Management of ulcerative colitis by dichloroacetate: Impact on NFATC1/NLRP3/IL1B signaling based on bioinformatics analysis combined with in vivo experimental verification.

The inflammatory response in ulcerative colitis (UC) could be relieved by the conventional immunomodulatory agents; 5-aminosalicylic acid, corticosteroids, or azathioprine. However, the low remission rates and the intolerance to these agents necessitate investigation of gene expression signature in UC that could influence the therapeutic efficacy of drugs, as well as the interference with persistence genes by novel therapeutic option. Three microarray datasets (GSE66407, GSE38713 and GSE14580) from the NCBI-GEO database were utilized. Differentially expressed genes between samples of patients with UC and healthy ones were analyzed using R software. In addition, in vivo study using oxazolone-induced UC in BALB/c mice was carried out to investigate the proposed therapeutic efficacy of dichloroacetate (DCA). The bioinformatics analysis revealed the persistence of NLRP3, NFATC1, and IL1B in UC despite treatment with common therapeutic agents. DCA administration to oxazolone-treated mice showed remarkable interference with those persistence genes. Western blotting analysis for NLRP3, NFATC1, nuclear/total NF-κB, and cleaved caspase-1 revealed the ability of DCA to reduce the expression levels of these proteins in oxazolone-treated mice. Additionally, the inflammatory cytokines IL-1ß and IL-13 were reduced in colonic tissue by DCA treatment. The therapeutic efficacy of DCA was further confirmed by the apparent reduction in histopathological scoring, disease activity index, and the normalization of colon length. Therefore, DCA could be suggested as a novel and promising therapeutic option in UC based on its ability to interfere with the persistence of NFATC1/NLRP3/IL1B signaling. That merits further safety/toxicological pre-clinical assessment and update of bioavailability/metabolism data prior to clinical investigation.

Unlocking the miRNA-34a-5p/TGF-ß and HMGB1/PI3K/Akt/mTOR crosstalk participate in the enhanced cardiac protection of liraglutide against isoproterenol-induced acute myocardial injury rat model.

Liraglutide (LIRA), a drug used to treat type 2 diabetes mellitus that belongs to the glucagon-like peptide-1 class, has recently drawn attention for its potential cardioprotective properties because of its anti-oxidative and anti-inflammatory properties. This current investigation was designed to assess the impact of LIRA on myocardial injury induced by isoproterenol (ISO). The experiment included 24 male Wistar rats in total, and they were divided into four groups: Control, LIRA (200 µg/kg/12 hrs., S.C.), ISO (85 mg/kg, S.C.), and ISO + LIRA. To assess the results, various biochemical and histopathological analyses were carried out. The findings showed elevated serum enzyme levels, a sign of cardiac injury. ISO-treated rats showed an upregulation of oxidative stress and inflammatory biomarkers like MDA, MPO, nitrites, NADPH oxidase, TNF-α, IL-1ß, IL-6, 8-Hydroxyguanosine (8-OHdG), and TGF-ß, as well as altered gene expressions like TLR-1 and miRNA-34a-5p. According to western blotting analysis, protein levels of AKT, PI3K, and mTOR were obviously enhanced. Additionally, ISO-treated samples showed altered tissue morphology, elevated caspase 3, and decreased Bcl2 concentrations. The levels of these dysregulated parameters were significantly normalized by LIRA therapy, demonstrating its cardioprotective function against ISO-induced myocardial injury in rats. This protective mechanism was linked to anti-inflammatory properties, redox balance restoration, and modulation of the miRNA-34a-5p/TGF-ß pathway.

Zafirlukast protects against hepatic ischemia-reperfusion injury in rats via modulating Bcl-2/Bax and NF-κB/SMAD-4 pathways.

Hepatic ischemia/reperfusion injury (IRI) is a clinical problem commonly during liver transplantation and other liver surgery. This study aimed to evaluate the protective effect of zafirlukast (ZFK) on IR-induced hepatic injury and investigate its relevant protective mechanism. Thirty-two male Wistar albino rats were randomly allocated to four groups: sham, IRI, ZFK, and ZFK + IR groups. ZFK was administered orally in a dose of 80 mg/kg/day for 10 consecutive days. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBL) levels, and gamma glutamyl transferase (GGT) activity were estimated. Liver tissues were used to assess oxidative stress biomarkers including malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NOx), and reduced glutathione (GSH) contents. Inflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-33 (IL-33), in addition to apoptosis biomarkers, BCL2 associated X protein (Bax), B-cell lymphoma 2 (Bcl2) and galactine-9 (GAL9) proteins were also assessed. Western blot analysis was performed for vascular endothelial growth factor (VEGF) and fibrinogen expressions. Immunohistochemical analysis for hepatic nuclear factor-kappa B (NF-κB) and SMAD-4 was done in addition to histopathological examination. Our study revealed that ZFK pre-treatment resulted in liver function restoration and oxidative stress correction. Moreover, inflammatory cytokines were significantly reduced and a remarkable reduction of apoptosis, angiogenesis, and clotting formation has been indicated. Additionally, a significant reduction in SMAD-4 and NF-kB protein expressions was observed. These results were supported by hepatic architecture improvement. Our findings revealed that ZFK possesses a potential protective effect against liver IR possibly through its antioxidant, anti-inflammatory and anti-apoptotic properties.

Analysis of cumulative antibiogram reports in intensive care units at an Egyptian University Hospital.

BACKGROUND: Institutions must have access to antibiograms to monitor changes in antimicrobial resistance and direct empirical antibiotic therapy. The first facility-specific cumulative antibiogram was launched in the ICU in 2019. Consequently, many antibiogram-operation-related actions have been adopted in the institution based on reported data. This study aimed to analyze the cumulative antibiogram reports for multiple intensive care units (ICUs) for 2020, and compare the antimicrobial susceptibility testing (AST) patterns between the 2019 and 2020 years in an academic medical center. METHODS: This cross-sectional study was performed of routine bacterial culture and AST data extracted from a laboratory information system in a 2252-bed capacity hospital. Only the first diagnostic isolate of a given species per patient per year was included in the study. Interpretation and reporting were done in accordance with the applicable Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing guidelines. RESULTS: Of the 46,791 clinical isolates, the Gram-negative bacilli isolation rate witnessed a significant increase: 35,670 isolates in 2020 versus. 33,652 isolates in 2019. Klebsiella pneumoniae showed a statistically significant increase, mainly in pediatric, emergency, and cardiothoracic ICUs (p < 0.001). Neonatal and pediatric ICUs showed statistically significant increases in Pseudomonas aeruginosa and Proteus mirabilis isolates (p < 0.001). A statistically significant decrease was noted in the prevalence of Acinetobacter, Escherichia coli, Burkholderia cepacia, and Enterobacter cloacae. The sensitivities of K. pneumoniae and E. coli to imipenem and tigecycline significantly improved (p < 0.001). The sensitivity to colistin was significantly decreased (p < 0.001). The sensitivity of P. aeruginosa isolates to colistin and carbapenems was improved (p < 0.001). We reported a statistically significant decrease in all Gram-positive cocci (11,121 in 2020 versus. 11,528 in 2019). Staphylococcus aureus showed a statistically significant increase (p < 0.001), particularly in the medical ICU. CONCLUSION: The high susceptibility rates of Enterobacteriaceae toward colistin and tigecycline, should be cautiously considered in empiric therapy while looking for alternatives. The majority of isolates of Gram-positive cocci were coagulase negative staphylococci (CONS), we still need to confirm whether they are true pathogens or commensals before considering anti-staphylococcal agents in the empirical therapy. We underscored some corrective actions that might have improved the susceptibility rates, such as antibiotic cycling.