Common and Potential Emerging Foodborne Viruses: A Comprehensive Review.

Human viruses and viruses from animals can cause illnesses in humans after the consumption of contaminated food or water. Contamination may occur during preparation by infected food handlers, during food production because of unsuitably controlled working conditions, or following the consumption of animal-based foods contaminated by a zoonotic virus. This review discussed the recent information available on the general and clinical characteristics of viruses, viral foodborne outbreaks and control strategies to prevent the viral contamination of food products and water. Viruses are responsible for the greatest number of illnesses from outbreaks caused by food, and risk assessment experts regard them as a high food safety priority. This concern is well founded, since a significant increase in viral foodborne outbreaks has occurred over the past 20 years. Norovirus, hepatitis A and E viruses, rotavirus, astrovirus, adenovirus, and sapovirus are the major common viruses associated with water or foodborne illness outbreaks. It is also suspected that many human viruses including Aichi virus, Nipah virus, tick-borne encephalitis virus, H5N1 avian influenza viruses, and coronaviruses (SARS-CoV-1, SARS-CoV-2 and MERS-CoV) also have the potential to be transmitted via food products. It is evident that the adoption of strict hygienic food processing measures from farm to table is required to prevent viruses from contaminating our food.

Vitamin B12 insufficiency and deficiency: a review of nondisease risk factors.

Vitamin B12 deficiency and insufficiency can lead to both hematological and neurological impairments. This review examines nondisease causes and risk factors associated with dietary availability, such as eating habits, food processing, cooking techniques, and bioavailability, as well as increased physiological needs and iatrogenic factors linked to medication use or surgical procedures. As a result of these nondisease influences, groups at higher risk include vegans, vegetarians, older adults, individuals with limited diets, breastfed and preterm infants, and those who primarily consume foods prepared or cooked in ways that reduce vitamin B12 content, as well as individuals on certain medications or who have undergone specific surgeries. Recognizing these diverse risk factors helps develop strategies for prevention and intervention to minimize the adverse health effects related to B12 deficiency and insufficiency.

Augmenting bioactivity by docking-generated multiple ligand poses to enhance machine learning and pharmacophore modelling: discovery of new TTK inhibitors as case study.

Dual specificity protein kinase threonine/Tyrosine kinase (TTK) is one of the mitotic kinases. High levels of TTK are detected in several types of cancer. Hence, TTK inhibition is considered a promising therapeutic anti-cancer strategy. In this work, we used multiple docked poses of TTK inhibitors to augment training data for machine learning QSAR modeling. Ligand-Receptor Contacts Fingerprints and docking scoring values were used as descriptor variables. Escalating docking-scoring consensus levels were scanned against orthogonal machine learners, and the best learners (Random Forests and XGBoost) were coupled with genetic algorithm and Shapley additive explanations (SHAP) to determine critical descriptors for predicting anti-TTK bioactivity and for pharmacophore generation. Three successful pharmacophores were deduced and subsequently used for in silico screening against the NCI database. A total of 14 hits were evaluated in vitro for their anti-TTK bioactivities. One hit of novel chemotype showed reasonable dose-response curve with experimental IC50 of 1.0 µM. The presented work indicates the validity of data augmentation using multiple docked poses for building successful machine learning models and pharmacophore hypotheses.

The Emerging Role of Heat Shock Factor 1 (HSF1) and Heat Shock Proteins (HSPs) in Ferroptosis.

Cells employ a well-preserved physiological stress response mechanism, termed the heat shock response, to activate a certain type of molecular chaperone called heat shock proteins (HSPs). HSPs are activated by transcriptional activators of heat shock genes known as heat shock factors (HSFs). These molecular chaperones are categorized as the HSP70 superfamily, which includes HSPA (HSP70) and HSPH (HSP110) families; the DNAJ (HSP40) family; the HSPB family (small heat shock proteins (sHSPs)); chaperonins and chaperonin-like proteins; and other heat-inducible protein families. HSPs play a critical role in sustaining proteostasis and protecting cells against stressful stimuli. HSPs participate in folding newly synthesized proteins, holding folded proteins in their native conformation, preventing protein misfolding and accumulation, and degrading denatured proteins. Ferroptosis is a recently identified type of oxidative iron-dependent cell demise. It was coined recently in 2012 by Stockwell Lab members, who described a special kind of cell death induced by erastin or RSL3. Ferroptosis is characterized by alterations in oxidative status resulting from iron accumulation, increased oxidative stress, and lipid peroxidation, which are mediated by enzymatic and non-enzymatic pathways. The process of ferroptotic cell death is regulated at multiple, and it is involved in several pathophysiological conditions. Much research has emerged in recent years demonstrating the involvement of HSPs and their regulator heat shock factor 1 (HSF1) in ferroptosis regulation. Understanding the machinery controlling HSF1 and HSPs in ferroptosis can be employed in developing therapeutic interventions for ferroptosis occurrence in a number of pathological conditions. Therefore, this review comprehensively summarized the basic characteristics of ferroptosis and the regulatory functions of HSF1 and HSPs in ferroptosis.

Vitamin B12 binding to mutated human transcobalamin, in-silico study of TCN2 alanine scanning and ClinVar missense mutations/SNPs.

Many missense mutations/SNPs of the TCN2 gene (which yield Transcobalamin (TC)) were reported in the literature but no study is available about their effect on binding to vitamin B12(B12) at the structural level experimentally nor computationally. Predict the effect of TC missense mutations/SNPs on binding affinity to B12 and characterize their contacts to B12 at the structural level. TC-B12 binding energy difference from the wildtype (ΔΔGmut) was calculated for 378 alanine scanning mutations and 76 ClinVar missense mutations, repeated on two distinct X-ray structures of holoTC namely 2BB5 and 4ZRP. Destabilizing mutations then went through 100 ns molecular dynamics simulation to study their effect on TC-B12 binding at the structural level employing 2BB5 structure. Out of the studied 454 mutations (378 alanine mutations + 76 ClinVar mutations), 19 were destabilizing representing 17 amino acid locations. Mutation energy results show a neutral effect on B12 binding of several missense SNPs reported in the literature including I23V, G94S, R215W, P259R, S348F, L376S, and R399Q. Compared to the wildtype, all the destabilizing mutations have higher average RMSD-Ligand in the last 25% of the MD simulation trajectories and lower average hydrogen bond count while the other parameters vary. Previously reported TCN2 SNPs with an unknown effect on TC-B12 binding were found to have a neutral effect in the current study based on mutation energy calculations. Also, we reported 17 possible amino acids that destabilize TC-B12 binding upon mutation (four listed in ClinVar) and studied their structural effect computationally.

Understanding the challenges to COVID-19 vaccines and treatment options, herd immunity and probability of reinfection.

Unlike pandemics in the past, the outbreak of coronavirus disease 2019 (COVID-19), which rapidly spread worldwide, was met with a different approach to control and measures implemented across affected countries. The lack of understanding of the fundamental nature of the outbreak continues to make COVID-19 challenging to manage for both healthcare practitioners and the scientific community. Challenges to vaccine development and evaluation, current therapeutic options, convalescent plasma therapy, herd immunity, and the emergence of reinfection and new variants remain the major obstacles to combating COVID-19. This review discusses these challenges in the management of COVID-19 at length and highlights the mechanisms needed to provide better understanding of this pandemic.

Experiences and perceptions of COVID-19 infection and vaccination among Palestinian refugees in Jerash camp and Jordanian citizens: a comparative cross-sectional study by face-to-face interviews.

BACKGROUND: During the COVID-19 vaccination, the access to vaccines has been unequal among countries and individuals, for example low-income countries displayed significant low levels of vaccination. Furthermore, most refugees are living in developing low-income countries which struggling to access the essential health-care services including vaccination. Thus, the objective of this study was to assess the experiences and perceptions of COVID-19 infection and vaccination among Palestine refugees in Jerash camp compared to resident Jordanian citizens. METHODS: A face-to-face interview-based comparative cross-sectional study was carried out among Palestine refugees in Jerash camp located in northern Jordan and Jordanian citizens from different cities in Jordan from October, 2021 to March, 2022. A Chi-square test was used to determine the differences in the experiences and perceptions of COVID-19 infection and vaccination between Palestinian refugees and resident Jordanian citizens. Logistic regression analysis was performed to predict factors associated with the beliefs, barriers and hesitancy towards COVID-19 vaccines. RESULTS: The total number of participants was 992, with 501 (50.5%) Palestinian refugees and 491 (49.5%) Jordanian citizens. Most participants (64.1%) who have never been tested for COVID-19 were from the refugees (P < 0.001), whereas about 80.3% of the participants tested for COVID-19 at private healthcare institutions were citizens (P < 0.001). While 70.0% of the participants who tested positive for COVID-19 (n = 303) were from the refugees (P < 0.001). Compared to the citizens, the refugees had significantly lower levels of beliefs about the safety (P = 0.008) and efficiency (P < 0.001) of COVID-19 vaccines. They also had lower rates of vaccine hesitancy (P = 0.002) and vaccine uptake (P < 0.001), and a higher rate of facing difficulties during registration for COVID-19 vaccination (P < 0.001). Furthermore, refugees have more negative attitudes toward the importance and implementation of COVID-19 precautionary activities, including wearing face masks, practicing social distancing and following proper prevention hygiene compared to citizens (P < 0.001). The regression analysis showed that gender (P < 0.001), age (P < 0.001) and level of education (P = 0.001) were significantly associated with COVID-19 vaccine hesitancy. Also, being a refugee (P < 0.001) and being a male (P = 0.012) were significantly associated with facing more difficulties upon the registration to receive a COVID-19 vaccine. CONCLUSIONS: This study showed that, compared to citizens, refugees had lower attitudes and practices toward COVID-19 infection and vaccination. They also had and a lower rate of COVID-19 vaccine hesitancy and uptake with limited access to vaccines. Government sectors and non-government organizations should implement policies and regulations to raise the awareness of refugees towards COVID-19 infection, testing, preventive measures, and the safety and efficacy of vaccines.

Comprehensive literature review of monkeypox.

The current outbreak of monkeypox (MPX) infection has emerged as a global matter of concern in the last few months. MPX is a zoonosis caused by the MPX virus (MPXV), which is one of the Orthopoxvirus species. Thus, it is similar to smallpox caused by the variola virus, and smallpox vaccines and drugs have been shown to be protective against MPX. Although MPX is not a new disease and is rarely fatal, the current multi-country MPX outbreak is unusual because it is occurring in countries that are not endemic for MPXV. In this work, we reviewed the extensive literature available on MPXV to summarize the available data on the major biological, clinical and epidemiological aspects of the virus and the important scientific findings. This review may be helpful in raising awareness of MPXV transmission, symptoms and signs, prevention and protective measures. It may also be of interest as a basis for performance of studies to further understand MPXV, with the goal of combating the current outbreak and boosting healthcare services and hygiene practices.Trial registration: ClinicalTrials.gov identifier: NCT02977715..Trial registration: ClinicalTrials.gov identifier: NCT03745131..Trial registration: ClinicalTrials.gov identifier: NCT00728689..Trial registration: ClinicalTrials.gov identifier: NCT02080767..

COVID-19 Vaccine Acceptance among Vulnerable Groups: Syrian Refugees in Jordan.

Despite the wide distribution of COVID-19 vaccines, refugees remain last in line for the intake of vaccines. Syrian refugees in Jordan reach up to 700,000 registered and almost up to 700,000 unregistered refugees. This study aims to assess the willingness of Syrian refugees in Jordan to take the COVID-19 vaccine. Participants in the Zaatari refugee camp in Jordan were invited through social media to complete the survey between January and March 2022. A total of 230 refugees participated in our study, with almost half the participants of male gender. The majority of the participants had secondary school as their highest education level and were unemployed, being below the social poverty line. Interestingly, Syrian refugees showed a high vaccine acceptance rate, as 89.6% were willing to take the vaccine. Moreover, they showed high knowledge regarding the vaccine, the disease, and the virus. Our findings highlight the importance of knowledge and awareness of the COVID-19 vaccine to increase the acceptance rate. This is very important as refugees represent a vulnerable group to infection and complications and require close attention, especially with their significant numbers in Jordon and challenges of providing adequate vaccine supplies at their camps. We hope that, with proper dissemination of knowledge and awareness and with easy accessibility to the vaccines, it will ensure high immunization to reach herd immunity in Jordan.

Acetic Acid Mediated for One-Pot Synthesis of Novel Pyrazolyl s-Triazine Derivatives for the Targeted Therapy of Triple-Negative Breast Tumor Cells (MDA-MB-231) via EGFR/PI3K/AKT/mTOR Signaling Cascades.

Here, we described the synthesis of novel pyrazole-s-triazine derivatives via an easy one-pot procedure for the reaction of ß-dicarbonyl compounds (ethylacetoacetate, 5,5-dimethyl-1,3-cyclohexadione or 1,3-cyclohexadionone) with N,N-dimethylformamide dimethylacetal, followed by addition of 2-hydrazinyl-4,6-disubstituted-s-triazine either in ethanol-acetic acid or neat acetic acid to afford a novel pyrazole and pyrazole-fused cycloalkanone systems. The synthetic protocol proved to be efficient, with a shorter reaction time and high chemical yield with broad substrates. The new pyrazolyl-s-triazine derivatives were tested against the following cell lines: MCF-7 (breast cancer); MDA-MB-231 (triple-negative breast cancer); U-87 MG (glioblastoma); A549 (non-small cell lung cancer); PANC-1 (pancreatic cancer); and human dermal fibroblasts (HDFs). The cell viability assay revealed that most of the s-triazine compounds induced cytotoxicity in all the cell lines tested. However, compounds 7d, 7f and 7c, which all have a piperidine or morpholine moiety with one aniline ring or two aniline rings in their structures, were the most effective. Compounds 7f and 7d showed potent EGFR inhibitory activity with IC50 values of 59.24 and 70.3 nM, respectively, compared to Tamoxifen (IC50 value of 69.1 nM). Compound 7c exhibited moderate activity, with IC50 values of 81.6 nM. Interestingly, hybrids 7d and 7f exerted remarkable PI3K/AKT/mTOR inhibitory activity with 0.66/0.82/0.80 and 0.35/0.56/0.66-fold, respectively, by inhibiting their concentrations to 4.39, 37.3, and 69.3 ng/mL in the 7d-treatment, and to 2.39, 25.34 and 57.6 ng/mL in the 7f-treatment compared to the untreated control.

Potential Composite Digenic Contribution of NPC1 and NOD2 Leading to Atypical Lethal Niemann-Pick Type C with Initial Crohn's Disease-like Presentation: Genotype-Phenotype Correlation Study.

Niemann-Pick disease type C (NPC) is an autosomal recessive neurovisceral disease characterized by progressive neurodegeneration with variable involvement of multisystemic abnormalities. Crohn's disease (CD) is an inflammatory bowel disease (IBD) with a multifactorial etiology influenced by variants in NOD2. Here, we investigated a patient with plausible multisystemic overlapping manifestations of both NPC and CD. Her initial hospitalization was due to a prolonged fever and non-bloody diarrhea. A few months later, she presented with recurrent skin tags and anal fissures. Later, her neurological and pulmonary systems progressively deteriorated, leading to her death at the age of three and a half years. Differential diagnosis of her disease encompassed a battery of clinical testing and genetic investigations. The patient's clinical diagnosis was inconclusive. Specifically, the histopathological findings were directed towards an IBD disease. Nevertheless, the diagnosis of IBD was not consistent with the patient's subsequent neurological and pulmonary deterioration. Consequently, we utilized a genetic analysis approach to guide the diagnosis of this vague condition. Our phenotype-genotype association attempts led to the identification of candidate disease-causing variants in both NOD2 and NPC1. In this study, we propose a potential composite digenic impact of these two genes as the underlying molecular etiology. This work lays the foundation for future functional and mechanistic studies to unravel the digenic role of NOD2 and NPC1.

Immunomodulatory Properties of Human Breast Milk: MicroRNA Contents and Potential Epigenetic Effects.

Infants who are exclusively breastfed in the first six months of age receive adequate nutrients, achieving optimal immune protection and growth. In addition to the known nutritional components of human breast milk (HBM), i.e., water, carbohydrates, fats and proteins, it is also a rich source of microRNAs, which impact epigenetic mechanisms. This comprehensive work presents an up-to-date overview of the immunomodulatory constituents of HBM, highlighting its content of circulating microRNAs. The epigenetic effects of HBM are discussed, especially those regulated by miRNAs. HBM contains more than 1400 microRNAs. The majority of these microRNAs originate from the lactating gland and are based on the remodeling of cells in the gland during breastfeeding. These miRNAs can affect epigenetic patterns by several mechanisms, including DNA methylation, histone modifications and RNA regulation, which could ultimately result in alterations in gene expressions. Therefore, the unique microRNA profile of HBM, including exosomal microRNAs, is implicated in the regulation of the genes responsible for a variety of immunological and physiological functions, such as FTO, INS, IGF1, NRF2, GLUT1 and FOXP3 genes. Hence, studying the HBM miRNA composition is important for improving the nutritional approaches for pregnancy and infant's early life and preventing diseases that could occur in the future. Interestingly, the composition of miRNAs in HBM is affected by multiple factors, including diet, environmental and genetic factors.

TBX5 variant with the novel phenotype of mixed­type total anomalous pulmonary venous return in Holt­Oram Syndrome and variable intrafamilial heart defects.

Variants in T­box transcription factor 5 (TBX5) can result in a wide phenotypic spectrum, specifically in the heart and the limbs. TBX5 has been implicated in causing non­syndromic cardiac defects and Holt­Oram syndrome (HOS). The present study investigated the underlying molecular etiology of a family with heterogeneous heart defects. The proband had mixed­type total anomalous pulmonary venous return (mixed­type TAPVR), whereas her mother had an atrial septal defect. Genetic testing through trio­based whole­exome sequencing was used to reveal the molecular etiology. A nonsense variant was identified in TBX5 (c.577G>T; p.Gly193*) initially showing co­segregation with a presumably non­syndromic presentation of congenital heart disease. Subsequent genetic investigations and more complete phenotyping led to the correct diagnosis of HOS, documenting the novel association of mixed­type TAPVR with HOS. Finally, protein modeling of the mutant TBX5 protein that harbored this pathogenic nonsense variant (p.Gly193*) revealed a substantial drop in the quantity of non­covalent bonds. The decrease in the number of non­covalent bonds suggested that the resultant mutant dimer was less stable compared with the wild­type protein, consequently affecting the protein's ability to bind DNA. The present findings extended the phenotypic cardiac defects associated with HOS; to the best of our knowledge, this is the first association of mixed­type TAPVR with TBX5. Prior to the current analysis, the molecular association of TAPVR with HOS had never been documented; hence, this is the first genetic investigation to report the association between TAPVR and HOS. Furthermore, it was demonstrated that the null­variants reported in the T­box domain of TBX5 were associated with a wide range of cardiac and/or skeletal anomalies on both the inter­and intrafamilial levels. In conclusion, genetic testing was highlighted as a potentially powerful approach in the prognostication of the proper diagnosis.

Applications of Alginate-Based Nanomaterials in Enhancing the Therapeutic Effects of Bee Products.

Since the ancient times, bee products (i.e., honey, propolis, pollen, bee venom, bee bread, and royal jelly) have been considered as natural remedies with therapeutic effects against a number of diseases. The therapeutic pleiotropy of bee products is due to their diverse composition and chemical properties, which is independent on the bee species. This has encouraged researchers to extensively study the therapeutic potentials of these products, especially honey. On the other hand, amid the unprecedented growth in nanotechnology research and applications, nanomaterials with various characteristics have been utilized to improve the therapeutic efficiency of these products. Towards keeping the bee products as natural and non-toxic therapeutics, the green synthesis of nanocarriers loaded with these products or their extracts has received a special attention. Alginate is a naturally produced biopolymer derived from brown algae, the desirable properties of which include biodegradability, biocompatibility, non-toxicity and non-immunogenicity. This review presents an overview of alginates, including their properties, nanoformulations, and pharmaceutical applications, placing a particular emphasis on their applications for the enhancement of the therapeutic effects of bee products. Despite the paucity of studies on fabrication of alginate-based nanomaterials loaded with bee products or their extracts, recent advances in the area of utilizing alginate-based nanomaterials and other types of materials to enhance the therapeutic potentials of bee products are summarized in this work. As the most widespread and well-studied bee products, honey and propolis have garnered a special interest; combining them with alginate-based nanomaterials has led to promising findings, especially for wound healing and skin tissue engineering. Furthermore, future directions are proposed and discussed to encourage researchers to develop alginate-based stingless bee product nanomedicines, and to help in selecting suitable methods for devising nanoformulations based on multi-criteria decision making models. Also, the commercialization prospects of nanocomposites based on alginates and bee products are discussed. In conclusion, preserving original characteristics of the bee products is a critical challenge in developing nano-carrier systems. Alginate-based nanomaterials are well suited for this task because they can be fabricated without the use of harsh conditions, such as shear force and freeze-drying, which are often used for other nano-carriers. Further, conjunction of alginates with natural polymers such as honey does not only combine the medicinal properties of alginates and honey, but it could also enhance the mechanical properties and cell adhesion capacity of alginates.

Discovery of new Cdc2-like kinase 4 (CLK4) inhibitors via pharmacophore exploration combined with flexible docking-based ligand/receptor contact fingerprints and machine learning.

Cdc2-like kinase 4 (CLK4) inhibitors are of potential therapeutic value in many diseases particularly cancer. In this study, we combined extensive ligand-based pharmacophore exploration, ligand-receptor contact fingerprints generated by flexible docking, physicochemical descriptors and machine learning-quantitative structure-activity relationship (ML-QSAR) analysis to investigate the pharmacophoric/binding requirements for potent CLK4 antagonists. Several ML methods were attempted to tie these properties with anti-CLK4 bioactivities including multiple linear regression (MLR), random forests (RF), extreme gradient boosting (XGBoost), probabilistic neural network (PNN), and support vector regression (SVR). A genetic function algorithm (GFA) was combined with each method for feature selection. Eventually, GFA-SVR was found to produce the best self-consistent and predictive model. The model selected three pharmacophores, three ligand-receptor contacts and two physicochemical descriptors. The GFA-SVR model and associated pharmacophore models were used to screen the National Cancer Institute (NCI) structural database for novel CLK4 antagonists. Three potent hits were identified with the best one showing an anti-CLK4 IC50 value of 57 nM.

Reported Adverse Effects and Attitudes among Arab Populations Following COVID-19 Vaccination: A Large-Scale Multinational Study Implementing Machine Learning Tools in Predicting Post-Vaccination Adverse Effects Based on Predisposing Factors.

Background: The unprecedented global spread of coronavirus disease 2019 (COVID-19) has imposed huge challenges on the healthcare facilities, and impacted every aspect of life. This has led to the development of several vaccines against COVID-19 within one year. This study aimed to assess the attitudes and the side effects among Arab communities after receiving a COVID-19 vaccine and use of machine learning (ML) tools to predict post-vaccination side effects based on predisposing factors. Methods: An online-based multinational survey was carried out via social media platforms from 14 June to 31 August 2021, targeting individuals who received at least one dose of a COVID-19 vaccine from 22 Arab countries. Descriptive statistics, correlation, and chi-square tests were used to analyze the data. Moreover, extensive ML tools were utilized to predict 30 post vaccination adverse effects and their severity based on 15 predisposing factors. The importance of distinct predisposing factors in predicting particular side effects was determined using global feature importance employing gradient boost as AutoML. Results: A total of 10,064 participants from 19 Arab countries were included in this study. Around 56% were female and 59% were aged from 20 to 39 years old. A high rate of vaccine hesitancy (51%) was reported among participants. Almost 88% of the participants were vaccinated with one of three COVID-19 vaccines, including Pfizer-BioNTech (52.8%), AstraZeneca (20.7%), and Sinopharm (14.2%). About 72% of participants experienced post-vaccination side effects. This study reports statistically significant associations (p < 0.01) between various predisposing factors and post-vaccinations side effects. In terms of predicting post-vaccination side effects, gradient boost, random forest, and XGBoost outperformed other ML methods. The most important predisposing factors for predicting certain side effects (i.e., tiredness, fever, headache, injection site pain and swelling, myalgia, and sleepiness and laziness) were revealed to be the number of doses, gender, type of vaccine, age, and hesitancy to receive a COVID-19 vaccine. Conclusions: The reported side effects following COVID-19 vaccination among Arab populations are usually non-life-threatening; flu-like symptoms and injection site pain. Certain predisposing factors have greater weight and importance as input data in predicting post-vaccination side effects. Based on the most significant input data, ML can also be used to predict these side effects; people with certain predicted side effects may require additional medical attention, or possibly hospitalization.

Exploiting activity cliffs for building pharmacophore models and comparison with other pharmacophore generation methods: sphingosine kinase 1 as case study.

Activity cliffs (ACs) are defined as closely analogous compounds of significant affinity discrepancies against certain biotarget. In this paper we propose to use AC pair(s) for extracting valid binding pharmacophores through exposing corresponding protein complexes to stochastic deformation/relaxation followed by applying genetic algorithm/machine learning (GA-ML) for selecting optimal pharmacophore(s) that best classify a long list of inhibitors. We compared the performances of ligand-based and structure-based pharmacophores with counterparts generated by this newly introduced technique. Sphingosine kinase 1 (SPHK-1) was used as case study. SPHK-1 is a lipid kinase that plays pivotal role in the regulation of a variety of biological processes including, cell growth, apoptosis, and inflammation. The new approach proved to yield pharmacophore and ML models of comparable accuracies to established ligand-based and structure-based pharmacophores. The resulting pharmacophores and ML models were used to capture hits from the national cancer institute list of compounds and predict their bioactivity categories. Two hits of novel chemotypes showed selective and low micromolar inhibitory IC50 values against SPHK-1.

1,4-Naphthoquinone Is a Potent Inhibitor of IRAK1 Kinases and the Production of Inflammatory Cytokines in THP-1 Differentiated Macrophages.

Quinones are a class of cyclic organic compounds that are widely distributed in nature and have been shown to exhibit anti-inflammatory, antioxidant, and anticancerous activities. However, the molecular mechanisms/signaling by which these molecules exert their effect are still not fully understood. In this study, a group of quinone-derived compounds were examined for their potential inhibitory effect against human IRAK1 and IRAK4 kinases in vitro. We have identified five compounds: 1,4-naphthoquinone, emodin, shikonin, plumbagin, and menadione (vitamin K3) as active and selective inhibitors of human IRAK1 enzyme in vitro. The biochemical binding and molecular interactions between the active compounds and IRAK1's catalytic site were demonstrated in silico using structural-based docking and dynamic simulation analysis. Also, 1,4-naphthoquinone was found to effectively inhibit the growth of cancer cell lines overexpressing IRAK1. Furthermore, 1,4-naphthoquinone potently suppressed the production and secretion of key proinflammatory cytokine proteins IL-8, IL-1ß, IL-10, TNF-α, and IL-6 in LPS-stimulated PMA-induced human THP-1 macrophages. In conclusion, 1,4-naphthoquinone is an effective inhibitor of IRAK1 kinases and their mediated inflammatory cytokines production in LPS-stimulated PMA-induced human THP-1 macrophages.

Investigating the association of CD36 gene polymorphisms (rs1761667 and rs1527483) with T2DM and dyslipidemia: Statistical analysis, machine learning based prediction, and meta-analysis.

CD36 (cluster of differentiation 36) is a membrane protein involved in lipid metabolism and has been linked to pathological conditions associated with metabolic disorders, such as diabetes and dyslipidemia. A case-control study was conducted and included 177 patients with type-2 diabetes mellitus (T2DM) and 173 control subjects to study the involvement of CD36 gene rs1761667 (G>A) and rs1527483 (C>T) polymorphisms in the pathogenesis of T2DM and dyslipidemia among Jordanian population. Lipid profile, blood sugar, gender and age were measured and recorded. Also, genotyping analysis for both polymorphisms was performed. Following statistical analysis, 10 different neural networks and machine learning (ML) tools were used to predict subjects with diabetes or dyslipidemia. Towards further understanding of the role of CD36 protein and gene in T2DM and dyslipidemia, a protein-protein interaction network and meta-analysis were carried out. For both polymorphisms, the genotypic frequencies were not significantly different between the two groups (p > 0.05). On the other hand, some ML tools like multilayer perceptron gave high prediction accuracy (≥ 0.75) and Cohen's kappa (κ) (≥ 0.5). Interestingly, in K-star tool, the accuracy and Cohen's κ values were enhanced by including the genotyping results as inputs (0.73 and 0.46, respectively, compared to 0.67 and 0.34 without including them). This study confirmed, for the first time, that there is no association between CD36 polymorphisms and T2DM or dyslipidemia among Jordanian population. Prediction of T2DM and dyslipidemia, using these extensive ML tools and based on such input data, is a promising approach for developing diagnostic and prognostic prediction models for a wide spectrum of diseases, especially based on large medical databases.