Apolipoprotein E ε4 Modifies the Effect of Possible Anticholinergic Drugs on Incident Dementia: The Shanghai Aging Study.

OBJECTIVES: To validate the hypothesis that apolipoprotein E (APOE) ε4 modifies the effect of possible anticholinergic drugs (PACDs) on incident dementia among older adults. DESIGN: A population-based prospective study. SETTING AND PARTICIPANTS: Dementia-free older adults in an urban community in Shanghai, China. METHODS: At baseline, PACDs were defined according to the Anticholinergic Cognitive Burden Scale. Standard daily dose (SDD) of PACDs was calculated. A battery of neuropsychological tests was used to assess cognition and the consensus diagnosis was conducted for incident dementia and Alzheimer's disease (AD). Multivariate Cox regression models were used to examine the association between PACD use and the risk of dementia and AD in APOE ε4 carriers and noncarriers. RESULTS: We followed 1406 dementia-free participants for a median of 5.3 years and defined 117 incident dementia cases, among which 89 were AD. Only in APOE ε4 carriers was PACD use associated with incident dementia [hazard ratio (HR) 5.71; 95% CI 2.04-15.94] and AD (HR 5.73; 95% CI 1.77-18.54); SDD was positively associated with incident dementia (HR 2.42; 95% CI 1.32-4.44) and AD (HR 2.16; 95% CI 1.06-4.41). CONCLUSIONS AND IMPLICATIONS: Using PACDs requires judicious consideration for the potential risk of dementia and AD in older adults carrying APOE ε4.

Potential herb-drug interactions in community-dwelling older adults in China: the Shanghai Aging Study.

BACKGROUND: Potential herb-drug interactions (pHDIs) often go unrecognized, and little is known about the prevalence of pHDIs in older adults. AIMS: This study aimed to investigate the prevalence of pHDIs in community-dwelling older adults in Shanghai and identify patterns and factors associated with pHDIs. METHODS: Baseline data from the Shanghai Aging Study, which was designed to establish a prospective community-based cohort of older adults in Shanghai, were analyzed regarding pHDIs with Lexi-Interact Online software. RESULTS: Among 1227 participants who used any combination of drug-herb or herb-herb, 43.3% were exposed to at least one pHDI. A total of 1641 different pHDIs were identified among the study samples. Only seven (0.4%) pHDIs were rated as risk category X, indicating that the combinations were contraindicated and should be avoided. Worryingly, 876 (53.4%) pHDIs were rated as risk category D, indicating that significant interactions may occur and therapeutic modification should be considered. Of particular concern is that 99.8% of pHDIs in risk category D involve herbs with anticoagulant/antiplatelet properties. Individuals with stroke (odds ratio [OR] 2.02), hyperlipidemia (OR 1.51) or heart diseases (OR 1.42) and the number of herbs (2.66), number of drugs (OR 1.21), and age (OR 1.02) were significantly associated with the risk of pHDIs. CONCLUSION: 43.3% of community-dwelling older adults who used any combination of drug-herb or herb-herb was exposed to pHDIs, and more than half of pHDIs were related to herbs with anticoagulant/antiplatelet properties. Awareness of the patterns and high-risk groups of these pHDIs may contribute to increased patient safety.

Carbocisteine Improves Histone Deacetylase 2 Deacetylation Activity via Regulating Sumoylation of Histone Deacetylase 2 in Human Tracheobronchial Epithelial Cells.

Histone deacetylase (HDAC) 2 plays a vital role in modifying histones to mediate inflammatory responses, while HDAC2 itself is commonly regulated by post-translational modifications. Small ubiquitin-related modifier (SUMO), as an important PTM factor, is involved in the regulation of multiple protein functions. Our previous studies have shown that carbocisteine (S-CMC) reversed cigarette smoke extract (CSE)-induced down-regulation of HDAC2 expression/activity in a thiol/GSH-dependent manner and enhanced sensitivity of steroid therapy. However, the mechanism by which S-CMC regulates HDAC2 is worth further exploring. Our study aimed to investigate the relationships between HDAC2 sumoylation and its deacetylase activity under oxidative stress and the molecular mechanism of S-CMC to regulate HDAC2 activity that mediates inflammatory responses in human bronchial epithelial cells. We found that modification of HDAC2 by SUMO1 and SUMO2/3 occurred in 16HBE cells under physiological conditions, and CSE induced SUMO1 modification of HDAC2 in a dose and time-dependent manner. K462 and K51 of HDAC2 were the two major modification sites of SUMO1, and the K51 site mediated deacetylation activity and function of HDAC2 on histone H4 that regulates IL-8 secretion. S-CMC inhibited CSE-induced SUMO1 modification of HDAC2 in the presence of thiol/GSH, increased HDAC activity, and decreased IL-8 expression. Our study may provide novel mechanistic explanation of S-CMC to ameliorate steroid sensitivity treatment in chronic obstructive pulmonary disease.