microtunnelling technique was performed for both the study groups under a surgical microscope. The primary parameters assessed were interdental Papillary height (PH) and Black triangle height (BTH) at baseline, with secondary parameters Visual analogue score by dentist (VAS-D) and patient (VAS-P) assessed at 6 months. Results: Both the control and test groups showed a significant reduction in BTH within their respective group at six months (p < 0.05). The gain in papillary height significantly improved only in the CTG group at 6 months. However, significant differences could not be demonstrated for any of the variables such as BTH (p value = 0.582) and PH (p-value = 0.892) between the study groups at 6 months. Conclusions: IDP reconstruction utilising a microtunnelling approach with CTG or PRF was successful without any significant differences between the groups for the parameters assessed at 6 months.

The Effect of Laser Micro Grooved Platform Switched Implants and Abutments on Early Crestal Bone Levels and Peri-Implant Soft Tissues Post 1 Year Loading among Diabetic Patients-A Controlled Clinical Trial.

Background and Objectives: The study aimed to compare the mean crestal bone level (CBL) and peri-implant soft tissue parameters in laser micro-grooved (LMG) platform switched implants and abutments (I&A) post 1 year of functional loading among non-diabetic and type II diabetic individuals. Materials and methods: Patients with an edentulous site having minimum bone height and width of ≥13 mm and ≥6 mm, respectively, were divided into two groups: (i) Non-diabetic-8 (control) and (ii) diabetic-8 (test). LMG Implants were placed and loaded immediately with a provisional prosthesis. Mean crestal bone level (MCBL) was evaluated radiographically at baseline and at 1 year. Peri-implant attachment level (PIAL) and relative position of the gingival margin (R-PGM) were recorded. Implant stability quotient (ISQ) level and implant survival rate (ISR) were evaluated at 1 year. Results: Early MCBL within the groups 1 year postloading was similar both mesially and distally (control-0.00 to 0.16 mm and 0.00 to 0.17 mm, respectively; test-0.00 to 0.21 mm and 0.00 to 0.22 mm, respectively) with statistical significance (p ≤ 0.003, p ≤ 0.001 and p ≤ 0.001, p ≤ 0.001, respectively). However, intergroup comparison showed no significant difference statistically in the MCBL in 1 year post functional loading. The peri-implant soft tissue parameters showed no significant difference between the groups. ISQ level between both groups did not reveal any significant changes (p ≤ 0.92), and ISR was 100%. Conclusions: LMG Implants resulted in minimal and comparable early crestal bone loss and soft tissue changes post 1 year of functional loading in moderately controlled diabetic and non-diabetic individuals, suggesting that this could be a reliable system for use in systemically compromised individuals.

Unveiling the therapeutic and nutritious potential of Vigna unguiculata in line with its phytochemistry.

Background: Vigna unguiculata, belonging to the Fabaceae family, commonly known as cowpea is an important edible legume, distributed mainly across the African and Asian countries. Traditionally, the plant has an outstanding background for the management of multiple diseases, animal feeding and human consumption. Objective: This review aims to mainly focus on the traditional applications, pharmacological activities, phytochemistry as well as nutritious composition of the V. unguiculata. Methods: Data present in the literature on the V. unguiculata, were collected from major scientific databases including Science Direct, SpringerLink, Google Scholar, Medline Plus, Web of Science, PubMed and Elsevier. Results: Number of compounds have been isolated including flavonoids, steroids, alkaloids, phenolic compounds, saponins, fatty acids, tannins, carbohydrates, vitamins, amino acids, carotenoids and fibers from various parts of plant. These compounds exhibit widespread pharmacological potentials both in-vitro and in-vivo including anthelmintic, antibacterial, antinociceptive, thrombolytic, antidiabetic, hypocholestrolemic and antiatherogenic effect, antimicrobial, anti-sickling, antioxidant, anti-covid activity, anticancer and neurobehavioral activities. These compounds have strong pharmacological background and might be responsible for the traditional uses of this plant that are not investigated. Conclusion: It is concluded that V. unguiculata possessed strong pharmacological, nutritious and phytochemical potential, therefore, it is strongly recommended for additional comprehensive investigations in order to determine its clinical utility.

mecA and fdh: markers of pathogenicity and commensalism in Staphylococcus epidermidis of pediatric origin from Pakistan.

Staphylococcus epidermidis is an opportunistic bacterial pathogen. The study screened isolates of S. epidermidis of pediatric origin for genetic markers of discriminatory potential. 103 isolates (n = 75 clinical; n = 28 community) were screened for methicillin resistance (mecA), formate dehydrogenase (fdh) and an array of virulence factors through multiplex PCR and Congo red assay. The isolates were typed in four distinct categories, based on the presence of selected virulent factors. The type A clinical isolates carrying icaADBC operon (n = 22; 29.3%, P = 0.117) were not significantly differentiating the origin of isolates. The type B clinical isolates representing methicillin resistant S. epidermidis (MRSE) (n = 73; 97.3%, P < 0.00001) and the type C clinical isolates lacking formate dehydrogenase fdh (n = 62; 82.6%, P < 0.00001) were having significant discriminatory potential of clinical isolates, respectively. All type D community isolates were carrying fdh (n = 28; 100%, P < 0.00001). MecA and fdh are significant differential markers of pathogenicity and commensalism in S. epidermidis of pediatric origin.

Alkaloids as drug leads in Alzheimer's treatment: Mechanistic and therapeutic insights.

Alzheimer's disease (AD) has few effective treatment options and continues to be a major global health concern. AD is a neurodegenerative disease that typically affects elderly people. Alkaloids have potential sources for novel drug discovery due to their diverse chemical structures and pharmacological activities. Alkaloids, natural products with heterocyclic nitrogen-containing structures, are considered potential treatments for AD. This review explores the neuroprotective properties of alkaloids in AD, focusing on their ability to regulate pathways such as amyloid-beta aggregation, oxidative stress, synaptic dysfunction, tau hyperphosphorylation, and neuroinflammation. The FDA has approved alkaloids such as acetylcholinesterase inhibitors like galantamine and rivastigmine. This article explores AD's origins, current market medications, and clinical applications of alkaloids in AD therapy. This review explores the development of alkaloid-based drugs for AD, focusing on pharmacokinetics, blood-brain barrier penetration, and potential adverse effects. Future research should focus on the clinical evaluation of promising alkaloids, developing recently discovered alkaloids, and the ongoing search for novel alkaloids for medical treatment. A pharmaceutical option containing an alkaloid may potentially slow down the progression of AD while enhancing its symptoms. This review highlights the potential of alkaloids as valuable drug leads in treating AD, providing a comprehensive understanding of their mechanisms of action and therapeutic implications.

Different modalities to manage rheumatoid arthritis: an A to Z story.

Aim: To investigate different approaches to RA treatment that might lead to greater efficacy and better safety profiles. Methods: The Search strategy was based on medical subject headings, and screening and selection were based on inclusion/exclusion criteria. Results & discussion: Early therapy is critical for disease control and loss of bodily function. The most promising outcomes came from the development of disease-modifying anti-rheumatic drugs. Different foods have anti-inflammatory and antioxidant qualities that protect against the development of rheumatoid arthritis (RA). Some dietary patterns and supplements have been shown to have potential protective benefits against RA. Conclusion: Improvement in the quality of life of RA patients requires a tailored management approach based on the current patient medical data.

Rheumatoid arthritis is a complex disease with an unclear origin that affects the joints. In this systematic review, we aimed to investigate different effective ways of treating rheumatoid arthritis. Study results indicate that rheumatoid arthritis treatment requires coordination between different healthcare teams. As much as we can, when we start disease treatment early, this will lead to a better disease cure. Different drugs showed promising results in the treatment of rheumatoid arthritis, but the most promising treatment results came from a group of medicinal agents called 'disease-modifying anti-rheumatic drugs'. Different foods have anti-inflammatory and antioxidant effect and help in protection against rheumatoid arthritis, but others, such as red meat and salt, have the opposite effect. Some dietary patterns and supplements, such as the Mediterranean Diet, vitamin D and probiotics, have been shown to have potential protective benefits against rheumatoid arthritis. Improvement in the quality of patient life requires an individualized management roadmap based on current patient medical data.

Rheumatoid arthritis treatment with zoledronic acid, a potentialinhibitorofGWAS-derived pharmacogenetics STAT3 and IL2 targets.

Rheumatoid arthritis (RA) is an inflammatory condition that primarily affects the joints and progress to affect other vital organs. Variety of drugs are being recommended to control the disease progression that benefits patients to perform day-to-day activities. Few of these RA drugs have noticeable side effects; therefore, it's crucial to choose the appropriate drug for treating RA with an understanding of the disease's pathophysiology. Herein, we investigated the RA genes from GWAS data to construct protein-protein interaction (PPI) network and to define appropriate drug targets for RA. The predicted drug targets were screened with the known RA drugs based on molecular docking. Further, the molecular dynamics simulations were performed to comprehend the conformational changes and stability of the targets upon binding of the selected top ranked RA drug. As a result, our constructed protein network from GWAS data revealed, STAT3 and IL2 could be potential pharmacogenetics targets that interlink most of the RA genes encoding proteins. These interlinked proteins of both the targets showed involvement in cell signaling, immune response, and TNF signaling pathway. Among the 192 RA drugs investigated, zoledronic acid had the lowest binding energy that inhibit both STAT3 (-6.307 kcal/mol) and IL2 (-6.231 kcal/mol). Additionally, STAT3 and IL2 trajectories on zoledronic acid binding exhibit notable differences in MD simulations as compared to a drug-free environment. Also, the in vitro assessment with the zoledronic acid confirms the outcome of our computational study. Overall, our study identify zoledronic acid could be potential inhibitor against these targets, that will benefits patients with RA. Comparative efficiency assessments between the RA drugs through clinical trials are needed to validate our findings in the treatment of RA.

Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients.

BACKGROUND: Human nucleotide triphosphate diphosphatase (NUDT15) is one of the essential proteins involved in the hydrolysis of anti-cancer drugs against leukemia. Polymorphisms in NUDT15 significantly affect the hydrolysis activity that leads to side effects, including leucopenia. Drugs having a better affinity with NUDT15 protein and contributing stable conformation may benefit patients from leucopenia. Most frequent NUDT15 polymorphisms causing structure variability and their association with leukemia were screened. The selected protein variants and anti-cancer drug structures were collected. Further, molecular docking was performed between drugs and NUDT15 variants along with the wild-type. Finally, molecular dynamics were executed for 100 ns to understand the stability of the protein with the anti-cancer drug based on molecular trajectories. RESULTS: Three-dimensional structures of NUDT15 wild, the most frequent variants (Val18Ile, Arg139Cys, and Arg139), and the anti-cancer drugs (azathioprine, mercaptopurine, and thioguanine) were selected and retrieved from structure databases. On molecular docking the binding energies of anti-cancer drugs against NUDT15 structures ranged from - 5.0 to - 5.9 kcal/mol. Among them, azathioprine showed the highest affinities (- 7.3 kcal/mol) for the wild and variant structures. Additionally, the molecular dynamics suggest all analyzed NUDT15 were stable with azathioprine based on the dynamic trajectories. CONCLUSION: Our results suggest azathioprine could be the preferable anti-cancer drug for the population with NUDT15 variants that could effectively be hydrolyzed as evidenced by molecular docking and dynamic simulation.

Virtual screening, molecular dynamics and density functional theory on pain inhibitors against TRPV1 associating inflammatory conditions.

Transient receptor potential vanilloid 1 protein (TRPV1) is expressed widely in skin and sensory neurons that contribute to pain/heat sensation in the human system. TRPV1 gene polymorphisms are susceptible to multiple diseases and it is considered a therapeutic target for various inflammatory conditions. Among the TRPV1 variants, rs8065080 (1911 A > G) plays a vital role in painful osteoarthritis and migraine. The presence of rs8065080 polymorphism may render drug efficacy. This study aimed to identify better antagonists against wild-type and variant TRPV1 that may help in the relief of pain/inflammation. We constructed suitable TRPV1 protein structures for wild-type and rs8065080 variant through a homology modelling approach. A total of 3363 anti-inflammatory compounds with high chemical diversity and good drug-like properties were collected and screened against the generated structures. Molecular docking showed that nobilamide B had the highest binding affinity (-5.83 kcal/mol) towards the wild-type. Whereas, isoquinoline analogue displayed highest binding potency with the variant TRPV1 (-11.65 kcal/mol). Besides those, C18H15F3N4O showed affinity towards both wild-type (-5.53 kcal/mol) and variant TRPV1 (-9.75 kcal/mol). Then, molecular dynamic simulation revealed stable conformation in wild-type and variant TRPV1 upon binding of nobilmaide B, isoquinoline analogue and C18H15F3N4O. Additionally, density functional theory (DFT) using B3LYP hybrid function showed high chemical reactiveness of nobilamie B, isoquinoline analogue and C18H15F3N4O. Overall, our systematic investigations provide, C18H15F3N4O could be a potential analgesic inhibiting both wild-type and variant TRPV1 against inflammatory conditions.

Comparative Evaluation of Salivary Parameters in Tobacco Substance Abusers.

BACKGROUND: Tobacco use by youth is ever-demanding, and it is increasingly distributed not only in India but also globally. Saliva is a complex oral bio-fluid, freely available, performing absolute tasks for maintaining oral health and homeostasis. It contains a plethora of significant constituents such as proline-rich proteins (PRPs), immunoglobulins, IgA, enzymes lysozyme, lactoferrin, peroxidases, amylase, etc. The basic ecological balance of the oral cavity is stabilized via salivary clearance by reduced aggregation and adherence of microorganisms by direct microbial activity. This balance of oral activity is also done by indirect mechanisms by immunological as well as non-immunological means and also by effectively regulating salivary pH flow rate. This institutional observational study was planned to assess and compare salivary parameters (pH, salivary flow rate), total proteins, α-amylase, calcium, phosphate, and IgA, of unstimulated whole saliva of both tobacco abusers and tobacco non-users. METHODS: The Study consisted of 270 participants (Tobacco habit) group, n = 135 and Control (Healthy) group, n = 135 and were in the age range of 20-50 years. They were assessed for oral health status, followed by the analysis of salivary pH, flow rate, total proteins, amylase, calcium, phosphates, and IgA of unstimulated whole saliva. RESULTS: Comparative evaluation of salivary parameters among groups found that varying tobacco abusers had increased salivary amylase, protein levels, and phosphate whereas decreased salivary pH, flow rate, IgA, and in the whole unstimulated saliva samples than those of non-tobacco users. This difference among groups was statistically significant. (p < 0.05), and calcium levels were not altered significantly. CONCLUSIONS: This study concludes that salivary parameters are altered in tobacco abusers when compared to those of non-abusers, and it was more significant in smokeless tobacco abusers than in any other form of tobacco abuse.

Molecular epidemiology, transmission and clinical features of 2022-mpox outbreak: A systematic review.

Background and Aims: The 2022-mpox outbreak has spread worldwide in a short time. Integrated knowledge of the epidemiology, clinical characteristics, and transmission of mpox are limited. This systematic review of peer-reviewed articles and gray literature was conducted to shed light on the epidemiology, clinical features, and transmission of 2022-mpox outbreak. Methods: We identified 45 peer-reviewed manuscripts for data analysis. The standards of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Statement and Cochrane Collaboration were followed for conducting the study. Results: The case number of mpox has increased about 100 times worldwide. About 99% of the cases in 2022 outbreak was from non-endemic regions. Men (70%-98% cases) were mostly infected with homosexual and bisexual behavior (30%-60%). The ages of the infected people ranged between 30 and 40 years. The presence of HIV and sexually transmitted infections among 30%-60% of cases were reported. Human-to-human transmission via direct contact and different body fluids were involved in the majority of the cases (90%-100%). Lesions in genitals, perianal, and anogenital areas were more prevalent. Unusually, pharyngitis (15%-40%) and proctitis (20%-40%) were more common during 2022 outbreak than pre-2022 outbreaks. Brincidofovir is approved for the treatment of smallpox by FDA (USA). Two vaccines, including JYNNEOSTM and ACAM2000®, are approved and used for pre- and post-prophylaxis in cases. About 100% of the cases in non-endemic regions were associated with isolates of IIb clade with a divergence of 0.0018-0.0035. Isolates from B.1 lineage were the most predominant followed by B.1.2 and B.1.10. Conclusion: This study will add integrated knowledge of the epidemiology, clinical features, and transmission of mpox.

Effects of Bacterial Metabolites on the Wnt4 Protein in Dental-Pulp-Stem-Cells-Based Endodontic Pulpitis Treatment.

Porphyromonas gingivalis is associated with endodontic pulpitis, causing damage to the dental pulp, leading to severe pain and a decline in quality of life. Regenerative pulp treatments using dental pulp stem cells (DPSCs) can be hindered by interactions between DPSCs and the infecting bacteria. The protein WNT family member 4 (Wnt4) plays a critical role in the differentiation of DPSCs and the regeneration of odontogenic tissue. However, the specific influence of P. gingivalis on Wnt4 remains unclear. In this study, we employed a computational approach to investigate the underlying mechanisms through which P. gingivalis-produced metabolites inhibit the Wnt4 protein, thereby diminishing the regenerative potential and therapeutic efficacy of odontogenic tissue. Among the metabolites examined, C29H46N7O18P3S-4 exhibited the strongest inhibitory effect on the Wnt4 protein, as evidenced by the lowest binding energy score of -6782 kcal/mol. Molecular dynamic simulation trajectories revealed that the binding of C29H46N7O18P3S-4 significantly altered the structural dynamics and stability of the Wnt4 protein. These alterations in protein trajectories may have implications for the molecular function of Wnt4 and its associated pathways. Overall, our findings shed light on the inhibitory impact of P. gingivalis-produced metabolites on the Wnt4 protein. Further in vitro, in vivo, and clinical studies are necessary to validate and expand upon our findings.

Eleven Crucial Pesticides Appear to Regulate Key Genes That Link MPTP Mechanism to Cause Parkinson's Disease through the Selective Degeneration of Dopamine Neurons.

Pesticides kill neurons, but the mechanism leading to selective dopaminergic loss in Parkinson's disease (PD) is unknown. Understanding the pesticide's effect on dopaminergic neurons (DA) can help to screen and treat PD. The critical uptake of pesticides by the membrane receptors at DA is hypothesized to activate a signaling cascade and accelerate degeneration. Using MPTP as a reference, we demonstrate the mechanisms of eleven crucial pesticides through molecular docking, protein networks, regulatory pathways, and prioritization of key pesticide-regulating proteins. Participants were recruited and grouped into control and PD based on clinical characteristics as well as pesticide traces in their blood plasma. Then, qPCR was used to measure pesticide-associated gene expression in peripheral blood mononuclear cells between groups. As a result of molecular docking, all eleven pesticides and the MPTP showed high binding efficiency against 274 membrane receptor proteins of DA. Further, the protein interaction networks showed activation of multiple signaling cascades through these receptors. Subsequent analysis revealed 31 biological pathways shared by all 11pesticides and MPTP that were overrepresented by 46 crucial proteins. Among these, CTNNB1, NDUFS6, and CAV1 were prioritized to show a significant change in gene expression in pesticide-exposed PD which guides toward therapy.

Prevalence and impact of long COVID-19 among patients with diabetes and cardiovascular diseases in Bangladesh.

Introduction: Co-prevalence of long-COVID-19, cardiovascular diseases and diabetes is one of the major health challenges of the pandemic worldwide. Studies on long-COVID-19 and associated health outcomes are absent in Bangladesh. The main aim of this study was to determine the prevalence and impact of long-COVID-19 on preexisting diabetes and cardiovascular diseases (CVD) on health outcomes among patients in Bangladesh. Methods: We collected data from 3,250 participants in Bangladesh, retrospectively. Multivariable logistic regression model was used to determine the odds ratio between independent and dependent variables. Kaplan-Meier survival curve was used to determine the cumulative survival. Results: COVID-19 was detected among 73.4% (2,385 of 3,250) participants. Acute long-COVID-19 was detected among 28.4% (678 of 2,385) and chronic long-COVID-19 among 71.6% (1,707 of 2,385) patients. CVD and diabetes were found among 32%, and 24% patients, respectively. Mortality rate was 18% (585 of 3,250) among the participants. Co-prevalence of CVD, diabetes and COVID-19 was involved in majority of fatality (95%). Fever (97%), dry cough (87%) and loss of taste and smell (85%) were the most prevalent symptoms. Patients with co-prevalence of CVD, diabetes and COVID-19 had higher risk of fatality (OR: 3.65, 95% CI, 2.79-4.24). Co-prevalence of CVD, diabetes and chronic long-COVID-19 were detected among 11.9% patients. Discussion: Risk of hospitalization and fatality reduced significantly among the vaccinated. This is one of the early studies on long-COVID-19 in Bangladesh.

Panoramic view of key cross-talks underpinning the oral squamous cell carcinoma stemness - unearthing the future opportunities.

The clinical management of oral cancer is often frequented with challenges that arise from relapse, recurrence, invasion and resistance towards the cornerstone chemo and radiation therapies. The recent conceptual advancement in oncology has substantiated the role of cancer stem cells (CSC) as a predominant player of these intricacies. CSC are a sub-group of tumor population with inherent adroitness to self-renew with high plasticity. During tumor evolution, the structural and functional reprogramming persuades the cancer cells to acquire stem-cell like properties, thus presenting them with higher survival abilities and treatment resistance. An appraisal on key features that govern the stemness is of prime importance to confront the current challenges encountered in oral cancer. The nurturing niche of CSC for maintaining its stemness characteristics is thought to be modulated by complex multi-layered components encompassing neoplastic cells, extracellular matrix, acellular components, circulatory vessels, various cascading signaling molecules and stromal cells. This review focuses on recapitulating both intrinsic and extrinsic mechanisms that impart the stemness. There are contemplating evidences that demonstrate the role of transcription factors (TF) in sustaining the neoplastic stem cell's pluripotency and plasticity alongside the miRNA in regulation of crucial genes involved in the transformation of normal oral mucosa to malignancy. This review illustrates the interplay between miRNA and various known TF of oral cancer such as c-Myc, SOX, STAT, NANOG and OCT in orchestrating the stemness and resistance features. Further, the cross-talks involved in tumor micro-environment inclusive of cytokines, macrophages, extra cellular matrix, angiogenesis leading pathways and influential factors of hypoxia on tumorigenesis and CSC survival have been elucidated. Finally, external factorial influence of oral microbiome gained due to the dysbiosis is also emphasized. There are growing confirmations of the possible roles of microbiomes in the progression of oral cancer. Given this, an attempt has been made to explore the potential links including EMT and signaling pathways towards resistance and stemness. This review provides a spectrum of understanding on stemness and progression of oral cancers at various regulatory levels along with their current therapeutic knowledge. These mechanisms could be exploited for future research to expand potential treatment strategies.

Leveraging technology-driven strategies to untangle omics big data: circumventing roadblocks in clinical facets of oral cancer.

Oral cancer is one of the 19most rapidly progressing cancers associated with significant mortality, owing to its extreme degree of invasiveness and aggressive inclination. The early occurrences of this cancer can be clinically deceiving leading to a poor overall survival rate. The primary concerns from a clinical perspective include delayed diagnosis, rapid disease progression, resistance to various chemotherapeutic regimens, and aggressive metastasis, which collectively pose a substantial threat to prognosis. Conventional clinical practices observed since antiquity no longer offer the best possible options to circumvent these roadblocks. The world of current cancer research has been revolutionized with the advent of state-of-the-art technology-driven strategies that offer a ray of hope in confronting said challenges by highlighting the crucial underlying molecular mechanisms and drivers. In recent years, bioinformatics and Machine Learning (ML) techniques have enhanced the possibility of early detection, evaluation of prognosis, and individualization of therapy. This review elaborates on the application of the aforesaid techniques in unraveling potential hints from omics big data to address the complexities existing in various clinical facets of oral cancer. The first section demonstrates the utilization of omics data and ML to disentangle the impediments related to diagnosis. This includes the application of technology-based strategies to optimize early detection, classification, and staging via uncovering biomarkers and molecular signatures. Furthermore, breakthrough concepts such as salivaomics-driven non-invasive biomarker discovery and omics-complemented surgical interventions are articulated in detail. In the following part, the identification of novel disease-specific targets alongside potential therapeutic agents to confront oral cancer via omics-based methodologies is presented. Additionally, a special emphasis is placed on drug resistance, precision medicine, and drug repurposing. In the final section, we discuss the research approaches oriented toward unveiling the prognostic biomarkers and constructing prediction models to capture the metastatic potential of the tumors. Overall, we intend to provide a bird's eye view of the various omics, bioinformatics, and ML approaches currently being used in oral cancer research through relevant case studies.

COVID-19 signalome: Pathways for SARS-CoV-2 infection and impact on COVID-19 associated comorbidity.

The COVID-19 pandemic has been the focus of research the past two years. The major breakthrough was made by discovering pathways related to SARS-CoV-2 infection through cellular interaction by angiotensin-converting enzyme (ACE2) and cytokine storm. The presence of ACE2 in lungs, intestines, cardiovascular tissues, brain, kidneys, liver, and eyes shows that SARS-CoV-2 may have targeted these organs to further activate intracellular signalling pathways that lead to cytokine release syndrome. It has also been reported that SARS-CoV-2 can hijack coatomer protein-I (COPI) for S protein retrograde trafficking to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), which, in turn, acts as the assembly site for viral progeny. In infected cells, the newly synthesized S protein in endoplasmic reticulum (ER) is transported first to the Golgi body, and then from the Golgi body to the ERGIC compartment resulting in the formation of specific a motif at the C-terminal end. This review summarizes major events of SARS-CoV-2 infection route, immune response following host-cell infection as an important factor for disease outcome, as well as comorbidity issues of various tissues and organs arising due to COVID-19. Investigations on alterations of host-cell machinery and viral interactions with multiple intracellular signaling pathways could represent a major factor in more effective disease management.

COVID-19 signalome: Potential therapeutic interventions.

The COVID-19 pandemic has triggered intensive research and development of drugs and vaccines against SARS-CoV-2 during the last two years. The major success was especially observed with development of vaccines based on viral vectors, nucleic acids and whole viral particles, which have received emergent authorization leading to global mass vaccinations. Although the vaccine programs have made a big impact on COVID-19 spread and severity, emerging novel variants have raised serious concerns about vaccine efficacy. Due to the urgent demand, drug development had originally to rely on repurposing of antiviral drugs developed against other infectious diseases. For both drug and vaccine development the focus has been mainly on SARS-CoV-2 surface proteins and host cell receptors involved in viral attachment and entry. In this review, we expand the spectrum of SARS-CoV-2 targets by investigating the COVID-19 signalome. In addition to the SARS-CoV-2 Spike protein, the envelope, membrane, and nucleoprotein targets have been subjected to research. Moreover, viral proteases have presented the possibility to develop different strategies for the inhibition of SARS-CoV-2 replication and spread. Several signaling pathways involving the renin-angiotensin system, angiotensin-converting enzymes, immune pathways, hypoxia, and calcium signaling have provided attractive alternative targets for more efficient drug development.

Assessing the Effect of Curcumin on the Oral Mucosal Cytomorphometry and Candidal Species Specificity in Tobacco Users: A Pilot Study.

OBJECTIVES: Tobacco consumption is of major concern for public health. Compromised oral hygiene accentuated by tobacco leads to alteration in the oral mucosa and microbiome, including Candida, and its species can be identified rapidly using CHROMagar. Curcumin, a naturally available compound possesses antioxidant, anti-inflammatory, anti-microbial, anti-carcinogenic, anti-fungal, and immunomodulatory properties. Hence, a comprehensive study was planned. AIM: To evaluate and compare cytomorphometric analysis and Candida colonization and speciation in tobacco users before and after the use of curcumin gel. MATERIALS AND METHODS: The study comprised a total of 120 participants (the study (tobacco habit) group, n = 60 and control (healthy) group, n = 60). The intervention was the application of curcumin gel over the lesion area three times daily for 2 months. All participants' oral health status was assessed, followed by cytomorphometric analysis and Candida colonization and speciation using CHROMagar. RESULTS: Cytomorphometric analysis showed statistically significant differences in the control and study group for cell diameter (CD), nuclear diameter (ND), CD:ND ratio, and micronuclei (p = 0.0001). Candida colonization had a significantly higher number of colonies in the habit group when compared to the control group. Candida tropicalis was predominant in the study group, whereas Candida albicans was predominant in the control group. In the study group, after intervention with curcumin, a statistically significant difference was seen in nuclear diameter, CD:ND ratio, and micronuclei. There was a reduction in the number of Candida colonies, and Candida albicans was the predominant species observed in the study group after the intervention of curcumin and discontinuation of habit. CONCLUSION: Curcumin was found to reduce the number of micronuclei and also decreased Candida colonization, along with the discontinuation of habit in tobacco users.