Exploration of comprehensive marine natural products database against dengue viral non-structural protein 1 using high-throughput computational studies.

Dengue virus (DENV) non-structural protein 1 (NS1) is a versatile quasi-protein essential for the multiplication of the virus. This study applied high-throughput virtual screening (HTVS) and molecular dynamics (MD) simulation to detect the potential marine natural compounds against the NS1 of DENV. The structure of the NS1 protein was retrieved from Protein Data Bank with (PDB ID: 4O6B). Missing residues were added using modeler software. Molecular operating environment (MOE) programme was used to prepare the protein before docking. Virtual screening was performed on PyRx software to identify natural compounds retrieved from Comprehensive Marine Natural Products Database (CMNPD) against the NS1 protein, and best-docked compounds were examined by molecular docking and molecular dynamic (MD) simulation. Out of 31,561 marine compounds, the top 10 compounds showed docking scores lesser than -8.0 kcal/mol. One of the best hit compounds, CMNPD6802, was further analyzed using MD simulation study at 100 nanoseconds and Molecular Mechanics with Generalized Born and Surface Area Solvation (MM/GBSA). Based on its total binding energy, determined using the MM/GBSA approach, CMNPD6802 was ranked first. Its pharmacokinetic properties concerning the target protein NS1 were also evaluated. The results of the MD simulation showed that CMNPD6802 remained in close contact with the protein throughout the activation period, mapped using principal component analysis. These findings suggest that CMNPD6802 could serve as an NS1 inhibitor and may be a potential candidate for treating DENV infections.Communicated by Ramaswamy H. Sarma.

Campesterol and dithymoquinone as a potent inhibitors of SARS cov-2 main proteases-promising drug candidates for targeting its novel variants.

The sudden outbreak of the COVID-19 pandemic has currently taken approximately 2.4 million lives, with no specific medication and fast-tracked tested vaccines for prevention. These vaccines have their own adverse effects, which have severely affected the global healthcare system. The discovery of the main protease structure of coronavirus (Mpro/Clpro) has resulted in the identification of compounds having antiviral potential, especially from the herbal system. In this study, the computer-associated drug design tools were utilised to analyze the reported phytoconstituents of Nigella sativa for their antiviral activity against the main protease. Fifty-eight compounds were subjected to pharmacological parameter analysis to determine their lead likeness in comparison to the standard drugs (chloroquine and nirmatrelvir) used in the treatment of SARS-CoV-2. Nearly 31 compounds were docked against five different SARS-CoV-2 main proteases, and all compounds showed better binding affinity and inhibition constant against the proteases. However, dithymoquinone and campesterol displayed the best binding scores and hence were further subjected to dynamics and MMPBSA study for 100 ns. The stability analysis shows that dithymoquinone and campesterol show less variation in fluctuation in residues compared to standard complexes. Moreover, dithymoquinone exhibited higher binding affinity and favorable interaction followed by campesterol as compared to the standard drug. The in silico computational analysis provides a promising hit for regulating the main proteases activity.Communicated by Ramaswamy H. Sarma.

HDAC inhibition by Nigella sativa L. sprouts extract in hepatocellular carcinoma: an approach to study anti-cancer potential.

A wide variety of natural products have been widely used in chemoprevention therapy because they have antioxidant, anti-inflammatory, and anticancer activity. In the present study, we shed light on the 5th day germinated sprouts of N. sativa seeds and evaluated them against HDAC inhibition and antioxidant activity. The extract from the seed and sprout was extracted and characterised by LC-MS/MS, FTIR, and NMR to reveal its chemical composition, especially thymol (THY) and thymoquinone (TQ). Hepatocellular carcinoma (HCC) is a global health concern as it is a major lifestyle disease. Hence, incorporating herbal-based therapeutic compounds into everyday routines has become an attractive alternative for preventing hepatic diseases. Histone deacetylase (HDAC) inhibition (HDACi) is emerging as a promising therapeutic strategy for managing various carcinomas including HCC. Therefore, the 5th day of N. sativa can be used as a potential anticancer agent by inhibiting HDAC activity, as it is reported to have an important role in the management of oxidative stress. The bioactive compound of N. sativa, i.e. thymoquinone, also showed a good binding affinity with the HDAC protein (3MAX) with a stable interaction in an in silico study as compared to the standard drug (Trichostatin A) and thymol.Communicated by Ramaswamy H. Sarma.

Evaluation of the Knowledge of the Most Common Cancers Among Health Students at Jazan University, Saudi Arabia: A Cross-Sectional Study.

BACKGROUND: Cancer is a major public health problem worldwide, and medical students are expected to have adequate knowledge and awareness of the most common types of cancer. This study aimed to assess the cancer knowledge of medical students at Jazan University, Saudi Arabia, focusing on breast cancer (BC), prostate cancer (PC), cervical cancer (CC), and colorectal cancer (CRC). METHODS: This study employed a self-administered survey to evaluate both general and specialized knowledge of cancer types. A total of 321 medical students from different academic years participated in the study. The questionnaire used a scoring system where each correct answer was given one point, and each incorrect answer or "I don't know" response was given zero points. RESULTS: The overall knowledge scores were 18.75 ± 4.43 out of 28 (67%). The students had a good level of general knowledge about cancer (5.26 ± 1.44 out of 7, 75%) and breast cancer (5.47 ± 1.44 out of 7, 78%) and a moderate knowledge level of prostate cancer (2.83 ± 1.07 out of 4, 71%), cervical cancer (2.74 ± 1.53 out of 5, 55%), and colorectal cancer (2.55 ± 1.61 out of 5, 50%). There were significant differences in cancer knowledge by gender, academic year, and having a relative or friend with cancer. All types of cancer knowledge were positively and significantly correlated with each other. CONCLUSION: This study revealed the strengths and weaknesses of cancer knowledge among medical students at Jazan University, Saudi Arabia. The overall score for knowledge indicated a moderate level. The students had some knowledge about cancer prevention, detection, and treatment, but some gaps and misconceptions need to be addressed. More education and awareness programs are necessary to improve cancer literacy among students and promote healthy behaviors that can reduce cancer risk.

A leaky gut contributes to postural dysfunction in patients with Alzheimer's disease.

Background: Postural dysfunction is a common problem in patients with Alzheimer's disease (AD) and may lead to functional dependency and increasing morbidity and mortality. However, the pathophysiology of postural dysfunction in AD patients remains poorly understood. Objectives: Elevated intestinal permeability is an underlying contributor to multiple diseases, including AD. We aimed to investigate the association of elevated intestinal permeability with postural dysfunction in AD patients. Design Setting Participants Measurements: We conducted a cross-sectional, observational study on older adults, including controls and AD patients. We investigated the associations of postural balance with plasma zonulin, a marker of elevated intestinal permeability in geriatric controls (n = 74) and patients with mild (n = 71) and moderate (n = 66) AD. We used a standardized physical performance battery to measure balance in supine, tandem, and semi-tandem positions. We also measured handgrip strength (HGS), and gait speed as markers of physical capacity. Results: AD patients exhibited lower balance scores, HGS, and gait speed and higher plasma zonulin than in controls (all p < 0.05). Plasma zonulin levels demonstrated significant areas under the curves in diagnosing poor balance in AD patients (all p < 0.05). Moderate AD was associated with lower balance and physical capacity, and higher zonulin than mild AD (ALL P < 0.05). Poor scores on balance scale were associated with higher expressions of markers of inflammation, oxidative stress, and muscle damage providing a mechanistic link between increased intestinal permeability and postural dysfunction in AD patients. Conclusion: The results of our study show that plasma zonulin measurement may be used to diagnose postural dysfunction in AD patients. The study is relevant to non-ambulant and/or comatose AD patients with postural dysfunction. Our findings also highlight the therapeutic potential of repairing the intestinal leak to improve postural control and reduce the risk of falls in AD patients.

Exploring the tumor immune microenvironment in ovarian cancer: a way-out to the therapeutic roadmap.

INTRODUCTION: Despite cancer treatment strides, mortality due to ovarian cancer remains high globally. While immunotherapy has proven effective in treating cancers with low cure rates, it has limitations. Growing evidence suggests that both tumoral and non-tumoral components of the tumor immune microenvironment (TIME) play a significant role in cancer growth. Therefore, developing novel and focused therapy for ovarian cancer is critical. Studies indicate that TIME is involved in developing ovarian cancer, particularly genome-, transcriptome-, and proteome-wide studies. As a result, TIME may present a prospective therapeutic target for ovarian cancer patients. AREAS COVERED: We examined several TIME-targeting medicines and the connection between TIME and ovarian cancer. The key protagonists and events in the TIME and therapeutic strategies that explicitly target these events in ovarian cancer are discussed. EXPERT OPINION: We highlighted various targeted therapies against TIME in ovarian cancer, including anti-angiogenesis therapies and immune checkpoint inhibitors. While these therapies are in their infancy, they have shown promise in controlling ovarian cancer progression. The use of 'omics' technology is helping in better understanding of TIME in ovarian cancer and potentially identifying new therapeutic targets. TIME-targeted strategies could account for an additional treatment strategy when treating ovarian cancer.

Natural and synthetic drugs and formulations for intravaginal HPV clearance.

BACKGROUND: Except for a few preventative Human Papillomavirus (HPV) vaccines, there is currently no cure for HPV infection. There are a number of cutting-edge strategies and potent medications or herbal formulations that can be applied topically for early clearance of HPV infection before HPV DNA gets integrated into host cell genome. This is facilitated due to cervical cancer having distinct and well-recognized long precancerous stages. OBJECTIVES: This review aims to outline every possible medication and formulation, both natural and synthetic, that can be applied topically as intravaginal application to help remove HPV infection at an early precancerous stage. RESULTS: Several anti-HPV/HPV clearance compounds and formulations for high-grade lesions are undergoing clinical trials. However, the majority of compounds are still in the early stages of development and require additional research to become viable HPV clearance candidates. Synthetic drugs may be more promising because they may have a more targeted effect; however, they may also have significant adverse effects. On the other hand, natural medications are safer to use. They are less specific, but have minimal to no adverse effects. CONCLUSIONS: This article may serve as a valuable resource of information for managing and preventing precancerous carcinogenic HPV infections. Research could be directed toward developing candidate drugs to make evidence-based decisions about advancing them to clinical trials and, eventually, to the market for potential use in the prevention and control of cervical cancer, which is almost always preventable or even curable if detected early.

Immunoinformatics Strategy to Develop a Novel Universal Multiple Epitope-Based COVID-19 Vaccine.

Currently available COVID vaccines are effective in reducing mortality and severity but do not prevent transmission of the virus or reinfection by the emerging SARS-CoV-2 variants. There is an obvious need for better and longer-lasting effective vaccines for various prevailing strains and the evolving SARS-CoV-2 virus, necessitating the development of a broad-spectrum vaccine that can be used to prevent infection by reducing both the transmission rate and re-infection. During the initial phases of SARS-CoV-2 infection, the nucleocapsid (N) protein is one of the most abundantly expressed proteins. Additionally, it has been identified as the most immunogenic protein of SARS-CoV-2. In this study, state-of-the-art bioinformatics techniques have been exploited to design novel multiple epitope vaccines using conserved regions of N proteins from prevalent strains of SARS-CoV-2 for the prediction of B- and T-cell epitopes. These epitopes were sorted based on their immunogenicity, antigenicity score, and toxicity. The most effective multi-epitope construct with possible immunogenic properties was created using epitope combinations. EAAAK, AAY, and GPGPG were used as linkers to connect epitopes. The developed vaccines have shown positive results in terms of overall population coverage and stimulation of the immune response. Potential expression of the chimeric protein construct was detected after it was cloned into the Pet28a/Cas9-cys vector for expression screening in Escherichia coli. The developed vaccine performed well in computer-based immune response simulation and covered a diverse allelic population worldwide. These computational findings are very encouraging for the further testing of our candidate vaccine, which could eventually aid in the control and prevention of SARS-CoV-2 infections globally.

Evaluation of the Knowledge, Attitudes, and Resulting Behavior Changes in Response to COVID-19 Among Students at the College of Applied Medical Sciences (CAMS), Jazan University, Saudi Arabia.

Background: The emergence of COVID-19 posed a threat to millions of lives worldwide. The pandemic impacts extended to affect people's psychological well-being, resulting in significant behavioural change. This study was designed to assess the knowledge regarding COVID-19 precautions among the College of Applied Medical Science students at Jazan University and to evaluate the general, psychosocial, and behavioral changes due to COVID-19. Methods: This is an observational study targeting 630 undergraduate students randomly selected during January 2020, using stratified random sampling. Data were collected using an online questionnaire. Linear regression models were used to evaluate the predictors of three outcome measures: knowledge, attitudes, and practice scores. Results: Knowledge of COVID-19 revealed that the students with correct answers ranged from 48.9 to 95%. Furthermore, significant gender differences are found regarding shortness of breath, fatigue, persistent chest discomfort, headache, and malaise (p < 0.05). Knowledge scores differed significantly across gender and academic level (p < 0.05) and so does attitude scores (p < 0.05). No significant difference was observed between practice scores according to socio-demographic background (p > 0.05). The linear regression model showed that females had significantly higher knowledge, attitudes, and practice scores (p < 0.05) as well as those within the 21-23 age group and above (p < 0.05). Students residing in urban and semi-urban places had significantly higher scores for knowledge, attitudes, and practice (p < 0.05). Conclusion: The results demonstrated moderate knowledge about COVID-19 among study participants, with significant differences between the responses of males and females and among the urban and rural populations. Outcomes suggest the need for interventions to bridge students' knowledge about COVID-19 and practice gaps. Students were concerned about basic life amenities and the inability to provide for their dear ones regarding behavioral changes.

Targeted Inhibition of Hsp90 in Combination with Metformin Modulates Programmed Cell Death Pathways in A549 Lung Cancer Cells.

The pathophysiology of lung cancer is dependent on the dysregulation in the apoptotic and autophagic pathways. The intricate link between apoptosis and autophagy through shared signaling pathways complicates our understanding of how lung cancer pathophysiology is regulated. As drug resistance is the primary reason behind treatment failure, it is crucial to understand how cancer cells may respond to different therapies and integrate crosstalk between apoptosis and autophagy in response to them, leading to cell death or survival. Thus, in this study, we have tried to evaluate the crosstalk between autophagy and apoptosis in A549 lung cancer cell line that could be modulated by employing a combination therapy of metformin (6 mM), an anti-diabetic drug, with gedunin (12 µM), an Hsp90 inhibitor, to provide insights into the development of new cancer therapeutics. Our results demonstrated that metformin and gedunin were cytotoxic to A549 lung cancer cells. Combination of metformin and gedunin generated ROS and promoted MMP loss and DNA damage. The combination further increased the expression of AMPKα1 and promoted the nuclear localization of AMPKα1/α2. The expression of Hsp90 was downregulated, further decreasing the expression of its clients, EGFR, PIK3CA, AKT1, and AKT3. Inhibition of the EGFR/PI3K/AKT pathway upregulated TP53 and inhibited autophagy. The combination was promoting nuclear localization of p53; however, some cytoplasmic signals were also detected. Further increase in the expression of caspase 9 and caspase 3 was observed. Thus, we concluded that the combination of metformin and gedunin upregulates apoptosis by inhibiting the EGFR/PI3K/AKT pathway and autophagy in A549 lung cancer cells.

A Potential Link Between Visceral Obesity and Risk of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia characterized by the deposition of amyloid beta (Aß) plaques and tau-neurofibrillary tangles in the brain. Visceral obesity (VO) is usually associated with low-grade inflammation due to higher expression of pro-inflammatory cytokines by adipose tissue. The objective of the present review was to evaluate the potential link between VO and the development of AD. Tissue hypoxia in obesity promotes tissue injury, production of adipocytokines, and release of pro-inflammatory cytokines leading to an oxidative-inflammatory loop with induction of insulin resistance. Importantly, brain insulin signaling is involved in the pathogenesis of AD and lower cognitive function. Obesity and enlargement of visceral adipose tissue are associated with the deposition of Aß. All of this is consonant with VO increasing the risk of AD through the dysregulation of adipocytokines which affect the development of AD. The activated nuclear factor kappa B (NF-κB) pathway in VO might be a potential link in the development of AD. Likewise, the higher concentration of advanced glycation end-products in VO could be implicated in the pathogenesis of AD. Taken together, different inflammatory signaling pathways are activated in VO that all have a negative impact on the cognitive function and progression of AD except hypoxia-inducible factor 1 which has beneficial and neuroprotective effects in mitigating the progression of AD. In addition, VO-mediated hypoadiponectinemia and leptin resistance may promote the progression of Aß formation and tau phosphorylation with the development of AD. In conclusion, VO-induced AD is mainly mediated through the induction of oxidative stress, inflammatory changes, leptin resistance, and hypoadiponectinemia that collectively trigger Aß formation and neuroinflammation. Thus, early recognition of VO by visceral adiposity index with appropriate management could be a preventive measure against the development of AD in patients with VO.

Community-Based Seroprevalence of SARS-CoV-2 Antibodies following the First Wave of the COVID-19 Pandemic in Jazan Province, Saudi Arabia.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread globally, causing unprecedented effects on global health and economies. Community-based serological data are essential for understanding the true prevalence of infections, specifically the subclinical infections, as COVID-19 asymptomatic infections are common. Such data would also be important for decision making around choosing appropriate epidemiological control measures, as well as for the true estimation of mortality rates in the population. Further, determining the seroprevalence of anti-SARS-CoV-2 antibodies in the population would provide important information on herd immunity. In this study, we conducted a population-based age-stratified serological study to understand the prevalence of SARS-CoV-2 in Jazan Province, Saudi Arabia. Out of 594 participants who were recruited from 29 August to 30 December 2020, just before the vaccination rollout program in Saudi Arabia, about 157 were seropositive for SARS-CoV-2, indicating an estimated seropositivity rate of 26%. Although no significant difference in seropositivity was seen between male and female participants, we found that lower seroprevalence was associated with the younger (below 18 years old) and older populations (older than 56 years) compared with other age groups (19-55 years). These data indicate a high prevalence of SARS-CoV-2 antibodies following the peak of COVID-19 spread in Jazan province; however, most of the population (three-quarters) remains susceptible to SARS-CoV-2 infection.