Novel potential nonsedating H1 antagonists related to the gauche rotamer of PROS-NH-histamine

On the basis of the most stable stereorotameric (R) forms of ^πNH-histamine (2), the trans (1-TR) and gauche (1-GR) forms have both been reported to be involved in potentiation of H₁-receptors. Apart from the known classic models of H₁-antagonists that mostly belong to 1-TR, a new topographic receptor map for 1-GR has been postulated. Twenty-seven new compounds pertaining to novel nonclassic molecular models related to 1-GR have been postulated as potential nonsedating, less toxic H₁-antagonists. Representative members of the new agents were investigated for H₁-blocking activity by using isolated segments from guinea pig ileum. Many of the tested new compounds exhibited activities comparable to that of acrivastine as a reference nonsedating drug. The C log P values of the new agents were lower than that of acrivastine (4.34), which might indicate decreased tendency to cross the blood–brain barrier. The most pronounced activity was displayed by the 5-substituted aminomethylenepyrimidine-2,4,6-triones (21, 23) since they displayed nearly equal 50% inhibition concentrations (IC₅₀) (6.12 × 10⁻⁶ M) and lower C log P values.     

DNA repair: from genome maintenance to biomarker and therapeutic target

A critical link exists between an individual's ability to repair cellular DNA damage and cancer development, progression, and response to therapy. Knowledge gained about the proteins involved and types of damage repaired by the individual DNA repair pathways has led to the development of a variety of assays aimed at determining an individual's DNA repair capacity. These assays and their use in the analysis of clinical samples have yielded useful though somewhat conflicting data. In this review article, we discuss the major DNA repair pathways, the proteins and genes required for each, assays used to analyze activity, and the relevant clinical studies to date. With the recent results from clinical trials targeting specific DNA repair proteins for the treatment of cancer, accurate, reproducible, and relevant analysis of DNA repair takes on an even greater significance. We highlight the strengths and limitations of these DNA repair studies and assays, with respect to the clinical assessment of DNA repair capacity to determine cancer development and response to therapy.     

Design, synthesis and anticancer evaluation of novel tetrahydroquinoline derivatives containing sulfonamide moiety

Sulfonamides posses many types of biological activities and have recently been reported to show substantial antitumor activity in vitro and/or in vivo. There are a variety of mechanisms for the anticancer activity and the most prominent of these is through the inhibition of carbonic anhydrase isozymes. The present work reports the synthesis of some novel quinoline and pyrimido[4,5-b]quinoline derivatives bearing a substituted or unsubstituted sulfonamide moiety. The design of the structures of these compounds complies with the general pharmacophore of the sulfonamide compounds that act as carbonic anhydrase (CA) inhibitors as this may play a role in their anticancer activity. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against breast cancer cell line (MCF7). Most of the screened compounds showed interesting cytotoxic activities compared to a reference drug.     

Synthesis of some novel quinolines and pyrimido [4,5-b] quinolines bearing A sulfonamide moiety as potential anticancer and radioprotective agents

Some novel 4-(quinolin-1-yl)-benzenesulfonamide and 4-(pyrimido[4,5-b]quinolin-10-yl)-benzenesulfonamide derivatives have been synthesized. All the newly synthesized target compounds were subjected to in vitro cytotoxic screening to be evaluated for their anticancer activity against Ehrlich ascites carcinoma cells. Among these new compounds, compounds 9a, 11, 12b, 18 and, in particular, 19 showed promising in vitro cytotoxic activity compared with doxorubicin (CAS 23214-92-8) as a reference drug. Moreover, compound 8 exhibited in vivo radioprotective activity against gamma-irradiation in mice.     

Development and radiosterilization of new hydrazono-quinoline hybrids as DNA gyrase and topoisomerase IV inhibitors: Antimicrobial and hemolytic activities against uropathogenic isolates with molecular docking study

This study aimed to synthesize new potent quinoline derivatives based on hydrazone moieties and evaluate their antimicrobial activity. The newly synthesized hydrazono-quinoline derivatives 2 , 5a , 9 , and 10b showed the highest antimicrobial activity with MIC values ≤1.0 μg/ml against bacteria and ≤8.0 μg/ml against the fungi. Further, these derivatives exhibited bactericidal and fungicidal effects with MBC/MIC and MFC/MIC ratio ≤4. Surprisingly, the most active compounds displayed good inhibition to biofilm formation with MBEC values ranging between (40.0 ± 10.0 – 230.0 ± 31.0) and (67.0 ± 24.0 – 347.0 ± 15.0) μg/ml against Staphylococcus aureus and Pseudomonas aeruginosa, respectively. The hemolytic assays confirmed that the hydrazono-quinoline derivatives are non-toxic with low % lysis values ranging from 4.62% to 14.4% at a 1.0 mg/ml concentration. Besides, compound 5a exhibited the lowest hemolytic activity value of ~4.62%. Furthermore, the study suggests that the hydrazono-quinoline analogs exert their antibacterial activity as dual inhibitors for DNA gyrase and DNA topoisomerase IV enzymes with IC₅₀ values ranging between (4.56 ± 0.3 – 21.67 ± 0.45) and (6.77 ± 0.4 – 20.41 ± 0.32) μM, respectively. Additionally, the recent work advocated that compound 5a showed the reference SAL at the ɣ-radiation dose of 10.0 kGy in the sterilization process without affecting its chemical structure. Finally, the in silico drug-likeness, toxicity properties, and molecular docking simulation were performed. Besides, the result exhibited good oral-bioavailability, lower toxicity prediction, and lower binding energy with good binding mode rather than the positive control.     

Characterization of a new efficient low molecular weight Bacillus subtilis NRC 16 levansucrase and its levan

Screening of 18 bacterial honey isolates revealed that all the isolates were levansucrase producers. The most potent isolate that achieved the highest activity (45.66 U/ml) was identified as Bacillus subtilis NRC based on morphological examination and 16S rRNA. The results recorded the necessity of starch (5 g/L), baker's yeast (12.5 g/L), and AlCl₃ (5 mM) in improvement of the enzyme productivity. The Bacillus subtilis levansucrase was eluted as a single protein in one purification step. The enzyme molecular weight was (14 kDa). It showed its optimum activity at 45°C and could retain 60% of its activity after incubation at 50°C for 2 h. Its optimum activity was obtained at pH 8.2 and the enzyme showed great pH stability in both acidic and alkaline ranges. Unlike, most levansucrases all tested metals had an adverse effect in enzyme activity. The enzyme had antioxidant activities and were characterized as spherical micro‐ and nanoparticles by transmission electron microscopy. The effect of growth conditions and medium composition in levan structure and its fibrinolytic activity was evaluated.     

Novel insights into the SLC7A11-mediated ferroptosis signaling pathways in preeclampsia patients: identifying pannexin 1 and toll-like receptor 4 as innovative prospective diagnostic biomarkers

Journal of Assisted Reproduction and Genetics - Ferroptosis is associated with oxidative stress (OS) and is caused by iron-dependent lipid-peroxidative damage, but its role in PE is unclear. The...     

Prevalence of CagA and antimicrobial sensitivity of <Emphasis Type="Italic">H. pylori</Emphasis> isolates of patients with gastric cancer in Egypt

Background

Helicobacter pylori (H. pylori) infection has been recognized as a significant threat for gastric cancer. However, studies that investigated the oncogenic factors and antimicrobial resistance of H. pylori in Egyptian isolates with gastric cancer are rare. The current study aimed to examine: (1) The pattern of antimicrobial resistance of H. pylori isolates of Egyptian gastric cancer patients, and (2) the prevalence of Cytotoxin-associated gene A (CagA).

Methods

Samples were collected from patients with gastric cancer. Isolation of H. pylori was performed using Columbia blood agar supplemented with 10% horse blood, and selective supplement of H. pylori for 3 to 5 days at 37 °C under microaerophilic condition. Isolates were identified by biochemical traits of H. pylori: oxidase, urease and catalase tests. Antimicrobial susceptibility of H. pylori isolates was examined against five antimicrobial agents using disc diffusion method. After that, extraction of DNA and Polymerase Chain Reaction (PCR) were performed to amplify the target genes.

Results

Twelve samples were collected from six males and six females Egyptian patients with cancer with an age range from 22 to 65 years. These cases are scarce and samples were collected over a period of almost eleven months. All isolates were confirmed as positive H. pylori through colony morphology and biochemical tests. The most effective antibiotic found was ciprofloxacin whereas all isolates showed resistance to metronidazole and erythromycin. The target CagA oncogene gene with expected product size was reported and seven (out of twelve) isolates (58%) were identified as CagA positive.

Conclusion

The current study is unique in two main aspects. First, it reported the pattern of antimicrobial susceptibility and prevalence of CagA gene in H. pylori from Egyptian patients. Second, it exclusively recruited isolates from gastric cancer patients which were confirmed by clinical and laparoscopic examination. The moderately high prevalence of CagA gene in Egyptian cancer patients calls for more vigilance against that oncogene.