Design, synthesis, and biological evaluation of some new 2-phenyl-3,6-pyridazinedione derivatives as PDE-5 inhibitors.

Various 2-phenyl-3,6-pyridazinedione derivatives 4a-j, 5a-c, 6a,b, 7a-c, 8, 9, 10a-d, and 11a-d, were effectivelysynthesized, and tested for their potential inhibition of phosphodiesterase enzyme at 10 µM. Then fourteen compounds exhibiting the highest inhibition 4b, 4d, 4e, 4g, 4h, 4i, 5a, 6a,b, 7c, 10a,b, 11a, and 11d were selected for screening their PDE-5 inhibition, where compounds 4b,g,h, and 11a revealed promising PDE-5 inhibition having IC50 values = 25, 53, 22, and 42 nM, respectively in comparison with Sildenafil (IC50 = 16 nM). Additionally, these four most active compounds were safe to normal fibroblast cell line WI-38. Moreover, 4f, 4h, 4j, 10d, and 11d had almost the same anti-proliferative effect against the aortic cell line as Sildenafil. Furthermore, molecular docking illustrated that the binding of the target compounds with the key amino acids in the binding site of PDE-5 (PDB 2H42) was like to that of the cocrystallized ligand Sildenafil. Additionally, molecular dynamics simulation for the most active compound 4h revealed high stability of the 4h -PDE5 complex explaining its promising activity as a PDE-5 inhibitor. Therefore, the 2-phenyl-3,6-pyridazinedione scaffold can be considered an important core for designing more promising PDE-5 inhibitors.

Serum plasminogen activator inhibitor-1 levels in patients with major depressive disorder vs. healthy controls: a systematic review and meta-analysis.

INTRODUCTION: Major depressive disorder (MDD) is a severe mental health condition that affects millions of people worldwide. Etiologically, several factors may play a role in its development. Previous studies have reported elevated plasminogen activator inhibitor-1 (PAI-1) levels in patients with depression, suggesting that PAI-1 levels might be linked to the etiology of MDD. METHODS: We systematically searched the following online databases: MEDLINE, Scopus, and Web of Science up to September 10, 2020, to identify studies in which PAI-1 levels were reported in subjects with MDD. Subsequently we used RevMan 5.3 to perform a meta-analysis of data extracted from the included studies using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and PICO criteria for the search and analysis. RESULTS: Six studies that reported mean ± standard deviation (SD) were included in the analysis, with a total of 507 MDD patients and 3,453 controls. The overall standardized mean difference (SMD) was 0.27 (95% confidence interval [95% CI] 0.01-0.53). PAI-1 serum levels were 0.27 SDs higher in MDD patients than in controls. The test for overall effect was significant (z = 2.04, p = 0.04). Substantial heterogeneity was detected among the studies, demonstrated by the inconsistency test (I² = 72%) and the chi-square test (χ² = 18.32; p = 0.003). CONCLUSIONS: This systematic review and meta-analysis showed that MDD might be related to elevated PAI-1 levels. We propose larger prospective clinical studies to further investigate this clinical correlation and validate the clinical significance of these observations.

Serum plasminogen activator inhibitor-1 levels in patients with major depressive disorder vs. healthy controls: a systematic review and meta-analysis

Abstract Introduction Major depressive disorder (MDD) is a severe mental health condition that affects millions of people worldwide. Etiologically, several factors may play a role in its development. Previous studies have reported elevated plasminogen activator inhibitor-1 (PAI-1) levels in patients with depression, suggesting that PAI-1 levels might be linked to the etiology of MDD. Methods We systematically searched the following online databases: MEDLINE, Scopus, and Web of Science up to September 10, 2020, to identify studies in which PAI-1 levels were reported in subjects with MDD. Subsequently we used RevMan 5.3 to perform a meta-analysis of data extracted from the included studies using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and PICO criteria for the search and analysis. Results Six studies that reported mean ± standard deviation (SD) were included in the analysis, with a total of 507 MDD patients and 3,453 controls. The overall standardized mean difference (SMD) was 0.27 (95% confidence interval [95% CI] 0.01-0.53). PAI-1 serum levels were 0.27 SDs higher in MDD patients than in controls. The test for overall effect was significant (z = 2.04, p = 0.04). Substantial heterogeneity was detected among the studies, demonstrated by the inconsistency test (I2 = 72%) and the chi-square test (χ2 = 18.32; p = 0.003). Conclusion This systematic review and meta-analysis showed that MDD might be related to elevated PAI-1 levels. We propose larger prospective clinical studies to further investigate this clinical correlation and validate the clinical significance of these observations.

Adherence to Insulin Therapy Among Children with Type 1 Diabetes: Reliability and Validity of the Arabic Version of the 4-Item Morisky Medication Adherence Scale.

Background: Inadequate adherence to insulin is a major concern, necessitating the use of reliable and valid metrics for assessing adherence. Up to date, there are no Arabic validated tools assessing adherence to insulin therapy among children with type 1 diabetes (T1DM). Thus, the aim of this study is to evaluate the psychometric properties of an Arabic version of the four-item Morisky Green Levine Medication Adherence Scale (MGLS-4) as a self-reported measure of adherence to insulin among a cohort of Egyptian children with T1DM. Methods: The MGLS-4 was translated using forward and backward translation. The Cronbach's alpha was used to assess reliability. Criterion validity of the scale was tested by examining the correlation coefficients between the compliance score (level of adherence) and the HbA1c levels. Results: A total of 400 patients completed the Arabic version of MGLS-4. 26.25% of the studied cohort was found to be non-adherent to insulin therapy; non-adherent patients were significantly older (P=0.001). Decreased maternal education level, decreased frequency of blood glucose monitoring and prolonged disease duration best predicted the occurrence of non-adherence among the studied cohort. The internal consistency of the current version showed good reliability (Cronbach's alpha = 0.857). The adherence score and adherence level showed very strong correlation with HbA1c level (rho = 0.830, P < 0.001 and rho = 0.808, P < 0.001, respectively). Conclusion: The Arabic version of MGLS-4 showed good reliability and validity as a self-administered tool for assessing adherence to insulin in pediatric patients with T1DM.

Coping strategies among children and adolescents: validity and reliability of the Arabic version of the Kidcope scale.

Coping strategies adopted by children and adolescents play a crucial role in their mental health. This study aimed to develop the Arabic version of the Kidcope, assess its psychometric properties, and examine age and gender differences in the use of coping strategies by children and adolescents. A total of 800 children and adolescents siblings of patients with type 1 Diabetes mellitus completed the Kidcope scale. The developed Arabic Kidcope was checked for its construct validity, reliability, reproducibility, and confirmed by confirmatory factor analysis (CFA). Age and gender differences in coping styles utilization were assessed by one-way analysis of variance (ANOVA) and student t tests. Kidcope chid version yielded a three factors model by exploratory factor analysis (EFA). Overall, the 15-items revealed good internal consistency, Cronbach's alpha (0.89), and an intra-class correlation coefficient (ICC) of 0.82. EFA identified a two-factor solution for adolescents' Kidcope version. Overall, the 11-items showed acceptable internal consistency, Cronbach's alpha (0.74), and satisfactory (ICC) of 0.84. For both versions, the CFA supported the yielded factors models with good model fit indices. Developmental age changes were apparent for problem-solving, emotional regulation, and distraction coping strategies, and girls showed an enhanced use of adaptive strategies (problem-solving, social support). The Arabic Kidcope version is a reliable and valid tool to measure coping strategies used by children and adolescents.

Role of metformin in suppressing 1,2-dimethylhydrazine-induced colon cancer in diabetic and non-diabetic mice: effect on tumor angiogenesis and cell proliferation.

Several studies indicated that type 2 diabetes mellitus and insulin resistance are associated with increased colon cancer risk. Recently, studies suggest that metformin can reduce cancer risk in diabetic or non-diabetic patients with unclear mechanisms. This work aimed to determine the effect of metformin on chemically-induced colon cancer in mice. Colon cancer was induced using 1,2-dimethylhydrazine (DMH, 20 mg/kg/week, s.c.) for fifteen weeks. Experiment I: healthy mice were fed with basal diet for four weeks and then allocated into seven groups, (i) saline, (ii) DMH, (iii) oxaliplatin, (iv-v): metformin (100 or 200 mg/kg) and (vi-vii): oxaliplatin+metformin (100 or 200 mg/kg), respectively. Experiment II: type 2 diabetes mellitus was induced by injection of STZ (30 mg/kg) after four weeks of high-fat feeding and then mice were allocated into seven groups similar to those reported in experiment I. Examination of the colonic tissue at the end of the experiment highlighted an increase in angiogenic markers and cell proliferation and showed a greater immunostaining for insulin growth factor I receptors and CD34 in the colon of diabetic mice compared to non-diabetics. In general, metformin downregulated tumor angiogenesis and augmented the antitumor effect of oxaliplatin. Overall, the current results showed that metformin protected against DMH-induced colon cancer in non-diabetic and diabetic mice. This therapeutic effect was, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms.