Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Association between MTHFR C677T variant and risk for congenital heart defects in Egyptian children: a case–control study including meta-analysis based on 147 cases and 143 controls

Abstract Background Stratification analysis studies showed that ethnicity has a significant association regarding MTHFR C677T variant and congenital heart diseases (CHDs) risk, and many published studies have controversial conclusions toward this association. Methods In this study, the association between the MTHFR C677T variant and the risk for CHDs was evaluated in 91 children with CHD and 95 healthy controls, as new cases, by using restriction fragment length polymorphism (RFLP) technique. Besides that, 2 case–control studies in the Egyptian population published before 2021 were included in this meta-analysis. The association was assessed by the odds ratio (OR) with a 95% confidence interval (CI) based on 294 alleles in CHD cases and 286 alleles in controls. Results The overall meta-analysis showed a significant association between MTHFR C677T variant and CHDs risk in Egyptian children with heterogeneity (Heterogeneity = 0.001) in all the genetic models with the highly significant association in T versus C allele (pooled OR 1.89, 95% CI 1.31–2.74; p value < 0.0004). The consistency of the genotypes was detected by Hardy–Weinberg equilibrium (HWE). Conclusions Our results support the MTHFR -677T allele as a susceptibility factor for CHDs in the Egyptian pediatric patients

Altered Adaptive Cellular Immune Function in a Group of Egyptian Children with Autism

Introduction: There is a growing evidence of immune system alteration in children with Autism Spectrum Disorder (ASD). These changes may include higher levels of pro-inflammatory cytokines in plasma, Cerebrospinal Fluid (CSF) and brain cells. Aim: To evaluate the imbalance of the immune system in autism through correlating some immunological markers (C3, C4, CD4, IL12 and IL17) with severity of ASD. Materials and Methods: The current case-control study included 120 subjects, 60 autistic children and 60 healthy control obtained from the Clinical Genetics Clinic, National Research Centre, Egypt from the period between December 2014 to December 2016. All candidates were subjected to full clinical evaluation in addition to ElectroEncephaloGraphy (EEG), hearing test and estimation of interleukins (IL12- IL17), C3-C4, CD4 levels in blood samples. Independent t-test, Chi-square test or McNemar test were used to analyse the data. Results: The levels of IL12 (27.47 ±7.15) and IL17 (1630.46±310.42) were significantly higher, (p= 0.026, 0.005) respectively, while levels of CD4 were significantly lower (37.93±3.25), (p<0.001) in autistic children compared to controls; however, there was no significant difference in C3 and C4 between the two groups. High statistically significant difference between autistic children with moderate and severe ASD in CD4 levels were seen, (p=0.018). Conclusion: Autistic children may suffer from immunological dysfunction. Further efforts should be exerted to find out the relation between immune imbalance and the progression of ASD

New drug-like small molecule antagonizes phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in patients with conotruncal heart defects

الملخص: أهداف البحث: عيوب القلب الوعائية وراثية بشكل كبير وحوالي ثلث عيوب القلب الخلقية ناتجة عن عيوب القلب الوعائية. باستخدام التحليل اللاحق لعيوب القلب المخروطية -بيانات دراسة الترابط الجينومي الكامل ذات الصلة، تم افتراض مسار جديد مفترض لنقل الإشارات، يسمى ''فارس2-بك3كا-أ ك ت''، المرتبط بعيوب القلب الوعائية. كنا نهدف بشكل أساسي إلى التحقق من مسار ''فارس2-بك3كا-أ ك ت” بشكل تجريبي باستخدام المقياسين ''فارس2” و ''بيب3” في كل من مرضى عيوب القلب والعينة الضابطة، وإنشاء مثبط ''بيب3''، كواحد من مسببات عيوب القلب الضارة ذات الصلة، باستخدام استراتيجية تصميم الأدوية القائمة على ''أ ك ت''. طرق البحث: تم إجراء التنميط الجيني ''ار اس 2517582” والتعبير النسبي لـ ''فارس2” في 207 أفراد باستخدام تفاعل البلمرة المتسلسل الكمي، إلى جانب ذلك تم أيضا قياس ''بيب3” المحررة فى البلازما لدى 190 فردا باستخدام تقنية المقايسة الامتصاصية المناعية للإنزيم المرتبط. استخدمنا نموذج ميزات ''أ ك ت''-حامل الخاصة الدوائية لاكتشاف خصم ''بيب3” باستخدام أدوات حسابية متعددة وأدوات تقدير شبيهة بالعقاقير. النتائج: تم تأكيد إمراض عيوب القلب الوعائية بسبب فرط التحفيز المفرط لـ ''فارس2-بك3كا-أ ك ت” عن طريق ''فارس2” المرتفع و ''بيب3” في مرضى عيوب القلب الوعائية. حددنا جزيئا صغيرا جديدا، يسمى ''بيسب322''، قادرا على أن يقاوم ارتباط ''بيب3''، وتم منحه الأولوية من خلال الفحص الافتراضي لـ 21 جزيئا صغيرا افتراضيا. أظهر ''بيسب322” الحد الأدنى من التغير النسبى لاختلاف موقع جزيئاته ''رمسد''، وتقارب ربط عال، وثابت تفكك أقل من مجمع بيب3-أ ك ت” بمقدار 1.99 كيلو كالوري/مول مما يؤدي إلى تحول التوازن التفضيلى نحو تكوين معقد ''بيسب322-أ ك ت''. عرضت ''بيسب322” الخصائص الدوائية المقبولة وخصائص تشابه الأدوية وفقا لقاعدة ليبنيسكي و قاعدة امتصاص وتوزيع وتمثيل الغذاء وإفرازه المكونة من خمسة مصنفات. هذا هو أول جزيء محتمل كشبيه علاجى الدواء لمرضى عيوب القلب الوعائية الذين يعانون من ارتفاع ''بيب3''. الاستنتاجات: ''بيب3” هي مؤشرات حيوية تشخيصية مفيدة لمرضى عيوب القلب. يعد نموذج ميزات ''أ ك ت''-حامل الخاصة الدوائية نهجا ممكنا لاكتشاف المزيد من مضادات تأثير''بيب3''. يوصى بإجراء المزيد من اختبارات التطوير لجزئ ''بيسب322''. Abstract: Objectives: Conotruncal heart defects (CTDs) are highly heritable, and approximately one-third of all congenital heart defects are due to CTDs. Through post-analysis of GWAS data relevant to CTDs, a new putative signal transduction pathway, called Vars2-Pic3ca-Akt, associated with CTD has been hypothesized. Here, we aimed to validate the Vars2-Pic3ca-Akt pathway experimentally by measuring Vars2 and PIP3 in patients with CTDs and controls, and to construct a PIP3 inhibitor, as one of harmful-relevant CTD pathogenesis, through an Akt-based drug design strategy. Methods: rs2517582 genotype and relative Vars2 expression in 207 individuals were determined by DNA sequencing and qPCR respectively, and free plasma PIP3 in 190 individuals was quantified through ELISA. An Akt-pharmacophore feature model was used to discover PIP3 antagonists with multiple computational and drug-like estimation tools. Results: CTD pathogenesis due to Vars2-Pic3ca-Akt overstimulation was confirmed by elevated Vars2 and PIP3 in patients with CTDs. We identified a new small molecule, 322PESB, that antagonizes PIP3 binding. This molecule was prioritized via virtual screening of 21 hypothetical small molecules and it showed minimal RMSD change, high binding affinity andlower dissociation constant than PIP3-Akt complex by 1.99 Kcal/Mol, thus resulting in an equilibrium shift toward 322PESB-Akt complex formation. Moreover, 322PESB exhibited acceptable pharmacokinetics and drug likeness features according to ADME and Lipinski's rule of five classifiers. This compound is the first potential drug-like molecule reported for patients with CTDs with elevated PIP3. Conclusion: PIP3 is a useful diagnostic biomarker for patients with CTDs. The Akt-pharmacophore feature model is a feasible approach for discovery of PIP3 signalling antagonists. Further 322PESB development and testing are recommended

Clinical and genetic characterization of ten Egyptian patients with Wolf–Hirschhorn syndrome and review of literature

Abstract Background Wolf–Hirschhorn syndrome (WHS) (OMIM 194190) is a multiple congenital anomalies/intellectual disability syndrome. It is caused by partial loss of genetic material from the distal portion of the short arm of chromosome. Methods We studied the phenotype–genotype correlation. Results We present the clinical manifestations and cytogenetic results of 10 unrelated Egyptian patients with 4p deletions. Karyotyping, FISH and MLPA was performed for screening for microdeletion syndromes. Array CGH was done for two patients. All patients exhibited the cardinal clinical manifestation of WHS. FISH proved deletion of the specific WHS locus in all patients. MLPA detected microdeletion of the specific locus in two patients with normal karyotypes, while array CGH, performed for two patients, has delineated the extent of the deleted segments and the involved genes. LETM1, the main candidate gene for the seizure phenotype, was found deleted in the two patients tested by array CGH; nevertheless, one of them did not manifest seizures. The study emphasized the previous. Conclusion WHS is a contiguous gene syndrome resulting from hemizygosity of the terminal 2 Mb of 4p16.3 region. The Branchial fistula, detected in one of our patients is a new finding that, to our knowledge, was not reported

Human variome project country nodes: Documenting genetic information within a country

The Human Variome Project (http://www.humanvariomeproject.org) is an international effort aiming to systematically collect and share information on all human genetic variation. The two main pillars of this effort are gene/disease specific databases and a network of Human Variome Project Country Nodes. The latter are nationwide efforts to document the genomic variation reported within a specific population. The development and successful operation of the Human Variome Project Country Nodes are of utmost importance to the success of Human Variome Project aims and goals, since they not only allow the genetic burden of disease to be quantified in different countries, but also provide diagnosticians and researchers access to an up-to date resource that will assist them in their daily clinical practice and biomedical research, respectively. Here, we report the discussions and recommendations that resulted from the inaugural meeting of the International Confederation of Countries Advisory Council, held on December 12th, 2011, during the 2011 Human Variome Project Beijing Meeting. We discuss the steps necessary to maximize the impact of the Country Node effort for developing regional and country-specific clinical genetics resources and summarize a few well-coordinated genetic data collection initiatives that would serve as paradigms for similar projects.status: publishe