Bioinformatics Prediction of Potential Inhibitors For the SARS-CoV-2 NTPase/Helicase Using Molecular Docking and Dynamics Simulation From Organic Phenolic Compounds

Background: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a disorder with human-to-human rapid transmission. Besides several vaccines that have been represented, it is crucial to discover effective drugs to combat this infection in a short-period therapeutic procedure. The NTPase/helicase contributes to playing an important role in the replication of the viral RNA. Materials and methods: We estimated the binding affinity of several natural polyphenolics, commonly found in fruits and vegetables, with the catalytic site of SARS-CoV-2 helicase by molecular docking analysis using the AutoDock tool. The stability of connections between top-ranked components inside the catalytic site of the helicase was evaluated by molecular dynamics (MD) simulations. The most active residues within the catalytic site of the helicase were ranked based on their degree in a phenolics-residue interaction (PRI) network. Results: Amentoflavone, theaflavin 3'-gallate, and procyanidin were estimated to be the most potential effective SARS-CoV-2 helicase inhibitors with the salient inhibition constant value (Ki) at the picomolar scale. The energy of binding of these compounds with the helicase catalytic site was estimated between -13.90 and -12.77 kcal/mol. Asp534 and Leu412 demonstrated more degrees than the other residues. Conclusion: The present study predicts that amentoflavone, theaflavin 3'-gallate, and procyanidin might be helpful for the treatment of COVID-19

Antiapoptotic and antioxidative effects of cerium oxide nanoparticles on the testicular tissues of streptozotocin-induced diabetic rats: An experimental study

Background: Cerium dioxide nanoparticles (CNPs) due to the antidiabetic and antioxidant activities are proposed for the treatment of oxidative stress-associated diseases. Objective: To examine the impact of CNPs on hyperglycemia-induced apoptosis and oxidative stress in the testis of diabetic rats. Materials and Methods: Twenty-four male rats were divided into four groups (n = 6/each) as diabetic rats, CNPs group, diabetic + CNPs rats, and controls. The control group was fed only mouse food and water. Rats became diabetic through receiving streptozotocin (STZ) 60 mg/kg. CNPs were given to the rats at a dose of 30 mg/kg daily for 2 wk. Malondialdehyde and total thiol group (TTG) levels were measured using spectrofluorometer. Expression of b-cell lymphoma protein 2-associated X protein (BAX) and b-cell lymphoma protein 2 (Bcl-2) were investigated using quantitative real-time polymerase chain reaction. Western blot analysis was used to examine caspase 3 protein levels. Results: The content of malondialdehyde significantly increased in the STZ-diabetic rats, while TTG levels demonstrated a remarkable decrease. Caspase-3, BAX, and BAX/Bcl-2 mRNA ratio raised significantly in the STZ-diabetic rats. On the other hand, Bcl-2 mRNA levels reduced in the testis of diabetic rats (p = 0.006). Intervention with CNPs caused a substantial increase in the TTG levels, while the malondialdehyde contents, caspase-3, BAX levels, as well as BAX/Bcl-2 mRNA ratio were considerably decreased following CNPs treatment. Administration of CNPs increased mRNA levels of Bcl-2 (p < 0.0001). Conclusion: CNPs treatment attenuates testicular apoptosis and oxidative stress induced by diabetes. This nanoparticle might be suggested for the treatment of diabetes-associated reproductive disorders. Key words: Apoptosis, Nanoceria, Diabetes, Oxidative stress, Testis

Predicting the Survival Time for Bladder Cancer Using an Additive Hazards Model in Microarray Data

Background: One substantial part of microarray studies is to predict patients’ survival based on their gene expression profile. Variable selection techniques are powerful tools to handle high dimensionality in analysis of microarray data. However, these techniques have not been investigated in competing risks setting. This study aimed to investigate the performance of four sparse variable selection methods in estimating the survival time. Methods: The data included 1381 gene expression measurements and clinical information from 301 patients with bladder cancer operated in the years 1987 to 2000 in hospitals in Denmark, Sweden, Spain, France, and England. Four methods of the least absolute shrinkage and selection operator, smoothly clipped absolute deviation, the smooth integration of counting and absolute deviation and elastic net were utilized for simultaneous variable selection and estimation under an additive hazards model. The criteria of area under ROC curve, Brier score and c-index were used to compare the methods. Results: The median follow-up time for all patients was 47 months. The elastic net approach was indicated to outperform other methods. The elastic net had the lowest integrated Brier score (0.137±0.07) and the greatest median of the over-time AUC and C-index (0.803±0.06 and 0.779±0.13, respectively). Five out of 19 selected genes by the elastic net were significant (P<0.05) under an additive hazards model. It was indicated that the expression of RTN4, SON, IGF1R and CDC20 decrease the survival time, while the expression of SMARCAD1 increase it. Conclusion: The elastic net had higher capability than the other methods for the prediction of survival time in patients with bladder cancer in the presence of competing risks base on additive hazards model

MicroRNAs: effective elements in ear-related diseases and hearing loss

miRNAs are important factors for post-transcriptional process that controls gene expression at mRNA level. Various biological processes, including growth and differentiation, are regulated by miRNAs. miRNAs have been demonstrated to play an essential role in development and progression of hearing loss. Nowadays, miRNAs are known as critical factors involved in different physiological, biological, and pathological processes, such as gene expression, progressive sensorineural hearing loss, age-related hearing loss, noise-induced hearing loss, cholesteatoma, schwannomas, and inner ear inflammation. The miR-183 family (miR-183, miR-96 and miR-182) is expressed abundantly in some types of sensory cells in inner ear specially mechanosensory hair cells that exhibit a great expression level of this family. The plasma levels of miR-24-3p, miR-16-5p, miR-185-5p, and miR-451a were upregulated during noise exposures, and increased levels of miR-21 have been found in vestibular schwannomas and human cholesteatoma. In addition, upregulation of pro-apoptotic miRNAs and downregulation of miRNAs which promote differentiation and proliferation in age-related degeneration of the organ of Corti may potentially serve as a helpful biomarker for the early detection of age-related hearing loss. This knowledge represents miRNAs as promising diagnostic and therapeutic tools in the near futur

MicroRNA-183 family in inner ear: Hair cell development and deafness

miRNAs are essential factors of an extensively conserved post-transcriptional process controlling gene expression at mRNA level. Varoius biological processes such as growth and differentiation are regulated by miRNAs. Web of Science and PubMed databases were searched using the Endnote software for the publications about the role miRNA-183 family in inner ear: hair cell development and deafness published from 2000 to 2016. A triplet of these miRNAs particularly the miR-183 family is highly expressed in vertebrate hair cells, as with some of the peripheral neurosensory cells. Point mutations in one member of this family, miR-96, underlie DFNA50 autosomal deafness in humans and lead to abnormal hair cell development and survival in mice. In zebrafish, overexpression of the miR-183 family induces extra and ectopic hair cells, while knockdown decreases the number of hair cell. The miR-183 family (miR-183, miR-96 and miR-182) is expressed abundantly in some types of sensory cell in the eye, nose and inner ear. In the inner ear, mechanosensory hair cells have a robust expression level. Despite much similarity of these miRs sequences, small differences lead to distinct targeting of messenger RNAs targets. In the near future, miRNAs are likely to be explored as potential therapeutic agents to repair or regenerate hair cells, cell reprogramming and regenerative medicine applications in animal models because they can simultaneously down-regulate dozens or even hundreds of transcripts. © 2016 The Korean Audiological Society

Genetic Identification of Echinococcus granulosus Isolates in Hamadan, Western Iran

Background: Cystic echinococcosis is a zoonotic infection and considered as a major economic and public health concern worldwide. This research was conducted to determine genotypic characteristics of livestock and human hydatid cyst isolates from Hamadan area, western Iran. Methods: Sampling was conducted in Hamadan industrial slaughterhouse and Beast Hospital of Hamadan City, western Iran, from 2015 to 2016. Overall, 74 livestock isolates including 69 sheep, 3 cattle and 2 goats and 9 human hydatid cysts were genotyped by PCR amplification of the rDNA ITS1 region and followed restriction fragment length polymorphism (RFLP) analysis with four restriction endonuclease enzymes, RsaI, HpaII, AluI, and TaqΙ, and sequencing. Results: The PCR amplicon size of each isolate was approximately 1 kb which was the same with that of sheep strain. According to the RFLP patterns, the isolates belonged to a single species, E. granulosus sensu stricto (G1–G3 complex). Furthermore, sequencing of representative amplicons confirmed that the RFLP-genotyped isolates corresponded to E. granulosus sensu stricto. Conclusion: E. granulosus sensu stricto is the prevailing species of E. granulosus sensu lato in the region and pointed out the importance of sheep/dog cycle in human transmission

In Silico and In Vitro Evaluation of Selected Herbal Compounds as Robust HER-2 Inhibitors for Effective Treatment of Breast Cancer

Background and objectives: Breast cancer is the most frequently reported malignancy in women worldwide and is a heterogeneous disease. Due to different levels of human epidermal growth factor receptor 2 (HER-2) and its critical role in tumor progression, HER-2 has been considered as a validated target in breast cancer therapy. The present study aimed to identify new and effective HER-2 inhibitors from selected plant-based compounds using a computational drug discovery approach. The anticancer effects of top-ranked compounds were then evaluated using cellular and molecular methods. Methods: The binding affinities of 47 herbal compounds (including 21 flavonoids, 16 anthraquinones, and 10 cinnamic acids) with the extracellular domain of HER-2 were evaluated using m­olecular docking analysis. The top hits were evaluated for their cell proliferation inhibition, apoptosis, and migration effects in high and low HER-2-overexpressing SKBR-3 and MCF-7 cell lines, respectively. Results:  Chrysin, chrysophanol, and chlorogenic acid revealed the highest binding affinity to the extracellular domain of HER-2; therefore, they were considered the top-ranked HER-2 inhibitors in this study. Each component inhibited cell proliferation and decreased migration activity of SKBR-3 and MCF-7 cell lines, while the SKBR-3 cells were affected more. The results of the apoptosis assay showed that chrysin was the only compound that could cause a significant induction of SKBR-3 cell apoptosis in comparison to MCF-7 cells. Conclusion: The results of the present study suggest that chrysophanol, chlorogenic acid, and especially chrysin may have anticancer effects and could be considered drug candidates for therapeutic aims in human HER-2 positive cancer

Study of common mitochondrial mutations in patients with nonsyndromic hearing loss

Hearing loss is the most common sensorineural disorder involving one out of 1000 people. Around 50% of hearing losses occur due to genetic causes. Three mitochondrial mutations, A1555G in MTRNR1, A3243G in MTTL1, and A7445G in MTTS1, are the most important non-syndromic sensorineural causes of hearing loss in some populations. The aim of this review was to study common mitochondrial mutations in people with hearing loss in Iran. EVIDENCE ACQUISITION: Directory of Open Access Journals (DOAJ), Google Scholar, PubMed (NLM), LISTA (EBSCO) and Web of Science were searched. EVIDENCE SYNTHESIS: Studies have indicated that the mitochondrial mutations A3243G, A1555G, and A7445G play no significant part in the development of hearing loss in Iran. Different variants of A7445C and G3316A have been identified in Iran. CONCLUSIONS: Further studies on other ethnicities and with a larger sample size are necessary to elucidate the role of these genes in hearing loss development in Iran

Cytotoxic effects of hydroalcoholic extract of Cuscuta chinensis on PC3 and MCF7 cancer cell lines

Objective: Chemoprevention of cancer by application of natural phytochemical compounds has been used to prevent, delay or suppress cancer progression. Cuscuta chinensis a traditional Iranian medicinal herb, has biological properties including anticancer, anti-aging, immuno-stimulatory and antioxidant effects. In this study, anti-proliferative effects of hydroalcoholic extract of C. chinensis on prostate (PC3) and breast (MCF7) cancer cell lines were investigated. Materials and Methods: In the current study, we investigated treatment of PC3 cells with different concentrations of C. chinensis (0, 100, 200, 300, 400, and 500 µg/ml) for 24 and 48 hr; also, MCF7 cells were treated with various concentrations (0-600 µg/ml) of C. chinensis for 48 and 72 hr and cell viability was assessed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. mRNA expression of BCL2 Associated X (Bax), B-cell lymphoma 2 (Bcl2), Cysteine-aspartic proteases (Caspase3) and Phosphatase and tensin homolog (PTEN) were analyzed by quantitative real-time PCR. Annexin V/PI staining and lactate dehydrogenase (LDH) cytotoxicity assay were used to detect apoptosis. Results: C. chinensis decreased PC3 and MCF7 cells viability in a dose- and time-dependent manner (p BAX/Bcl2 ratio, Caspase3 and PTEN increased in C. chinensis-treated cells compared to the control group. C. chinensis induced apoptosis (p <0.001) and LDH activity (p Conclusion: Our findings suggest that C. chinensis extract is able to inhibit proliferation and induce apoptosis in PC3 and MCF7 cell lines. Therefore, C. chinensis extract exerts antitumor activity against cancer cells

BC4707 Is a Major Facilitator Superfamily Multidrug Resistance Transport Protein from Bacillus cereus Implicated in Fluoroquinolone Tolerance

Transcriptional profiling highlighted a subset of genes encoding putative multidrug transporters in the pathogen Bacillus cereus that were up-regulated during stress produced by bile salts. One of these multidrug transporters (BC4707) was selected for investigation. Functional characterization of the BC4707 protein in Escherichia coli revealed a role in the energized efflux of xenobiotics. Phenotypic analyses after inactivation of the gene bc4707 in Bacillus cereus ATCC14579 suggested a more specific, but modest role in the efflux of norfloxacin. In addition to this, transcriptional analyses showed that BC4707 is also expressed during growth of B. cereus under non-stressful conditions where it may have a role in the normal physiology of the bacteria. Altogether, the results indicate that bc4707, which is part of the core genome of the B. cereus group of bacteria, encodes a multidrug resistance efflux protein that is likely involved in maintaining intracellular homeostasis during growth of the bacteria.Peer reviewe