Colchicine effect on biomarkers of cardiac remodelling and atherosclerosis in ST-elevation myocardial infarction: A randomized controlled trial.

AIMS: Owing to its underlying inflammatory nature, atherosclerotic cardiovascular disease remains the leading global cause of mortality, particularly post-ST-elevation myocardial infarction (STEMI), a condition with significant risk for further cardiovascular events and mortality. This study aimed to investigate colchicine's effect on inflammation, cardiac remodelling and atherosclerotic risk in STEMI patients. METHODS: We conducted a randomized controlled study on 88 STEMI patients undergoing percutaneous coronary intervention. Eligible patients were randomly assigned to 1 of 2 groups. The control group received the guideline-directed medical therapy for STEMI, and the test group received guideline-directed medical therapy and 0.5 mg colchicine twice daily for 3 months. The soluble suppressor of tumorigenicity (sST2), interleukin-1ß, lipid profile parameters, triglyceride (TG)/high-density lipoprotein (HDL-C) ratio levels and left ventricular ejection fraction were evaluated for patients at baseline and the end of the 3 months. RESULTS: No significant effects were reported for colchicine on sST2, interleukin-1ß levels or left ventricular ejection fraction. Colchicine significantly lowered TG levels vs. controls, 134 (46-353) vs. 176 (72-825) respectively, P = .02, as well as TG/HDL-C ratio levels, 4.16 (2.75-5.24) vs. 5.11 (3.51-8.33),` respectively, P = .024. sST2 levels of the studied cohort were positively correlated with their TG/HDL-C ratio levels (R = .459, P < .001) at the end of follow-up. CONCLUSION: Our study highlights a promising impact of colchicine on atherosclerosis and cardiac remodelling factors in STEMI patients. Colchicine significantly reduced TG levels and TG/HDL-C ratio and was safe and well tolerated. Larger long-term studies powered to assess clinical outcomes of remodelling are necessary to confirm its beneficial effects in STEMI. GOV REGISTRATION ID: NCT06054100.

Genetic characterization of a novel Salinicola salarius isolate applied for the bioconversion of agro-industrial wastes into polyhydroxybutyrate.

BACKGROUND: Polyhydroxybutyrate (PHB) has emerged as a promising eco-friendly alternative to traditional petrochemical-based plastics. In the present study, we isolated and characterized a new strain of Salinicola salarius, a halophilic bacterium, from the New Suez Canal in Egypt and characterized exclusively as a potential PHB producer. Further genome analysis of the isolated strain, ES021, was conducted to identify and elucidate the genes involved in PHB production. RESULTS: Different PHB-producing marine bacteria were isolated from the New Suez Canal and characterized as PHB producers. Among the 17 bacterial isolates, Salinicola salarius ES021 strain showed the capability to accumulate the highest amount of PHB. Whole genome analysis was implemented to identify the PHB-related genes in Salinicola salarius ES021 strain. Putative genes were identified that can function as phaCAB genes to produce PHB in this strain. These genes include fadA, fabG, and P3W43_16340 (encoding acyl-CoA thioesterase II) for PHB production from glucose. Additionally, phaJ and fadB were identified as key genes involved in PHB production from fatty acids. Optimization of environmental factors such as shaking rate and incubation temperature, resulted in the highest PHB productivity when growing Salinicola salarius ES021 strain at 30°C on a shaker incubator (110 rpm) for 48 h. To maximize PHB production economically, different raw materials i.e., salted whey and sugarcane molasses were examined as cost-effective carbon sources. The PHB productivity increased two-fold (13.34 g/L) when using molasses (5% sucrose) as a fermentation media. This molasses medium was used to upscale PHB production in a 20 L stirred-tank bioreactor yielding a biomass of 25.12 g/L, and PHB of 12.88 g/L. Furthermore, the produced polymer was confirmed as PHB using Fourier-transform infrared spectroscopy (FTIR), gas chromatography-mass spectroscopy (GC-MS), and nuclear magnetic resonance spectroscopy (NMR) analyses. CONCLUSIONS: Herein, Salinicola salarius ES021 strain was demonstrated as a robust natural producer of PHB from agro-industrial wastes. The detailed genome characterization of the ES021 strain presented in this study identifies potential PHB-related genes. However, further metabolic engineering is warranted to confirm the gene networks required for PHB production in this strain. Overall, this study contributes to the development of sustainable and cost-effective PHB production strategies.

Long-Term Outcome of Transcutaneous Posterior Tibial Nerve Stimulation in the Treatment of Functional Non-Retentive Fecal Incontinence in Children.

BACKGROUND: Functional non-retentive fecal incontinence (FNRFI) is a psychologically upsetting and embarrassing issue and affects children's quality of life negatively. AIM OF THIS STUDY: Evaluation of the short and long-term effect of Bilateral transcutaneous posterior tibial nerve stimulation (BTPTNS) in the treatment of FNRFI in children and its impact on the quality of life (QoL). Methodology: The current randomized controlled study included 94 Children with FNRFI who were randomly allocated into two equal groups. Group A received BTPTNS and Group B Received Sham BTPTNS. Follow-up was planned for 24 months for manometric findings, incontinence score, Incontinence episodes, and the QoL. RESULTS: The incontinence score was significantly decreases in Group A more than what was reported in Group B at 6, 12, 24 months follow up . In group A 53.2% of the included children who received BTPTNS showed a decrease in the incontinence episodes more than 75% and among them, 23.4% were fully continent. All the QoL domains were significantly improved in Group A after 6, 12, and 24 months when compared with Group B. CONCLUSION: BTPTNS can be a good modality in the treatment of FNRFI with favorable long-term maintenance of its effect together with a remarkable positive impact on all domains of QoL.

Performance of microbial inoculation and tricalcium phosphate on nitrogen retention and conversion: Core microorganisms and enzyme activity during kitchen waste composting.

The substantial release of NH3 during composting leads to nitrogen (N) losses and poses environmental hazards. Additives can mitigate nitrogen loss by adsorbing NH3/NH4, adjusting pH, and enhancing nitrification, thereby improving compost quality. Herein, we assessed the effects of combining bacterial inoculants (BI) (1.5%) with tricalcium phosphate (CA) (2.5%) on N retention, organic N conversion, bacterial biomass, functional genes, network patterns, and enzyme activity during kitchen waste (KW) composting. Results revealed that adding of 1.5%/2.5% (BI + CA) significantly (p < 0.05) improved ecological parameters, including pH (7.82), electrical conductivity (3.49 mS/cm), and N retention during composting. The bacterial network properties of CA (265 node) and BI + CA (341 node) exhibited a substantial niche overlap compared to CK (210 node). Additionally, treatments increased organic N and total N (TN) content while reducing NH4+-N by 65.42% (CA) and 77.56% (BI + CA) compared to the control (33%). The treatments, particularly BI + CA, significantly (p < 0.05) increased amino acid N, hydrolyzable unknown N (HUN), and amide N, while amino sugar N decreased due to bacterial consumption. Network analysis revealed that the combination expanded the core bacterial nodes and edges involved in organic N transformation. Key genes facilitating nitrogen mediation included nitrate reductase (nasC and nirA), nitrogenase (nifK and nifD), and hydroxylamine oxidase (hao). The structural equation model suggested that combined application (CA) and microbial inoculants enhance enzyme activity and bacterial interactions during composting, thereby improving nitrogen conversion and increasing the nutrient content of compost products.

Impact of implementing virtual journal club on developing competencies for critical appraisal among post-graduate nursing students.

BACKGROUND: Virtual journal clubs (VJCs) are innovative technologies with the potential to foster collaboration, facilitate multilingual communication, improve cultural competencies, and expand global professional networks. This allowed participants to be exposed to critical appraisal of the articles. However, its long-term impact on competency development has been debated. This study aimed to investigate the impact of implementing VJCs on developing competencies for critical appraisal among postgraduate nursing students. METHODS: A quasi-experimental (pretest/posttest one-group) research design was used with a convenience sample of 40 participants from the community health nursing department, Faculty of Nursing, Mansoura University, Egypt who agreed to participate. The participants received an online self-administered knowledge and attitude data collection tool through Google Forms. However, critical appraisal skills were evaluated by an observational checklist with a rubric through synchronized mode. Eleven VJC sessions were conducted for each participant. Descriptive analysis served as the primary method for analyzing participants' responses. Students' t-test and one-way analysis of variance (ANOVA) were used to measure differences between the pretest and post-test. The study also used a correlation test to assess the relationship of variables. RESULTS: The findings indicated a highly statistically significant difference among the participants regarding knowledge, critical appraisal skills, and attitudes toward VJC before, immediately, and six months after VJC session implementation. In addition, a positive significant correlation with a highly statistically significant difference between the participants' total knowledge score levels, total practice score levels, and total attitude score levels in the immediate post and after six months of VJC session implementation (p < 0.001). CONCLUSION: The findings indicate this intervention has the potential to enhance critical appraisal competencies among postgraduate students. Therefore, VJCs should be included regularly to enhance critical appraisal competencies in academic settings for continued professional development.

Association of single nucleotide polymorphisms in Neuropeptide Y (NPY) and Phosphoglycerate Mutase 2 (PGAM2) genes with growth traits in rabbits.

Genetic improvement of local rabbit breeds using modern approaches such as marker-assisted selection requires accurate and precise information about marker‒trait associations in animals with different genetic backgrounds. Therefore, this study was designed to estimate the association between two mutations located in the Neuropeptide Y (NPY, g.1778G > C) and Phosphoglycerate Mutase 2 (PGAM2, c.195 C > T) genes in New Zealand White (NZW), Baladi (BR), and V-line rabbits. The first mutation was genotyped using high-resolution melting, and the second mutation was genotyped using the PCR-RFLP method. The results revealed significant associations between the NPY mutation and body weight at 10 (V-line) and 12 weeks of age (NZW, BR, and V-line), body weight gain (BWG) from 10 to 12 weeks of age (BR), BWG from 6 to 12 weeks of age (NZW, BR, and V-line), average daily gain (NZW, BR, and V-line, and BR), growth rate (GR) from 8 to10 weeks (V-line), 10 to 12 weeks (BR), and GR from 6 to 12 weeks of age (BR, and V-line). The PGAM2 mutation was associated with body weight at 10 (V-line) and 12 (NZW, and V-line) weeks of age, with significant positive additive effects at 12 weeks of age in all breeds, and was associated with BWG from 8 to 10 and 10 to 12 in BR, and BWG from 6 to 12 weeks of age (NZW, and BR), and average daily gain (NZW, and BR), and was associated with GR form 8 to 10 weeks (BR), from10 to 12 weeks (BR, and V-line) and from 6 to 12 weeks (BR). The results highlighted the importance of the two mutations in growth development, and the possibility of considering them as candidate genes for late growth in rabbits.

Selenomethionine mis-incorporation and redox-dependent voltage-gated sodium channel gain of function.

Selenomethionine (SeMet) readily replaces methionine (Met) residues in proteins during translation. Long-term dietary SeMet intake results in the accumulation of the amino acid in tissue proteins. Despite the high rates of SeMet incorporation in proteins and its stronger susceptibility to oxidation compared to Met, little is known about the effect of SeMet mis-incorporation on electrical excitability and ion channels. Fast inactivation of voltage-gated sodium (NaV ) channels is essential for exact action potential shaping with even minute impairment of inactivation resulting in a plethora of adverse phenotypes. Met oxidation of the NaV channel inactivation motif (Ile-Phe-Met) and further Met residues causes a marked loss of inactivation. Here, we examined the impact of SeMet mis-incorporation on the function of NaV channels. While extensive SeMet incorporation into recombinant rat NaV 1.4 channels preserved their normal function, it greatly sensitized the channels to mild oxidative stress, resulting in loss of inactivation and diminished maximal current, both reversible by dithiothreitol-induced reduction. SeMet incorporation similarly affected human NaV 1.4, NaV 1.2, NaV 1.5, and NaV 1.7. In mouse dorsal root ganglia (DRG) neurons, 1 day of SeMet exposure exacerbated the oxidation-mediated broadening of action potentials. SeMet-treated DRGs also exhibited a stronger increase in the persistent NaV current in response to oxidation. SeMet incorporation in NaV proteins coinciding with oxidative insults may therefore result in hyperexcitability pathologies, such as cardiac arrhythmias and neuropathies, like congenital NaV channel gain-of-function mutations.

Novel N-Arylmethyl-aniline/chalcone hybrids as potential VEGFR inhibitors: synthesis, biological evaluations, and molecular dynamic simulations.

Significant advancements have been made in the domain of targeted anticancer therapy for the management of malignancies in recent times. VEGFR-2 is characterised by its pivotal involvement in angiogenesis and subsequent mechanisms that promote tumour cells survival. Herein, novel N-arylmethyl-aniline/chalcone hybrids 5a-5n were designed and synthesised as potential anticancer and VEGFR-2 inhibitors. The anticancer activity was evaluated at the NCI-USA, resulting in the identification of 10 remarkably potent molecules 5a-5j that were further subjected to the five-dose assays. Thereafter, they were explored for their VEGFR-2 inhibitory activity where 5e and 5h emerged as the most potent inhibitors. 5e and 5h induced apoptosis with cell cycle arrest at the SubG0-G1 phase within HCT-116 cells. Moreover, their impact on some key apoptotic genes was assessed, suggesting caspase-dependent apoptosis. Furthermore, molecular docking and molecular dynamics simulations were conducted to explore the binding modes and stability of the protein-ligand complexes.

Novel hydrazone-isatin derivatives as potential EGFR inhibitors: Synthesis and in vitro pharmacological profiling.

Merging isatin and arylhydrazone moieties constitutes an efficient strategy to access new potential anticancer derivatives. Consequently, 14 hydrazone-isatin derivatives were synthesized and evaluated for their antiproliferative activity against the NCI-60 cancer cell line panel. A kinase assay demonstrated that compound VIIIb inhibited the epidermal growth factor receptor (EGFR), which was confirmed by docking studies, molecular dynamics, and binding free energy calculations. Further characterizations showed that this compound possesses drug-likeness properties, showed a significant decrease of the cell population in the G2/M phase and led to a significant increase in early and late apoptosis, comparable to erlotinib. Also, VIIIb increased the expression of caspase-3 and Bax and decreased the expression of Bcl-2, confirming its potential as a new proapoptotic compound.

Physicians' adherence to evidence-based guidelines as a major predictor of anticoagulant-related medication error incidence and severity.

AIMS: Anticoagulants represent a main source of medication errors (MEs) and complications that have catastrophic implications, posing an obligation on health care providers to assess anticoagulant-related MEs and factors affecting their occurrence. This study investigates the occurrence and severity of prescribing MEs in patients on anticoagulants and explores their potential predictors. METHODS: This study was a prospective cohort study in a tertiary hospital on 116 patients with a total of 2166 anticoagulant doses. RESULTS: Forty-four percent of prescribed anticoagulant doses resulted in MEs with low molecular weight heparin (LMWH) and unfractionated heparin (UFH) causing 61% and 34%, respectively, of the total MEs. More than 50% of all MEs were incorrect doses (high and low) shared between heparin and tinzaparin. The highest severity of error was Category D followed by Category F and Category C. A Poisson regression analysis model revealed that female (incidence rate ratio [IRR] 1.32, 95% confidence interval [CI] 1.13-1.54, P < .001), bridging (IRR 1.52; 95% CI 1.10-2.09; P = .011), venous thromboembolism (VTE) prophylaxis (IRR 7.65; 95% CI 4.88-12.02; P < .001), physician non-adherence (IRR 2.71; 95% CI 2.22-3.29; P < .001), and polypharmacy (IRR 1.68; 95% CI 1.26-2.23; P = .036) were predictors of the higher incidence of MEs. Ordinal logistic regression analysis demonstrated that physician non-adherence (OR 24.67; 95% CI 5.54-207; P < .001) was the main predictor of increased error severity. CONCLUSION: The major predictor in increasing both the incidence and severity of MEs is physician adherence to evidence-based guidelines (EBG). Strict regulations for anticoagulant prescribing through an anticoagulant stewardship program are a necessity.

Development of a loop-mediated isothermal amplification (LAMP) assay for molecular identification of Trueperella abortisuis isolated from pigs.

The first description of Trueperella (T.) abortisuis was presented in Japan in 2009 by Azuma and colleagues. In the current study, eight T. abortisuis strains were identified by a newly developed loop-mediated isothermal amplification (LAMP) assay based on the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) encoding gene gap. Two T. abortisuis strains were obtained from prepuce of a seven-month-old boar and pooled foetal stomach contents in the United Kingdom, while the other six T. abortisuis strains were recovered from aborted foetal material of six pigs from a single farm in Germany. The developed LAMP assay showed an analytical sensitivity of 22 pg µL-1T. abortisuis DNA. T. abortisuis DSM 19515T and field strain T. abortisuis P504054/19/1 were directly detectable in artificially contaminated vaginal swabs up to concentrations of 980 CFU and 770 CFU per swab, respectively. There was no cross reactivity with control strains representing six species of genus Trueperella and six species of the closely related genus Arcanobacterium and Schaalia (Actinomyces) hyovaginalis. Further field research is required to determine the usefulness of the designed LAMP assay for identifying T. abortisuis isolated from pigs of various origins and from test samples directly obtained at farm level.

3-Substituted-2,3-Dihydrothiazole as a promising scaffold to design EGFR inhibitors.

The overexpression of EGFR has been recognized as the driver mechanism in the development of several human malignancies and the clinical use of EGFR inhibitors currently constitutes the standard of care for a wide range of malignancies, including colorectal cancer. However, the clinical efficacy of EGFR targeted inhibitors is limited by the development of intrinsic or acquired resistance, requiring the discovery of new compounds with different structural characteristics from those already developed. In this context, we explored the replacement of the aminoquinazoline pharmacophore of several FDA-approved EGFR inhibitors by its bioisosteric hydrazinothiazole moiety. A series of 14 new compounds were designed, synthesized, and evaluated as potential EGFR inhibitors. Compound 5i was active against 12 different cell lines in the NCI-60 cell line panel and showed an IC50 of 6.9 ± 0.013 µM against HCT-116 cells, with no significant toxicity against normal human fibroblasts (WI-38). Further studies showed that this compound showed submicromolar activity against EGFR and was able to induce tumor cell cycle arrest and cell apoptosis. Additionally, docking experiments, molecular dynamics and binding free energy calculations were performed and confirmed the potential of 2-hydrazino-2,3-dihydrothiazole derivatives as new EGFR inhibitors.

Validity of B-Type Natriuretic Peptide, Growth Differentiation Factor 15, and High-Sensitivity Troponin I Levels in Ischemic Heart Failure.

BACKGROUND: Heart failure (HF) is a major medical, and epidemiological problems with ischemic heart disease (IHD) is the most common cause of HF. We aimed to assess the plasma B-type natriuretic peptide (BNP) levels, serum growth differentiation factor 15 (GDF15), and high-sensitivity troponin I (hsTnI) in HF patients with and without IHD. METHODS: The study included 120 HF patients, categorized into 51 patients with IHD and 69 patients without apparent IHD. Clinical and echocardiographic assessments of the included patients were performed. ELISA assays of plasma BNP and serum GDF15 were done, while serum hsTnI was measured using chemiluminescent immunoassay. RESULTS: There were significantly higher median values of serum levels for GDF15 (pg/mL) and hsTnI (pg/mL) among IHD group (1,630.5 and 141.8, respectively) compared to non-IHD group (895 and 14.3, respectively, p ˂ 0.05 for both), with non-significant differences regarding to the BNP plasma levels (p ˃ 0.05). In the IHD group, significant positive correlations were observed between GDF15 with both BNP (r = 0.655, p = < 0.001) and hsTnI (r = 0.496, p = < 0.001). Serum GDF15 at a cutoff of ≤ 717 pg/mL has the highest specificity [85.51% vs. 50.72% for BNP (at cutoff > 264 pg/mL) and 59.42% for hsTnI]. Additionally, hsTnI at a cutoff of > 45.2 pg/mL has the highest sensitivity (70.59% vs. 68.63% for BNP and 33.33% for GDF15) in discriminating heart failure with IHD from heart failure without IHD. CONCLUSIONS: A multimarker approach, particularly GDF15 and hsTnI, is helpful in identifying HF patients with underlying IHD, thus enabling their proper management.

Anti-Cryptosporidium efficacy of Citrus sinensis peel extract: Histopathological and ultrastructural experimental study.

BACKGROUND: Cryptosporidiosis is a crucial zoonotic global health concern which can be treated by alternative medicinal plants extracts. AIM OF THE STUDY: The study was carried out to assess the therapeutic efficacy of Citrus sinensis peel ethanolic extract on Cryptosporidium-infected mice. METHODS: Two doses of Citrus sinensis extract; high dose (30 mg/kg) and low dose (15 mg/kg) were investigated compared to the common commercial drug nitazoxanide (NTZ). Assessment of the extract was carried out by calculating oocysts count in fecal samples, in addition to histopathological and electron microscopic examination of intestinal mucosa.. RESULTS: There was a statistically significant reduction in the percentage of oocyst shedding more in high dose than low dose Citrus-treated mice group till negligible numbers of oocysts were found at day 22nd post infection. Histopathologically, the intestinal tissues from high dose Citrus-treated group showed improvement of the pathological changes, the villi retained their normal appearance with minimal inflammatory cells in comparison to infected control mice groups. Also, ultra-structurally, the high dose Citrus-treated mice showed few Cryptosporidium trophozoites, while moderate number of parasitic stages and mucous in the low dose Citrus-treated mice, and large numbers of parasitic stages with sever mucous in the control infected non-treated mice epithelium. CONCLUSION: Our study established for the first time that Citrus sinensis is a promising natural candidate that could be efficiently used for developing of new anti-cryptospordial drugs.

Design, synthesis, molecular modeling and biological evaluation of novel Benzoxazole-Benzamide conjugates via a 2-Thioacetamido linker as potential anti-proliferative agents, VEGFR-2 inhibitors and apoptotic inducers.

A novel series of 2-thioacetamide linked benzoxazole-benzamide conjugates 1-15 was designed as potential inhibitors of the vascular endothelial growth factor receptor-2 (VEGFR-2). The prepared compounds were evaluated for their potential antitumor activity and their corresponding selective cytotoxicity was estimated using normal human fibroblast (WI-38) cells. Compounds 1, 9-12 and 15 showed good selectivity and displayed excellent cytotoxic activity against both HCT-116 and MCF-7 cancer cell lines compared to sorafenib, used as a reference compound. Furthermore, compounds 1 and 11 showed potent VEGFR-2 inhibitory activity. The cell cycle progression assay showed that 1 and 11 induced cell cycle arrest at G2/M phase, with a concomitant increase in the pre-G1 cell population. Further pharmacological studies showed that 1 and 11 induced apoptosis and inhibited the expression of the anti-apoptotic Bcl-2 and Bcl-xL proteins in both cell lines. Therefore, compounds 1 and 11 might serve as promising candidates for future anticancer therapy development.

Cell viability assay as a tool to study activity and inhibition of hepatitis C p7 channels.

The p7 viroporin of the hepatitis C virus (HCV) forms an intracellular proton-conducting transmembrane channel in virus-infected cells, shunting the pH of intracellular compartments and thus helping virus assembly and release. This activity is essential for virus infectivity, making viroporins an attractive target for drug development. The protein sequence and drug sensitivity of p7 vary between the seven major genotypes of the hepatitis C virus, but the essential channel activity is preserved. Here, we investigated the effect of several inhibitors on recombinant HCV p7 channels corresponding to genotypes 1a-b, 2a-b, 3a and 4a using patch-clamp electrophysiology and cell-based assays. We established a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-based cell viability assay for recombinant p7 expressed in HEK293 cells to assess channel activity and its sensitivity to inhibitors. The results from the cell viability assay were consistent with control measurements using established assays of haemadsorption and intracellular pH, and agreed with data from patch-clamp electrophysiology. Hexamethylene amiloride (HMA) was the most potent inhibitor of p7 activity, but possessed cytotoxic activity at higher concentrations. Rimantadine was active against p7 of all genotypes, while amantadine activity was genotype-dependent. The alkyl-chain iminosugars NB-DNJ, NN-DNJ and NN-DGJ were tested and their activity was found to be genotype-specific. In the current study, we introduce cell viability assays as a rapid and cost-efficient technique to assess viroporin activity and identify channel inhibitors as potential novel antiviral drugs.

Impact of lipophilic vs hydrophilic statins on the clinical outcome and biomarkers of remodelling in heart failure patients: A prospective comparative randomized study.

AIMS: There are insufficient direct comparative studies addressing the impact of the type of statin on their respective efficacy in heart failure (HF). The aim of the current study was to compare the effects of lipophilic (atorvastatin) vs hydrophilic (rosuvastatin) on left ventricular function, inflammatory and fibrosis biomarkers in patients with chronic HF. METHODS: This was a prospective, randomized, comparative, parallel study. A total of 85 patients with chronic HF optimized on guideline directed therapy were randomized to receive either atorvastatin 40 mg (n = 42) or rosuvastatin 20 mg (n = 43) for 6 months. Baseline and follow-up assessment included 2D echocardiography, measurement of N-terminal pro-brain natriuretic peptide, interleukin-6 and soluble suppression of tumorigenicity 2 (sST2) levels, liver enzymes and lipid profile. RESULTS: The increase in left ventricular ejection fraction was significantly higher in the atorvastatin group compared to the rosuvastatin group (6.5% [3-11] vs 4% [2-5], P = .006). The reduction in left ventricular end diastolic and end systolic volume was comparable between the 2 groups. The decrease in sST2 levels in pg/mL was significantly higher in the atorvastatin compared to the rosuvastatin group (-255 [-383 to -109.8 vs - 151 [-216 to -69], P = .003). There was a significant reduction in N-terminal pro-brain natriuretic peptide and interleukin-6 levels in both groups, yet the reduction was comparable in both groups. CONCLUSION: The study results suggest that lipophilic atorvastatin is superior to hydrophilic rosuvastatin in increasing left ventricular ejection fraction and reducing fibrosis marker sST2 in HF patients. Trial registration ID: NCT03255044, registered on 21 August 2017.

Edaravone mitigates hemorrhagic cystitis by modulating Nrf2, TLR-4/NF-κB, and JAK1/STAT3 signaling in cyclophosphamide-intoxicated rats.

Hemorrhagic cystitis is a potentially deadly complication associated with radiation therapy and chemotherapy. This study explored the protective effect of edaravone (ED) on cyclophosphamide (CP)-induced hemorrhagic cystitis, oxidative stress, and inflammation in rats. The animals received 20 mg/kg ED for 10 days and a single injection of 200 mg/kg CP on day 7. CP induced tissue injury manifested by the diffuse necrotic changes, disorganization of lining mucosa, focal hemorrhagic patches, mucosal/submucosal inflammatory cells infiltrates, and edema. CP increased malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-alpha, and interleukin 6 (IL-6), decreased IL-10, and upregulated toll-like receptor 4 (TLR-4), nuclear factor-kappa B (NF-κB) p65, Janus kinase 1 (JAK1), and signal transducer and activator of transcription 3 (STAT3) in the urinary bladder of rats. ED effectively prevented the histopathological alterations, decreased MDA, NO, and inflammatory mediators, and downregulated TLR-4, NF-κB, JAK1, and STAT3 in CP-induced rats. Treatment with ED upregulated ikß kinase ß, IL-10, nuclear factor-erythroid 2 related factor 2 (Nrf2), and cytoglobin, and boosted glutathione, superoxide dismutase, and glutathione S-transferase. Molecular docking simulations revealed the ability of ED to bind TLR-4, NF-κB, JAK1, and STAT3. In vitro, ED increased the cytotoxic activity of CP against HeLa, Caco-2, and K562 cell lines. In conclusion, ED prevented CP-induced hemorrhagic cystitis in rats by attenuating oxidative stress, suppressing TLR-4/NF-κB, and JAK1/STAT3 signaling and boosted Nrf2, cytoglobin, and antioxidants.

Discovery of pyridine- sulfonamide hybrids as a new scaffold for the development of potential VEGFR-2 inhibitors and apoptosis inducers.

New sulfonamide derivatives have been synthesized and tested as antitumor agents. All newly synthesized compounds were tested in vitro against 60 lines of human cancer cells. Compound VIIb shows broad-spectrum activity with a mean inhibition value of 91.67% against all cell lines. It exhibited potent anticancer activity with GI50 values of 1.06-8.92 µM relative to most of the tested cancer cell lines. Compound VIIb has been tested for enzyme inhibition activity toward vascular endothelial growth factor receptor 2, where VEGFR-2 was potently inhibited at a lower IC50 value of 3.6 µM, compared with sorafenib (IC50 = 4.8 µM). Hybrid VIIb was also able to induce cell cycle disturbance and apoptosis in Renal UO-31 cells, as shown by DNA flow cytometry and Annexin V-FITC/PI assays. It has also revealed lower Bcl-2 protein expression anti-apoptotic levels and higher BAX, p53, and caspases 3 expression levels.

Development of pyridazine derivatives as potential EGFR inhibitors and apoptosis inducers: Design, synthesis, anticancer evaluation, and molecular modeling studies.

Novel hybrids of pyridazine-pyrazoline were synthesized aiming to develop new antiproliferative candidates. All compounds were submitted to the National Cancer Institute (NCI), USA, and many were proved to have significant antiproliferative activity. In addition, in vitro studies of the epidermal growth factor receptor (EGFR) inhibition showed that compounds IXn, IXg, IXb and IXl exhibited excellent inhibitory effect (IC50 = 0.65, 0.75, 0.82 and 0.84 µM, respectively) compared to Erlotinib (IC50 = 0.95 µM). The mechanistic effectiveness in cell cycle progression, apoptotic induction and gene regulation were assessed for the promising compounds IXg and IXn due to their significant EGFR inhibition. Flow cytometeric analysis indicated that compounds IXg and IXn result in increased cell numbers in phase G2/M, suggesting cell cycle arrest in phase G2/M in UO-31cells. Furthermore, real time PCR assay illustrated that compounds IXg and IXn elevated Bax/Bcl2 ratio which confirmed the mechanistic pathway of them. Moreover, the apoptotic induction of UO-31 renal cancer cells was enhanced effectively through activation of caspase-3 by compounds IXg and IXn. On the other hand, molecular docking study was performed to investigate binding mode of interaction of compounds with EGFR-PK in the active site with the aim of rationalizing its promising inhibitory activity. Finally, based on the aforementioned findings, compounds IXg and IXn could be considered as effective apoptosis modulators and promising leads for future development of new anti-renal cancer agents.