A therapeutic intervention for Alzheimer's disease using ginsenoside Rg3: its role in M2 microglial activation and non-amyloidogenesis.

Previously, we have reported that ginsenoside Rg3 has typical activities for neuroprotection and Aß42 clearance by modulating microglia. In this study, we determined the pivotal role of ginsenoside Rg3 in microglia and neuronal cells. In human microglia, Rg3 and its stereoisomers significantly restored inflammatory M1 to normal M0 state and promoted M2 activation by up-regulating acute cytokines such as interleukin-10 and Arginase 1. Moreover, scavenger receptor type A (SRA) was significantly elevated in the presence of ginsenoside Rg3 and 20(S)-Rg3. This indicated that ginsenoside Rg3 could play a crucial role in Aß uptake and clearance under activated M2 state. We also observed that soluble amyloid precursor protein-alpha (sAPPα) and ADAM10 levels were increased in APP swe-transfected Nuro-2a neuronal cells, whereas sAPPß was not processed, suggesting that ginsenoside Rg3 was involved in non-amyloidogenic processing. In immunocytochemistry, SRA and a disintegrin and metalloproteinase 10 (desintegrin and metalloproteinase-containing protein 10, ADAM10) were coincidently upregulated in the presence of ginsenoside Rg3 and its stereoisomers compared to those in normal control. Taken together, these results suggested that ginsenoside Rg3 could boost acute activation of microglia, promote Aß uptake, and elevate the sAPPα processing under activated M2 state. Although in vivo studies need to be performed, it is certain that ginsenoside Rg3 is highly involved in ameliorating the pathogenesis of neurodegeneration and can be a promising candidate for treating Alzheimer's disease as a new therapeutic intervention.

The correlation between amylin and insulin by treatment with 2-deoxy-D-glucose and/or mannose in rat insulinoma ins-1E cells.

Amylin or islet amyloid polypeptide (IAPP) is a peptide synthesized and secreted with insulin by the pancreatic ß-cells. A role for amylin in the pathogenesis of type 2 diabetes (T2D) by causing insulin resistance or inhibiting insulin synthesis and secretion has been suggested by in vitro and in vivo studies. These studies are consistent with the effect of endogenous amylin on pancreatic ßcells to modulate and/or restrain insulin secretion. Here, we reported the correlation between amylin and insulin in rat insulinoma INS-1E cells by treating 2-deoxy-D-glucose (2-DG) and/or mannose. Cell viability was not affected by 24 h treatment with 2-DG and/or mannose, but it was significantly decreased by 48 h treatment with 5 and 10 mM 2-DG. in the 24 h treatment, the synthesis of insulin in the cells and the secretion of insulin into the media showed a significant inverse association. in the 48-h treatment, amylin synthesis vs. the secretion and insulin synthesis vs. the secretion showed a significant inverse relation. The synthesis of amylin vs. insulin and the secretion of amylin vs. insulin showed a significant inverse relationship. The p-ERK, antioxidant enzymes (Cu/Zn-superoxide dismutase (SOD), Mn-SOD, and catalase), and endoplasmic reticulum (ER) stress markers (cleaved caspase-12, CHOP, p-SAPK/JNK, and BiP/GRP78) were significantly increased or decreased by the 24 h and 48 h treatments. These data suggest the relative correlation to the synthesis of amylin by cells vs. the secretion into the media, the synthesis of amylin vs. insulin, and the secretion of amylin vs. insulin under 2-DG and/or mannose in rat insulinoma INS-1E cells. Therefore, these results can provide primary data for the hypothesis that the amylin-insulin relationships may be involved with the human amylin toxicity in pancreatic beta cells.

Nanomolar melatonin influences insulin synthesis and secretion in rat insulinoma INS-1E cells.

Pancreatic beta-cell dysfunction results in reductions of insulin synthesis/secretion, cell survival, and insulin sensitivity thereby inducing diabetes mellitus. In this study, how nanomolar melatonin regulates insulin synthesis and secretion in rat insulinoma INS-1E cells was investigated. At melatonin concentrations of 10 - 100 nM for 48 hours, melatonin significantly increased the insulin protein level in INS-1E cells above the level in control cells without melatonin or glucose treatments and decreased the insulin level in media with glucose: increases in insulin synthesis and decreases in insulin secretion occurred in dose-dependent manners. Luzindole or 4-phenyl-2-propionamidotetralin (4P-PDOT), melatonin receptor antagonists, inhibited the melatonin-induced insulin level in cells and media. Levels of membrane vesicle trafficking-related proteins including Rab5, GOPC, phospho-caveolin-1, EEA1, and clathrin proteins significantly increased with melatonin treatment above that in control cells without melatonin or glucose treatments, whereas expressions of APPL1 and syntaxin-6 proteins significantly decreased with melatonin treatment. The increases in the phosphorylation of mammalian target of rapamycin (p-mTOR), raptor protein, and mTOR complex 1 (mTORC1) levels were consistent with the increments in the expressions of p-Akt (Ser473, Thr308) and stress-induced IRE1α/p-eIF2α proteins in the endoplasmic reticulum following melatonin treatment. also, expression levels of Bcl-2 and Bcl-xl proteins were significantly increased compared to those in control cells without melatonin or glucose treatments, whereas the Bax protein level decreased. These results indicate that nanomolar melatonin regulates insulin synthesis and secretion associated with membrane vesicle trafficking-related proteins, including Rab5, GOPC, p-Caveolin-1, EEA1, and clathrin, through the Akt/mTOR pathway.

12-Month comorbidity patterns and associated factors in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: Comorbidity patterns of 12-month mood, anxiety and alcohol disorders and socio-demographic factors associated with comorbidity were studied among the general population of six European countries. METHOD: Data were derived from the European Study of the Epidemiology of Mental Disorders (ESEMeD), a cross-sectional psychiatric epidemiological study in a representative sample of adults aged 18 years or older in Belgium, France, Germany, Italy, the Netherlands and Spain. The diagnostic instrument used was the Composite International Diagnostic Interview (WMH-CIDI). Data are based on 21 425 completed interviews. RESULTS: In general, high associations were found within the separate anxiety disorders and between mood and anxiety disorders. Lowest comorbidity associations were found for specific phobia and alcohol abuse-the disorders with the least functional disabilities. Comorbidity patterns were consistent cross-nationally. Associated factors for comorbidity of mood and anxiety disorders were female gender, younger age, lower educational level, higher degree of urbanicity, not living with a partner and unemployment. Only younger people were at greater risk for comorbidity of alcohol disorder with mood, anxiety disorders or both. CONCLUSION: High levels of comorbidity are found in the general population. Comorbidity is more common in specific groups. To reduce psychiatric burden, early intervention in populations with a primary disorder is important to prevent comorbidity.

Sampling and methods of the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: The European Study of Epidemiology of Mental Disorders (ESEMeD) project was designed to evaluate the prevalence, the impact and the treatment patterns in Europe. This paper presents an overview of the methods implemented in the project. METHOD: ESEMeD is a cross-sectional study in a representative sample of 21 425 adults, 18 or older, from the general population of Belgium, France, Germany, Italy, the Netherlands and Spain. The Composite International Diagnostic Interview (WMH-CIDI) was administered by home interviews from January 2001 to August 2003 using Computer Assisted Personal Interview (CAPI) technology. Data quality was controlled to ensure reliability and validity of the information obtained. RESULTS: Response rate varied from 78.6% in Spain to 45.9% in France. Less than 4% of the individuals had errors in the checking procedures performed. CONCLUSION: The sampling methodologies, comprehensive psychiatric instruments and quality control procedures used have rendered the ESEMeD database a unique and important source of information about the prevalence, the disability burden and unmet medical needs of mental disorders within Europe.

Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: To describe the 12-month and lifetime prevalence rates of mood, anxiety and alcohol disorders in six European countries. METHOD: A representative random sample of non-institutionalized inhabitants from Belgium, France, Germany, Italy, the Netherlands and Spain aged 18 or older (n = 21425) were interviewed between January 2001 and August 2003. DSM-IV disorders were assessed by lay interviewers using a revised version of the Composite International Diagnostic Interview (WMH-CIDI). RESULTS: Fourteen per cent reported a lifetime history of any mood disorder, 13.6% any anxiety disorder and 5.2% a lifetime history of any alcohol disorder. More than 6% reported any anxiety disorder, 4.2% any mood disorder, and 1.0% any alcohol disorder in the last year. Major depression and specific phobia were the most common single mental disorders. Women were twice as likely to suffer 12-month mood and anxiety disorders as men, while men were more likely to suffer alcohol abuse disorders. CONCLUSION: ESEMeD is the first study to highlight the magnitude of mental disorders in the six European countries studied. Mental disorders were frequent, more common in female, unemployed, disabled persons, or persons who were never married or previously married. Younger persons were also more likely to have mental disorders, indicating an early age of onset for mood, anxiety and alcohol disorders.

Disability and quality of life impact of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: This manuscript examines the impact of mental health state and specific mental and physical disorders on work role disability and quality of life in six European countries. METHOD: The ESEMeD study was conducted in: Belgium, France, Germany, Italy, the Netherlands and Spain. Individuals aged 18 years and over who were not institutionalized were eligible for an in-home computer-assisted interview. Common mental disorders, work loss days (WLD) in the past month and quality of life (QoL) were assessed, using the WMH-2000 version of the CIDI, the WHODAS-II, and the mental and physical component scores (MCS, PCS) of the 12-item short form, respectively. The presence of five chronic physical disorders: arthritis, heart disease, lung disease, diabetes and neurological disease was also assessed. Multivariate regression techniques were used to identify the independent association of mental and physical disorders while controlling for gender, age and country. RESULTS: In each country, WLD and loss of QoL increased with the number of disorders. Most mental disorders had approximately 1.0 SD-unit lower mean MCS and lost three to four times more work days, compared with people without any 12-month mental disorder. The 10 disorders with the highest independent impact on WLD were: neurological disease, panic disorder, PTSD, major depressive episode, dysthymia, specific phobia, social phobia, arthritis, agoraphobia and heart disease. The impact of mental vs. physical disorders on QoL was specific, with mental disorders impacting more on MCS and physical disorders more on PCS. Compared to physical disorders, mental disorders had generally stronger 'cross-domain' effects. CONCLUSION: The results suggest that mental disorders are important determinants of work role disability and quality of life, often outnumbering the impact of common chronic physical disorders.

Use of mental health services in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: Comprehensive information about access and patterns of use of mental health services in Europe is lacking. We present the first results of the use of health services for mental disorders in six European countries as part of the ESEMeD project. METHOD: The study was conducted in: Belgium, France, Germany, Italy, the Netherlands and Spain. Individuals aged 18 years and over who were not institutionalized were eligible for an computer-assisted interview done at home. The 21 425 participants were asked to report how frequently they consulted formal health services due to their emotions or mental health, the type of professional they consulted and the treatment they received as a result of their consultation in the previous year. RESULTS: An average of 6.4% of the total sample had consulted formal health services in the previous 12 months. Of the participants with a 12-month mental disorder, 25.7% had consulted a formal health service during that period. This proportion was higher for individuals with a mood disorder (36.5%, 95% CI 32.5-40.5) than for those with anxiety disorders (26.1%, 95% CI 23.1-29.1). Among individuals with a 12-month mental disorder who had contacted the health services 12 months previously, approximately two-thirds had contacted a mental health professional. Among those with a 12-month mental disorder consulting formal health services, 21.2% received no treatment. CONCLUSION: The ESEMeD results suggest that the use of health services is limited among individuals with mental disorders in the European countries studied. The factors associated with this limited access and their implications deserve further research.

Psychotropic drug utilization in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: To assess psychotropic drug utilization in the general population of six European countries, and the pattern of use in individuals with different DSM-IV diagnoses of 12-month mental disorders. METHOD: Data were derived from the European Study of the Epidemiology of Mental Disorders (ESEMeD/MHEDEA 2000), a cross-sectional psychiatric epidemiological study in a representative sample of 21 425 adults aged 18 or older from six European countries (e.g. Belgium, France, Germany, Italy, the Netherlands and Spain). Individuals were asked about any psychotropic drug use in the past 12 months, even if they used the drug(s) just once. A colour booklet containing high-quality pictures of psychotropic drugs commonly used to treat mental disorders was provided to help respondents recall drug use. RESULTS: Psychotropic drug utilization is generally low in individuals with any 12-month mental disorder (32.6%). The extent of psychotropic drug utilization varied according to the specific DSM-IV diagnosis. Among individuals with a 12-month diagnosis of pure major depression, only 21.2% had received any antidepressants within the same period; the exclusive use of antidepressants was even lower (4.6%), while more individuals took only anxiolytics (18.4%). CONCLUSION: These data question the appropriateness of current pharmacological treatments, particularly for major depression, in which under-treatment is coupled with the high use of non-specific medications, such as anxiolytics.

Hematopoietic effect of ginsenoside Rg3 in ICR mouse primary cultures and its application to a biological response modifier.

Ginsenoside Rg3, which is obtained as a by-product during the steaming of red ginseng, at 300 microg/ml enhanced the proliferation of the total spleen and bone marrow (BM) cells in both the cyclophosphamide (CYC)-treated and non-CYC-treated groups.