Screening of Natural Compounds as Inhibitor of Mpro SARS-CoV-2 Protein; A Molecular Dynamics Approach.

Background: New strains of SARS-CoV-2 are continually emerging worldwide. Recently, WHO warned of a severe new wave in Europe. Current vaccines cannot fully prevent reinfection in vaccinated individuals.

Zinc Ortho Methyl Carbonodithioate Improved Pre and Post-Synapse Memory Impairment via SIRT1/p-JNK Pathway against Scopolamine in Adult Mice.

Alzheimer's disease (AD) is globally recognized as a prominent cause of dementia for which efficient treatment is still lacking. New candidate compounds that are biologically potent are regularly tested. We, therefore, hypothesized to study the neuroprotective potential of Zinc Ortho Methyl Carbonodithioate (thereafter called ZOMEC) against Scopolamine (SCOP) induced Alzheimer's disease (AD) model using adult albino mice.

A novel homozygous nonsense mutation in NECTIN4 gene in a Pakistani family with ectodermal dysplasia syndactyly syndrome 1.

Background: Ectodermal dysplasia syndactyly syndrome 1 (EDSS1) is a rare hereditary disorder characterized by defects in teeth, hair, and nails in association with a fusion of the digits. Genetically, the disease phenotypes are caused by homozygous and compound heterozygous variants in NECTIN4 gene.

Objective: The main objective of the study was to identify the pathogenic sequence variant(s) for family screening and identification of carriers.

A Novel Homozygous Nonsense Variant in the Underlies Dyggve-Melchior-Clausen Syndrome in Large Consanguineous Family.

(1) Background: Dyggve-Melchior-Clausen Syndrome is a skeletal dysplasia caused by a defect in the gene (OMIM number 607461). Pathogenic variants in the gene have been reported to cause Dyggve-Melchior-Clausen (DMC; OMIM 223800) dysplasia and Smith-McCort (SMC; OMIM 607326) dysplasia. (2) Methods: In the present study, large consanguineous families with five affected individuals with osteochondrodysplasia phenotypes were recruited.

ZOMEC via the p-Akt/Nrf2 Pathway Restored PTZ-Induced Oxidative Stress-Mediated Memory Dysfunction in Mouse Model.

A new mechanistic approach to overcome the neurodegenerative disorders caused by oxidative stress in Alzheimer's disease (AD) is highly stressed in this article. Thus, a newly formulated drug (zinc -methyl carbonodithioate (ZOMEC)) was investigated for five weeks on seven-week-old BALB/c male mice. ZOMEC 30 mg/kg was postadministered intraperitoneally during the third week of pentylenetetrazole (PTZ) injection.

A novel homozygous variant in the GLI1 underlies postaxial polydactyly in a large consanguineous family with intra familial variable phenotypes.

Polydactyly is a human inherited disorder caused by to anomalies in the genes involved in autopod development. The disorder segregates in both autosomal recessive and autosomal dominant form. Up till now, eleven genes causing non-syndromic polydactyly, have been identified.

Sulindac acetohydrazide derivative attenuates against cisplatin induced organ damage by modulation of antioxidant and inflammatory signaling pathways.

This study aimed to explore the mechanisms of action of a sulindac acetohydrazide derivative, N'-(4-dimethylaminobenzylidene)-2-1-(4-(methylsulfinyl) benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl) acetohydrazide, against anticancer drug cisplatin induced organ damage. Using a rodent model, various markers of organ function and signaling pathways were examined and validated by molecular docking studies. The study involves five groups of animals: control, DMSO, CDDP, CDDP + DMFM, and DMFM.

Hg(II) sensing, catalytic, antioxidant, antimicrobial, and anticancer potential of Garcinia mangostana and α-mangostin mediated silver nanoparticles.

This study reports synthesis of Garcinia mangostana fruit pericarp (unwanted waste material) and α-mangostin mediated silver nanoparticles (AgNPs). These AgNPs were efficiently produced using 1:10 (extract and salt) ratio under stirring and heating, which was confirmed by surface plasmon resonance (SPR) band in UV-Visible spectroscopic analysis, and size of 73-91 nm determined by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The synthesized AgNPs were used for Hg(II) detection in tap water, where the limits of detection and quantification were 2.

Genomic Characterization of SARS-CoV2 from Peshawar Pakistan Using Next-Generation Sequencing.

This study aimed to characterize the whole genome of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) isolated from an oropharyngeal swab specimen of a Pashtun Pakistani patient using next-generation sequencing. Upon comparing the SARS-CoV2 genome to the reference genome, a total of 10 genetic variants were identified. Among the 10 genetic variants, 1 missense mutation (c.

Drug repositioning against COVID-19: a first line treatment.

COVID-19 disease caused by the SARS-CoV-2 virus has shaken our health and wealth foundations. Although COVID-19 vaccines will become available allowing for attenuation of disease progression rates, distribution of vaccines can create other challenges and delays. Hence repurposed drugs against SARS-CoV-2 can be an attractive parallel strategy that can be integrated into routine clinical practice even in poorly-resourced countries.

Whole Exome Sequencing Confirms Molecular Diagnostics of Three Pakhtun Families With Autosomal Recessive Epidermolysis Bullosa.

Epidermolysis bullosa (EB) is a genetic skin disorder that shows heterogeneous clinical fragility. The patients develop skin blisters congenitally or in the early years of life at the dermo-epithelial junctions, including erosions, hyperkeratosis over the palms and soles. The other associated features are hypotrichosis on the scalp, absent or dystrophic nails, and dental anomalies.

Association of endothelial nitric oxide synthase gene variants with preeclampsia.

Background: Preeclampsia (PE) is a complex pregnancy hypertensive disorder with multifaceted etiology. The endothelial nitric oxide synthase (eNOS) gene and nitric oxide (NO) levels has been reported to be associated with PE predisposition in various populations. Therefore, present study was designed to investigate the role of NO levels and eNOS gene variants in preeclamptic women in Pakistan.

Molecular docking, pharmacokinetic studies, and in vivo pharmacological study of indole derivative 2-(5-methoxy-2-methyl-1H-indole-3-yl)-N'-[(E)-(3-nitrophenyl) methylidene] acetohydrazide as a promising chemoprotective agent against cisplatin induced organ damage.

Cisplatin is an efficient anticancer drug against various types of cancers however, its usage involves side effects. We investigated the mechanisms of action of indole derivative, 2-(5-methoxy-2-methyl-1H-indol-3-yl)-N'-[(E)-(3-nitrophenyl) methylidene] acetohydrazide (MMINA) against anticancer drug (cisplatin) induced organ damage using a rodent model. MMINA treatment reversed Cisplatin-induced NO and malondialdehyde (MDA) augmentation while boosted the activity of glutathione peroxidase (GPx), and superoxide dismutase (SOD).

Drug designing against NSP15 of SARS-COV2 via high throughput computational screening and structural dynamics approach.

The rapid outbreak of the COVID-19 also known as SARS-CoV2 has been declared pandemic with serious global concern. As there is no effective therapeutic against COVID-19, there is an urgent need for explicit treatment against it. The focused objective of the current study is to propose promising drug candidates against the newly identified potential therapeutic target (endonuclease, NSP15) of SARS-CoV2.

Elucidation of PLK1 Linked Biomarkers in Oesophageal Cancer Cell Lines: A Step Towards Novel Signaling Pathways by p53 and PLK1-Linked Functions Crosstalk.

Background: Oesophgeal adenocarcinoma (OAC) is the most frequent cause of cancer death. POLO-like kinase 1 (PLK1) is overexpressed in broad spectrum of tumors and has prognostic value in many cancers including esophageal cancer, suggesting its potential as a therapeutic target. p53, the guardian of genome is the most important tumor suppressors that represses the promoter of PLK1, whereas tumor cells with inactive p53 are arrested in mitosis due to DNA damage.

Identification and Computational Analysis of Novel and Gene Mutations in Pakistani Families With Identical Non-syndromic Oculocutaneous Albinism.

Non-syndromic oculocutaneous albinism (nsOCA) is an inherited disorder of melanin biosynthesis with autosomal recessive mode of inheritance, presenting either hypopigmented or depigmented skin, hair, and eyes. It is genetically heterogeneous with seven loci (OCA1-OCA7) reported to date. In the present study, we have reported three consanguineous families (A, B, C) presenting identical nsOCA phenotypes.

Viroinformatics approach to explore the inhibitory mechanism of existing drugs repurposed to fight against COVID-19.

The rapid breakout of the coronavirus disease of 2019 (COVID-19) has been declared pandemic with serious global concern due to high morbidity and mortality. As we enter the phase beyond limitations there is an urgent need for explicit treatment against COVID-19. To face this immediate global challenge, drug development from scratch is a lengthy process and unrealistic to conquer this battle.

Homozygous variants of EDAR underlying hypohidrotic ectodermal dysplasia in three consanguineous families.

Background: Hypohidrotic ectodermal dysplasia (HED) is a congenital anomaly characterized by hypohydrosis, hypotrichosis and hypodontia. Mutations in at least four genes (EDAR, EDARADD, WNT10A, TRAF6) have been reported to cause both autosomal recessive and autosomal dominant forms of HED. Mutations in two other genes (EDA and IKBKG) have been reported to cause X-linked HED.

Sequence Variants in the and Genes Underlying Isolated Split-Hand/Split-Foot Malformation.

Split-hand/split-foot malformation (SHFM) is a developmental and congenital limb malformation characterized by variable degrees of medial clefting or absence of one or more digits in hands and/or feet. The aim of this study was to identify the underlying cause of three consanguineous Pakistani families showing various types of SHFM-related features. Standard molecular methods, including whole-genome sequencing (WGS), whole-exome sequencing (WES), microsatellite markers-based genotyping, and Sanger sequencing were performed to search for the likely causative variants.

A review on Zika virus outbreak, epidemiology, transmission and infection dynamics.

Zika virus (ZIKV) is a newly emergent relative of the Flaviviridae family and linked to dengue (DENV) and Chikungunya (CHIVKV). ZIKV is one of the rising pathogens promptly surpassing geographical borders. ZIKV infection was characterized by mild disease with fever, headache, rash, arthralgia and conjunctivitis, with exceptional reports of an association with Guillain-Barre syndrome (GBS) and microcephaly.

Screening and computational analysis of colorectal associated non-synonymous polymorphism in CTNNB1 gene in Pakistani population.

Background: Colorectal cancer (CRC) is categorized by alteration of vital pathways such as β-catenin (CTNNB1) mutations, WNT signaling activation, tumor protein 53 (TP53) inactivation, BRAF, Adenomatous polyposis coli (APC) inactivation, KRAS, dysregulation of epithelial to mesenchymal transition (EMT) genes, MYC amplification, etc. In the present study an attempt was made to screen CTNNB1 gene in colorectal cancer samples from Pakistani population and investigated the association of CTNNB1 gene mutations in the development of colorectal cancer.

Methods: 200 colorectal tumors approximately of male and female patients with sporadic or familial colorectal tumors and normal tissues were included.

Inhibitory Mechanism of An Anticancer Drug, Bexarotene Against Amyloid β Peptide Aggregation: Repurposing Via Neuroinformatics Approach.

Background: Aggregation of Amyloid β (Aβ) peptide is a crucial feature of Alzheimer disease (AD) pathogenesis. In fact, Aβ peptides are misfolded and aggregated to frame Amyloid fibrils, which is considered as one of the major contributing events in the onset of AD. All these observations have prompted the researchers to design therapeutic molecules with robust anti-Aβ aggregation potential.

Screening and Identification of PLK1-Polo Box Binding Peptides by High-Throughput Sequencing of Phage-Selected Libraries.

Background: Human proteome contains a plethora of short linear peptide motifs that is crucial for signaling and other cellular processes. These motifs are difficult to identify due to lack of systematic approach for their detection.

Objectives: Here we demonstrate the use of peptide phage display in combination with high throughput next generation sequencing to identify enriched peptide sequences through biopanning process against polo box domain (PBD) of mitotic polo like kinase 1 (Plk1).

An Integrative "Omics" Approach, for Identification of Bona Fides PLK1 Associated Biomarker in Esophageal Adenocarcinoma.

Background: The rapid expansion of genome-wide profiling techniques offers the opportunity to utilize various types of information collected in the study of human health and disease. Overexpression of Polo like kinase 1 (PLK1) is associated with esophageal adenocarcinoma (OAC), however biological functions and molecular targets of PLK1 in OAC are still unknown.

Objectives: Here we performed integrative analysis of two "omics" data sources to reveal high-level interactions of PLK1 associated with OAC.