p53 Regulates Mitochondrial Dynamics in Vascular Smooth Muscle Cell Calcification.

Arterial calcification is an important characteristic of cardiovascular disease. It has key parallels with skeletal mineralization; however, the underlying cellular mechanisms responsible are not fully understood. Mitochondrial dynamics regulate both bone and vascular function. In this study, we therefore examined mitochondrial function in vascular smooth muscle cell (VSMC) calcification. Phosphate (Pi)-induced VSMC calcification was associated with elongated mitochondria (1.6-fold increase, p < 0.001), increased mitochondrial reactive oxygen species (ROS) production (1.83-fold increase, p < 0.001) and reduced mitophagy (9.6-fold decrease, p < 0.01). An increase in protein expression of optic atrophy protein 1 (OPA1; 2.1-fold increase, p < 0.05) and a converse decrease in expression of dynamin-related protein 1 (DRP1; 1.5-fold decrease, p < 0.05), two crucial proteins required for the mitochondrial fusion and fission process, respectively, were noted. Furthermore, the phosphorylation of DRP1 Ser637 was increased in the cytoplasm of calcified VSMCs (5.50-fold increase), suppressing mitochondrial translocation of DRP1. Additionally, calcified VSMCs showed enhanced expression of p53 (2.5-fold increase, p < 0.05) and ß-galactosidase activity (1.8-fold increase, p < 0.001), the cellular senescence markers. siRNA-mediated p53 knockdown reduced calcium deposition (8.1-fold decrease, p < 0.01), mitochondrial length (3.0-fold decrease, p < 0.001) and ß-galactosidase activity (2.6-fold decrease, p < 0.001), with concomitant mitophagy induction (3.1-fold increase, p < 0.05). Reduced OPA1 (4.1-fold decrease, p < 0.05) and increased DRP1 protein expression (2.6-fold increase, p < 0.05) with decreased phosphorylation of DRP1 Ser637 (3.20-fold decrease, p < 0.001) was also observed upon p53 knockdown in calcifying VSMCs. In summary, we demonstrate that VSMC calcification promotes notable mitochondrial elongation and cellular senescence via DRP1 phosphorylation. Furthermore, our work indicates that p53-induced mitochondrial fusion underpins cellular senescence by reducing mitochondrial function.

Retraction notice to "Amelioration of imiquimod-induced psoriasis-like dermatitis in mice by DSW therapy inspired hydrogel" [BIOMAT 6 (2021) 299-311].

[This retracts the article DOI: 10.1016/j.bioactmat.2020.08.007.].

Impact of a Collaborative Pharmaceutical Care Service for Patients With Parkinson's Disease.

Objective: To identify the impact of a collaborative pharmaceutical care service (CPCS) on medication safety and establish the impact of the CPCS on patient reported outcomes for Parkinson's disease (PD) patients. Methods: Initially, PD outpatients receiving the CPCS between March 2017 and March 2019 were compared with PD patients receiving standard of care to identify differences in management. Pharmacist interventions data were coded and patients with PD receiving the CPCS were compared with those receiving standard of care to determine differences in medicines prescribed and dosage associated with these. Following this, data of patients receiving CPCS at baseline and 3-months follow-up were collected using a questionnaire consisting of validated measures of two patient-reported outcomes [adherence and quality of life (QoL)]. Mean scores for continuous variables were calculated, with descriptive analysis of categorical variables consisting of frequency counts and percentages. Change in adherence score before and after CPCS was investigated using a Wilcoxon sign rank sum test, spearman correlation analysis was used to correlate the changes in QoL before and after CPCS with the number of interventions, and p < 0.05 indicates that the difference is statistically significant. Results: A total of 331 PD outpatients received CPCS over 490 outpatient visits with an average age of 71.83 (±12.54). Five hundred and forty-five drug related problems were recorded as pharmacist interventions, of which most involved change to dosage (n = 226, 41.47%), adverse drug reactions (n = 135, 24.77%), and change in a medication (n = 102, 18.72%). Compared with those receiving standard of care, patients receiving CPCS were significantly less likely to have been prescribed pramipexole (18.52 versus 23.77%, p < 0.001) and more likely to have been prescribed amantadine (5.40 versus 3.70%, p = 0.02) and selegiline (17.36 versus 11.64%, p < 0.001). Lower dosages of levodopa/benserazide (0.51 ± 0.31 g versus 0.84 ± 0.37 g, p < 0.001), levodopa/carbidopa (0.33 ± 0.23 g versus 0.66 ± 0.47 g, p < 0.001), pramipexole (1.14 ± 1.63 mg versus 1.27 ± 0.69 mg, p = 0.01), and entacapone (130.00 ± 79.76 mg versus 173.09 ± 97.86 mg, p < 0.001) were also recorded. At baseline 119 PD outpatients with an average age of 69.98 (±9.90) were recruited for the longitudinal study. At 3-month follow-up, participants reported improvement in bodily pain subscale (baseline versus 3-months follow-up, 30.04 ± 22.21 versus 23.01 ± 20.98, p = 0.037) and medication adherence (6.19 ± 1.50 versus 6.72 ± 1.73, p = 0.014). Frequency of CPCS use was related to activity of daily living subscale (p = 0.047), the bodily pain subscale (p = 0.026), and medication adherence (p = 0.011). Total score of PDQ-39 was associated with patient education (p = 0.005) and usage and dosage combined with patient education (p = 0.006), while medication adherence score was associated with usage and dosage (p = 0.005). Conclusion: The CPCS was effective in resolving drug-related problems and in improving patients' medication regimens, medication adherence, and QoL through patient education and dosage adjustments. This is the first step in the development and feasibility testing of pharmacy services for PD patients in China.

Content and impact of pharmacy services for patients with Parkinson's disease: A systematic review and meta-analysis.

BACKGROUND: Medicines optimisation is important for the management of Parkinson's disease (PD). As many patients with PD have other long-term conditions, treatment is complex and risk of adverse events for these patients is high. OBJECTIVE: To explore the role of pharmacists and impact of pharmacy interventions for PD patients. METHODS: We comprehensively searched PubMed, Embase, the Cochrane Library and Chinese databases Sinomed, China National Knowledge Infrastructure to identify studies reporting pharmacist interventions and pharmacy services for PD patients using a predefined search strategy. The search period was from inception to March 2019. We also manually searched the reference list of included studies and ClinicalTrials.gov. We conducted meta-analyses to synthesize the evidence quantitatively. RESULTS: A total of 1607 studies were identified by applying the search criteria. After screening, 19 cross-sectional and case-controlled studies with 1458 PD patients from 9 countries were included. Pharmacist interventions for PD patients most commonly related to adverse drug reactions (ADRs) (13 studies), adherence assessment (12 studies), medication review (12 studies), identification of drug interactions (11 studies), monitoring response to medication therapy (11 studies), identification of inappropriate medication (11 studies), and patient education (10 studies). Most pharmacy services were provided in outpatient settings (13 studies). Reported impact measures included adherence (8 studies), quality of life (7 studies), and identification of drug-related problems (6 studies) such as ADRs (393 times out of 1760 times, 22.33%, 6 studies), inappropriate drug choice (349 times, 19.83%, 6 studies), inappropriate dosage (335 times, 19.03%, 6 studies), inappropriate drug use (257 times, 14.60%, 3 studies) and drug-drug interactions (146 times, 8.3%, 4 studies). Pooled results from 3 studies indicated no statistically significant impact of pharmacy services on all subscales of PD Questionnaire-39. CONCLUSION: ADRs were the most widely reported drug-related problems for PD patients; pharmacy services may have a role to play in medication adherence but were not found to impact on quality of life.

Efficacy and safety of sertraline for the treatment of premature ejaculation: Systematic review and meta-analysis.

BACKGROUD: Evidence on the efficacy and safety of sertraline in patients with premature ejaculation (PE) was inconsistent. The objective of this article is to evaluate the efficacy and safety of sertraline for the treatment of PE. METHODS: We searched Medline (OVID), Embase, the Cochrane Library, and 2 Chinese databases for randomized controlled trials (RCTs) and randomized crossover trials (RTs) that evaluated the efficacy and safety of sertraline in patients with PE. A meta-analysis was performed to calculate their pooled estimates with 95% confidence interval. RESULTS: Of the 645 records obtained, we included 12 RCTs and 2 RTs (n = 977). Meta-analysis showed that sertraline prolonged intravaginal ejaculation latency time (IELT) in PE patients ((standard mean difference (SMD) = 2.14, 95% CI 1.20 to 3.08). Subgroup analyses indicated a prolonged IELT for different treatment courses: 4 weeks (SMD = 2.66, 1.06 to 4.26), 6 weeks (SMD = 0.95, 0.31 to 1.58), and 8 weeks (SMD = 1.81, 0.78 to 2.85). The sexual satisfaction rates of patients (SMD = 2.20, 1.57 to 2.84) and spouses (SMD = 2.27, 1.44 to 3.09) were also improved. We observed a significant increased risk of gastrointestinal upset (risk ratio = 2.71, 1.39 to 5.28) in the sertraline group. CONCLUSION: Sertraline can prolong IELT of PE patients, improve sexual satisfaction rates of patients and spouses, but increase risk of gastrointestinal upset.