CCDC144NL-AS1/hsa-miR-143-3p/HMGA2 interaction: In-silico and clinically implicated in CRC progression, correlated to tumor stage and size in case-controlled study; step toward ncRNA precision.

Unravel the regulatory mechanism of lncRNA CCDC144NL-AS1 in CRC hsa-miR-143-3p, downstream protein HMGA2 interaction arm, association with clinicopathological characteristics. Using peripheral blood as liquid biopsy from 60 CRC patients and 30 controls. The expression levels of CCDC144NL-AS1 and hsa-miR-143-3p detected by qRT-PCR. CCDC144NL-AS1 expression was significantly upregulated in CRC patients' sera, associated with worse CRC clinicopathological features regarding the depth of tumor invasion and highly significant difference between tumor stages 3 and 4 and tumor stages 2 and 4. While, hsa-miR-143-3p expression was downregulated in CRC patients by 4.5-fold change when compared to the control subjects (p < 0.0001) and HMGA2 increased in CRC patients than controls 19.59 ng/µL and 5.377 ng/µL, respectively (p < 0.0001) with significant difference between tumor stages 3 and 4 as well as tumor stages 2 and 4. CRC patients with large tumor size showed upregulation in CCDC144NL-AS1 expression and HMGA2 levels compared to those with small tumor size (p-value = 0.0365 and 0.013, respectively). CCDC144NL-AS1 and HMGA2 were positively correlated, whereas lncRNA CCDC144NL-AS1 and hsa-miR-143-3p were negatively correlated. Conclusion: As an interaction arm CCDC144NL-AS1/hsa-miR-143-3p/HMGA2 were correlated to CRC stages 2-4. Therefore, this interaction arm expression clinically and in silico approved, would direct treatment precision in the near future.

Monocytes subsets altered distribution and dysregulated plasma hsa-miR-21-5p and hsa-miR-155-5p in HCV-linked liver cirrhosis progression to hepatocellular carcinoma.

PURPOSE: The authors aim to investigate the altered monocytes subsets distribution in liver cirrhosis (LC) and subsequent hepatocellular carcinoma (HCC) in association with the expression level of plasma Homo sapiens (has)-miR-21-5p and hsa-miR-155-5p. A step toward non-protein coding (nc) RNA precision medicine based on the immune perturbation manifested as altered monocytes distribution, on top of LC and HCC. METHODS: Seventy-nine patients diagnosed with chronic hepatitis C virus (CHCV) infection with LC were enrolled in the current study. Patients were sub-classified into LC group without HCC (n = 40), LC with HCC (n = 39), and 15 apparently healthy controls. Monocyte subsets frequencies were assessed by flow cytometry. Real-time quantitative PCR was used to measure plasma hsa-miR-21-5p and hsa-miR-155-5p expression. RESULTS: Hsa-miR-21-5p correlated with intermediate monocytes (r = 0.30, p = 0.007), while hsa-miR-155-5p negatively correlated with non-classical monocytes (r = - 0.316, p = 0.005). ROC curve analysis revealed that combining intermediate monocytes frequency and hsa-miR-21 yielded sensitivity = 79.5%, specificity = 75%, and AUC = 0.84. In comparison, AFP yielded a lower sensitivity = 69% and 100% specificity with AUC = 0.85. Logistic regression analysis proved that up-regulation of intermediate monocytes frequency and hsa-miR-21-5p were independent risk factors for LC progression to HCC, after adjustment for co-founders. CONCLUSION: Monocyte subsets differentiation in HCC was linked to hsa-miR-21-5p and hsa-miR-155-5p. Combined up-regulation of intermediate monocytes frequency and hsa-miR-21-5p expression could be considered a sensitive indicator of LC progression to HCC. Circulating intermediate monocytes and hsa-miR-21-5p were independent risk factors for HCC evolution, clinically and in silico proved.

Genetic and Epigenetic Regulation of MEFV Gene and Their Impact on Clinical Outcome in Auto-Inflammatory Familial Mediterranean Fever Patients.

Epigenetic modifications play a pivotal role in autoimmune/inflammatory disorders and could establish a bridge between personalized medicine and disease epidemiological contexts. We sought to investigate the role of epigenetic modifications beside genetic alterations in the MEFV gene in familial Mediterranean fever (FMF). The study comprised 63 FMF patients diagnosed according to the Tel Hashomer criteria: 37 (58.7%) colchicine-responders, 26 (41.3%) non-responders, and 19 matched healthy controls. MEFV mutations were detected using a CE/IVD-labeled 4-230 FMF strip assay. DNA methylation of MEFV gene exon 2 was measured using bisulfite modification and related to pyrin level, phenotypic picture, MEFV mutations, disease severity, serum amyloid A (SAA), CRP, ESR, disease severity, and colchicine response. Our results showed that FMF patients exhibited significantly higher methylation percentage (p < 0.001) and lower pyrin levels (p < 0.001) compared to the control. The MEFV gene M694I mutation was the most commonly reported mutation (p < 0.004). High methylation percentage of the MEFV exon 2 and low pyrin concentration were correlated with disease severity, high SAA, ESR levels, H-pylori, and renal calculi. In conclusion, this study highlights the relation between high methylation percentage, reduced pyrin level, and different biomarkers in FMF, which underscores their role in the pathogenesis of FMF and could be considered as potential therapeutic targets.

Interactome battling of lncRNA CCDC144NL-AS1: Its role in the emergence and ferocity of cancer and beyond.

Long non-coding RNAs (lncRNAs) were, once, viewed as "noise" for transcription. Recently, many lncRNAs are functionally linked to several human disorders, including cancer. Coiled-Coil Domain Containing 144 N-Terminal-Like antisense1 (CCDC144NL-AS1) is a newly discovered cytosolic lncRNA. Aberrant CCDC144NL-AS1 expression was discovered in hepatocellular carcinoma (HCC), ovarian cancer (OC), gastric cancer (GC), non-small cell lung cancer (NSCLC), and osteosarcoma. CCDC144NL-AS1 could be a promising prognostic biological marker and therapeutic target for cancer. In this review, we will collect and highlight the available information about CCDC144NL-AS1 role in various cancers. Moreover, we will discuss the diagnostic and prognostic utility of CCDC144NL-AS1 as a new molecular biomarker for several human malignancies, besides its potential therapeutic importance.

Bone Marrow Mesenchymal Stem Cells and Their Derived Extracellular Vesicles Attenuate Non-Alcoholic Steatohepatitis-Induced Cardiotoxicity via Modulating Cardiac Mechanisms.

Cardiovascular-disease (CVD)-related mortality has been fueled by the upsurge of non-alcoholic steatohepatitis (NASH). Mesenchymal stem cells (MSCs) were extensively studied for their reparative power in ameliorating different CVDs via direct and paracrine effects. Several reports pointed to the importance of bone marrow mesenchymal stem cells (BM-MSCs) as a reliable therapeutic approach for several CVDs. Nevertheless, their therapeutic potential has not yet been investigated in the cardiotoxic state that is induced by NASH. Thus, this study sought to investigate the molecular mechanisms associated with cardiotoxicity that accompany NASH. Besides, we aimed to comparatively study the therapeutic effects of bone-marrow mesenchymal-stem-cell-derived extracellular vesicles (BM-MSCs-EV) and BM-MSCs in a cardiotoxic model that is induced by NASH in rats. Rats were fed with high-fat diet (HFD) for 12 weeks. At the seventh week, BM-MSCs-EV were given a dose of 120 µg/kg i.v., twice a week for six weeks (12 doses per 6 weeks). Another group was treated with BM-MSCs at a dose of 1 × 106 cell i.v., per rat once every 2 weeks for 6 weeks (3 doses per 6 weeks). BM-MSCs-EV demonstrated superior cardioprotective effects through decreasing serum cardiotoxic markers, cardiac hypoxic state (HIF-1) and cardiac inflammation (NF-κB p65, TNF-α, IL-6). This was accompanied by increased vascular endothelial growth factor (VEGF) and improved cardiac histopathological alterations. Both BM-MSCs-EV and BM-MSCs restored the mitochondrial antioxidant state through the upregulation of UCP2 and MnSOD genes. Besides, mitochondrial Parkin-dependent and -independent mitophagies were regained through the upregulation of (Parkin, PINK1, ULK1, BNIP3L, FUNDC1) and (LC3B). These effects were mediated through the regulation of pAKT, PI3K, Hypoxia, VEGF and NF-κB signaling pathways by an array of secreted microRNAs (miRNAs). Our findings unravel the potential ameliorative effects of BM-MSCs-EV as a comparable new avenue for BM-MSCs for modulating cardiotoxicity that is induced by NASH.

Deciphering epigenetic(s) role in modulating susceptibility to and severity of COVID-19 infection and/or outcome: a systematic rapid review.

COVID-19 pandemic waves hitting worldwide result in drastic postinfection complications with interindividual variations, which raised the question for the cause of these observed variations. This urged to think "the impact of environment-affected genes"? In an attempt to unravel the impact of environment-affected genes, a systematic rapid review was conducted to study "the impact of host or viral epigenetic modulation on COVID-19 infection susceptibility and/or outcome." Electronic databases including Web of Science, SCOPUS, Cochrane Central Register of Controlled Trials, PubMed, and Google Scholar, and other databases were searched. The search strings included "COVID-19" OR "SARS-CoV-2" AND (Epigenetics'). Articles with randomized clinical trials (RCTs) and observational study designs, conducted on humans and available in the English language, were selected, with respect to "The interplay between the SARS-CoV-2 virus and Epigenetics" published from 2020 to February 2021 (but not limited to 2020, being expanded to 2015). Database search yielded 1330 articles; after screening, exclusion, and further filtrations, 51 articles were included. Susceptibility to COVID-19 infection is related to the viral-microRNAs (miRNAs) which alter virulence of the transmitted SARS-CoV-2 strains and impact host-miRNA-related innate immunity. Host-DNA methylation and/or chromatin remodeling may be implicated in severe cytokine storm that can ultimately results in fatal outcome.

Upregulation of miR-96-5p by bone marrow mesenchymal stem cells and their exosomes alleviate non-alcoholic steatohepatitis: Emphasis on caspase-2 signaling inhibition.

Non-alcoholic steatohepatitis (NASH) has evolved as the most common and devastating chronic liver disease. This study aimed to explore the underlined mechanism for the therapeutic potentials of bone marrow mesenchymal stem cells (BM-MSCs) and their derived exosomes (BM-MSCs-Exo) in an experimental model of high fat diet (HFD) induced NASH. Rats were fed with HFD for 12 weeks. At the seventh week, BM-MSCs were given at a dose of 1x106 cell i.v., per rat. A total of three doses of BM-MSCs were given per each rat in six weeks. BM-MSCs-Exo were given at a dose of 15, 30 and 120 µg/kg i.v., twice per week for six weeks. Perfect homing to the liver was detected. Beneficial effects were reported to BM-MSCs or BM-MSCs-Exo cotreatment; where the highest anti-steatotic effects were attributed to BM-MSCs-Exo (120 µg/kg) showing significant downregulation of fatty acid synthesis (SREB1, 2, ACC), downregulation in lipid uptake (CD36); accompanied by significant upregulation in fatty acid oxidation (PPARα, CPT1). These events were associated with abrogation of hepatic steatosis and ballooning in HFD-induced NASH. BM-MSCs or BM-MSCs-Exo cotreatment exerted significant anti-apoptotic effects mediated by significant decrease in Bax/Bcl2 ratio. Besides, significant increase in mitochondrial mitophagy genes (Parkin, PINK1, ULK1, BNIP3L, ATG5, ATG7, ATG12) were detected in BM-MSCs or BM-MSCs-Exo cotreated groups. These findings are thought to be modulated through upregulation of miRNA-96-5p which leads to downregulation of its downstream target caspase-2. Being a critical player in NASH development, caspase-2 targeting by miRNA-96-5p could be a promising therapeutic modality to treat NASH.

BRCA1 and BRCA2 truncating mutations and variants of unknown significance in Egyptian female breast cancer patients.

BACKGROUND: Breast cancer is the most common malignancy among women worldwide and the leading cause of cancer death in economically developing countries. We sought to study the contribution of BRCA1/2 mutations to the burden of breast cancer in Egypt. PATIENTS AND METHODS: 103 Egyptian female breast cancer patients, unselected for age of onset or family history, were included in the study. Mutational screening of some exons of BRCA1/2 genes was performed using High Resolution Melting analysis followed by direct sequencing of detected variants. RESULTS: Twenty sequence variants were identified. According to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, 8 variants were classified as pathogenic (Class 5), 1 as likely pathogenic and 11 as variants of unknown significance (Class 3). The pathogenic variants comprised 5 novel frameshift mutations; BRCA1 c.5205delA and BRCA2 (c.3641delT, c.3291dupT, c.3292delA, and c.787dupA) mutations; 1 novel nonsense mutation (BRCA2 c.3280A>T) and 2 previously described missense mutations (BRCA1 c.117T>G, c.110C>A). CONCLUSION: This study provides the results of our attempt to delineate the genetic aspect of breast cancer among the Egyptian population and emphasizes the necessity of implementing screening strategies for early diagnosis and counseling for breast cancer in Egypt.

Comparing cefotaxime and ceftriaxone in combating meningitis through nose-to-brain delivery using bio/chemoinformatics tools.

Bio/chemoinformatics tools can be deployed to compare antimicrobial agents aiming to select an efficient nose-to-brain formulation targeting the meningitis disease by utilizing the differences in the main structural, topological and electronic descriptors of the drugs. Cefotaxime and ceftriaxone were compared at the formulation level (by comparing the loading in gelatin and tripalmitin matrices as bases for the formation of nanoparticulate systems), at the biopharmaceutical level (through the interaction with mucin and the P-gp efflux pumps) and at the therapeutic level (through studying the interaction with S. pneumoniae bacterial receptors). GROMACS v4.6.5 software package was used to carry-out all-atom molecular dynamics simulations. Higher affinity of ceftriaxone was observed compared to cefotaxime on the investigated biopharmaceutical and therapeutic macromolecules. Both drugs showed successful docking on mucin, P-gp efflux pump and S. pneumoniae PBP1a and 2b; but ceftriaxone showed higher affinity to the P-gp efflux pump proteins and higher docking on mucin. Ceftriaxone showed less out-of-matrix diffusion and higher entrapment on the gelatin and the tripalmitin matrices. Accordingly, Ceftriaxone gelatin nanospheres or tripalmitin solid lipid nanoparticles may pose a more feasible and efficient nose-to-brain formulation targeting the meningitis disease compared to the cefotaxime counterparts.

Chloroquine and hydroxychloroquine for combating COVID-19: Investigating efficacy and hypothesizing new formulations using Bio/chemoinformatics tools.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are undergoing several clinical trials for evaluating their efficacy and safety as antiviral drugs. Yet, there is still a great debate about their efficacy in combating COVID-19. This study aimed to evaluate the feasibility of intranasal and/or pulmonary administration of CQ/HCQ for COVID-19 using Bio/chemoinformatics tools. We, hereby, hypothesize the success of the intranasal and the pulmonary routes through a gelatin matrix to overcome several challenges related to CQ and HCQ pharmacodynamics and pharmacokinetics properties and to increase their local concentrations at the sites of initial viral entry while minimizing the potential side effects. Molecular docking on the gelatin-simulated matrix demonstrated high loading values and a sustained release profile. Moreover, the docking on mucin as well as various receptors including Angiotensin-converting enzyme 2 (ACE-2), heparin sulphate proteoglycan and Phosphatidylinositol binding clathrin assembly protein (PICALM), which are expressed in the lung and intranasal tissues and represent initial sites of attachment of the viral particles to the surface of respiratory cells, has shown good binding of CQ and HCQ to these receptors. The presented data provide an insight into the use of a novel drug formulation that needs to be tested in adequately powered randomized controlled clinical trials; aiming for a sustained prophylaxis effect and/or a treatment strategy against this pandemic viral infection.