Luteolin Protects Against 6-Hydoroxydopamine-Induced Cell Death via an Upregulation of HRD1 and SEL1L.

Parkinson's Disease (PD) is caused by many factors and endoplasmic reticulum (ER) stress is considered as one of the responsible factors for it. ER stress induces the activation of the ubiquitin-proteasome system to degrade unfolded proteins and suppress cell death. The ubiquitin ligase 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation 1 (HRD1) and its stabilizing molecule, the suppressor/enhancer lin-12-like (SEL1L), can suppress the ER stress via the ubiquitin-proteasome system, and that HRD1 can also suppress cell death in familial and nonfamilial PD models. These findings indicate that HRD1 and SEL1L might be key proteins for the treatment of PD. Our study aimed to identify the compounds with the effects of upregulating the HRD1 expression and suppressing neuronal cell death in a 6-hydroxydopamine (6-OHDA)-induced cellular PD model. Our screening by the Drug Gene Budger, a drug repositioning tool, identified luteolin as a candidate compound for the desired modulation of the HRD1 expression. Subsequently, we confirmed that low concentrations of luteolin did not show cytotoxicity in SH-SY5Y cells, and used these low concentrations in the subsequent experiments. Next, we demonsrated that luteolin increased HRD1 and SEL1L mRNA levels and protein expressions. Furthermore, luteolin inhibited 6-OHDA-induced cell death and suppressed ER stress response caused by exposure to 6-OHDA. Finally, luteolin did not reppress 6-OHDA-induced cell death when expression of HRD1 or SEL1L was suppressed by RNA interference. These findings suggest that luteolin might be a novel therapeutic agent for PD due to its ability to suppress ER stress through the activation of HRD1 and SEL1L.

MicroRNA-101 Regulates 6-Hydroxydopamine-Induced Cell Death by Targeting Suppressor/Enhancer Lin-12-Like in SH-SY5Y Cells.

Endoplasmic reticulum (ER) stress has been reported as a cause of Parkinson's disease (PD). We have previously reported that the ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and its stabilizing factor suppressor/enhancer lin-12-like (SEL1L) participate in the ER stress. In addition, we recently demonstrated that neuronal cell death is enhanced in the cellular PD model when SEL1L expression is suppressed compared with cell death when HRD1 expression is suppressed. This finding suggests that SEL1L is a critical key molecule in the strategy for PD therapy. Thus, investigation into whether microRNAs (miRNAs) regulate SEL1L expression in neurons should be interesting because relationships between miRNAs and the development of neurological diseases such as PD have been reported in recent years. In this study, using miRNA databases and previous reports, we searched for miRNAs that could regulate SEL1L expression and examined the effects of this regulation on cell death in PD models created by 6-hydroxydopamine (6-OHDA). Five miRNAs were identified as candidate miRNAs that could modulate SEL1L expression. Next, SH-SY5Y cells were exposed to 6-OHDA, following which miR-101 expression was found to be inversely correlated with SEL1L expression. Therefore, we selected miR-101 as a candidate miRNA for SEL1L modulation. We confirmed that miR-101 directly targets the SEL1L 3' untranslated region, and an miR-101 mimic suppressed the 6-OHDA-induced increase in SEL1L expression and enhanced cell death. Furthermore, an miR-101 inhibitor suppressed this response. These results suggest that miR-101 regulates SEL1L expression and may serve as a new target for PD therapy.

Impact of physician-pharmacist collaborative protocol-based pharmacotherapy management for HIV outpatients: a retrospective cohort study.

BACKGROUND: Effective treatment for human immunodeficiency virus (HIV) infection requires close cooperation among healthcare professionals. This is because maintaining continuity with treatment regimens is important in anti-HIV therapy. In addition, explaining medication use is more important than that for other diseases. Since 2010, pharmacists at the Mie University Hospital have been interviewing patients, selecting drugs, and formulating medication plans for HIV-positive patients. In August 2011, we established the physician and pharmacist-led collaborative Protocol-based Pharmacotherapy Management (PBPM) to increase the efficacy and safety of treatment, while reducing the burden on physicians. In the present study, we evaluated the outcomes associated with PBPM for HIV pharmacotherapy. METHODS: We prepared protocols for drug selection, timing of interventions, and methods of intervention according to various guidelines. This study included 40 HIV-positive patients receiving outpatient care between January 2009 and February 2017. Of these patients, 17 received treatment before implementing PBPM and 23 patients received treatment afterward. We compared the intervention parameters between before and after the implementation of PBPM. RESULTS: The proportion of patients receiving prescription proposals from pharmacists was markedly higher after introducing PBPM (6 out of 17 patients vs. 23 out of 23 patients). All prescription proposals were accepted by physicians before and after PBPM. The number of interviews before antiretroviral therapy (ART) initiation (median [range]) decreased from 2 [1-5] to 1 [1-3] after PBPM introduction, suggesting the time to introduction of treatment has been shortened. Before the introduction of PBPM, nine patients required a change in their ART prescriptions and four patients were hospitalized (one patient was hospitalized due to an error in the self-administration of anti-HIV medicines, two patients were hospitalized due to interruptions in medication, and one patient was hospitalized for the treatment of other diseases). Only one patient was hospitalized after PBPM, and was unrelated to drug adherence. The proportion of patients with a reduced HIV-RNA load increased from 71 to 100%. Furthermore, the proportion of patients who maintained levels below the limit of quantitation increased from 59 to 91% after implementing PBPM. CONCLUSION: The implementation of PBPM for HIV outpatients improves the efficacy and safety of HIV pharmacotherapy.