Reserpine modulates neurotransmitter release to extend lifespan and alleviate age-dependent Aβ proteotoxicity in Caenorhabditis elegans

Aging is a debilitating process often associated with chronic diseases such as diabetes, cardiovascular and neurodegenerative diseases like Alzheimer's disease (AD). AD occurs at a very high incidence posing a huge burden to the society. Model organisms such as C. elegans become essential to understand aging or lifespan extension - the etiology, molecular mechanism and identification of new drugs against age associated diseases. The AD model, manifesting Aβ proteotoxicity, in C. elegans is well established and has provided valuable insights. Earlier, we have reported that Reserpine, an FDA-approved antihypertensive drug, increases C. elegans lifespan with a high quality of life and ameliorates Aβ toxicity in C. elegans. But reserpine does not seem to act through the known lifespan extension pathways or inhibition of its known target, vesicular monoamine transporter, VMAT. Reserpine's mode of action and the pathways it activates are not known. Here, we have evaluated the presynaptic neurotransmitter(s) release pathway and identified acetylcholine (ACh) as the crucial player for reserpine's action. The corroborating evidences are: i) lack of lifespan extension in the ACh loss of function (hypomorphic) - synthesis (cha-1) and transport (unc-17) mutants; ii) mitigation of chronic aldicarb effect; iii) lifespan extension in dopamine (cat-2) and dopamine and serotonin (bas-1) biosynthetic mutants; iv) no rescue from exogenous serotonin induced paralysis in the AD model worms; upon reserpine treatment. Thus, modulation of acetylcholine is essential for reserpine's action.     

Prevalence and correlates of alcohol use disorders in the Singapore Mental Health Survey

Aims To establish the prevalence, correlates, comorbidity and treatment gap of alcohol use disorders in the Singapore resident population. Design The Singapore Mental Health Study is a cross‐sectional epidemiological survey. Setting A nationally representative survey of the resident (citizens and permanent residents) population in Singapore. Participants A total of 6616 Singaporean adults aged 18 years and older. Measurements The diagnoses were established using the World Mental Health Composite International Diagnostic Interview (WMH‐CIDI) diagnostic modules for life‐time and 12‐month prevalence of selected mental illnesses including alcohol use disorders. Findings The life‐time prevalence of alcohol abuse and alcohol dependence was 3.1% and 0.5%, while the 12‐month prevalence of alcohol abuse and alcohol dependence was 0.5% and 0.3%, respectively. The life‐time and 12‐month prevalence of alcohol use disorders was 3.6% and 0.8%, respectively. Those with alcohol use disorder had significantly higher odds of having major depressive disorder [odds ratio (OR) 3.1] and nicotine dependence (OR 4.5). Compared to the rest of the population, those with an alcohol use disorder had significantly higher odds of having gastric ulcers (OR 3.0), respiratory conditions (OR 2.1) and chronic pain (OR 2.1). Only one in five of those with alcohol use disorder had ever sought treatment. Conclusions The prevalence of alcohol use disorders is relatively low in the Singapore adult population. Comorbidity with mental and physical disorders is significant, emphasizing the need to screen people with alcohol use disorders for these comorbidities.     

Mental disorders: employment and work productivity in Singapore

Aim

To examine the association between mental disorders and work disability in the adult resident population in Singapore.

Method

Data are from the Singapore Mental Health Study, which was a household survey of a nationally representative sample. The main instrument used was the Composite International Diagnostic Interview (CIDI). Employment-related information was collected using the modified employment module of the CIDI.

Results

A total of 6,429 respondents were included in the analysis, 71 % (n = 4,594) were employed, 24.5 % (n = 1,522) were economically inactive and 4.5 % (n = 313) were unemployed. Among the employed, 2.3 % had a 12-month prevalence of at least one mental disorder, while 5.3 % of the unemployed had at least one mental disorder. The average number of work loss days (absenteeism) per capita among those with a mental disorder was 0.5 per month that is equivalent to an annualized national projection of approximately 0.3 million productivity days. The average work-cutback days (presenteeism) were 0.4 days among this group. Of the mentally ill in the workforce, a high proportion (86.5 %) did not ever seek help for problems related to mental health.

Conclusion

Our findings provide information on the significant consequences of mental disorders on the workforce in terms of lost work productivity, which could pave the way for a more rational allocation of scarce resources.     

A Qualitative Exploration of the Views of Policymakers and Policy Advisors on the Impact of Mental Health Stigma on the Development and Implementation of Mental Health Policy in Singapore

Few studies have examined the views of policy makers regarding the impact of mental health stigma on the development and implementation of mental health policies. This study aimed to address this knowledge gap by exploring policymakers’ and policy advisors’ perspectives regarding the impact of mental health stigma on the development and implementation of mental health programmes, strategies, and services in Singapore. In all 13 participants were recruited for the study comprising practicing policymakers, senior staff of organisations involved in implementing the various mental health programmes, and policy advisors. Data was collected through semi-structured interviews, which were transcribed verbatim and analysed using reflexive thematic analysis. Data analysis revealed three superordinate themes related to challenges experienced by the policymakers/advisors when dealing with mental health policy and implementation of programmes. These themes included stigma as a barrier to mental health treatment, community-level barriers to mental health recovery, and mental health being a neglected need. Policymakers/advisors demonstrated an in-depth and nuanced understanding of the barriers (consequent to stigma) to mental healthcare delivery and access. Policymakers/advisors were able to associate the themes related to the stigma towards mental illness with help-seeking barriers based on personal experiences, knowledge, and insight gained through the implementation of mental health programmes and initiatives.

     

Niacin affects cell adhesion molecules and plasminogen activator inhibitor-1 in HepG2 cells

BACKGROUND: Beyond lipid-modifying actions, niacin lowers the risk of atherothrombotic events by lowering prothrombotic factors like fibrinogen. Plasminogen activator inhibitor type 1 (PAI-1) is a potential factor for atherogenesis and thrombosis, increased in acute myocardial infarctions and restenosis after angioplasty. Cell adhesion molecules (CAM) mediate adhesion, recruitment and migration of white blood cells through vascular surfaces, an essential process in atherogenesis. ICAM-1 is a significant predictor of future coronary events. Whether niacin affects ICAM-1 expression is unknown. We studied the effects of niacin on PAI-1 and CAM using HepG2 cells. METHODS: HepG2 cells were cultured in DMEM until 90% confluent. After serum starvation, cells were exposed to DME/F12 containing niacin. Transforming growth factor-beta (TGF-beta) was added directly to cell media. Cell lysate and conditioned media were collected for measurement of PAI-1 by ELISA. For measurement of ICAM, cells were treated with tumor necrosis factor-alpha (TNF-alpha) instead. The effect of niacin on mRNA expression of ICAM-1 was studied using RT-PCR. RESULTS: Niacin reduced the TGF-beta-induced rise by 30% to 55% (p=0.002). The differences in degree of PAI-1 reduction, between different niacin concentrations, were not statistically significant. Niacin reduced TNF-alpha-induced rise in ICAM-1 levels by 66% to 89% (p<0.0001), but did not significantly affect TNF-alpha-induced rise in PECAM-1. Semiquantitative RT-PCR analysis showed that reduced TNF-alpha-induced rise in ICAM-1 mRNA expression significantly by 17% (p=0.001). CONCLUSIONS: Treatment with niacin suppressed PAI-1 and ICAM-1 levels in HepG2 cells. Further studies to understand the mechanistic pathways of this suppression, could further explain benefits of niacin in prevention of atherosclerotic disease, and offer therapeutic avenues against the rising burden of atherothrombotic disease.