Pyrrolizine-5-carboxamides: Exploring the impact of various substituents on the anti-inflammatory and anticancer activities

Towards optimization of the pyrrolizine-5-carboxamide scaffold, a novel series of six derivatives (4a-c and 5a-c) was prepared and evaluated for their anti-inflammatory, analgesic and anticancer activities. The (EZ)-7-cyano-6-((4-hydroxybenzylidene)amino)-N-(p-tolyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (4b) and (EZ)-6-((4-chlorobenzylidene)-amino)-7-cyano-N-(p-tolyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (5b) bearing the electron donating methyl group showed the highest anti-inflammatory activity while (EZ)-6-((4-chlorobenzylidene)amino)-7-cyano-N-phenyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide (5a) was the most active analgesic agent. Cytotoxicity of the new compounds was evaluated against the MCF-7, A2780 and HT29 cancer cell lines using the MTT assay. Compounds 4b and 5b displayed high anticancer activity with IC50 in the range of 0.30–0.92 µmol L–1 against the three cell lines, while compound (EZ)-N-(4-chlorophenyl)-7-cyano-6-((4-hydroxybenzylidene)-amino)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (4c) was the most active against MCF-7 cells (IC50 = 0.08 µmol L–1). Both the anti-inflammatory and anticancer activities of the new compounds were dependent on the type of substituent on the phenyl rings. Substituents with opposite electronic effects on the two phenyl rings are preferable for high cytotoxicity against the MCF-7 and A2780 cells. COX inhibition was suggested as the molecular mechanism of the anti-inflammatory activity of the new compounds while no clear relationship could be observed between COX inhibition and anticancer activity. Compound 5b, the most active against the three cell lines, induced dose-dependent early apoptosis with 0.1–0.2 % necrosis in MCF-7 cells. New compounds showed promising drug-likeness scores while the docking study revealed high binding affinity to COX-2. Taken together, this study highlighted the significant impact of the substituents on the anti-inflammatory and anticancer activity of pyrrolizine-5-carboxamides, which could help in further optimization to discover good leads for the treatment of cancer and inflammation

Efficacy of Semi-Rigid Ureteroscopy and Holmium:YAG Laser Lithotripsy in the Treatment of Ureteric Calculi, a Retrospective Study

Background: Urolithiasis is a common worldwide health problem. Many endosurgical treatments became available for urinary calculi.Objectives: To find out the success clearance and complication rates of ureteric stone treatment using semi-rigid ureteroscopy and Holmium:YAG laser lithotripsy as a day case procedure.Methods: In the period from April 2011 to October 2013, a total of 64 patients who were treated by laser lithotripsy were reviewed retrospectively using Fedail Hospital data. Diagnosis was radiologically confirmed. Semi-rigid ureteroscopy and Holmium:YAG laser lithotripsy was conducted as a day case surgery. Operative details, clearance of stone fragments, failure and complications were analysed. Cases were followed clinically and radiologically after one week and one month.Results: The studied cases were 47 males and 17 females with average age of 47.3 years and ASA I in 52(81.3%). Those who had left ureteric stones were 28(43.8%) patients, only one patient had bilateral stones and 60(93.8%) patients had single stones. The largest stone diameter was 1.9cm. 68.8% had distal ureteric stones, 14.1% had mid third stones, and 17.2% had upper third stones. Most cases 96.9% were operated under spinal anaesthesia with mean operation time 61.2 minutes. Seven patients needed VUJ balloon dilatation to get access to the ureter.20 watt Holmium:YAG laser fibres were used for stone disintegration. 92.2% of cases had uncomplicated clearance, 3.1% minor complications and 4.7% failure of the procedure.100% clearance was confirmed during follow up. Conclusion: Semi-rigid ureteroscopy and Holmium:YAG laser lithotripsy is a safe treatment for ureteric calculi and can be conducted as a day case with high success rate and very low morbidity.Key words: ureteric stone, Semi-rigid ureteroscopy, Holmium:YAG laser lithotripsy

Ecological Distribution of Virulent Multidrug-Resistant Staphylococcus aureus in Livestock, Environment, and Dairy Products

Staphylococcus aureus is one of the most common causes of mastitis, leading to severe economic losses in the dairy industry. It is also zoonotic, with potential risks to public health. This study aimed to detect the occurrence of S. aureus-resistant strains isolated from cattle, buffalo, their environment, milk and dairy products; and to investigate the extent of animal, ecological, and food contamination by methicillin-resistant (MRSA) or enterotoxigenic S. aureus. Samples (n = 350) were collected from four animal (two cattle and two buffalo) farms, i.e., their environment. Thirty Karish cheese samples were collected from 10 markets in Mansoura, Egypt. S. aureus was detected in 17.9%, 17.6%, and 16.7% of samples collected from cattle, buffalo and Karish cheese, respectively. About 19% of isolated S. aureus strains carried the mecA gene. The distribution of the mecA gene was high in isolates from Karish cheese (60%), followed by samples collected from buffalo (16.2%) and cattle (16%). More than 34% of isolated S. aureus strains were enterotoxigenic, and the presence of enterotoxin genes was higher in isolates from Karish cheese (80%) than those from cattle (48%) and buffalo (18.9%). The most predominant enterotoxin gene among isolated S. aureus strains was the sea gene (26.9%), followed by sec (4.5%) and sed (3%) genes. Isolated strains were resistant to clindamycin (100%), kanamycin (97%), nalidixic acid (86.6%), cefotaxime (73.1%) sulphamethazole—trimethoprim (65.6%). Meanwhile, 95.5%, 94%, 86.6% and 77.7% of S. aureus strains were sensitive to ciprofloxacin, amikacin, imipenem and both cefoxitin and gentamycin, respectively. In conclusion, the presence of enterotoxigenic- and methicillin-resistant S. aureus strains in animals, their environment, and dairy products represents a public health concern, particularly in small-scale dairy farms in Egypt. To reduce the risk of infection of livestock and humans with resistant strains, strict regulations and guidelines for antimicrobial use in such a system are urgently required

Genska karakterizacija, kloniranje i ekspresija Toll-like receptora 1 mRNA nilske tilapije (Oreochromis niloticus)

Toll-like receptors (TLRs) are the most studied group of pathogen recognition receptor categories that detects infectious agents in vertebrates. Fish TLRs exhibit clear, distinct features, structure and a larger diversity than in other vertebrates. This study focused on identifying and detecting the structure of Oreochromis niloticus (Nile tilapia) Toll- like receptor-1 (TLR1|) as a model in freshwater bony fish. The full-length cDNA sequence of Oreochromis niloticus TLR1 mRNA was cloned. Cloning and sequence analysis revealed that the complete cDNA sequence of Oreochromis niloticus TLR1 consists of 2355 base pairs and encodes a polypeptide of 785 amino acids. The molecular analysis of the amino acid sequence indicated that Oreochromis niloticus TLR1 has the standard structural features and major components of amino acids of TLR family members, and is considered an orthologue to the vertebrate TLR1, not a paralogue. The translated amino acid analysis showed 96%, 88%, 85%, and 85% degrees of identity with Zebra Mbuna, Sea bass, Damsel fish, and Clownfish, respectively; and showed 66% identity t with electric eels and 61% with starlets. Phylogenetic analysis revealed that the Nile tilapia TLR1 is closely related to Larimichthys crocea, Epinephelus coioides, and Takifugu rubripes TLR1. Oreochromis niloticus TLR1 was expressed in the kidneys, brain, spleen, intestines, muscle, liver, gills, heart and skin. Quantitative RT-PCR showed differences in the expression levels between the tested tissues. In conclusion, this study is the first report (according to our knowledge) and provides a complete molecular and functional characterization of Oreochromis niloticus toll-like receptor 1, which is considered to be functionally orthologous to TLR1 in other species models.Toll-like receptori (TLR) najviše su istraživana skupina receptora za prepoznavanje uzročnika bolesti u kralježnjaka. TLR u riba pokazuju jasna razlikovna svojstva, strukturu i veliku raznolikost u odnosu na druge kralježnjake. Ovo je istraživanje usredotočeno na identifikaciju i otkrivanje Toll-like receptora 1 (TLR1) u nilske tilapije (Oreochromis niloticus) kao predstavnika slatkovodnih riba. Klonirana je puna sekvencija cDNA TLR1 mRNA. Utvrđeno je da se kompletna sekvencija cDNA TLR1 nilske tilapije sastoji od 2355 baznih parova i kodira polipeptid od 785 aminokiselina. Molekularna analiza sekvencija aminokiselina upućuje na to da TLR1 nilske tilapije ima standardna strukturna svojstva i glavne komponente porodice TLR receptora i smatra se ortologom, ne paralogom TLR1 kralježnjaka. Analiza prevedenih aminokiselina pokazala je stupanj identičnost od 96 % s mbuna zebrom, 88 % s lubinom, 85 % s damsel ribom i 85 % s ribom klaun, dok je stupanj identičnosti s električnom jeguljom bio 66 %, a s ribom starlet 61 %. Filogenetska analiza pokazala je da je TLR1 nilske tilapije usko povezan s TLR1 vrsta Larimichthys crocea, Epinephelus coioides i Takifugu rubripes. TLR1 nilske tilapije bio je izražen u bubrezima, mozgu, slezeni, crijevima, mišiću, jetri, škrgama, srcu i na koži. Kvantitativni RT-PCR pokazao je razlike u razini ekspresije među testiranim tkivima. Prema našim podacima ovo je istraživanje prvo koje donosi kompletnu molekularnu i funkcionalnu karakterizaciju Toll-like receptora 1 nilske tilapije, te se smatra funkcionalnim ortologom TLR1 u drugih vrsta

Whole-genome sequencing of Listeria innocua recovered from retail milk and dairy products in Egypt

The similarity of the Listeria innocua genome with Listeria monocytogenes and their presence in the same niche may facilitate gene transfer between them. A better understanding of the mechanisms responsible for bacterial virulence requires an in-depth knowledge of the genetic characteristics of these bacteria. In this context, draft whole genome sequences were completed on five L. innocua isolated from milk and dairy products in Egypt. The assembled sequences were screened for antimicrobial resistance and virulence genes, plasmid replicons and multilocus sequence types (MLST); phylogenetic analysis of the sequenced isolates was also performed. The sequencing results revealed the presence of only one antimicrobial resistance gene, fosX, in the L. innocua isolates. However, the five isolates carried 13 virulence genes involved in adhesion, invasion, surface protein anchoring, peptidoglycan degradation, intracellular survival, and heat stress; all five lacked the Listeria Pathogenicity Island 1 (LIPI-1) genes. MLST assigned these five isolates into the same sequence type (ST), ST-1085; however, single nucleotide polymorphism (SNP)-based phylogenetic analysis revealed 422–1,091 SNP differences between our isolates and global lineages of L. innocua. The five isolates possessed an ATP-dependent protease (clpL) gene, which mediates heat resistance, on a rep25 type plasmids. Blast analysis of clpL-carrying plasmid contigs showed approximately 99% sequence similarity to the corresponding parts of plasmids of L. monocytogenes strains 2015TE24968 and N1-011A previously isolated from Italy and the United States, respectively. Although this plasmid has been linked to L. monocytogenes that was responsible for a serious outbreak, this is the first report of L. innocua containing clpL-carrying plasmids. Various genetic mechanisms of virulence transfer among Listeria species and other genera could raise the possibility of the evolution of virulent strains of L. innocua. Such strains could challenge processing and preservation protocols and pose health risks from dairy products. Ongoing genomic research is necessary to identify these alarming genetic changes and develop preventive and control measures

Novel 1,5-diaryl pyrazole-3-carboxamides as selective COX-2/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxicity effects

Funding Information: The authors extend their appreciation to the Deanship of Scientific Research at Jouf University for funding this work through research grant number (DSR2020-04-421 )Peer reviewedPostprin

A systematic review and meta-analysis of the impact of the left atrial appendage closure on left atrial function.

BACKGROUND: Left atrial (LA) appendage closure (LAAC) is effective in patients with atrial fibrillation who are not candidates for long-term anticoagulation. However, the impact of LAAC on LA function is unknown. The aim of this study is to evaluate the impact of LAAC on atrial function. METHODS: This meta-analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A search strategy was designed to utilize PubMed/Medline, EMBASE, and Google scholar for studies showing the effect of LAAC on the LA function from inception to November 20, 2021. The standardized mean difference (SMD) was calculated from the means and standard deviations. RESULTS: Of 247 studies initially identified, 8 studies comprising 260 patients were included in the final analysis. There was a significant increase in LA emptying fraction following LAAC compared with preoperative function (SMD: 0.53; 95% confidence interval [CI]: 0.04-1.01; p = .03; I2  = 75%). In contrast, there were no significant differences in LA volume (SMD: -0.07; 95% CI: -0.82-0.69; p = .86; I2  = 92%) peak atrial longitudinal strain (SMD: 0.50; 95% CI: -0.08-1.08; p = .09; I2  = 89%), peak atrial contraction strain (SMD: 0.38; 95% CI: -0.22-0.99; p = .21; I2  = 81%), strain during atrial contraction (SMD: -0.24; 95% CI: -0.61-0.13; p = .20; I2  = 0%), strain during ventricular systole (SMD: 0.47; 95% CI: -0.32-1.27; p = .24; I2  = 89%), strain during ventricular diastole (SMD: 0.09; 95% CI: -0.32-0.51; p = .66; I2  = 65%). CONCLUSION: LAAC is associated with improvement in the left atrial emptying fraction, but did not significantly influence other parameters

Role of oesophageal cooling in the prevention of oesophageal injury in atrial fibrillation catheter ablation: a systematic review and meta-analysis of randomized controlled trials.

AIMS: To evaluate the efficacy of oesophageal cooling in the prevention of oesophageal injury in patients undergoing atrial fibrillation (AF) catheter ablation. METHODS AND RESULTS: Comprehensive search of MEDLINE, EMBASE, and Cochrane databases through April 2022 for randomized controlled trials (RCTs) evaluating the role of oesophageal cooling compared with control in the prevention of oesophageal injury during AF catheter ablation. The study primary outcome was the incidence of any oesophageal injury. The meta-analysis included 4 RCTs with a total of 294 patients. There was no difference in the incidence of any oesophageal injury between oesophageal cooling and control [15% vs. 19%; relative risk (RR) 0.86; 95% confidence interval (CI) 0.31-2.41]. Compared with control, oesophageal cooling showed lower risk of severe oesophageal injury (1.5% vs. 9%; RR 0.21; 95% CI 0.05-0.80). There were no significant differences among the two groups in mild to moderate oesophageal injury (13.6% vs. 12.1%; RR 1.09; 95% CI 0.28-4.23), procedure duration [standardized mean difference (SMD) -0.03; 95% CI -0.36-0.30], posterior wall radiofrequency (RF) time (SMD 0.27; 95% CI -0.04-0.58), total RF time (SMD -0.50; 95% CI -1.15-0.16), acute reconnection incidence (RR 0.93; 95% CI 0.02-36.34), and ablation index (SMD 0.16; 95% CI -0.33-0.66). CONCLUSION: Among patients undergoing AF catheter ablation, oesophageal cooling did not reduce the overall risk of any oesophageal injury compared with control. Oesophageal cooling might shift the severity of oesophageal injuries to less severe injuries. Further studies should evaluate the long-term effects after oesophageal cooling during AF catheter ablation

Discovery of novel oxazole-based macrocycles as anti-coronaviral agents targeting SARS-CoV-2 main protease

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Synthesis of a New Chelating Iminophosphorane Derivative (Phosphazene) for U(VI) Recovery

A new synthetic chelating N–hydroxy–N–trioctyl iminophosphorane (HTIP) was prepared through the reaction of trioctylphosphine oxide (TOPO) with N–hydroxylamine hydrochloride in the presence of a Lewis acid (AlCl3 ). Specifications for the HTIP chelating ligand were successfully determined using many analytical techniques,13C–NMR,1H–NMR, FTIR, EDX, and GC–MS analyses, which assured a reasonable synthesis of the HTIP ligand. The ability of HTIP to retain U(VI) ions was investigated. The optimum experimental factors, pH value, experimental time, initial U(VI) ion concentration, HTIP dosage, ambient temperature, and eluents, were attained with solvent extraction techniques. The utmost retention capacity of HTIP/CHCl3 was 247.5 mg/g; it was achieved at pH = 3.0, 25◦C, with 30 min of shaking and 0.99 × 10−3 mol/L. From the stoichiometric calculations, approximately 1.5 hydrogen atoms are released during the extraction at pH 3.0, and 4.0 moles of HTIP ligand were responsible for chelation of one mole of uranyl ions. According to kinetic studies, the pseudo–first order model accurately predicted the kinetics of U(VI) extraction by HTIP ligand with a retention power of 245.47 mg/g. The thermodynamic parameters ∆S◦, ∆H◦, and ∆G◦ were also calculated; the extraction process was predicted as an exothermic, spontaneous, and advantageous extraction at low temperatures. As the temperature increased, the value of ∆G◦ increased. The elution of uranium ions from the loaded HTIP/CHCl3 was achieved using 2.0 mol of H2SO4 with a 99.0% efficiency rate. Finally, the extended variables were used to obtain a uranium concentrate (Na2U2O7, Y.C) with a uranium grade of 69.93% and purity of 93.24%. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Princess Nourah Bint Abdulrahman University, PNU: PNURSP2022R13The authors express their gratitude for the support from Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R13), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia