S-Palmitoylation of the serotonin transporter promotes its cell surface expression and serotonin uptake.

The neurotransmitter serotonin (5-HT) is transported back into serotonergic neurons by the serotonin transporter (SERT). SERT is a main target of antidepressants, and much effort has therefore focused on finding relationships between SERT and depression. However, it is not fully understood how SERT is regulated at the cellular level. Here, we report post-translational regulation of SERT by S-palmitoylation, in which palmitate is covalently attached to cysteine residues of proteins. Using AD293 cells (a human embryonic kidney 293-derived cell line with improved cell adherence) transiently transfected with FLAG-tagged human SERT, we observed S-palmitoylation of immature SERT containing high-mannose type N-glycans or no N-glycan, which is presumed to be localized in the early secretory pathway, such as the endoplasmic reticulum. Mutational analysis by alanine substitutions shows that S-palmitoylation of immature SERT occurs at least at Cys-147 and Cys-155, juxtamembrane cysteine residues within the first intracellular loop. Furthermore, mutation of Cys-147 reduced cellular uptake of a fluorescent SERT substrate that mimics 5-HT without decreasing SERT on the cell surface. On the other hand, combined mutation of Cys-147 and Cys-155 inhibited SERT surface expression and reduced the uptake of the 5-HT mimic. Thus, S-palmitoylation of Cys-147 and Cys-155 is important for both the cell surface expression and 5-HT uptake capacity of SERT. Given the importance of S-palmitoylation in brain homeostasis, further investigation of SERT S-palmitoylation could provide new insights into the treatment of depression.

The relationship between the houseboundedness and frailty of community-dwelling elderly persons.

This study aimed to verify whether the incidence of frailty in elderly individuals is higher among those who are housebound than those who are not. This study found no correlation between elderly people's houseboundedeness and physical, mental, social, and overall frailty. However, the Tilburg Frailty Indicator (TFI) frailty score and grip strength value were higher in non-housebound elderly persons than in housebound elderly ones. This suggests that being housebound may lead to frailty. On the other hand, it is thought that individual interaction with family and friends, and lack of anxiety about falls correlates with the prevention of frailty in housebound elderly persons. The results of the study also suggest that the basic checklist may be effective for ascertaining the actual situation of housebound elderly people who may be manifesting frailty.

A cohort study on elderly individuals newly certified as requiring long-term care: comparison of rates of care-needs certifications between basic checklist respondents/specific health examinees and non-respondents/non-examinees of 37,000 elderlies in a city.

Objective: The rates of care-needs certification were mainly compared between two cohorts: 7,820 specific health checkup examinees/basic checklist respondents and 29,234 non-examinees/non-respondents. Subjects and Methods: Among approximately 37,000 elderly citizens of X City, the number of individuals newly certified as requiring long-term care were observed from the date of the first specific health checkup in 2008 to March 31, 2013. The aggregated totals of these individuals and associated factors were evaluated. Results: 1. Support Required 1, Support Required 2, and Long-term Care Required (level 1) certified individuals accounted for approximately 80% of newly certified individuals aged 65-74 years. Newly certified individuals aged 75 years and over had similar results with 37.2% of them being certified Support Required 1, 19.4% certified Support Required 2, and 22.9% certified Long-term Care Required (level 1). 2. The primary factors for care-needs certification in individuals aged 65-74 years were arthritic disorder in 27.6%, falls and bone fractures in 11.3%, and malignant neoplasm and cerebrovascular disease, among others. This was similar for individuals aged 75 years or over. 3. Of the 7,820 specific health checkup examinees/basic checklist respondents, 1,280 were newly certified as requiring long-term care (16.4%) compared to 7,878 (26.9%) of the 29,234 non-examinees/non-respondents. Therefore, the latter cohort had a significantly higher rate of individuals who were newly certified as requiring long-term care. Conclusion: Both specific health checkups and basic checklists are effective health policies to protect frailty in community elderlies.

A retrospective cohort study on the risk assessment of newly certificated long-term care need of elderly individuals in a community: Basic checklist and specific health checkup.

Objective: This study aimed to examine the factors influencing the requirement of a certificate of long-term care using a basic checklist and items listed in the Special Health Checkup. Method: This study included 7,820 individuals living in Uji city, who were selected from among 8,000 elderly individuals who, in 2008, underwent a specific health checkup (hereafter referred to as the 'specific health checkup for the old-old elderly individuals') for those aged 75 years and above. They answered questions from basic checklists at the time, and 180 individuals were excluded as they had already qualified for requiring the certificate of long-term care at the time of the checkup. The follow-up period extended from the day of the specific health checkup for the old-old elderly individuals to March 31, 2013. The data were analyzed using the certificate of needing long-term care as the response variable. The explanatory variables were the basic attributes, items listed in the specific health checkup for the old-old elderly individuals, interview sheets, and basic checklists. Cox proportional hazards regression analysis was conducted. Results: In total, 1,280 elderly individuals qualified for requiring the certificate of needing long-term care. The risk factors for the young-old elderly individuals aged 65 to 74 years were as follows: hepatic dysfunction (hazard ratio {HR}=1.69), the presence of subjective symptoms (HR=1.41), an above-normal abdominal circumference (HR=1.36), old age (HR=1.13), a reduced frequency of going out since the previous year (HR=1.87), the use of support for standing up after being seated on a chair (HR=1.86), no deposit or withdrawals made (HR=1.84), the anxiety of falling down (HR=1.50), an inability to climb stairs without holding a railing or wall (HR=1.49), as well as an increased difficulty in eating tough food items compared with 6 months prior (HR=1.44). The risk factors for the old-old elderly individuals were as follows: a positive reaction on proteinuria (HR=1.27), anemia (HR=1.18), old age (HR=1.10), inability to travel on a bus or train by themselves (HR=1.53), the inability to climb stairs without holding a railing or wall (HR=1.48), weight loss (HR=1.36), a reduced sense of appreciation of the activities they had previously participated in, over a span of 2 weeks (HR=1.30), the use of support for standing up after being seated on a chair (HR=1.23), and the anxiety of falling down (HR=1.20). Conclusion: The items listed in the specific medical checkup as well as the basic checklists were found to be risk factors for both the young-old elderly individuals and the old-old elderly individuals, indicating the need to utilize these lists for the prevention of nursing even in the late stages of life. Moreover, these results suggest the importance of screening elderly individuals suffering from hyperkinesis using the basic checklist and conducting preventive interventions in order to maintain and improve their physical functions.

Medicinal flowers. XXVII. New flavanone and chalcone glycosides, arenariumosides I, II, III, and IV, and tumor necrosis factor-alpha inhibitors from everlasting, flowers of Helichrysum arenarium.

The methanolic extract from the flowers of Helichrysum arenarium L. MOENCH was found to show inhibitory effect on tumor necrosis factor-alpha (TNF-alpha, 1 ng/ml)-induced cytotoxicity in L929 cells. From the methanolic extract, 50 constituents including four new flavanone and chalcone glycosides named arenariumosides I (1), II (2), III (3), and IV (4) were isolated. The stereostructures of 1-4 were elucidated on the basis of chemical and physicochemical evidence. Among the constituents, naringenin 7-O-beta-D-glucopyranoside (7), apigenin 7-O-beta-D-glucopyranoside (14), apigenin 7-O-gentiobioside (16), and apigenin 7,4'-di-O-beta-D-glucopyranoside (17) significantly inhibited TNF-alpha-induced cytotoxicity in L929 cells at 30 microM.