In-silico study MM/GBSA binding free energy and molecular dynamics simulation of some designed remdesivir derivatives as the inhibitory potential of SARS-CoV-2 main protease.

Background and purpose: Coronavirus disease (COVID-19) is one of the greatest challenges of the twentieth century. Recently, in silico tools help to predict new inhibitors of SARS-CoV-2. In this study, the new compounds based on the remdesivir structure (12 compounds) were designed. Experimental approach: The main interactions of remdesivir and designed compounds were investigated in the 3CLpro active site. The binding free energy of compounds by the MM-GBSA method was calculated and the best compound (compound 12 with the value of -88.173 kcal/mol) was introduced to the molecular dynamics simulation study. Findings/Results: The simulation results were compared with the results of protein simulation without the presence of an inhibitor and in the presence of remdesivir. Additionally, the RMSD results for the protein backbone showed that compound 12 in the second 50 nanoseconds has less fluctuation than the protein alone and in the presence of remdesivir, which indicates the stability of the compound in the active site of the Mpro protein. Furthermore, protein compactness was investigated in the absence of compounds and the presence of compound 12 and remdesivir. The Rg diagram shows a fluctuation of approximately 0.05 A, which indicates the compressibility of the protein in the presence and absence of compounds. The results of the RMSF plot also show the stability of essential amino acids during protein binding. Conclusion and implications: Supported by the theoretical results, compound 12 could have the potential to inhibit the 3CLpro enzyme, which requires further in vitro studies and enzyme inhibition must also be confirmed at protein levels.

Identification of Prognostic Biomarkers in Papillary Thyroid Cancer and Developing Non-Invasive Diagnostic Models Through Integrated Bioinformatics Analysis.

BACKGROUND: Papillary thyroid cancer (PTC) is the most frequent subtype of thyroid carcinoma, mainly detected in patients with benign thyroid nodules (BTN). Due to the invasiveness of accurate diagnostic tests, there is a need to discover applicable biomarkers for PTC. So, in this study, we aimed to identify the genes associated with prognosis in PTC. Besides, we performed a machine learning tool to develop a non-invasive diagnostic approach for PTC. METHODS: For the study purposes, the miRNA dataset GSE130512 was downloaded from the GEO database and then analyzed to identify the common differentially expressed miRNAs in patients with non-metastatic PTC (nm-PTC)/metastatic PTC (m-PTC) compared with BTNs. The SVM was also applied to differentiate patients with PTC from those patients with BTN using the common DEMs. A protein-protein interaction network was also constructed based on the targets of the common DEMs. Next, functional analysis was performed, the hub genes were determined, and survival analysis was then executed. RESULTS: A total of three common miRNAs were found to be differentially expressed among patients with nm-PTC/m-PTC compared with BTNs. In addition, it was established that the autophagosome maturation, ciliary basal body-plasma membrane docking, antigen processing as ubiquitination & proteasome degradation, and class I MHC mediated antigen processing & presentation are associated with the pathogenesis of PTC. Furthermore, it was illustrated that RPS6KB1, CCNT1, SP1, and CHD4 might serve as new potential biomarkers for PTC prognosis. CONCLUSION: RPS6KB1, CCNT1, SP1, and CHD4 may be considered new potential biomarkers used for prognostic aims in PTC. However, performing validation tests is inevitable in the future.

Introducing Transthyretin as a Differentially Expressed Protein in Washing Subtype of Obsessive-Compulsive Disorder.

INTRODUCTION: Obsessive-Compulsive Disorder (OCD) as one of the important mental problems is valuable topic for proteomic research studies to better understand the underlying mechanisms of this disorder. METHODS: In this paper, gel-based proteomic was used to investigate the proteome profile of 16 female patients with OCD, washing subtype before and after treatment with fluoxetine and comparing them with 20 healthy female controls. RESULTS: One of the abnormally expressed protein spots in this study was introduced and examined for protein-protein interaction network analysis via Cytoscape and its plug-ins. Transthyretin (TTR) protein showed significant expression changes (fold change=1.7, P<0.05). While the expression level of TTR is significantly decreased in OCD patients before any treatments, the trend is partially normalized after treatment with fluoxetine in positive responders. Furthermore, TTR interaction profile shows that the proteins interacting with this protein may get affected as this protein expression trend changes in OCD patients. CONCLUSION: TTR can be considered for further studies to be validated as a potential biomarker for OCD.

Lavandula angustifolia Effects on Rat Models of Alzheimer's Disease Through the Investigation of Serum Metabolic Features Using NMR Metabolomics.

BACKGROUND: Alzheimer's Disease (AD) is the most prevalent cause of memory impairment in the elderly population, but the diagnosis and treatment of the disease is still challenging. Lavender aqueous extract has recently been shown to have the potential in clearing Amyloid-beta plaques from AD rat hippocampus. To elucidate the therapeutic mechanisms of lavender, serum metabolic fingerprint of Aß-induced rat Alzheimer's models was investigated through nuclear magnetic resonance spectrometry. METHODS: For the establishment of rat Alzheimer's models, 10 µg of Amyloid beta 1-42 was injected to male Wistar rats. The lavender aqueous extract was injected 20 days after the establishment of the models, once daily for 20 days. Serum samples were collected and metabolite fingerprints were obtained using 500 MHz 1H-NMR spectrometry, following multivariate statistical analyses. The resulted metabolites were then subjected to pathway analysis tools to reveal metabolic pathways affected by the lavender extract treatment. RESULTS: Levels of 10 metabolite markers including alanine, glutamine, serine, isoleucine, valine, carnitine, isobutyrate, pantothenate, glucose and asparagine were reversed nearly to control values after treatment with lavender extract. The results revealed that the most significantly affected pathways during treatment with lavender extract belonged to carbohydrate and amino acid metabolism, including pantothenate and CoA metabolism, glyoxilate and dicarboxylate metabolism, alanine, aspartate and glutamate metabolism, cysteine and methionine metabolism. CONCLUSION: As lavender extract reversed the direction of changes of some metabolites involved in AD pathogenesis, it was concluded that the extract might play a role in the disease improvement and serve as a potential therapeutic option for the treatment of AD. Moreover, the metabolites which were found in AD rats could serve as a potential marker panel for the disease; however, much further investigation and validation of the results is needed.

Metabolomics diagnostic approach to mustard airway diseases: a preliminary study.

OBJECTIVES: This study aims to evaluate combined proton nuclear magnetic resonance (1H NMR) spectroscopy and gas chromatography-mass spectrometry (GC-MS) metabolic profiling approaches, for discriminating between mustard airway diseases (MADs) and healthy controls and for providing biochemical information on this disease. MATERIALS AND METHODS: In the present study, analysis of serum samples collected from 17 MAD subjects and 12 healthy controls was performed using NMR. Of these subjects, 14 (8 patients and 6 controls) were analyzed by GC-MS. Then, their spectral profiles were subjected to principal component analysis (PCA) and orthogonal partial least squares regression discriminant analysis (OPLS-DA). RESULTS: A panel of twenty eight metabolite biomarkers was generated for MADs, sixteen NMR-derived metabolites (3-methyl-2-oxovaleric acid, 3-hydroxyisobutyrate, lactic acid, lysine, glutamic acid, proline, hydroxyproline, dimethylamine, creatine, citrulline, choline, acetic acid, acetoacetate, cholesterol, alanine, and lipid (mainly VLDL)) and twelve GC-MS-derived metabolites (threonine, phenylalanine, citric acid, myristic acid, pentadecanoic acid, tyrosine, arachidonic acid, lactic acid, propionic acid, 3-hydroxybutyric acid, linoleic acid, and oleic acid). This composite biomarker panel could effectively discriminate MAD subjects from healthy controls, achieving an area under receiver operating characteristic curve (AUC) values of 1 and 0.79 for NMR and GC-MS, respectively. CONCLUSION: In the present study, a robust panel of twenty-eight biomarkers for detecting MADs was established. This panel is involved in three metabolic pathways including aminoacyl-tRNA biosynthesis, arginine, and proline metabolism, and synthesis and degradation of ketone bodies, and could differentiate MAD subjects from healthy controls with a higher accuracy.

Pro-oxidant-antioxidant balance in Iranian veterans with sulfur mustard toxicity and different levels of pulmonary disorders.

OBJECTIVE: Sulfur mustard (SM) is a strong alkylating agent that primarily targets the skin, eye and lung. The current study evaluated the pro-oxidant-antioxidant balance (PAB) assay in human serum of SM-exposed patients. DESIGN AND METHODS: sera of 35 SM-exposed patients and 19 healthy volunteers were recruited. Both groups had nonsmoker and nonalcoholic people with no diseases such as diabetes, heart disease and other pulmonary diseases (COPD because of smoking, asthma and so on). All patients had documented exposure to SM. The PAB was measured. RESULTS: SM-exposed patients with normal values for pulmonary function test and severe obstructive pulmonary disease demonstrated a significant increase in PAB value in compared with healthy volunteers (the PAB values in healthy volunteers, normal and severe patients were 48.74 ± 21.07 HK, 101.45 ± 32.68 HK and 120.23 ± 31.55 HK, respectively). However, the level of oxidation is not related to the severity of disease defined by spirometry findings. A significant negative correlation was established between the PAB value and FEV1. CONCLUSIONS: The increased PAB value in chemical casualties showed that these patients are exposed to oxidative stress.

The metabolomics of airway diseases, including COPD, asthma and cystic fibrosis.

Chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis (CF) are characterized by airway obstruction and an inflammatory process. Reaching early diagnosis and discrimination of subtypes of these respiratory diseases are quite a challenging task than other chronic illnesses. Metabolomics is the study of metabolic pathways and the measurement of unique biochemical molecules generated in a living system. In the last decade, metabolomics has already proved to be useful for the characterization of several pathological conditions and offers promises as a clinical tool. In this article, we review the current state of the metabolomics of COPD, asthma and CF with a focus on the different methods and instrumentation being used for the discovery of biomarkers in research and translation into clinic as diagnostic aids for the choice of patient-specific therapies.

The concentration of serum zinc in celiac patients compared to healthy subjects in Tehran.

AIM: This study evaluated serum levels of zinc in patient with CD compare to healthy subjects. BACKGROUND: Celiac disease (CD) is characterized by small intestinal malabsorption of nutrients as a consequence of ingestion of wheat gluten. Zinc is an essential trace element that it has vital biological functions. PATIENTS AND METHODS: Sera of 30 celiac cases and 30 healthy normal cohorts as control group were obtained. Atomic absorption spectrophotometer was employed for estimating serum zinc level. RESULTS: Zinc concentrations in patients diagnosed with CD were significantly lower than healthy subjects (75.97±12 compared with 92.83±18, P-value < 0.0001). CONCLUSION: The result of this study shows that serum zinc concentration is decreased in celiac patients compare to healthy controls. Serum zinc may thus be a marker of CD in adults presenting with gastrointestinal symptoms.

Metabonomics based NMR in Crohn's disease applying PLS-DA.

AIM: The aim of this study was to search for metabolic biomarkers of Crohn's disease (CD). BACKGROUND: Crohn's disease (CD) is a type of inflammatory bowel disease that causing a wide variety of symptoms. CD can influence any part of the gastrointestinal tract from mouth to anus. CD is not easily diagnosed because monitoring tools are currently insufficient. Thus, the discovery of proper methods is needed for early diagnosis of CD. PATIENTS AND METHODS: We utilized metabolic profiling using proton nuclear magnetic resonance spectroscopy ((1)HNMR) to find the metabolites in serum. Classification of CD and healthy subject was done using partial least squares discriminant analysis (PLS-DA). RESULTS: According to PLS-DA model, we concluded that just using one descriptor CD and control groups could be classified separately. The level of lipid in blood serum of CD compared to healthy cohorts was decreased. For the external test set, the classification model showed a 94% correct classification of CD and healthy subject. CONCLUSION: The result of classification model presents that NMR based metabonomics is key tool as well as insight into potential targets for disease therapy and prevention.

Dynamic stereochemistry of Topiramate (anticonvulsant drug) in solution: theoretical approaches and experimental validation.

Topiramate, an antiepileptic drug, was synthesized with an improved protocol and identified by (1)H NMR, (13)C NMR, (1)H-(1)H COSY, HMQC and HMBC spectrum. In parallel, density functional theory (DFT) using B3LYP functional and split-valance 6-311++G** basis set has been used to optimize the structures and conformers of Topiramate. Also experimental and theoretical methods have been used to correlate the dependencies of (1)J and (2)J involving (1)H and (13)C on the C1-C2 (ω) and C1-O1 (θ) torsion angles in the glycosidic part of Topiramate. New Karplus equations are proposed to assist in the structural interpretation of these couplings. Importantly, due to the sensitivity of some couplings, most notably (2)J(H1R,H1S), (2)J(C2,H1R) and (2)J(C2,H1S) values depend on both C-C (ω) and C-O (θ) torsion angles. Analyses of experimental coupling constants for protons on the pyranose ring of Topiramate indicate a twist boat structure for Topiramate in solution. In all calculations solvent effects were considered using a polarized continuum model (PCM).