Our knowledge of the evolution and the role of untranslated region (UTR) in SARS-CoV-2 pathogenicity is very limited. Leader sequence, originated from UTR, is found at the 5′ ends of all encoded SARS-CoV-2 transcripts, highlighting its importance. Here, evolution of leader sequence was compared between human pathogenic and non-pathogenic coronaviruses. Then, profiling of microRNAs that can inactivate the key UTR regions of coronaviruses was carried out. A distinguished pattern of evolution in leader sequence of SARS-CoV-2 was found. Mining all available microRNA families against leader sequences of coronaviruses resulted in discovery of 39 microRNAs with a stable thermodynamic binding energy. Notably, SARS-CoV-2 had a lower binding stability against microRNAs. hsa-MIR-5004-3p was the only human microRNA able to target the leader sequence of SARS and to a lesser extent, also SARS-CoV-2. However, its binding stability decreased remarkably in SARS-COV-2. We found some plant microRNAs with low and stable binding energy against SARS-COV-2. Meta-analysis documented a significant (p < 0.01) decline in the expression of MIR-5004-3p after SARS-COV-2 infection in trachea, lung biopsy, and bronchial organoids as well as lung-derived Calu-3 and A549 cells. The paucity of the innate human inhibitory microRNAs to bind to leader sequence of SARS-CoV-2 can contribute to its high replication in infected human cells.
Introduction: The aim of this study was to investigate various biochemical and hematological parameters in patients with type 2 diabetes mellitus (T2DM) and compare those with non-diabetic subjects (control group). Subjects: The study was conducted on 405 subjects (ages ranging from 26-65 years old; sex matched) who were classified into two groups: diabetic (n=205 subjects; males-105, females-100) and non-diabetic subjects (n=200; males-100, females-100). The study was carried out during the period of November 2016 to April 2017 in the Department of Clinical Laboratory Sciences at the College of Applied Medical Science Al-Dawadmi, Shaqra University in Saudi Arabia (with the collaboration of the General Hospital Al-Dawadmi). Methods: The following various parameters were assessed for all subjects: body mass index (BMI), systolic and diastolic blood pressure (SBP-DBP), fasting blood sugar (FBS), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatise (ALP), total cholesterol (T. Ch), triglyceride (TG), low-density lipoprotein (LDL), high density lipoprotein (HDL), hemoglobin (HB), red blood cell count (RBC), hematocrit (Ht), mean corpuscular volume (MCV), mean corpuscle hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), red cell distribution width (RDW), platelet count (Plt), mean platelet volume (MPV), platelet distribution width (PDW), total white blood cell count (WBC), lymphocyte count (L), neutrophil count (N), eosinophil count (E), monocyte count (M), basophil count (B), neutrophil/lymphocyte ratio (N/L), and platelet/lymphocyte ratio (P/L). Results: The results showed an increase in the mean values of SGPT, alkaline phosphatase, urea, serum creatinine, total cholesterol, triglyceride, and LDL in the T2DM group relative to the control group. Meanwhile, the mean value of HDL was significantly decreased in the T2DM group compared to the control group (p<0.05). The mean values of hemoglobin, RBC, MCV, MCHC and MCH were significantly decreased in the T2DM group compared to the control group. In contrast, the red cell distribution width significantly increased in the T2DM group versus control group (p<0.05). The mean platelet count was not significantly changed in the T2DM group compared to the control group (p> 0.05), but the mean values of PDW and MPV were significantly higher in the T2DM group compared to the control group (p<0.05). The mean white blood cell count and differential white blood cell was significantly higher in the T2DM group compared to control group (p<0.05). Lastly, the mean neutrophil/lymphocyte ratio and platelet/lymphocyte ratio was not significantly different in the T2DM group compared to control group (p>0.05). Conclusion: In diabetes mellitus type 2 patients, certain biochemical and hematological changes are distinct from healthy subjects. It is important to follow up and monitor these parameters carefully in diabetic patients. Peer Review Details Peer review method: Single-Blind (Peer-reviewers: 02) Peer-review policy Plagiarism software screening?: Yes Date of Original Submission: 30 September 2017 Date accepted: 05 November 2017 Peer reviewers approved by: Dr. Lili Hami Editor who approved publication: Dr. Phuc Van Pham
A considerable number of deposited variants has provided new possibilities for knowledge discovery in different types of prostate cancer. Here, we analyzed variants located on 3′UTR, 5′UTR, CDs, Intergenic, and Intronic regions in castration‐resistant prostate cancer (8496 variants), familial prostate cancer (3241 variants), metastatic castration‐resistant prostate cancer (3693 variants), and prostate cancer (16599 variants). Chromosome regions 10p15‐p14 and 2p13 were highly enriched (P < 0.00001) for variants located in 3′UTR, 5′UTR, CDs, intergenic, and intronic regions in castration‐resistant prostate cancer. In contrast, 10p15‐p14, 10q23.3, 12q13.11, 13q12.3, 1q25, and 8p22 regions were enriched (P < 0.001) in familial prostate cancer. In metastatic castration‐resistant prostate cancer, 10p15‐p14, 10q23.3, 11q22‐q23, 14q21.1, and 14q32.13 were highly variant regions (P < 0.001). Chromosome 2 and chromosome 1 hosted many enriched variant regions. AKR1C3, BRCA1, BRCA2, CHGA, CYP19A1, HOXB13, KLK3, and PTEN contained the highest number of 3′UTR, 5′UTR, CDs, Intergenic, and Intronic variants. Network analysis showed that these genes are upstream of important functions including prostate gland development, tumor recurrence, prostate cancer‐specific survival, tumor progression, cancer mortality, long‐term survival, cancer recurrence, angiogenesis, and AR. Interestingly, all of EGFR, JAK2, NR3C1, PDZD2, and SEMA3C genes had single nucleotide polymorphisms (SNP) in castration‐resistant prostate cancer, consistent with high selection pressure on these genes during drug treatment and consequent resistance. High occurrence of variants in 3′UTRs suggests the importance of regulatory variants in different types of prostate cancer; an area that has been neglected compared with coding variants. This study provides a comprehensive overview of genomic regions contributing to different types of prostate cancer.
Microwave-assisted synthesis and spectral analysis of certain novel derivatives of 3,4-diaminothieno[2,3-b]thiophene-2,5-dicarbonitrile 1–7 were carried out. Compounds 1–7 were examined for cytotoxicity against MCF-7 and A549 cell lines using the quantitative MTT method, and gefitinib and erlotinib were used as reference standards. Compounds 1–7 were shown to be more active than erlotinib against the two cell lines tested. Compound 2 outperformed regular erlotinib by 4.42- and 4.12-fold in MCF-7 and A549 cells, respectively. The most cytotoxic compounds were subsequently studied for their suppression of kinase activity using the homogeneous time-resolved fluorescence assay versus epidermal growth factor receptor (EGFRWT) and EGFR790M. With IC50 values of 0.28 ± 0.03 and 5.02 ± 0.19, compound 2 was demonstrated to be the most effective against both forms of EGFR. Furthermore, compound 2 also had the best antioxidant property, decreasing the radical scavenging activity by 78%. Molecular docking research, on the other hand, was carried out for the analyzed candidates (1–7) to study their mechanism of action as EGFR inhibitors. In silico absorption, distribution, metabolism, excretion, and toxicity tests were also performed to explain the physicochemical features of the examined derivatives.
Obstructive cholestasis characterized by biliary pressure increase leading to leakage of bile back that causes liver injury. The present study aims to evaluate the effects of artemisinin in obstructive cholestasis in mice. The present study was carried out on 40 adult healthy mice that were divided into 4 groups, 10 mice each; the negative control group didn’t receive any medication. The normal group was fed normally with 100 mg/kg of artemisinin extract orally. The cholestatic group fed on 1% lithocholic acid (LCA) mixed into control diet and cholestatic group co-treated with 100 mg/kg of artemisinin extract orally. Mice were treated for 1 month then killed at end of the experiment. A significant increase in alanine aminotransferase, aspartate aminotransferase, and total and direct bilirubin was detected in mice exposed to LCA toxicity. That increase was significantly reduced to normal values in mice co-treated with artemisinin. LCA toxicity causes multiple areas of necrosis of irregular distribution. However, artemisinin co-treatment showed normal hepatic architecture. Moreover, LCA causes down-regulation of hepatic mRNA expressions of a set of genes that are responsible for ATP binding cassette and anions permeability as ATP-binding cassette sub-family G member 8, organic anion-transporting polypeptide, and multidrug resistance-associated protein 2 genes that were ameliorated by artemisinin administration. Similarly, LCA toxicity significantly down-regulated hepatic mRNA expression of constitutive androstane receptor, OATP4, and farnesoid x receptor genes. However, artemisinin treatment showed a reasonable prevention. In conclusion, the current study strikingly revealed that artemisinin treatment can prevent severe hepatotoxicity and cholestasis that led via LCA exposure.
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