Therapeutic potential of lipid nanosystems for the treatment of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. The degeneration of dopaminergic neurons in the midbrain is primarily responsible for the onset of the disease. The major challenge faced in the treatment of PD is the blood-brain barrier (BBB), which impedes the delivery of therapeutics to targeted locations. To address this issue, lipid nanosystems have been used for the precise delivery of therapeutic compounds in anti-PD therapy. In this review, we will discuss the application and clinical significance of lipid nanosystem in delivering therapeutic compounds for anti-PD treatment. These medicinal compounds include ropinirole, apomorphine, bromocriptine, astaxanthin, resveratrol, dopamine, glyceryl monooleate, levodopa, N-3,4-bis(pivaloyloxy)- dopamine and fibroblast growth factor, which have significant potential to treat PD in the early stage. This review, in a nutshell, will pave the way for researchers to develop diagnostic and potential therapeutic approaches using nanomedicine to overcome the challenges posed by the BBB in delivering therapeutic compounds for PD.

Potential Regulation of miRNA-29 and miRNA-9 by Estrogens in Neurodegenerative Disorders: An Insightful Perspective.

Finding a link between a hormone and microRNAs (miRNAs) is of great importance since it enables the adjustment of genetic composition or cellular functions without needing gene-level interventions. The dicer-mediated cleavage of precursor miRNAs is an interface link between miRNA and its regulators; any disruption in this process can affect neurogenesis. Besides, the hormonal regulation of miRNAs can occur at the molecular and cellular levels, both directly, through binding to the promoter elements of miRNAs, and indirectly, via regulation of the signaling effects of the post-transcriptional processing proteins. Estrogenic hormones have many roles in regulating miRNAs in the brain. This review discusses miRNAs, their detailed biogenesis, activities, and both the general and estrogen-dependent regulations. Additionally, we highlight the relationship between miR-29, miR-9, and estrogens in the nervous system. Such a relationship could be a possible etiological route for developing various neurodegenerative disorders.

Mouth rinses efficacy on salivary SARS-CoV-2 viral load: A randomized clinical trial.

Considering the global trend to confine the COVID-19 pandemic by applying various preventive health measures, preprocedural mouth rinsing has been proposed to mitigate the transmission risk of SARS-CoV-2 in dental clinics. The study aimed to investigate the effect of different mouth rinses on salivary viral load in COVID-19 patients. This study was a single-center, randomized, double-blind, six-parallel-group, placebo-controlled clinical trial that investigated the effect of four mouth rinses (1% povidone-iodine, 1.5% hydrogen peroxide, 0.075% cetylpyridinium chloride, and 80 ppm hypochlorous acid) on salivary SARS-CoV-2 viral load relative to the distilled water and no-rinse control groups. The viral load was measured by quantitative reverse transcription PCR (RT-qPCR) at baseline and 5, 30, and 60 min post rinsing. The viral load pattern within each mouth rinse group showed a reduction overtime; however, this reduction was only statistically significant in the hydrogen peroxide group. Further, a significant reduction in the viral load was observed between povidone-iodine, hydrogen peroxide, and cetylpyridinium chloride compared to the no-rinse group at 60 min, indicating their late antiviral potential. Interestingly, a similar statistically significant reduction was also observed in the distilled water control group compared to the no-rinse group at 60 min, proposing mechanical washing of the viral particles through the rinsing procedure. Therefore, results suggest using preprocedural mouth rinses, particularly hydrogen peroxide, as a risk-mitigation step before dental procedures, along with strict adherence to other infection control measures.

Potential Disruption of Systemic Hormone Transport by Tobacco Alkaloids Using Computational Approaches.

Tobacco/nicotine is one of the most toxic and addictive substances and continues to pose a significant threat to global public health. The harmful effects of smoking/nicotine affect every system in the human body. Nicotine has been associated with effects on endocrine homeostasis in humans such as the imbalance of gonadal steroid hormones, adrenal corticosteroid hormones, and thyroid hormones. The present study was conducted to characterize the structural binding interactions of nicotine and its three important metabolites, cotinine, trans-3'-hydroxycotinine, and 5'-hydroxycotinine, against circulatory hormone carrier proteins, i.e., sex-hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), and thyroxine-binding globulin (TBG). Nicotine and its metabolites formed nonbonded contacts and/or hydrogen bonds with amino acid residues of the carrier proteins. For SHBG, Phe-67 and Met-139 were the most important amino acid residues for nicotine ligand binding showing the maximum number of interactions and maximum loss in ASA. For CBG, Trp-371 and Asn-264 were the most important amino acid residues, and for TBG, Ser-23, Leu-269, Lys-270, Asn-273, and Arg-381 were the most important amino acid residues. Most of the amino acid residues of carrier proteins interacting with nicotine ligands showed a commonality with the interacting residues for the native ligands of the proteins. Taken together, the results suggested that nicotine and its three metabolites competed with native ligands for binding to their carrier proteins. Thus, nicotine and its three metabolites may potentially interfere with the binding of testosterone, estradiol, cortisol, progesterone, thyroxine, and triiodothyronine to their carrier proteins and result in the disbalance of their transport and homeostasis in the blood circulation.

The Relationship between Psychological Disability and Religious Practice and Coping Strategies in Caregivers of Children with Traumatic Brain Injury in Pakistani Population.

BACKGROUND: Traumatic brain injury (TBI) is a serious issue and a leading cause of death and disability worldwide. Caregivers of TBI patients experience psychological distress and a variety of social and financial issues. The present study aims to investigate the caregiver's burden and the factors that influence this burden. Furthermore, the present study will find out the association of religious practice, religious coping relations and psychological distress among caregivers of children affected with TBI. METHODS: A cross-sectional survey was conducted on 302 caregivers of children with TBI using Duke University Religion Index (DURL) for religious practice. General Health Questionaire-12 (GHQ-12) was used for anxiety and depression and Brief Religious Coping Scale (RCOPE) was used for coping strategies. The caregivers were conveniently chosen from different regions of Khyber Pakhtunkhwa province and data was collected from different tertiary care hospitals in Peshawar. RESULTS: Forty-nine (49) % of caregivers score ≥ 3 on GHQ suffer from psychological distress with a Mean of 20.957 ± 4.175). Positive coping methods were mostly used by caregivers than negative coping have a low level of distress with a Mean Positive Coping (P-COPE ) of 6.93 ± 0.41, Mean of Negative Coping (N-COPE) 0.486 ± 1.023. In religious practice, caregivers mostly participate in Organized Reliogious Activities (ORA) or some Non-Organized Reliogious Activities (NORA) with a Mean ORA of 4.20 ± 1.27, and NORA Mean of 4.17 ± 1.37 used by the caregivers. Coping methods were related to Caregiver psychological distress (GHQ-12 and P-COPE co-relation scores are (ρ -0.022, p b 0.05); GHQ-12 scores and N-COPE (ρ + 0.221=, p b 0.001). There is a negative correlation between GHQ 12 and PCOPE, while GHQ12 is positively correlated with NCOPE. CONCLUSION: According to this study, there is a significant association between religious coping methods, religious practice, and psychological distress among caregivers of children with traumatic brain injury.

A literature perspective on the pharmacological applications of yohimbine.

Introduction: Phytochemicals have garnered much attention because they are useful in managing several human diseases. Yohimbine is one such phytochemical with significant pharmacological potential and could be exploited for research by medicinal chemists. It is an indole alkaloid obtained from various natural/synthetic sources.Aims and Results: The research on yohimbine started early, and its use as a stimulant and aphrodisiac by humans has been reported for a long time. The pharmacological activity of yohimbine is mediated by the combined action of the central and peripheral nervous systems. It selectively blocks the pre and postsynaptic α2-adrenergic receptors and has a moderate affinity for α1 and α2 subtypes. Yohimbine also binds to other behaviourally relevant monoaminergic receptors in the following order: α-2 NE > 5HT-1A>, 5HT-1B > 1-D > D3 > D2 receptors.Conclusion: The current review highlights some significant findings that contribute to developing yohimbine-based drugs. It also highlights the therapeutic potential of yohimbine against selected human diseases. However, further research is recommended on the pharmacokinetics, molecular mechanisms, and drug safety requirements using well-designed randomized clinical trials to produce yohimbine as a pharmaceutical agent for human use.Key MessagesYohimbine is a natural indole alkaloid with significant pharmacological potential.Humans have used it as a stimulant and aphrodisiac from a relatively early time.It blocks the pre- and postsynaptic α2-adrenergic receptors that could be exploited for managing erectile dysfunction, myocardial dysfunction, inflammatory disorders, and cancer.

Where do T cell subsets stand in SARS-CoV-2 infection: an update.

An outbreak of coronavirus disease 2019 (COVID-19) emerged in China in December 2019 and spread so rapidly all around the globe. It's continued and spreading more dangerously in India and Brazil with higher mortality rate. Understanding of the pathophysiology of COVID-19 depends on unraveling of interactional mechanism of SARS-CoV-2 and human immune response. The immune response is a complex process, which can be better understood by understanding the immunological response and pathological mechanisms of COVID-19, which will provide new treatments, increase treatment efficacy, and decrease mortality associated with the disease. In this review we present a amalgamate viewpoint based on the current available knowledge on COVID-19 which includes entry of the virus and multiplication of virus, its pathological effects on the cellular level, immunological reaction, systemic and organ presentation. T cells play a crucial role in controlling and clearing viral infections. Several studies have now shown that the severity of the COVID-19 disease is inversely correlated with the magnitude of the T cell response. Understanding SARS-CoV-2 T cell responses is of high interest because T cells are attractive vaccine targets and could help reduce COVID-19 severity. Even though there is a significant amount of literature regarding SARS-CoV-2, there are still very few studies focused on understanding the T cell response to this novel virus. Nevertheless, a majority of these studies focused on peripheral blood CD4+ and CD8+ T cells that were specific for viruses. The focus of this review is on different subtypes of T cell responses in COVID-19 patients, Th17, follicular helper T (TFH), regulatory T (Treg) cells, and less classical, invariant T cell populations, such as δγ T cells and mucosal-associated invariant T (MAIT) cells etc that could influence disease outcome.

Amplifying Lateral Flow Assay Signals for Rapid Detection of COVID-19 Specific Antibodies.

Rapid lateral flow immune-assays are point-of-care diagnostic tools that are easy to use, cheap, and do not need centralized infrastructure. Therefore, these devices are appealing for rapid detection of the humoral immune responses to infections, particularly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel technique introduced here uses a complex of anti-SARS-CoV-2 N-protein antibodies conjugated to gold nanoparticles that are bound to five SARS-CoV-2 N protein conjugated to gold nanoparticles to amplify the signals obtained from the conjugated SARS-CoV-2 N protein and to enhance the assay detection limit. To validate the performance of the adopted lateral flow, serum from SARS-CoV-2 seropositive individuals and prepandamic negative samples are tested and compared to a validated enzyme-linked immunosorbent assay (ELISA) for the detection of SARS-CoV-2 N protein specific IgG and IgM antibodies. The data shows that the designed lateral flow assay has an excellent sensitivity and specificity upon detecting IgM and IgG antibodies by applying only 2 µL from the serum sample to the adopted strips. Taken together, the developed lateral flow immunoassay assay provides a rapid, specific, and highly sensitive means to detect the immune responses against SARS-CoV-2 with only 2 µL from the serum sample.

Identification of Potential Poly (ADP-Ribose) Polymerase-1 Inhibitors Derived from Rauwolfia serpentina: Possible Implication in Cancer Therapy.

Poly (ADP-ribose) polymerase-1 (PARP-1) has been recognized as a prospective target for the development of novel cancer therapeutics. Several PARP-1 inhibitors are currently being considered for anticancer drug development and clinical investigation. Lately, natural compounds seem to be excellent alternative drug candidates for cancer treatment. Rauwolfia serpentina is a medicinal plant traditionally used in Indian subcontinents to treat various diseases. This study has been designed to identify the bioactive compounds derived from R. serpentina for possible binding and inhibition of PARP-1 using the molecular docking approach. Thirteen compounds were found to interact with the target with a binding affinity greater than the value of -9.0 kcal/mol. After screening the physicochemical properties, only 5 ligands (ajmalicine, yohimbine, isorauhimbine, rauwolscine, and 1,2-dihydrovomilenine) were found to obey all the parameters of Lipinski's rule of five, showed maximum drug-likeness, and possess no significant toxicity. These ligands displayed strong interactions with target PARP-1 via several hydrogen bonds and hydrophobic interactions. Therefore, these identified compounds derived from R. serpentina can be considered for drug development against cancer-targeting PARP-1.

Immunogenicity of The BNT162b2 COVID-19 mRNA and ChAdOx1 nCoV-19 Vaccines in Patients with Hemoglobinopathies.

INTRODUCTION: Studies assessing immune responses following Pfizer-BioNTech BNT162b2 mRNA COVID-19 (Pfizer) and ChAdOx1 nCoV-19 AZD1222 (AstraZeneca) vaccines in patients with hemoglobinopathy are non-existent in the literature despite being thought at high risk of infection. METHODS: Prospectively, we collected serum from patients with hemoglobinopathies at least 14 days post vaccine and measured neutralizing antibodies (nAb) in addition to binding antibodies using in-house assays. RESULTS: All 66 participants mounted a significant binding antibody response (100%), but nAbs were detected in (56/66) post-vaccine with a rate of 84.5%. Age, gender, vaccine type, spleen status, hydroxyurea use, and hyperferritinemia did not affect the rate significantly. While 23/32 (71.8%) patients receiving only one dose of the vaccine were able to mount a positive response, 33/34 (97.05%) of those who had two doses of any vaccine type had a significant nAbs response. Patients who had anti-nucleocapsid (N), signifying asymptomatic infection in the past, were able to produce nAbs (31/31). No nAbs were detected in 10/35 (28.5%) patients with no anti-N antibodies. CONCLUSION: Our results provide supportive data when advising patients with hemoglobinopathy to receive COVID-19 vaccines and ensure booster doses are available for better immunity. Whenever available, measurement of nAb is recommended.

Elucidating Antiangiogenic Potential of Rauwolfia serpentina: VEGFR-2 Targeting-Based Molecular Docking Study.

Angiogenesis plays a critical role in tumorigenesis as it provides the necessary blood supply to the newly grown solid tumor. It helps maintain the tumor microenvironment, promotes tumor development, progression, and metastasis. The vascular epithelial growth factor (VEGF), interacting with the tyrosine kinase receptor VEGFR-2 on endothelial cells, exerts its proangiogenic activity. Hence, targeting the VEGFR-2 signaling is considered a promising strategy to inhibit angiogenesis and thus cancer treatment. This study aims to identify the bioactive compounds derived from the medicinal herb Rauwolfia serpentina that effectively binds with VEGFR-2. The bioactive compounds of R. serpentina were first screened for their physicochemical properties using the DataWarrior program (version 5.5.0). Finally, 17 compounds that obeyed Lipinski's rule of five and showed good drug-likeness were selected for molecular docking studies. Molecular docking results showed that the ligands ajmalicidine, 1, 2-dihydrovomilenine, rauwolscine, yohimbine, ajmaline, and papaverine interact strongly with the target VEGFR-2 receptor. Hydrogen bonds and hydrophobic interactions stabilized the interactions of these compounds with VEGFR-2. These compounds showed favourable drug-like properties and possess no significant toxicity. Therefore, the findings of this study indicate that the compounds derived from R. serpentina can be considered for the development of antiangiogenic drug candidates by targeting VEGFR-2.

Molecular determinants of etoposide resistance in HL60 cells.

Chemotherapy resistance is the main reason for treatment failure in acute myeloid leukemia (AML) and the major cause of its mortality. Etoposide is a DNA topoisomerase-II inhibitor that is used either as a single agent or in combination with cytarabine, azacytidine, vinca alkaloids, and anthracyclines for the treatment of relapsed /refractory AML. In this study, we sought to determine and understand the mechanism of etoposide resistance in AML using the HL60 cell line.HL60 cells were treated with incremental doses of etoposide and resistant colonies were isolated by culturing the resistant cells in semi-solid culture media. Three clones were selected for etoposide resistance namely, HL60-EtopR H1A, HL60-EtopR H1B, and HL60-EtopR H1C which demonstrated 4.78, 2.39, and 4.42-fold higher resistance to etoposide compared with the parental cells. To determine molecular differences between the etoposide-resistant HL60-EtopR cells and the parental cells, microarray-based gene expression profiling was performed. We found up regulation of members of the src tyrosine kinase family genes in the etoposide resistant cells. Further studies are required to evaluate the role of Src inhibitors in targeting etoposide resistant cells.

Low clinical utility of testing for anti-platelet factor 4 in asymptomatic individuals after ChAdOx1 nCoV-19 vaccine.

INTRODUCTION: The development of anti-platelet factor 4 (PF4) antibodies is linked to a rare thrombotic complication described now as vaccine-induced immune thrombotic thrombocytopenia (VITT). This clinical syndrome with thrombosis and thrombocytopenia was reported after exposure to the Oxford-AstraZeneca COVID-19 vaccine, ChAdOx1 nCoV-19 vaccine (AZD1222), and Ad26.COV2.S vaccine (Janssen/Johnson & Johnson). In the absence of the clinical features, the incidence of positive anti-PF4 antibodies in asymptomatic individuals post-vaccination is unclear. METHODS: The aim of this study was to evaluate the development of anti-PF4 antibodies in asymptomatic individuals 14-21 days after receiving the first dose of ChAdOx1 nCoV-19 vaccine (AZD1222) and BNT162b2 vaccine. Prospectively, we collected serum from individuals before and after ChAdOx1 nCoV-19 vaccine and BNT162b2 vaccine and measured anti-PF4 antibodies using the Asserachrom HPIA IgG ELISA (Stago, Asnieres, France). RESULTS: We detected positive anti-PF4 antibodies in 5 of 94 asymptomatic individuals post-vaccine with a rate of 5.3% with low titers (OD 0.3-0.7). Four of 5 individuals who tested positive after the vaccine had also positive anti-PF4 antibodies before the vaccine, which indicates that a majority of the positive results are due to preexisting anti-PF4 antibodies. We did not find a relation between the development of anti-PF4 antibodies and the immune response to the vaccine, status of prior COVID-19 infection, and baseline characteristics of participants. None of the participants developed thrombosis nor thrombocytopenia. CONCLUSION: Our results provide new evidence to guide the diagnostic algorithm of suspected cases of VITT. In the absence of thrombosis and thrombocytopenia, there is a low utility of testing for anti-PF4 antibodies.

Organotin Antifouling Compounds and Sex-Steroid Nuclear Receptor Perturbation: Some Structural Insights.

Organotin compounds (OTCs) are a commercially important group of organometallic compounds of tin used globally as polyvinyl chloride stabilizers and marine antifouling biocides. Worldwide use of OTCs has resulted in their ubiquitous presence in ecosystems across all the continents. OTCs have metabolic and endocrine disrupting effects in marine and terrestrial organisms. Thus, harmful OTCs (tributyltin) have been banned by the International Convention on the Control of Harmful Antifouling Systems since 2008. However, continued manufacturing by non-member countries poses a substantial risk for animal and human health. In this study, structural binding of common commercial OTCs, tributyltin (TBT), dibutyltin (DBT), monobutyltin (MBT), triphenyltin (TPT), diphenyltin (DPT), monophenyltin (MPT), and azocyclotin (ACT) against sex-steroid nuclear receptors, androgen receptor (AR), and estrogen receptors (ERα, ERß) was performed using molecular docking and MD simulation. TBT, DBT, DPT, and MPT bound deep within the binding sites of AR, ERα, and Erß, showing good dock score, binding energy and dissociation constants that were comparable to bound native ligands, testosterone and estradiol. The stability of docking complex was shown by MD simulation of organotin/receptor complex with RMSD, RMSF, Rg, and SASA plots showing stable interaction, low deviation, and compactness of the complex. A high commonality (50-100%) of interacting residues of ERα and ERß for the docked ligands and bound native ligand (estradiol) indicated that the organotin compounds bound in the same binding site of the receptor as the native ligand. The results suggested that organotins may interfere with the natural steroid/receptor binding and perturb steroid signaling.

Seroprevalence of SARS-CoV-2 Binding and Neutralizing Antibodies in Healthcare Workers during the Epidemic Peak in Referral Hospitals and Quarantine Sites: Saudi Arabia.

Healthcare workers (HCWs) are at high risk for SARS-CoV-2 infection compared to the general population. Here, we aimed to evaluate and characterize the SARS-CoV-2 seropositivity rate in randomly collected samples among HCWs from the largest referral hospitals and quarantine sites during the peak of the COVID-19 epidemic in the city of Jeddah, the second largest city in Saudi Arabia, using a cross-sectional analytic study design. Out of 693 participants recruited from 29 June to 10 August 2020, 223 (32.2%, 95% CI: 28.8-35.8) were found to be confirmed seropositive for SARS-CoV-2 antibodies, and among those 197 (88.3%) had never been diagnosed with COVID-19. Seropositivity was not significantly associated with participants reporting COVID-19 compatible symptoms as most seropositive HCW participants 140 (62.8%) were asymptomatic. The large proportion of asymptomatic SARS-CoV-2 cases detected in our study demands periodic testing as a general hospital policy.

Cellular and Humoral Immunogenicity of a Candidate DNA Vaccine Expressing SARS-CoV-2 Spike Subunit 1.

The urgent need for effective, safe and equitably accessible vaccines to tackle the ongoing spread of COVID-19 led researchers to generate vaccine candidates targeting varieties of immunogens of SARS-CoV-2. Because of its crucial role in mediating binding and entry to host cell and its proven safety profile, the subunit 1 (S1) of the spike protein represents an attractive immunogen for vaccine development. Here, we developed and assessed the immunogenicity of a DNA vaccine encoding the SARS-CoV-2 S1. Following in vitro confirmation and characterization, the humoral and cellular immune responses of our vaccine candidate (pVAX-S1) was evaluated in BALB/c mice using two different doses, 25 µg and 50 µg. Our data showed high levels of SARS-CoV-2 specific IgG and neutralizing antibodies in mice immunized with three doses of pVAX-S1. Analysis of the induced IgG subclasses showed a Th1-polarized immune response, as demonstrated by the significant elevation of spike-specific IgG2a and IgG2b, compared to IgG1. Furthermore, we found that the immunization of mice with three doses of 50 µg of pVAX-S1 could elicit significant memory CD4+ and CD8+ T cell responses. Taken together, our data indicate that pVAX-S1 is immunogenic and safe in mice and is worthy of further preclinical and clinical evaluation.

A Direct Method for RT-PCR Detection of SARS-CoV-2 in Clinical Samples.

INTRODUCTION: the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of acute respiratory disease (COVID-19). SARS-CoV-2 is a positive-strand RNA virus and its genomic characterization has played a vital role in the design of appropriate diagnostics tests. The current RT-PCR protocol for SARS-CoV-2 detects two regions of the viral genome, requiring RNA extraction and several hours. There is a need for fast, simple, and cost-effective detection strategies. METHODS: we optimized a protocol for direct RT-PCR detection of SARS-CoV-2 without the need for nucleic acid extraction. Nasopharyngeal samples were diluted to 1:3 using diethyl pyrocarbonate (DEPC)-treated water. The diluted samples were incubated at 95 °C for 5 min in a thermal cycler, followed by a cooling step at 4 °C for 5 min. Samples then underwent reverse transcription real-time RT-PCR in the E and RdRp genes. RESULTS: our direct detection protocol showed 100% concordance with the standard protocol with an average Ct value difference of 4.38 for the E region and 3.85 for the RdRp region. CONCLUSION: the direct PCR technique was found to be a reliable and sensitive method that can be used to reduce the time and cost of the assay by removing the need for RNA extraction. It enables the use of the assay in research, diagnostics, and screening for COVID-19 in regions with fewer economic resources, where supplies are more limited allowing for wider use for screening.

mTOR Targeted Cancer Chemoprevention by Flavonoids.

Over the past several decades, plant-derived products (phytochemicals) have been suggested to possess immense therapeutic potential. Among these phytochemicals, different flavonoids have been reported for their potent anticancer activity. To exhibit their anticancer potential, these flavonoids modulate different signaling pathways. Among these pathways, the mammalian target of rapamycin (mTOR) and associated phosphatidyl-inositol 3-kinase (PI3K)/protein kinase B (Akt) signaling cascade have been reported as a pivotal modulator of cell survival, proliferation, and death/apoptosis. Hence, targeting this cascade could be an ideal strategy to alleviate apoptosis and inhibit proliferation in different forms of cancer. The targeting of PI3K/Akt/mTOR by flavonoids have been well documented in the scientific literature. In the current study, we have studied the anticancer potential of various flavonoids, especially flavones, flavonols, and isoflavones that include apigenin, luteolin, baicalein, tangeretin, epigallocatechin- 3-gallate, genistein, and daidzein especially dealing with mTOR targeting.

Molecular characterisation in tongue squamous cell carcinoma reveals key variants potentially linked to clinical outcomes.

BACKGROUND: Oral tongue squamous cell carcinoma (OTSCC) is a highly aggressive malignancy characterized by frequent recurrence, poor survival with relatively few therapeutic options due to the late diagnosis in many cases. OBJECTIVES: Understanding the molecular pathways underlying OTSCC tumourigenesis and the discovery of diagnostic and/or prognostic biomarkers. METHODS: We performed high-throughput mutational analysis of 44 OTSCC formalin-fixed paraffin-embedded (FFPE) cases using the Cancer Hotspots Panel (CHP) v2 on the Ion Torrent™platform. We determined the frequency of human papilloma virus (HPV) using PCR and Epstein bar virus (EBV) positivity using immunohistochemistry. As a control for EBV infection we screened matched non-tumourous tissues. RESULTS: Sequencing analysis identified missense, nonsense and frameshift mutations in TP53 (66%), PIK3CA (27%), CDKN2A (25%), EGFR (18%), and PTEN (14%). Interestingly, no significant associations were found between damaging mutations and clinicopathological data. A total of 10/44 of the OTSCC samples (23%) tested was positive for HPV18 DNA. OTSCC patients with positive HPV infection had worse overall survival compared to HPV-negative cases as determined by Kaplan-Meier survival (p= 0.023). Furthermore, EBNA1 expression showed a strong tumour-enriched expression pattern in 20 out of 21 samples (95%) in the epithelial compartments of the tissues analysed. CONCLUSIONS: Taken together, this study highlights that the two most common events in OTSCC are TP53 mutations and EBV positivity. Helping to understand the contribution of TP53 mutations and EBV infection events could serve as useful biomarkers for OTSCC.

The Effect Sizes of PPARγ rs1801282, FTO rs9939609, and MC4R rs2229616 Variants on Type 2 Diabetes Mellitus Risk among the Western Saudi Population: A Cross-Sectional Prospective Study.

Type 2 diabetes mellitus (T2DM) is a common polygenic disease with associated comorbidities. Obesity is a major risk factor for the development of T2DM. The aim of this study is to determine the allele and genotype frequency of peroxisome proliferator-activated receptor-γ (PPARγ) rs1801282, fat mass and obesity-associated protein (FTO) rs9939609, and melanocortin 4 receptor (MC4R) rs2229616 polymorphisms and their association with risk of T2DM in the western Saudi population as mediators of adiposity phenotypes. In a cross-sectional prospective study, genomic DNA from control and T2DM patients were isolated and genotyped for these single-nucleotide polymorphisms. There was a significant association of the MC4R rs2229616 variant with T2DM, but no association with T2DM was detected with PPARγ rs1801282 or FTO rs9939609. The combination of C/C for PPARγ rs1801282, A/A for FTO rs9939609, and C/C for MC4R rs2229616 increased the risk of T2DM by 1.82. The A/T genotype for FTO rs9939609 was predicted to decrease the risk of T2DM when combined with C/C for PPARγ rs1801282 and C/C for MC4R rs2229616 or C/C for PPARγ rs1801282 and C/T MC4R rs2229616. In conclusion, our study showed the risk of the assessed variants for the development of T2DM in the Saudi population.