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Aims Cardiovascular side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs), which all inhibit cyclooxygenase (COX)-2, have prevented development of new drugs that target prostaglandins to treat inflammation and cancer. Microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors have efficacy in the NSAID arena but their cardiovascular safety is not known. Our previous work identified asymmetric dimethylarginine (ADMA), an inhibitor of eNOS, as a potential biomarker of cardiovascular toxicity associated with blockade of COX-2. Here we have used pharmacological tools and genetically modified mice to delineate mPGES-1 and COX-2 in the regulation of ADMA. Methods and Results Inhibition of COX-2 but not mPGES-1 deletion resulted in increased plasma ADMA levels. mPGES-1 deletion but not COX-2 inhibition resulted in increased plasma prostacyclin levels. These differences were explained by distinct compartmentalisation of COX-2 and mPGES-1 in the kidney. Data from prostanoid synthase/receptor knockout mice showed that the COX-2/ADMA axis is controlled by prostacyclin receptors (IP and PPARβ/δ) and the inhibitory PGE2 receptor EP4, but not other PGE2 receptors. Conclusions These data demonstrate that inhibition of mPGES-1 spares the renal COX-2/ADMA pathway and define mechanistically how COX-2 regulates ADMA.

Our aim was to assess sleep quality in different subgroups of preclinical medical students, and then to identify specific lifestyle factors, academic and social factors as well as Corona virus related factors that were associated with poor sleeping quality and poor psychological health. Study participants were all medical students at King Saud University of Medical Sciences in the first and second years (648 students), and the study was conducted from December 2021 to January 2022. We administered the survey on paper as well as online. We used three types of questionnaires in this study. The first was a self-administered questionnaire, the second was a validated Insomnia Severity Index (ISI) for finding sleeping problems, and the third was a validated DASS 10 for determining Depression, Anxiety, and Stress. A total of 361 pre-clinical medical students consisted of 146 (40.4%) males and 215 (59.5%) females. The majority of the students, 246 (68.1%), were in their second year. Furthermore, in the current study, students who had poor academic performance (15.8%), satisfactory academic performance (21.3%), or good academic performance (30.7%) had significant sleeping problems found (χ2 = 19.4; p = 0.001), among them poor academic performance students 21.6%, satisfactory academic performance students (29.3%), and good academic performance students (29.3%) had moderate to severe levelled sleeping problems. Similarly, poor, satisfactory, and good academic performers experienced the highest levels of anxiety (poor = 21.5%; satisfactory = 22.1%; and good = 22.8%); stress (poor = 22.4%; satisfactory = 25.2%; and good = 22.4%); and depression (poor = 40.5%; satisfactory = 40.5%; and good = 11.9%). The majority of students (64.8%) reported that during the pandemic crisis their anxiety levels were high. Additionally, students reported significantly high sleeping issues (χ2 = 10.6; p = 0.001) and also serious psychological issues (Anxiety = 34.9 (0.000); Stress = 32.5 (0.000); and Depression = 5.42 (0.01)). There was a high prevalence of sleep issues, anxiety, stress, and depression among the pre-clinical medical students, with significantly higher sleeping disorders, anxiety, stress, and depression levels among those medical students who struggle with their academic performances, poor lifestyle factor, and poor Social and COVID management.