An affordable label-free ultrasensitive immunosensor based on gold nanoparticles deposited on glassy carbon electrode for the transferrin receptor detection.

In recent decades, there has been a concerning and consistent rise in the incidence of cancer, posing a significant threat to human health and overall quality of life. The transferrin receptor (TfR) is one of the most crucial protein biomarkers observed to be overexpressed in various cancers. This study reports on the development of a novel voltammetric immunosensor for TfR detection. The electrochemical platform was made up of a glassy carbon electrode (GCE) functionalized with gold nanoparticles (AuNPs), on which anti-TfR was immobilized. The surface characteristics and electrochemical behaviors of the modified electrodes were comprehensively investigated through scanning electron microscopy, XPS, Raman spectroscopy FT-IR, electrochemical cyclic voltammetry and impedance spectroscopy. The developed immunosensor exhibited robust analytical performance with TfR fortified buffer solution, showing a linear range (LR) response from 0.01 to 3000 µg/mL, with a limit of detection (LOD) of 0.01 µg/mL and reproducibility (RSD <4 %). The fabricated sensor demonstrated high reproducibility and selectivity when subjected to testing with various types of interfering proteins. The immunosensor designed for TfR detection demonstrated several advantageous features, such as being cost-effective and requiring a small volume of test sample making it highly suitable for point-of-care applications.

Multi-targeted therapeutic potential of stigmasterol from the Euphorbia ammak plant in treating lung and breast cancer.

Cancer is the most prevalent disease globally, which presents a significant challenge to the healthcare industry, with breast and lung cancer being predominant malignancies. This study used RNA-seq data from the TCGA database to identify potential biomarkers for lung and breast cancer. Tumor Necrosis Factor (TNFAIP8) and Sulfite Oxidase (SUOX) showed significant expression variation and were selected for further study using structure-based drug discovery (SBDD). Compounds derived from the Euphorbia ammak plant were selected for in-silico study with both TNFAIP8 and SUOX. Stigmasterol had the greatest binding scores (normalized scores of -8.53 kcal/mol and -9.69 kcal/mol) with both proteins, indicating strong stability in their binding pockets throughout the molecular dynamics' simulation. Although Stigmasterol first changed its initial conformation (RMSD = 0.5 nm with the starting conformation) in SUOX, it eventually reached a stable conformation (RMSD of 1.5 nm). The compound on TNFAIP8 showed a persistent shape (RMSD of 0.35 nm), indicating strong protein stability. The binding free energy of the complex was calculated using the MM/GBSA technique; TNFAIP8 had a ΔGTOTAL of -24.98 kcal/mol, with TYR160 being the most significant residue, contributing -2.52 kcal/mol. On the other hand, the SUOX complex had a binding free energy of -16.87 kcal/mol, with LEU151 being the primary contributor (-1.17 kcal/mol). Analysis of the complexes' free energy landscape unveiled several states with minimum free energy, indicating robust interactions between the protein and ligand. In its conclusion, this work emphasises the favourable ability of Stigmasterol to bind with prospective targets for lung and breast cancer, indicating the need for more experimental study.

Correction: Jamal et al. Preparation of 6-Mercaptopurine Loaded Liposomal Formulation for Enhanced Cytotoxic Response in Cancer Cells. Nanomaterials 2022, 12, 4029.

In the original publication [...].

Prediction of anticancer peptides derived from the true lectins of Phoenix dactylifera and their synergetic effect with mitotane.

Background and aims: Cancer continues to be a significant source of both illness and death on a global scale, traditional medicinal plants continue to serve as a fundamental resource of natural bioactive compounds as an alternative source of remedies. Although there have been numerous studies on the therapeutic role of Phoenix dactylifera, the study of the role of peptides has not been thoroughly investigated. This study aimed to investigate the anticancer activity of lectin peptides from P. dactylifera using in silico and in vivo analysis. Methods: Different computational tools were used to extract and predict anticancer peptides from the true lectins of P. dactylifera. Nine peptides that are bioactive substances have been investigated for their anticancer activity against MCF-7 and T47D (two forms of breast cancer). To counteract the unfavorable effects of mitotane, the most potent peptides (U3 and U7) were combined with it and assessed for anticancer activity against MCF-7 and HepG2. Results: In silico analysis revealed that nine peptides were predicted with anticancer activity. In cell lines, the lowest IC50 values were measured in U3 and U7 against MCF-7 and T47D cells. U3 or U7 in combination with mitotane demonstrated the lowest IC50 against MCF-7 and HepG2. The maximum level of cell proliferation inhibition was 22% when U3 (500 µg/mL) and 25 µg/mL mitotane were combined, compared to 41% when 25 µg/mL mitotane was used alone. When mitotane and U3 or U7 were combined, it was shown that these bioactive substances worked synergistically with mitotane to lessen its negative effects. The combination of peptides and mitotane could be regarded as an efficient chemotherapeutic medication having these bioactive properties for treating a variety of tumors while enhancing the reduction of side effects.

In Silico Insights into the Arsenic Binding Mechanism Deploying Application of Computational Biology-Based Toolsets.

An assortment of environmental matrices includes arsenic (As) in its different oxidation states, which is often linked to concerns that pose a threat to public health worldwide. The current difficulty lies in addressing toxicological concerns and achieving sustained detoxification of As. Multiple conventional degradation methods are accessible; however, they are indeed labor-intensive, expensive, and reliant on prolonged laboratory evaluations. Molecular interaction and atomic level degradation mechanisms for enzyme-As exploration are, however, underexplored in those approaches. A feasible approach in this case for tackling this accompanying concern of As might be to cope with undertaking multivalent computational methodologies and tools. This work aimed to provide molecular-level insight into the enzyme-aided As degradation mechanism. AutoDock Vina, CABS-flex 2.0, and Desmond high-performance molecular dynamics simulation (MDS) were utilized in the current investigation to simulate multivalent molecular processes on two protein sets: arsenate reductase (ArsC) and laccase (LAC) corresponding arsenate (ART) and arsenite (AST), which served as model ligands to comprehend binding, conformational, and energy attributes. The structural configurations of both proteins exhibited variability in flexibility and structure framework within the range of 3.5-4.5 Å. The LAC-ART complex exhibited the lowest calculated binding affinity, measuring -5.82 ± 0.01 kcal/mol. Meanwhile, active site residues ILE-200 and HIS-206 were demonstrated to engage in H-bonding with the ART ligand. In contrast to ArsC, the ligand binding affinity of this bound complex was considerably greater. Additional validation of docked complexes was carried out by deploying Desmond MDS of 100 ns to capture protein and ligand conformation behavior. The system achieved stability during the 100 ns simulation run, as confirmed by the average P-L RMSD, which was ∼1 Å. As a preliminary test of the enzyme's ability to catalyze As species, corresponding computational insights might be advantageous for bridging gaps and regulatory consideration.

Virtual screening and site-directed mutagenesis-derived aptamers for precise Salmonella typhimurium prediction: emphasizing OmpD targeting and G-quadruplex stability.

The efficient detection of the foodborne pathogen Salmonella typhimurium has historically been hampered by the constraints of traditional methods, characterized by protracted culture periods and intricate DNA extraction processes for PCR. To address this, our research innovatively focuses on the crucial and relatively uncharted virulence factor, the Outer Membrane Protein D (OmpD) in Salmonella typhimurium. By harmoniously integrating the power of virtual screening and site-directed mutagenesis, we unveiled aptamers exhibiting marked specificity for OmpD. Among these, aptamer 7ZQS stands out with its heightened binding affinity. Capitalizing on this foundation, we further engineered a repertoire of mutant aptamers, wherein APT6 distinguished itself, reflecting unmatched stability and specificity. Our rigorous validation, underpinned by cutting-edge bioinformatics tools, amplifies the prowess of APT6 in discerning and binding OmpD across an array of Salmonella typhimurium strains. This study illuminates a transformative approach to the prompt and accurate detection of Salmonella typhimurium, potentially redefining boundaries in applied analytical chemistry and bolstering diagnostic precision across diverse research and clinical domains.Communicated by Ramaswamy H. Sarma.

Fabrication of an affordable and sensitive corticosteroid-binding globulin immunosensor based on electrodeposited gold nanoparticles modified glassy carbon electrode.

Herein, we fabricated an ultrasensitive electrochemical immunosensor for the quantitative detection of corticosteroid-binding globulin (CBG). CBG is a protein that regulates glucocorticoid levels and is an important biomarker for inflammation. A decrease in CBG levels is a key biomarker for inflammatory diseases, such as septic shock. To enhance the electrochemical performance and provide a large surface area for anti-CBG immobilization, we functionalized the glassy carbon electrode surface with AuNPs. Electrochemical characterization methods including cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were used to examine the construction of the fabricated immunosensor. The electrochemical signal demonstrated a remarkable sensitivity to the CBG antigen, with a detection range from 0.01 to 100 µg/mL and a limit of detection of 0.012 µg/mL, making it suitable for both clinical and research applications. This label-free immunosensor offers significant advantages, including high sensitivity, low detection limits and excellent selectivity, making it a promising tool for detecting CBG in complex biological samples. Its potential applications include early disease diagnosis, treatment monitoring and studying CBG-related physiological processes.

New paracetamol hybrids as anticancer and COX-2 inhibitors: Synthesis, biological evaluation and docking studies.

Drug repurposing is an emerging field in drug development that has provided many successful drugs. In the current study, paracetamol, a known antipyretic and analgesic agent, was chemically modified to generate paracetamol derivatives as anticancer and anticyclooxygenase-2 (COX-2) agents. Compound 11 bearing a fluoro group was the best cytotoxic candidate with half-maximal inhibitory concentration (IC50 ) values ranging from 1.51 to 6.31 µM and anti-COX-2 activity with IC50 = 0.29 µM, compared to the standard drugs, doxorubicin and celecoxib. The cell cycle and apoptosis studies revealed that compound 11 possesses the ability to induce cell cycle arrest in the S phase and apoptosis in colon Huh-7 cells. These results were strongly supported by docking studies, which showed strong interactions with the amino acids of the COX-2 protein, and in silico pharmacokinetic predictions were found to be favorable for these newly synthesized paracetamol derivatives. It can be concluded that compound 11 could block cell growth and proliferation by inhibiting the COX-2 enzyme in cancer therapy.

Mass Spectrometry-Based Detection of Mycotoxins in Imported Meat and Their Perspective Role on Myocardial Apoptosis.

BACKGROUND: Fungal mycotoxins are the secondary metabolite and are harmful to plants, animals, and humans. Common aflatoxins present and isolated from feeds and food comprises aflatoxins B1, B2, G1, and G2. Public health threats or risk of foodborne disease posed by mycotoxins, especially the export or import of such meat products are of primary concern. This study aims to determine the concentration of the level of aflatoxins B1, B2, G1, G2 M1, and M2 respectively in imported burger meat. METHOD: The present work is designed to select and collect the various sample of meat products from different sources and subjected to mycotoxin analysis by LCMS/MS. Random selection was made on sites of burger meat that was for sale. RESULTS: Simultaneous presence of several mycotoxins in the same sample of imported meat under the set conditions of LCMS/MS detected 26% (18 samples) were positive for various mycotoxins. The most frequent mycotoxins proportion in the analyzed samples was aflatoxin B1 (50%) followed by aflatoxin G1 (44%), aflatoxin G2 (38.8%), aflatoxin B2 (33%) respectively were least among all with 16.66 and 11.11%. DISCUSSION: A positive correlation is deduced between CVD and mycotoxin present in burger meat. Isolated mycotoxins initiate death receptor-mediated apoptosis, death receptor-mediated necrosis, mitochondrial-mediated apoptosis, mitochondrial-mediated necrosis, and immunogenic cell deaths through various pathways that can damage the cardiac tissues. CONCLUSION: The presence of these toxins in such samples is just the tip of the iceberg. Further investigation is necessary for complete clarifications of toxins on human health especially on CVD and other related metabolic complications.

Association of peptidyl prolyl cis/trans isomerase Rrd1 with C terminal domain of RNA polymerase II.

The largest subunit of RNAPII extends as the conserved unstructured heptapeptide consensus repeats Y1S2P3T4S5P6S7 and their posttranslational modification, especially the phosphorylation state at Ser2, Ser5 and Ser7 of CTD recruits different transcription factors involved in transcription. In the current study, fluorescence anisotropy, pull down assay and molecular dynamics simulation studies employed to conclude that peptidyl-prolyl cis/trans-isomerase Rrd1 has strong affinity for unphosphorylated CTD rather than phosphorylated CTD for mRNA transcription. Rrd1 preferentially interacts with unphosphorylated GST-CTD in comparison to hyperphosphorylated GST-CTD in vitro. Fluorescence anisotropy revealed that recombinant Rrd1 prefers to bind unphosphorylated CTD peptide in comparison to phosphorylated CTD peptide. In computational studies, the RMSD of Rrd1-unphosphorylated CTD complex was greater than the RMSD of Rrd1-pCTD complex. During 50 ns MD simulation run Rrd1-pCTD complex get dissociated twice viz. 20 ns to 30 ns and 40 ns to 50 ns, while Rrd1-unpCTD complex remain stable throughout the process. Additionally, the Rrd1-unphosphorylated CTD complexes acquire comparatively higher number of H-bonds, water bridges and hydrophobic interactions occupancy than Rrd1-pCTD complex, concludes that the Rrd1 interacts more strongly with the unphosphorylated CTD than the pCTD.

Current Update on Role of Hesperidin in Inflammatory Lung Diseases: Chemistry, Pharmacology, and Drug Delivery Approaches.

Inflammation is a common feature of many respiratory diseases, such as pneumonia, asthma, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), lung cancer, acute lung injury, and COVID-19. Flavonoids have demonstrated their anti-inflammatory and antioxidant effects by influencing inflammation at different stages and majorly impacting several respiratory diseases' onset and development. According to current studies, hesperidin, one of the most abundant polyphenols, can inhibit transcription factors or regulatory enzymes essential for controlling inflammation-linked mediators, including nuclear factor-kappa B (NF-κB), Inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). It also improved cellular antioxidant defences by activating the ERK/Nrf2 signalling pathway. Therefore, this review provides the latest studies on the effect of hesperidin in different respiratory diseases, its pharmacokinetic profile, and innovative drug delivery methods.

Phytochemical analysis and nephroprotective potential of Ajwa date in doxorubicin-induced nephrotoxicity rats: Biochemical and molecular docking approaches.

The purpose of this study is to evaluate the likely defensive impact of Ajwa date aqueous extract (AJDAE) in alleviating the nephrotoxicity generated by doxorubicin (DOX) injection in rats. Sixty male Wister albino rats were randomly and equally separated into six groups (n = 10), and they were treated as follows: untreated control group, extract groups administered with 0.75 and 1.5 mg kg bw of AJDAE, toxicant control group administered with DOX, and prophylactic groups were treated with 0.75 and 1.5 mg/kg of AJDAE and 15 mg/kg DOX. Biochemical parameters, antioxidant enzymes, renal functions, DNA integrity, and histopathology were studied to evaluate the nephroprotective activity of AJDAE. Furthermore, bioactive compounds were utilized for in silico molecular docking. AJDAE treatment resulted in significant improvements in the amended renal biomarkers (urea, creatinine, calcium, phosphorous, and uric acid), antioxidative markers, and MDA. Noticeable histopathological improvements supported this result. Results of in silico studies revealed that d-Mannitol, 6TMS derivative, palmitic acid, and TMS derivative had a higher docking score with human soluble epoxide hydrolase (-10.9 kcal/mol) and NF-κB-DNA (-7 kcal/mol). The present findings indicated that AJDAE could decrease ROS generation and lipid peroxidation (LPO) and repair the DOX injection-related DNA damage.

Potential Anticancer Activity of Juniperus procera and Molecular Docking Models of Active Proteins in Cancer Cells.

Medicinal plants provide a wide range of active compounds that can be exploited to create novel medicines with minimal side effects. The current study aimed to identify the anticancer properties of Juniperus procera (J. procera) leaves. Here, we demonstrate that J. procera leaves' methanolic extract suppresses cancer cells in colon (HCT116), liver (HepG2), breast (MCF-7), and erythroid (JK-1) cell lines. By applying GC/MS, we were able to determine the components of the J. procera extract that might contribute to cytotoxicity. Molecular docking modules were created that used active components against cyclin-dependent kinase 5 (Cdk5) in colon cancer, aromatase cytochrome P450 in the breast cancer receptor protein, the -N terminal domain in the erythroid cancer receptor of the erythroid spectrin, and topoisomerase in liver cancer. The results demonstrate that, out of the 12 bioactive compounds generated by GC/MS analysis, the active ingredient 2-imino-6-nitro-2H-1-benzopyran-3-carbothiamide proved to be the best-docked chemical with the chosen proteins impacted by DNA conformational changes, cell membrane integrity, and proliferation in molecular docking studies. Notably, we uncovered the capacity of J. procera to induce apoptosis and inhibit cell growth in the HCT116 cell line. Collectively, our data propose that J. procera leaves' methanolic extract has an anticancer role with the potential to guide future mechanistic studies.

Enhanced textile dye removal from wastewater using natural biosorbent and Shewanella algae B29: Application of Box Behnken design and genomic approach.

In this study, Box-Behnken design combining seven factors at three levels were used to optimize the elimination of CI Reactive Red 66 in artificial seawater, by the combination of eco-friendly bio-sorbents and acclimated halotolerant microbial strain. Results showed that macro-algae and cuttlebone (2 %) were the best natural bio-sorbent. Additionally, the selected halotolerant strain able to rapidly remove dye was identified as Shewanella algae B29. The optimization process revealed that decolourization of CI Reactive Red 66 yields reached 91.04 % under the following variable values: dyes concentration (100 mg/l), salinity (30 g/l), peptone (2 %), pH (5), algae C (3 %), cuttlebone (1.5 %) and agitation (150 rpm). The whole genome analysis of S. algae B29 demonstrated the presence of several genes coding for valuable enzymes involved in textile dyes biotransformation, adaptation to stress as well as biofilm formation implying its potential use in biological textile wastewater treatment.

Direct Identification of Label-Free Gram-Negative Bacteria with Bioreceptor-Free Concentric Interdigitated Electrodes.

This investigation demonstrates an electrochemical method for directly identifying unlabeled Gram-negative bacteria without other additives or labeling agents. After incubation, the bacterial cell surface is linked to the interdigitated electrode through electroadsorption. Next, these cells are exposed to a potential difference between the two electrodes. The design geometry of an electrode has a significant effect on the electrochemical detection of Gram-negative bacteria. Therefore, electrode design geometry is a crucial factor that needs to be considered when designing electrodes for electrochemical sensing. They provide the area for the reaction and are responsible for transferring electrons from one electrode to another. This work aims to study the available design in the commercial market to determine the most suitable electrode geometry with a high detection sensitivity that can be used to identify and quantify bacterial cells in normal saline solutions. To work on detecting bacterial cells without the biorecognition element, we have to consider the microelectrode's design, which makes it very susceptible to bacteria size. The concentration-dilution technique measures the effect of the concentration on label-free Gram-negative bacteria in a normal saline solution without needing bio-recognized elements for a fast screening evaluation. This method's limit of detection (LOD) cannot measure concentrations less than 102 CFU/mL and cannot distinguish between live and dead cells. Nevertheless, this approach exhibited excellent detection performance under optimal experimental conditions and took only a few hours.

Computational insights into the stereo-selectivity of catechins for the inhibition of the cancer therapeutic target EGFR kinase.

The epidermal growth factor receptor (EGFR) plays a crucial role in regulating cellular growth and survival, and its dysregulation is implicated in various cancers, making it a prime target for cancer therapy. Natural compounds known as catechins have garnered attention as promising anticancer agents. These compounds exert their anticancer effects through diverse mechanisms, primarily by inhibiting receptor tyrosine kinases (RTKs), a protein family that includes the notable member EGFR. Catechins, characterized by two chiral centers and stereoisomerism, demonstrate variations in chemical and physical properties due to differences in the spatial orientation of atoms. Although previous studies have explored the membrane fluidity effects and transport across cellular membranes, the stereo-selectivity of catechins concerning EGFR kinase inhibition remains unexplored. In this study, we investigated the stereo-selectivity of catechins in inhibiting EGFR kinase, both in its wild-type and in the prevalent L858R mutant. Computational analyses indicated that all stereoisomers, including the extensively studied catechin (-)-EGCG, effectively bound within the ATP-binding site, potentially inhibiting EGFR kinase activity. Notably, gallated catechins emerged as superior EGFR inhibitors to their non-gallated counterparts, revealing intriguing binding trends. The top four stereoisomers exhibiting high dock scores and binding energies with wild-type EGFR comprise (-)-CG (-)-GCG (+)-CG, and (-)-EGCG. To assess dynamic behavior and stability, molecular dynamics simulations over 100 ns were conducted for the top-ranked catechin (-)-CG and the widely investigated catechin (-)-EGCG with EGFR kinase. This study enhances our understanding of how the stereoisomeric nature of a drug influences inhibitory potential, providing insights that could guide the selection of specific stereoisomers for improved efficacy inexisting drugs.

Identification and Characterization of Novel Mutations in Chronic Kidney Disease (CKD) and Autosomal Dominant Polycystic Kidney Disease (ADPKD) in Saudi Subjects by Whole-Exome Sequencing.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a condition usually caused by a single gene mutation and manifested by both renal and extrarenal features, eventually leading to end-stage renal disease (ESRD) by the median age of 60 years worldwide. Approximately 89% of ADPKD patients had either PKD1 or PKD2 gene mutations. The majority (85%) of the mutations are in the PKD1 gene, especially in the context of family history. Objectives: This study investigated the genetic basis and the undiscovered genes that are involved in ADPKD development among the Saudi population. Materials and Methods: In this study, 11 patients with chronic kidney disease were enrolled. The diagnosis of ADPKD was based on history and diagnostic images: CT images include enlargement of renal outlines, renal echogenicity, and presence of multiple renal cysts with dilated collecting ducts, loss of corticomedullary differentiation, and changes in GFR and serum creatinine levels. Next-generation whole-exome sequencing was conducted using the Ion Torrent PGM platform. Results: Of the 11 Saudi patients diagnosed with chronic kidney disease (CKD) and ADPKD, the most common heterozygote nonsynonymous variant in the PKD1 gene was exon15: (c.4264G > A). Two missense mutations were identified with a PKD1 (c.1758A > C and c.9774T > G), and one patient had a PKD2 mutation (c.1445T > G). Three detected variants were novel, identified at PKD1 (c.1758A > C), PKD2L2 (c.1364A > T), and TSC2 (deletion of a'a at the 3'UTR, R1680C) genes. Other variants in PKD1L1 (c.3813_381 4delinsTG) and PKD1L2 (c.404C > T) were also detected. The median age of end-stage renal disease for ADPK patients in Saudi Arabia was 30 years. Conclusion: This study reported a common variant in the PKD1 gene in Saudi patients with typical ADPKD. We also reported (to our knowledge) for the first time two novel missense variants in PKD1 and PKD2L2 genes and one indel mutation at the 3'UTR of the TSC2 gene. This study establishes that the reported mutations in the affected genes resulted in ADPKD development in the Saudi population by a median age of 30. Nevertheless, future protein−protein interaction studies to investigate the influence of these mutations on PKD1 and PKD2 functions are required. Furthermore, large-scale population-based studies to verify these findings are recommended.

Preparation of 6-Mercaptopurine Loaded Liposomal Formulation for Enhanced Cytotoxic Response in Cancer Cells.

6-Mercaptopurine (6-MP) is a well-known immunosuppressive medication with proven anti-proliferative activities. 6-MP possesses incomplete and highly variable oral absorption due to its poor water solubility, which might reduce its anti-cancer properties. To overcome these negative effects, we developed neutral and positively charged drug-loaded liposomal formulations utilizing the thin-film hydration technique. The prepared liposomal formulations were characterized for their size, polydispersity index (PDI), zeta potential, and entrapment efficiency. The average size of the prepared liposomes was between 574.67 ± 37.29 and 660.47 ± 44.32 nm. Positively charged liposomes (F1 and F3) exhibited a lower PDI than the corresponding neutrally charged ones (F2 and F4). Entrapment efficiency was higher in the neutral liposomes when compared to the charged formulation. F1 showed the lowest IC50 against HepG2, HCT116, and MCF-7 cancer cells. HepG2 cells treated with F1 showed the highest level of inhibition of cell proliferation with no evidence of apoptosis. Cell cycle analysis showed an increase in the G1/G0 and S phases, along with a decrease in the G2/M phases in the cell lines treated with drug loaded positively charged liposomes when compared to free positive liposomes, indicating arrest of cells in the S phase due to the stoppage of priming and DNA synthesis outside the mitotic phase. As a result, liposomes could be considered as an effective drug delivery system for treatment of a variety of cancers; they provide a chance that a nanoformulation of 6-MP will boost the cytotoxicity of the drug in a small pharmacological dose which provides a dosage advantage.

Co-Occurrence of ß-Lactam and Aminoglycoside Resistance Determinants among Clinical and Environmental Isolates of Klebsiella pneumoniae and Escherichia coli: A Genomic Approach.

The presence of antimicrobial-resistance genes (ARGs) in mobile genetic elements (MGEs) facilitates the rapid development and dissemination of multidrug-resistant bacteria, which represents a serious problem for human health. This is a One Health study which aims to investigate the co-occurrence of antimicrobial resistance determinants among clinical and environmental isolates of K. pneumoniae and E. coli. Various bioinformatics tools were used to elucidate the bacterial strains' ID, resistome, virulome, MGEs, and phylogeny for 42 isolates obtained from hospitalized patients (n = 20) and environmental sites (including fresh vegetables, fruits, and drinking water) (n = 22). The multilocus sequence typing (MLST) showed that K. pneumoniae belonged to ten sequence types (STs) while the E. coli belonged to seventeen STs. Multidrug-resistant isolates harbored ß-lactam, aminoglycoside resistance determinants, and MGE were detected circulating in the environment (drinking water, fresh vegetables, and fruits) and in patients hospitalized with postoperative infections, neonatal sepsis, and urinary tract infection. Four K. pneumoniae environmental isolates (7E, 16EE, 1KE, and 19KE) were multidrug-resistant and were positive for different beta-lactam and aminoglycoside resistance determinants. blaCTX-M-15 in brackets of ISEc 9 and Tn 3 transposases was detected in isolates circulating in the pediatrics unit of Soba hospital and the environment. This study documented the presence of bacterial isolates harboring a similar pattern of antimicrobial resistance determinants circulating in hospitals and environments. A rapid response is needed from stakeholders to initiate a program for infection prevention and control measures to detect such clones disseminated in the communities and hospitals.

Structural-Guided Identification of Small Molecule Inhibitor of UHRF1 Methyltransferase Activity.

Ubiquitin-like containing plant homeodomain Ring Finger 1 (UHRF1) protein is recognized as a cell-cycle-regulated multidomain protein. UHRF1 importantly manifests the maintenance of DNA methylation mediated by the interaction between its SRA (SET and RING associated) domain and DNA methyltransferase-1 (DNMT1)-like epigenetic modulators. However, overexpression of UHRF1 epigenetically responds to the aberrant global methylation and promotes tumorigenesis. To date, no potential molecular inhibitor has been studied against the SRA domain. Therefore, this study focused on identifying the active natural drug-like candidates against the SRA domain. A comprehensive set of in silico approaches including molecular docking, molecular dynamics (MD) simulation, and toxicity analysis was performed to identify potential candidates. A dataset of 709 natural compounds was screened through molecular docking where chicoric acid and nystose have been found showing higher binding affinities to the SRA domain. The MD simulations also showed the protein ligand interaction stability of and in silico toxicity analysis has also showed chicoric acid as a safe and nontoxic drug. In addition, chicoric acid possessed a longer interaction time and higher LD50 of 5000 mg/kg. Moreover, the global methylation level (%5 mC) has been assessed after chicoric acid treatment was in the colorectal cancer cell line (HCT116) at different doses. The result showed that 7.5 µM chicoric acid treatment reduced methylation levels significantly. Thus, the study found chicoric acid can become a possible epidrug-like inhibitor against the SRA domain of UHRF1 protein.