Bis-Cinnamamide Derivatives as APE/Ref-1 Inhibitors for the Treatment of Human Melanoma.

Human malignant melanoma exhibits imbalances in redox status, leading to activation of many redox-sensitive signaling pathways. APE/Ref-1 is a multifunctional protein that serves as a redox chaperone that regulates many nuclear transcription factors and is an important mechanism in cancer cell survival of oxidative stress. Previous studies showed that APE/Ref-1 is a potential druggable target for melanoma therapy. In this study, we synthesized a novel APE/Ref-1 inhibitor, bis-cinnamoyl-1,12-dodecamethylenediamine (2). In a xenograft mouse model, compound 2 treatment (5 mg/kg) significantly inhibited tumor growth compared to the control group, with no significant systemic toxicity observed. We further synthesized compound 2 analogs to determine the structure-activity relationship based on their anti-melanoma activities. Among those, 4-hydroxyphenyl derivative (11) exhibited potent anti-melanoma activities and improved water solubility compared to its parental compound 2. The IC50 of compound 11 was found to be less than 0.1 µM. Compared to other known APE/Ref-1 inhibitors, compound 11 exhibited increased potency in inhibiting melanoma proliferation. As determined by luciferase reporter analyses, compound 2 was shown to effectively inhibit H2O2-activated AP-1 transcription activities. Targeting APE/Ref-1-mediated signaling using pharmaceutical inhibitors is a novel and effective strategy for melanoma treatment with potentially high impact.

Association of acute stress with multiple sclerosis onset and relapse in Saudi Arabia.

OBJECTIVES: To determine if there is a relationship between acute stress and either the onset or relapse of multiple sclerosis (MS) and to discover how different types of acute stressors may be involved. Methods:  This study was carried out in Saudi Arabia between September 2017 and June 2018 and involved King Fahad University Hospital in Eastern province, Arfa Multiple Sclerosis Society in the Central and Western province of Saudi Arabia. A cross-sectional descriptive study was performed using an Arabic self-constructed questionnaire consisted of 4 sections: 1) demographic data and time of diagnosis; 2) emotional/psychological stressors; 3) environmental/physical stressors; and 4) 4 specific stressors measuring their effect on the severity and recurrence of attacks. Results: A total of 370 patients participated in the study. Almost half of patients reported no effect of family problems on their disease, whereas the other reported that family problems have an impact on the onset or relapse of the disease. Majority of patients reported that work and social life stressors affect the recurrence of attacks. Cold weather showed no effect on MS; however, hot weather and physical activity increased the number of attacks. Continuous thinking about social stress and problems, mood swings, and sleep deprivation showed an impact on the severity and recurrence of attacks. Financial problems showed no effect.  Conclusion: Study indicates that an association exists between acute stress and relapse in MS but not the disease onset.

Exploring Drug-Related Problems in Diabetic Patients during Ramadan Fasting in Saudi Arabia: A Mixed-Methods Study.

This study aimed to identify any drug-related problems (DRPs) in diabetic patients during Ramadan fasting in Saudi Arabia. The study used a mixed-methods approach consisting of two phases and was conducted in Makkah, Saudi Arabia from December 2017 to March 2018. The first phase of the study involved qualitative semi-structured individual interviews with diabetic patients. A 13-item questionnaire was used in the second phase to further identify DRPs in the wider population. The data was mainly presented as frequencies and percentages. Inferential statistics was performed using Statistical Package for Social Sciences (SPSS) version 21 to compare relevant variables/questions using the chi-square test. Twenty patients (10 male, 10 female) attended face-to-face interviews during the first phase of the study while 95 (40 male, 55 female) completed the questionnaire in the second phase of the study. Two possible risk factors for DRPs were identified from the qualitative data: patient-related factors, including changes in their medicine intake during fasting, and healthcare professionals-related factors, including lack of advice from healthcare professionals regarding fasting. The quantitative results indicated that 52 (54%) of the 95 participants who observed fasting reported to have changed the way they were taking their medicines. Furthermore, 41% of the participants experienced general healthcare problems such as hypoglycemia, hyperglycemia, fatigue, excessive sweating, and gastrointestinal disturbances. Healthcare professionals need to educate patients who are at risk of DRPs by providing structured education and counseling.