Zunera Khalid

ABSTRACT Ovarian cancer (OC) continues to be the deadliest gynecological malignancy and a significant cause of cancer‐related mortality among women worldwide. Standard treatment strategies typically entail platinum‐based chemotherapy in conjunction with cytoreductive surgery. Nevertheless, the efficacy of therapeutic interventions is frequently restricted by substantial drug resistance and treatment‐related toxicity, resulting in poor long‐term survival and high recurrence rates. The majority of OC cases are classified as epithelial ovarian cancer (EOC), which is an exceedingly heterogeneous condition. The molecular profiles, clinical outcomes, and treatment responses of the five major histological subtypes of EOC, high‐grade serous, low‐grade serous, clear cell, endometrioid, and mucinous differ significantly. Recent discoveries regarding the pathogenesis of high‐grade serous carcinoma (HGSC) indicate that a significant number of cases originate of precursor lesions in the fallopian tube fimbria. This paradigm shift has redefined the classification of OC and offered a promising preventive approach through opportunistic salpingectomy. Meanwhile, the global incidence patterns indicate a decrease in high‐income countries, which may be attributed to earlier detection and increased contraceptive use. Conversely, a rise in incidence is observed in low‐ and middle‐income settings, which is attributed to changes in reproductive behaviors and lifestyle factors. The early diagnosis, prognosis, and selection of targeted therapies depend on the screening and validation of reliable biomarkers, including CA‐125, HE4, BRCA1 and BRCA2 mutations, and homologous recombination deficiency (HRD) status. Many current biomarkers lack the specificity and sensitivity required for effective clinical decision‐making, despite ongoing advancements. This review offers a comprehensive examination of the epidemiology, molecular and histological subtypes, and evolving classification of OC. It critically evaluates the advancements in targeted therapy, highlights the significance of the tumor biomarkers in the development of precision medicine, and explores preventive strategies, including salpingectomy. Subsequently, it outlines the current challenges and future directions in the discovery of biomarkers and personalized treatment approaches, aiming to improve clinical outcomes and patient survival rates for this devastating disease.

Papillary Thyroid Cancer (PTC) is one of the most prevalent endocrine malignancies, and its incidence rate has almost tripled over the past three decades. The current study aimed to identify gene alterations and biomarkers contributing to PTC progression. Based on PTC transcriptome sequencing data, differential gene expression analysis is used to systematically categorize hub genes associated with PTC progression. A total of 1550 overlapping differentially expressed genes (DEGs) were identified in PTC compared to normal thyroid tissues, including 1149 upregulated and 401 downregulated genes. In addition, 3192 DEGs were detected in PTC relative to their normal adjacent tissues (NATs), comprising 1431 upregulated and 1761 downregulated genes. KEGG pathway analysis revealed pathways associated with cancer, proteoglycans in cancer, parathyroid hormone synthesis, and chemical carcinogenesis receptor activity. Protein-protein interaction (PPI) network analysis identified FN1, SDC1, and MAPK1 as highly ranked hub genes among the upregulated genes involved in several cancer pathways, including the PID Syndecan-1 pathway, Proteoglycans in cancer, and the CCL18 signaling pathway. The gene expression validation through Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR) further validated the significance of the above findings, demonstrating substantial upregulation of FN1 (7.4-fold increase), SDC1 (5.2-fold increase), and MAPK1 (5.8-fold increase) in papillary thyroid tissues relative to their adjacent normal tissues. Western blot analysis further validated the upregulation of FN1 at the protein level. These findings highlight a strong association between the identified hub genes (FN1, SDC1, and MAPK1) and papillary thyroid cancer, supporting their potential as diagnostic biomarkers and therapeutic targets. Further validation through in vivo experiments and functional assays will be essential to confirm their roles in PTC pathogenesis and to elucidate their clinical implications.

In this study, the synthesis of polyphenol oxidase (PPO)-functionalized aluminum oxide (Al 2 O[Formula: see text] nanoconjugates (NCs) using Pleurotus ostreatus extracts has been carried out, which also assesses their antioxidant, phenolic degradation, and molecular interaction capabilities through the combined experimental and computational methods. PPO extraction optimization showed optimal enzyme activity (maximum of 130 U/mL) to be at 3% biomass concentration, 25 mL of extractant, 120 min of incubation time, and [Formula: see text]C. The structural characterization revealed that PPO was successfully synthesized onto Al 2 O 3 NCs, and the presence of crystalline Al 2 O 3 NCs phases, enzyme-to-nanoparticle interactions via Fourier transform infrared (FTIR) spectroscopy, morphology (spherical to global) via scanning electron microscopy (SEM), and particle sizes (nanoscale) via dynamic light scattering (DLS) process were found. PPO-coated Al 2 O 3 NCs performed better antioxidant capacity, with the highest diphenyl-1-picrylhydrazyl (DPPH) radical scavenging rate of 66.64 ± 3.33%, which was better than both the free Al 2 O 3 NCs and the natural antioxidant ascorbic acid in the same solution. The use of immobilized Al 2 O 3 NCs in assays of phenolic wastewater treatment showed better degradation efficiency, which yielded a 1.69-fold increase in enzyme activity under fluorescent light and a 1.86-fold increase in enzyme activity under photocatalytic conditions, suggesting an effective catalytic turnover and adsorption of the pollutant. Molecular docking showed that the phenolics in mushrooms had a high binding affinity with PPO-related targets, and rutin (−123.16 kcal/mol), catechin (−118.90 kcal/mol), and apigenin (−118.23 kcal/mol) had significantly high binding affinities compared with ascorbic acid (−85.22 kcal/mol). The adsorption, distribution, metabolism, excretion (ADME), and toxicity studies confirmed positive pharmacokinetics and low predicted toxicity in lead compounds, and density functional theory (DFT) calculations revealed reduced highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy gaps and increased electronic reactivity in apigenin as compared to ascorbic acid. Taken together, these results ensure the use of PPO-coated Al 2 O 3 NCs as an efficient, sustainable, and multi-functional platform of antioxidant applications and phenolic wastewater treatment.

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed millions of people and continues to wreak havoc across the globe. This sudden and deadly pandemic emphasizes the necessity for anti-viral drug development that can be rapidly administered to reduce morbidity, mortality, and virus propagation. Thus, lacking efficient anti-COVID-19 treatment, and especially given the lengthy drug development process as well as the critical death tool that has been associated with SARS-CoV-2 since its outbreak, drug repurposing (or repositioning) constitutes so far, the ideal and ready-to-go best approach in mitigating viral spread, containing the infection, and reducing the COVID-19-associated death rate. Indeed, based on the molecular similarity approach of SARS-CoV-2 with previous coronaviruses (CoVs), repurposed drugs have been reported to hamper SARS-CoV-2 replication. Therefore, understanding the inhibition mechanisms of viral replication by repurposed anti-viral drugs and chemicals known to block CoV and SARS-CoV-2 multiplication is crucial, and it opens the way for particular treatment options and COVID-19 therapeutics. In this review, we highlighted molecular basics underlying drug-repurposing strategies against SARS-CoV-2. Notably, we discussed inhibition mechanisms of viral replication, involving and including inhibition of SARS-CoV-2 proteases (3C-like protease, 3CLpro or Papain-like protease, PLpro) by protease inhibitors such as Carmofur, Ebselen, and GRL017, polymerases (RNA-dependent RNA-polymerase, RdRp) by drugs like Suramin, Remdesivir, or Favipiravir, and proteins/peptides inhibiting virus-cell fusion and host cell replication pathways, such as Disulfiram, GC376, and Molnupiravir. When applicable, comparisons with SARS-CoV inhibitors approved for clinical use were made to provide further insights to understand molecular basics in inhibiting SARS-CoV-2 replication and draw conclusions for future drug discovery research.

Background: COVID-19 is still instigating significant social and economic chaos worldwide; however, there is no approved antiviral drug yet. Here, we used in silico analysis to screen potential SARS-CoV-2 main protease (M pro ) inhibitors extracted from the essential oil of Thymus schimperi which could contribute to the discovery of potent anti-SARS-CoV-2 phytochemicals. Methods: The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of compounds were determined through SwissADME and ProToxII servers. AutoDock tools were used for molecular docking analysis studies, while Chimera, DS studio, and LigPlot were used for post-docking studies. Molecular dynamic simulations were performed for 200 ns under constant pressure. Results: All compounds exhibited a bioavailability score of ≥ 0.55 entailing that at least 55% of the drugs can be absorbed unchanged. Only five (9%), nine (16%) and two (3.6%) of the compounds showed active hepatotoxicity, carcinogenicity, and immunotoxicity, respectively. Except for flourazophore P, which showed a little mutagenicity, all other compounds did not show mutagenic properties. On the other hand, only pinene beta was found to have a little cytotoxicity. Five compounds demonstrated effective binding to the catalytic dyad of the SARS-CoV-2 M pro substrate binding pocket, while two of them (geranylisobutanoate and 3-octane) are found to be the best hits that formed hydrogen bonds with Glu 166 and Ser 144 of SARS-CoV-2 M pro . Conclusion: Based on our in silico analysis, top hits from Thymus schimperi may serve as potential anti-SARS-CoV-2 compounds. Further in vitro and in vivo studies are recommended to characterize these compounds for clinical applications. Keywords: structural analysis, SARS-CoV-2, main protease, inhibitors, Thymus schimperi

Due to fast transmission and various circulating SARS-CoV-2 variants, a significant increase of coronavirus 2019 infection cases with acute respiratory symptoms has prompted worries about the efficiency of current vaccines. The possible evasion from vaccine immunity urged scientists to identify novel therapeutic targets for developing improved vaccines to manage worldwide COVID-19 infections. Our study sequenced pooled peripheral blood mononuclear cells transcriptomes of SARS-CoV-2 patients with moderate and critical clinical outcomes to identify novel potential host receptors and biomarkers that can assist in developing new translational nanomedicines and vaccine therapies. The dysregulated signatures were associated with humoral immune responses in moderate and critical patients, including B-cell activation, cell cycle perturbations, plasmablast antibody processing, adaptive immune responses, cytokinesis, and interleukin signaling pathway. The comparative and longitudinal analysis of moderate and critically infected groups elucidated diversity in regulatory pathways and biological processes. Several immunoglobin genes (IGLV9-49, IGHV7-4, IGHV3-64, IGHV1-24, IGKV1D-12 , and IGKV2-29) , ribosomal proteins (RPL29, RPL4P2, RPL5 , and RPL14) , inflammatory response related cytokines including Tumor Necrosis Factor (TNF, TNFRSF17 , and TNFRSF13B) , C-C motif chemokine ligands (CCL3, CCL25, CCL4L2, CCL22 , and CCL4) , C-X-C motif chemokine ligands (CXCL2, CXCL10 , and CXCL11) and genes related to cell cycle process and DNA proliferation ( MYBL2, CDC20, KIFC1 , and UHCL1 ) were significantly upregulated among SARS-CoV-2 infected patients. 60S Ribosomal protein L29 (RPL29) was a highly expressed gene among all COVID-19 infected groups. Our study suggested that identifying differentially expressed genes (DEGs) based on disease severity and onset can be a powerful approach for identifying potential therapeutic targets to develop effective drug delivery systems against SARS-CoV-2 infections. As a result, potential therapeutic targets, such as the RPL29 protein, can be tested in vivo and in vitro to develop future mRNA-based translational nanomedicines and therapies to combat SARS-CoV-2 infections.

Wingless type mouse mammary tumor virus (MMTV) integration site-10B (Wnt10B) is an important member of the Wnt protein family that functions as cellular messenger in paracrine manner. Aberrant Wnt10B activity is the cause of several abnormalities including cancers of breast, cervix, liver, gastric tract, esophagus and pancreas as well as physiological problems like obesity and osteoporosis. The objective of this study was to determine the possible inhibitors against aberrant expression of Wnt10B in order to prevent and treat the physiological disorders associated with it. Wnt10B3D structure was predicted by using comparative modeling and then analyzed by PROCHECK, Verify3D and Errat. The model having 84.54 % quality value was selected and acylated to satisfy the hydrophobic nature of Wnt10b. For search of inhibitors virtul screening was performed on Natural Products (NP) database . The compounds were filtered and Ligand based screening was performed using the antagonist for mouse Wnt-3a. This resulted in a library of 272 unique compounds having most potent drug like activities for Wnt-4. Out of the 271 molecules analyzed three small molecules ZINC35442871, ZINC85876388 and ZINC00754234 having activity against Wnt4 abbarent expression were found common through docking experiment of Wnt10B. Therefore, the three molecules ZINC35442871, ZINC85876388 and ZINC00754234 can be considered as lead compounds for performing further drug designing experiments against aberrant Wnt expressions.

Purpose: The involvement of Wnt-8b in Wnt signaling pathway leads to various cancers. The purpose of this study was to determine the therapeutic compounds from the available library by targeting Wnt-8b using molecular docking analyses.Methods: Threading and comparative modeling approaches were employed to predict the 3D structure of Wnt-8b. Sixty-eight models were evaluated using molprobity, ERRAT and rampage evaluation tools and the model having 82.456 % overall quality value was selected for further analyses. The acyl group was added to the suitable model to satisfy the hydrophobic nature of the Wnt-8b. Literature-derivedcompounds were selected for comparative molecular docking studies using GOLD, AutoDock and AutoDock Vina. Furthermore, docked complexes were analyzed and visualized using Chimera and Ligplot.Results: The compound ZINC04029462 exhibited high binding potential with Wnt-8b and palmitoleic acid and was found common among top 20 compounds of each tool. His-183, Val-185, Ser-186, Gly-187, Ser-188 and Thr-190 residues commonly interacted with compounds and palmitoleic acid and considered as potential interacting residues.Conclusion: Common interacting residues from top 20 compounds of each tool suggest that these compounds may be utilized to inhibit aberrant expression of Wnt-8b. The common inhibitor ZINC04029462 may act as a lead compound for further drug designing against Wnt family.Keywords: Wnt-8b, Cancer, Homology modeling, Molecular docking, AutoDock

The macro evolutionary events lead to anatomical complexity achieved by higher vertebrates. The extensive gene duplications result in widespread existence of gene families in modern vertebrates. Kv channel-interacting proteins are encoded by the KCNIP gene in humans. The gene encodes a member of the family of voltage-gated potassium (K v ) channel-interacting proteins. The paralogues (KCNIP1, KCNIP2, KCNIP3 and KCNIP4) of KCNIP gene family served as small calcium binding proteins. K+ channels act as primary subunits that contribute to transient, voltage-dependent K+ currents in the nervous system and heart. They regulate channel density, inactivation kinetics and also function as transcriptional repressors. The colossal amount of diversified protein dataset for a wide variety of vertebrates, invertebrates was used to derive mode of evolution and conservation of functionally significant diverse gene family residing on human chromosomes.The phylogenetic analysis of KCNIP gene family revealed that three vertebrate specific duplications occur before the split of fish-tetrapods. Fishes split into “a” and “b” in-paralogs by lineage specific duplications in KCNIP1 and KCNIP3. Phylogenetic tree reflects that KCNIP carries small scale duplications which occur at different time points during chordate evolution. The analysis assists the evolutionary biologists to understand the historical emergence of Kv channel-interacting proteins and their evolutionary relationship with different species. Keywords: EF-hand-like domains, transcriptional repressors, lineage specific duplications Cite this Article Muhammad Waqas Khokhar, Zunera Khalid. Insight into Historical Emergence of Kv Channel-interacting Proteins (KCNIPs) Gene Family. Research & Reviews: Journal of Computational Biology. 2016; 5(2):    1–6p.