A novel fluorescent probe based imprinted polymer-coated magnetite for the detection of imatinib leukemia anti-cancer drug traces in human plasma samples.

Myeloid leukemia is a chronic cancer, which associated with abnormal BCR-ABL tyrosine kinase activity. Imatinib (IMB) acts as a tyrosine kinase inhibitor and averts tumor growth in cancer cells by controlling cell division, so it is urgent to develop an effective assay to detect and monitor its IMB concentration. Therefore, an innovative fluorescent biomimetic sensor is a promising sensing material that constructed for the efficient recognition of IMB and displays excellent selectivity and sensitivity stemming from molecularly imprinted polymer@Fe3O4 (MIP@Fe3O4). The detection strategy depends on the recognition of IMB molecules at the imprinted sites in the presence of coexisting molecules, which are then transferred to the fluorescence signal. The synthesized MIP@Fe3O4 was characterized using Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and atomic force microscopy (AFM). Furthermore, computational studies of the band gap (EHOMO-ELUMO) of the monomers, IMB, and their complexes were performed. These results confirmed that the copolymer is the most appropriate and has high stability (Binding energy; 0.004 x 10-19 KJ) and low reactivity. A comprehensive linear response over IMB concentrations from 5 × 10-6 mol/L to 8 × 10-4 mol/L with a low detection limit of 9.3 × 10-7 mol/L was achieved. Furthermore, the proposed technique displayed long-term stability (over 2 months), high intermediate precision (RSD<2.1 %), good reproducibility (RSD <1.9 %), and outstanding selectivity toward IMB over analogous molecules with similar chemical and spatial structure (no interference by 100 to 150-fold of the competitors). Owing to these merits, the proposed fluorescence sensor was utilized to detect IMB in drug tablets and human plasma, and satisfactory results (99.3-100.4 %) were obtained. Thus, the synthesized fluorescence sensor is a promising platform for IMB sensing in various applications.

A rational study of transduction mechanisms of different materials for all solid contact-ISEs.

The new era of solid contact ion selective electrodes (SC-ISEs) miniaturized design has received an extensive amount of concern. Because it eliminated the requirement for ongoing internal solution composition optimization and created a two-phase system with stronger detection limitations. Herein, the determination of venlafaxine HCl is based on a comparison study between different ion- to electron transduction materials (such as; multiwalled carbon nanotubes (MWCNTs), polyaniline (PANi), and ferrocene) and illustrating their mechanisms in their applied sensors. Their different electrochemical features (such as bulk resistance (Rb**), double-layer capacitance (Cdl), geometric capacitance (Cg), and specific capacitance (Cp)) were evaluated and discussed by using the Electrochemical Impedance Spectroscopy (EIS), Chronopotentiometry (CP), and Cyclic Voltammetry (CV) experiments. The results indicated that each transducer's influence on the proposed sensor's electrochemical characteristics is determined by their unique chemical and physical properties. The electrochemical features vary for different solid contact materials used in transduction mechanisms. The results confirm that the MWCNT sensor revealed the best electrochemical behavior with the potentiometric response of a near-Nernestian slope of 56.1 ± 0.8 mV/decade with detection limits of 3.8 × 10-6 mol/L (r2 = 0.999) and a low potential drift (∆E/∆t) of 34.6 µV/s. Also, the selectivity study was performed in the presence of different interfering species either in single or complex matrices. This demonstrates excellent selectivity, stability, conductivity, and reliability as a VEN-TPB ion pair sensor for accurately measuring VEN in its various formulations. The proposed method was compared to HPLC reported technique and confirmed no significant difference between them. So, the proposed sensors fulfill their solutions' demand features for VEN appraisal.

In silico and in vitro prediction of new synthesized N-heterocyclic compounds as anti-SARS-CoV-2.

Computer-aided drug design has been employed to get the medicinal effects against Corona virus from different pyridine derivatives after synthesizing the new compounds. Additionally, various computational studies are also employed between the newly prepared pyridine derivatives and three controls against three proteins (6Y2E, 6M71 and 6M3M). Different methods were employed to synthesize new pyridine derivatives according to the literature using different reaction mediums. MTT was performed for cytotoxicity study and IC50 for inhibitory concentration. Additionally, in-silico studies including DFT, molecular docking, molecular dynamics, MMPBSA, ADME, pharmacokinetics and Lipinski rules were evaluated. The chemical structures of all new compounds were elucidated based on spectroscopic investigation. A molecular docking study demonstrated that compounds 5, 11, and 12 have the best binders of the SARS-CoV-2 main protease enzyme, with energy scores of - 7.5 kcal/mol, - 7.2 kcal/mol, and - 7.9 kcal/mol, respectively. The net binding energy values of the 11-Mpro, 12-Mpro, and 5-Mpro complexes revealed their highly stable nature in terms of both intermolecular interactions and docked conformation across the simulation time. ADME properties, besides the pharmacokinetics and Lipinski rules, showed that all seven newly synthesized compounds follow Lipinski rules with high GI absorption. The In Vitro antiviral study against SARS-CoV-2 using MTT methods confirms that compound 5 has more potential and is safer than other tested compounds. The study shows that the newly synthesized pyridine derivatives have medicinal properties against SARS-CoV-2 without violating Lipinski rules. Compounds 5, 11, and 12, particularly compound 5, may serve as promising potential candidate for COVID-19.

A computational investigation of galactopyranoside esters as antimicrobial agents through antiviral, molecular docking, molecular dynamics, pharmacokinetics, and bioactivity prediction.

One of the most common viral infections worldwide is the Human Papilloma Virus (HPV) which has been linked to cancer and other diseases in many countries. Monosaccharide esters are significant in the field of carbohydrate chemistry because they are efficient in the synthesis of pharmacologically active compounds. Therefore, the present study aimed to perform thermodynamic, molecular docking and molecular dynamics study of a series of previously designed monosaccharaides, methyl ß-d-galactopyranoside (MGP, 1) esters (2-10) with along with their physicochemical and pharmacokinetic properties. We have optimized the MGP esters employing the DFT study at the B3LYP/6-311 + G (d,p) level of theory. The subsequent analysis also investigated the electronic energies, enthalpies, entropies, polarizability, and natural bond orbital (NBO) of these modified esters. Then, MGP esters were docked into CTX-M-15 extended-spectrum beta-lactamase from Escherichia coli (PDB: 4HBT) and E2 DNA-binding domain from human papillomavirus type 31 (PDB: 1A7G), and the results revealed that most of the esters can efficiently bind to the target. Desmond was used to doing molecular dynamics simulations at 200 ns in addition to molecular docking to look at the binding conformational stability of the protein-ligand complex. Based on RMSD and RMSF, it was determined that the stability of the protein-ligand combination was maintained during the whole 200 ns simulations for all compounds. Finally, a pharmacokinetic study suggests that modified esters of MGP exhibited better pharmacokinetic characteristics and were less hazardous than the parent drug. This work demonstrated that potential MGP esters can efficiently bind to 4HBT and 1A7G proteins and opened avenues for the development of newer antimicrobial agents that can target dangerous pathogens.Communicated by Ramaswamy H. Sarma.

Nanoparticles of a Pyrazolo-Pyridazine Derivative as Potential EGFR and CDK-2 Inhibitors: Design, Structure Determination, Anticancer Evaluation and In Silico Studies.

The strategic planning of this study is based upon using the nanoformulation method to prepare nanoparticles 4-SLNs and 4-LPHNPs of the previously prepared 4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-3-amine (4) after confirming its structure with single crystal X-ray analysis. These nanoparticles exhibited promising cytotoxic activity against HepG-2, HCT-116 and MCF-7 cancer cell lines in comparison with the reference doxorubicin and the original derivative 4. Moreover, their inhibitory assessment against EGFR and CDK-2/cyclin A2 displayed improved and more favorable impact than the parent 4 and the references. Detection of their influence upon cancer biomarkers revealed upregulation of Bax, p53 and caspase-3 levels and downregulation of Bcl-2 levels. The docking simulation demonstrated that the presence of the pyrazolo[3,4-c]pyridazin-3-amine scaffold is amenable to enclosure and binding well within EGFR and CDK-2 receptors through different hydrophilic interactions. The pharmacokinetic and physicochemical properties of target 4 were also assessed with ADME investigation, and the outcome indicated good drug-like characteristics.

Investigation of the potential roles of adipose stem cells and substances of natural origin in the healing process of E. coli infected wound model in Rats.

Skin infections by pathogenic microorganisms are a serious problem due to the potential of dissemination through the bloodstream to various organs causing toxic effects that may be up to mortality. Escherichia coli (E. coli) is one of the most predominant Gram-negative bacterial species present globally with great attention for investigation. The current study is designed to investigate the possible role of adipose tissue-derived stem cells (ADSCs), as well as natural products such as Trichoderma viride (T. viride) extract, Saccharomyces boulardii (S. boulardii) solution in the enhancement of wound healing process in the infected skin with E. coli. Ninety-six female rats were divided into 8 groups (12 animal/group): normal skin, wounded skin, wounded skin infected with E. coli, infected-wounded skin treated by ADSCs, infected-wounded skin treated by T. viride extract, infected-wounded skin treated by S. boulardii solution, infected-wounded skin treated a combination of treatments, infected-wounded skin treated by gentamicin. At day 21 animal weights and bacterial count were detected and compared. Animals were sacrificed and skin from various groups was investigated using a light microscope for sections stained by (hematoxylin eosin, Masson trichrome, and PCNA) as well as transmission electron microscopy. Pro-inflammatory (IL-1ß, TNF- α, and IL-13), anti-inflammatory cytokine (IL-4), and antioxidant enzymes (Superoxide dismutase, glutathione, and catalase) were assessed in various groups revealing that ADSCs lightly shift levels of these parameters in various rat groups to regular levels, while administration of T. viride extract, S. boulardii solution, their combination with ADSCs and gentamicin treatment drive the tested cytokines and enzymes to significant levels similar to a normal level where combination therapy gave the best result. The current findings revealed the possibility of using certain natural products as possible substitutes to regularly applied antibiotics with successive protective results in the wound infection model.

Evaluation of the effect of direct-acting antiviral agents on melatonin level and lipid peroxidation in chronic hepatitis C patients.

Background: Oxidative stress and its end products, such as malondialdehyde (MDA) play a leading role in the pathogenesis of hepatitis C. Melatonin is a hormone that helps regulate circadian rhythms, which likely play a role in infectious diseases in terms of susceptibility, clinical expression, and outcome. Objective: The present study was conducted to assess serum malondialdehyde and melatonin levels in patients with chronic hepatitis C infection before and after the intake of direct-acting antivirals. Method: Forty hepatitis C patients were the subjects of this study. While ten healthy volunteers who matched in age and socioeconomic status served as the control subjects. Malondialdehyde and melatonin were assayed in the serum of the three groups, and the results were statistically analyzed. Results: Hepatitis C patients had significantly higher malondialdehyde (p < 0.001) but significantly lower melatonin (p < 0.001) as compared to the healthy controls. After 12 weeks of treatment with direct-acting antivirals, the malondialdehyde level decreased significantly (p < 0.001) and the melatonin level increased significantly (p < 0.001). A significant negative correlation between malondialdehyde and melatonin was observed. Conclusion: The present findings suggest that treatment of hepatitis C patients with Direct-acting antivirals improves liver function parameters and antioxidant profiles.

Generation of myoglobin (MB)-knockout human embryonic stem cell (hESC) line (KAIMRCe002-A-1S) using CRISPR/Cas9 technology.

Myoglobin (MB) is a cytoplasmic hemoprotein that is predominantly expressed in the heart and oxidative myofibers of skeletal muscle. It has been demonstrated that MB binds to oxygen and promotes its diffusion for energy production in the mitochondria. Recently, MB was found to be expressed in different forms of malignant tumors and cancer cell lines. Further studies using gene disruption technology will enhance the understanding of MB's role in human cardiovascular biology and cancers. Here, we describe the generation of a homozygous MB knockout in human embryonic stem cells (hESC-MB-/-) via CRISPR/Cas9 to study MB function in human biology and diseases.

Evaluation of Branched-Chain Amino Acids in Children with Autism Spectrum Disorder and Epilepsy.

Autism spectrum disorder (ASD) and epilepsy run hand-to-hand in their pathophysiology. Epilepsy is not an uncommon finding in patients with ASD. The aim of the present study was to identify the metabolic abnormalities of BCAAs (leucine, isoleucine, and valine) in children with ASD with and without seizures in comparison with neurotypical controls. Also, this study aimed to investigate the presence of epileptiform discharges on electroencephalography (EEG) in ASD patients and to describe the types and frequency of seizures observed. The study included 90 children aged 2-7 years, 30 of whom were diagnosed with both ASD and epilepsy. The other 30 children were diagnosed as ASD without epilepsy, and a comparable 30 normally developed children served as a control group. The groups were matched by age and gender. All patients were referred to the Autism Disorders Clinic for interviews and examinations. The Childhood Autism Rating Scale (CARS) was applied to all study participants to assess the degree of autism. The present study results show that all types of seizures may be identified in ASD children. The median serum levels of BCAAs were lower in ASD children with and without epilepsy than in neurotypical controls. This opens the door for discussion about new etiologies and better categorizations of ASD based on genotype and genetic abnormalities detected. More studies with larger samples are needed to understand ASD better and to more reliable evaluate the association between ASD, EEG changes, seizures, and BCAAs.

Analysis and prediction pathways of natural products and their cytotoxicity against HeLa cell line protein using docking, molecular dynamics and ADMET.

Natural product such as flavonoids and their derivatives have a discernible capability to inhibit tumor formation and the growth of cancer cell, which have a vital link between diet and chronic disease prevention. Several plants and spices that contain flavonoid derivatives have been used in traditional medicine as disease preventative and therapeutic agents. Therefore, flavonoids could be used as chemotherapeutic drugs, indicating their potential clinical utility in cancer treatment. The purpose of this research was to discover and produce innovative pharmaceuticals from natural sources by introducing structural changes into flavonoids' backbones and changing their structures to improve biological activity and anticancer effects. In the current study, it was expected that the percent unbound values for the 15 compounds in human plasma would be low, ranging between 0.188 and 0.391. However, all compounds have a safe range and are not toxic to the brain. Compounds 2, 10, and 13 were shown to be permeable to the CNS (log PS > -3), but all other compounds had difficulty penetrating the CNS. Furthermore, all compounds had a low total clearance, ranging from 0.038 to 1.216 ml/min/kg, indicating that these compounds have a long half-life. None of the compounds caused skin sensitization (SS), and only compounds 1, 11, and 12 are expected to be AMES-positive, suggesting that the other compounds are not mutagenic. The result of the study showed based on the Drug-likeness and ADMET studies, only 3 compounds, including 3, 4, and 15, have a good pharmacokinetics propriety, the lowest toxicity, and good binding affinity towards Caspase 3 V266APDB (ID: 5I9B) as potential inhibitor candidates for the HeLa cell line, they have a low total clearance property and no AMES mutagenicity or hERG inhibition properties. These compounds (3,4,15) were examined to act as new cytotoxic drug candidates and would have an interest as starting point for designing compounds against the HeLa cell line.Communicated by Ramaswamy H. Sarma.

Design, synthesis, spectroscopic characterization, in-vitro antibacterial evaluation and in-silico analysis of polycaprolactone containing chitosan-quercetin microspheres.

Aim of present study was to synthesize a novel chitosan-quercetin (CTS-QT) complex by making a carbodiimide linkage using maleic anhydride as cross-linker and to investigate its enhanced antibacterial and antioxidant activities as compare to pure CTS and QT. Equimolar concentration of QT and maleic anhydride were used to react with 100 mg CTS to form CTS-QT complex. For this purpose, three bacterial strains namely E. Coli, S. Aureus and P. Aeruginosa were used for in-vitro antibacterial analysis (ZOI, MIC, MBC, checker board and time kill assay). Later molecular docking studies were performed on protein structure of E. Coli to assess binding affinity of pure QT and CTS-QT complex. MD simulations with accelerated settings were used to explore the protein-ligand complex's binding interactions and stability. Antioxidant profile was determined by performing DPPH• radical scavenging assay, total antioxidant capacity (TAC) and total reducing power (TRP) assays. Delivery mechanism to CTS-QT complex was improved by synthesizing polycaprolactone containing microspheres (CTS-QT-PCL-Levo-Ms) using Levofloxacin as model drug to enhance their antibacterial profile. Resulted microspheres were evaluated by particle size, charge, surface morphology, in-vitro drug release and hemolytic profile and are all were found within limits. Antibacterial assay revealed that CTS-QT-PCL-Levo-Ms showed more than two folds increased bactericidal activity against E. Coli and P. Aeruginosa, while 1.5 folds against S. Aureus. Green colored formation of phosphate molybdate complexes with highest 85 ± 1.32% TAC confirmed its antioxidant properties. Furthermore, molecular docking and dynamics studies revealed that CTS-QT was embedded nicely within the active pocket of UPPS with binding energy greater than QT with RSMD value of below 1.5. Conclusively, use of maleic acid, in-vitro and in-silico antimicrobial studies confirm the emergence of CTS-QT complex containing microspheres as novel treatment strategy for all types of bacterial infections.Communicated by Ramaswamy H. Sarma.

Human targeted phenobarbital presents a poor substrate of gut microbiome deciphering new drug targets beyond pharmacokinetic curbs.

BACKGROUND: The gut microbiome, a new organ of the body, can potentially alter the pharmacokinetics of orally administered drugs through microbial enzymes. However, absorption of orally administered non-antibiotic drugs by the gut microbiome, during drug-microbiome interaction, is barely addressed. Structural homology studies confirm similar membrane transport proteins in gut epithelial cells and the gut microbiome of the host that may compete for drug substrates with the host itself for its absorbance. Therefore, it is hypothesized that orally administered human targeted phenobarbital may interact and/or be uptake by the gut microbiome during its transit through the small intestine. METHODS: In the current in vivo study, thirty-six male Wistar albino rats were divided into six groups including one control and 5 treatment groups, each having an equal number of rats (n = 6). Phenobarbital was administered orally (single dose of 15 mg/kg bw) to treatment groups. Animals were subsequently sacrificed to harvest microbial mass pallets residing in the small intestine after 2, 3, 4, 5, and 6 h of phenobarbital administration. Phenobarbital absorbance by the microbiome in the microbial lysate was estimated through RP-HPLC-UV at a wavelength of 207 nm. RESULTS: Maximum phenobarbital absorbance (149.0 ± 5.93 µg) and drug absorbance per milligram of microbial mass (1.19 ± 0.05 µg) were found significantly higher at 4 h of post-administration in comparison to other groups. Percent dose recovery of phenobarbital was 5.73 ± 0.19% at 4 h while the maximum intestinal transit time was 5 h till the drug was absorbed by the microbes. Such results pronounce the idea of the existence of structural homology between membrane transporters of the gut microbiome and intestinal enterocytes of the host that may competitively absorb orally administered phenobarbital during transit in the small intestine. The docking studies revealed that the phenobarbital is a poor substrate for the gut microbiome. CONCLUSION: Gut microbiome may competitively absorb the non-antibiotics such as phenobarbital as novel substrates due to the presence of structurally homologous transporting proteins as in enterocytes. This phenomenon suggests the microbiome as a potential candidate that can significantly alter the pharmacokinetics of drugs.

Fabrication and characterization of electrospun nanofibers using biocompatible polymers for the sustained release of venlafaxine.

Recently, drug-controlled release nanotechnology has gained special attention in biomedicine. This work focuses on developing novel electrospun polymeric nanofibers (NFs) for buccal delivery of VEN to avoid the hepatic metabolism and enzymatic degradation in the GIT and develop an effective control of drug release. The optimized NFs were obtained by blending polylactic acid (PLA), and poly (ɛ-caprolactone) (PCL) fixed at a ratio of 1:1. It was characterized for morphology, drug-loading, FTIR, XRD, DSC, and in vitro drug release. Ex vivo permeability of the blend NFs was assessed using chicken pouch mucosa compared to VEN suspension, followed by histopathological examination. Further, the cytotoxic effect in three different cell lines using WST-1 assay. SEM morphologies refer to defect-free uniform NFs of PLA, PCL, and PLA/PCL mats. These fibers had a diameter ranging from 200 to 500 nm. The physico-thermal characterization of NFs depicted that the drug was successfully loaded and in an amorphous state in the PLA/PCL NFs. In vitro release of NFs substantiated a bi-phasic profile with an initial burst release of about 30% in the initial 0.5 h and a prolonged cumulative release pattern that reached 80% over 96 h following a non-Fickian diffusion mechanism. Ex vivo permeation emphasizes the major enhancement of the sustained drug release and the noticeable decrease in the permeability of the drug from NFs. Cytotoxicity data found that IC50 of VEN alone was 217.55 µg/mL, then VEN-NFs recorded an IC50 value of 250.62 µg/mL, and plain NFs showed the lowest toxicity and IC50 440.48 µg/mL in oral epithelial cells (OEC). Histopathology and cell toxicity studies demonstrated the preserved mucosal architecture and the preclinical safety. The developed PLA/PCL NFs can be promising drug carriers to introduce a step-change in improved psychiatric treatment healthcare.

Self-assembly of new cobalt complexes based on [Co (SCN)4], synthesis, empirical, antioxidant activity, and quantum theory investigations.

The cobalt (II) complexes have been synthesized from the reaction of the cationic entities (3,4-dimethylaniline (1) and histamine (2)) with metallic salt CoCl2⋅6H2O and thiocyanate ion (SCN-) as a ligand in H2O/ethanolic solution and processing by the evaporation crystal growth method at room temperature to get crystals. The synthesized complex has been fully characterized by single-crystal X-ray diffraction. UV-Visible, FTIR spectroscopy, TGA analysis, and DFT circulations were also performed. The crystal structural analysis reveals that the solid (1) {[Co(SCN)4] (C8H12N)3}·Cl crystallizes in the monoclinic system with the space group P21/n and the solid (2) {[Co(SCN)4](C5H11N3)2}·2Cl crystallizes in the monoclinic space group P21/m. Metal cations are joined into corrugated chains parallel to the b-axis direction in (1) and (2) by four thiocyanate anions. The crystal structures of (1) and (2) were calculated using XRPD data, indicating that they are closely connected to the DRX mono-crystal results. Different interactions pack the system into a ring formed by N-H⋯Cl and N-H⋯S hydrogen bonds. C-H⋯π and the π⋯π stacking of anilinuim ring for (1) and N-H⋯S intermolecular interactions for (1) and (2) increase the crystals' robustness. Hirshfeld surface analysis cum 2D fingerprint plots visualize the main intermolecular interactions with their contributions in the solid-state phase. The molecular geometries of both complexes obtained from the crystal structure were used for quantum chemical calculation. Here, frontier orbital analysis and electrostatic potential illustrate the chemical reactivities of metal-organic complexes. QTAIM and NCI analysis reveal the strength of interactions at the electronic level.

Voltammetric estimation of residual nitroxynil in food products using carbon paste electrode.

A simple and sensitive voltammetric method was developed and validated for the recognition of the veterinary drug nitroxynil (NTX). The method is based on studying its voltammetric behavior at a carbon paste electrode. Square wave voltammetry (SWV) was successfully applied in this study. The anodic peak current obtained was a linear function of NTX concentration in Britton Robinson buffer of pH 3 over the range of 3.9 × 10-6-1.0 × 10-4 M with lower detection and quantitation limits of 3.1 × 10-7 and 9.4 × 10-7 M, respectively. The proposed method was first applied to the assessment of the drug in commercial vials. The method was further used to monitor the residual amounts of the drug in bovine meat, kidney, fat, and milk samples. The results obtained were favourably compared with those given by reference method. The interference likely to be introduced by co-administered drugs was evaluated. The electrode reaction was elucidated, and electron transfer kinetics were studied.

All-Solid-State Potentiometric Platforms Modified with a Multi-Walled Carbon Nanotubes for Fluoxetine Determination.

Novel cost-effective screen-printed potentiometric platforms for simple, fast, and accurate assessment of Fluoxetine (FLX) were designed and characterized. The potentiometric platforms integrate both the FLX sensor and the reference Ag/AgCl electrode. The sensors were based on the use of 4'-nitrobenzo-15-crown-5 (ionophore I), dibenzo-18-crown-6 (ionophore II), and 2-hydroxypropyl-ß-cyclodextrin (2-HP-ß-CD) (ionophore III) as neutral carriers within a plasticized PVC matrix. Multiwalled carbon nanotubes (MWCNTs) were used as a lipophilic ion-to-electron transducing material and sodium tetrakis [3,5-bis(trifluoromethyl)phenyl] borate (NaTFPB) was used as an anionic excluder. The presented platforms revealed near-Nernstian potentiometric response with slopes of 56.2 ± 0.8, 56.3 ± 1.7 and 64.4 ± 0.2 mV/decade and detection limits of 5.2 × 10-6, 4.7 × 10-6 and 2.0 × 10-7 M in 10 mM Tris buffer solution, pH 7 for sensors based on ionophore I, II, and III, respectively. All measurements were carried out in 10 mM tris buffer solution at pH 7.0. The interfacial capacitance before and after insertion of the MWCNTs layer was evaluated for the presented sensors using the reverse-current chronopotentiometry. The sensors were introduced for successful determination of FLX drug in different pharmaceutical dosage forms. The results were compared with those obtained by the standard HPLC method. Recovery values were calculated after spiking fixed concentrations of FLX in different serum samples. The presented platforms can be potentially manufacturable at large scales and provide a portable, rapid, disposable, and cost-effective analytical tool for measuring FLX.

New Benzimidazole-, 1,2,4-Triazole-, and 1,3,5-Triazine-Based Derivatives as Potential EGFRWT and EGFRT790M Inhibitors: Microwave-Assisted Synthesis, Anticancer Evaluation, and Molecular Docking Study.

A new series of benzimidazole, 1,2,4-triazole, and 1,3,5-triazine derivatives were designed and synthesized using a microwave irradiation synthetic approach utilizing 2-phenylacetyl isothiocyanate (1) as a key starting material. All the new analogues were evaluated as anticancer agents against a panel of cancer cell lines utilizing doxorubicin as a standard drug. Most of the tested derivatives exhibited selective cytotoxic activity against MCF-7 and A-549 cancer cell lines. Furthermore, the new target compounds 5, 6, and 7 as the most potent antiproliferative agents have been assessed as in vitro EGFRWT and EGFRT790M inhibitors compared to the reference drugs erlotinib and AZD9291. They represented more potent suppression activity against the mutated EGFRT790M than the wild-type EGFRWT. Moreover, the compounds 5, 6, and 7 down-regulated the oncogenic parameter p53 ubiquitination. A docking simulation of compound 6b was carried out to correlate its molecular structure with its significant EGFR inhibition potency and its possible binding interactions within the active site of EGFRWT and the mutant EGFRT790M.

Necrostatin-1 mitigates renal ischaemia-reperfusion injury - time dependent - via aborting the interacting protein kinase (RIPK-1)-induced inflammatory immune response.

The recently defined necroptosis process participates in the pathophysiology of several tissue injuries. Targeting the necroptosis mediator receptor-interacting protein kinase (RIPK1) by necrostatin-1 in different phases of ischaemia-reperfusion injury (IRI) may provide new insight into the protection against renal IRI. The rat groups included (n = 8 in each group): 1) Sham; 2) Renal IRI; 3) Necrostatin-1 treatment 20 min before ischaemia induction in a dose of 1.65 mg/kg/intravenous; 4) Necrostatin-1 injection just before reperfusion; 5) Necrostatin-1 injection 20 min after reperfusion establishment; and 6) drug injection at both the pre-ischaemia and at reperfusion time in the same dose. Timing dependent, necrostatin-1 diminished RIPK1 (p < 0.001), and aborted the necroptosis-induced renal cell injury. Necrostatin-1 decreased the renal chemokine (CXCL1), interleukin-6, intercellular adhesion molecule (ICAM-1), myeloperoxidase, and the nuclear factor (NFκB), concomitant with reduced inducible nitric oxide synthase (iNOS), inflammatory cell infiltration, and diminished cell death represented by apoptotic cell count and the BAX/Bcl2 protein ratio. In group 6, the cell injury was minimal and the renal functions (creatinine, BUN and creatinine clearance) were almost normalised. The inflammatory markers were diminished (p < 0.001) compared to the IRI group. The results were confirmed by histopathological examination. In conclusion, RIPK1 inhibition ameliorates the inflammatory immune response induced by renal IRI. The use of two doses was more beneficial as the pathophysiology of cell injury is characterised.

Evaluation of the Postnatal Effects Induced by Diazinon on the Growth of the Mice Offspring and the Development of Their Cerebellar Cortex.

Diazinon (DZN) is a commonly used organophosphorus pesticide. Exposure to the residuals of DZN may lead to toxic effects. The current work was performed to clarify the possible physical variations and cellular changes in the developing cerebellar cortex of mice offspring after administration of DZN to their pregnant mothers. 27 adult males and 54 adult females were housed for mating. In the morning, vaginal smears were done to detect vaginal plug. Pregnant mice were divided into 3 groups: GI (control), GII (DZN), and GIII (sham control). Their offspring were subdivided into 3 subgroups (a) at birth, (b) on postnatal day 7 (PD7), and (c) on postnatal day 14 (PD14). At the end of the experiment, fetal crown-rump length and weight were measured. The cerebellar cortex was extracted, and samples were prepared for tissue homogenate, light and electron microscopic examination, morphometric and statistical studies. DZN treatment induced a statistically significant difference in pups' crown-rump length and weight associated with a highly statistically significant decrease in acetylcholinesterase enzyme level. A histopathological degenerative change was observed in the cerebellum of GII. Postnatally, a separation between cerebellar layers occurred along with shrunken cells leading to multiple enfolding and vacuolated matrix. At PD14, pericellular halos and hemorrhage between the pia matter and external granular layer were noticed. Ultrastructural examination revealed dilated rough endoplasmic reticulum, swollen mitochondria, and shrunken hyperchromatic nuclei. Moreover, morphometric studies detected a statistically significant increase in external granular layer thickness and a statistical decrease in Purkinje cell numbers. These findings demonstrated that prenatal administration of DZN to pregnant mice adversely influenced the developing cerebellum of the offspring and leads to neurodegenerative changes.

Diagnostic, Prognostic, Predictive, and Monitoring Role of Neutrophil CD11b and Monocyte CD14 in Neonatal Sepsis.

BACKGROUND: Sepsis is a critical medical condition that requires additional diagnostic considerations. Recently, focus has shifted to the diagnosis of sepsis using new markers to overcome the limitations of traditional laboratory diagnostic modalities. Neutrophil CD11b (nCD11b) and monocyteCD14 (mCD14) cell surface antigens have been shown to be useful in such diagnostic consideration. AIM: To investigate the diagnostic, monitoring, prognostic, and predictive roles of nCD11b and mCD14 as sepsis biomarkers in comparison to each other and to traditional laboratory sepsis parameters in order to select the best fit for routine daily use in neonatal intensive care units (NICUs). SUBJECT: The study included 188 neonates from Ain Shams University Hospitals' NICUs, who were divided into two groups: the control group (n = 100) and the sepsis group (n = 88). Highly sensitive CRP (hs-CRP), complete blood count (CBC), blood culture, and nCD11b and mCD14 evaluations were all part of the laboratory sepsis evaluation (done by flow cytometry technology). Positive blood culture results (BACT/ALERT system) confirmed the sepsis diagnosis. Twenty-four enrolled sepsis neonates were subjected to follow-up assessments, and they were divided into two groups based on clinical improvement: improved sepsis and sepsis without improvement. In order to predict performance evaluation, the subjected neonates were reclassified according to their outcome into survivors' and nonsurvivors' group. RESULTS: Sepsis patients had a significant increase in mCD14 MFI values when compared to controls. With sensitivity 75.4 percent, specificity 71.9 percent, efficacy 73.3 percent, and AUC 0.703, mCD14 MFI at cutoff 9.36 could distinguish the presence of septicemia. Significant increases in both mCD14 MFI and nCD11b MFI (P = 0.001) were observed in the severe sepsis/septic shock group compared to the nonsevere sepsis group. The combined measurement of CD14 MFI at cutoff 9.97 and CD14 percent at cutoff 44.7 percent yielded the best predictive performance. CONCLUSION: Sepsis patients had a significant increase in mCD14 MFI comparable to the controls. mCD14 MFI demonstrated better diagnostic, prognostic, and predictive results than nCD11b. hs-CRP outperformed mCD14 and nCD11b in terms of diagnostic efficacy and AUC. In the monitoring of sepsis patients, both mCD14 and nCD11b produced unsatisfactory results. Currently, the routine use of mCD14 or nCD11b as sepsis biomarkers in neonatal ICUs is not justified.