Liraglutide Attenuates Glucolipotoxicity-Induced RSC96 Schwann Cells' Inflammation and Dysfunction.

Diabetic neuropathy (DN) is a type of sensory nerve damage that can occur in patients with diabetes. Although the understanding of pathophysiology is incomplete, DN is often associated with structural and functional alterations of the affected neurons. Among all possible causes of nerve damage, Schwann cells (SCs) are thought to play a key role in repairing peripheral nerve injury, suggesting that functional deficits occurring in SCs may potentially exhibit their pathogenic roles in DN. Therefore, elucidating the mechanisms that underlie this pathology can be used to develop novel therapeutic targets. In this regard, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently attracted great attention in ameliorating SCs' dysfunction. However, the detailed mechanisms remain uncertain. In the present study, we investigated how GLP-1 RA Liraglutide protects against RSC96 SCs dysfunction through a diabetic condition mimicked by high glucose and high free fatty acid (FFA). Our results showed that high glucose and high FFAs reduced the viability of RSC96 SCs by up to 51%, whereas Liraglutide reduced oxidative stress by upregulating antioxidant enzymes, and thus protected cells from apoptosis. Liraglutide also inhibited NFκB-mediated inflammation, inducing SCs to switch from pro-inflammatory cytokine production to anti-inflammatory cytokine production. Moreover, Liraglutide upregulated the production of neurotrophic factors and myelination-related proteins, and these protective effects appear to be synergistically linked to insulin signaling. Taken together, our findings demonstrate that Liraglutide ameliorates diabetes-related SC dysfunction through the above-mentioned mechanisms, and suggest that modulating GLP-1 signaling in SCs may be a promising strategy against DN.

Development and Validation of KASP Assays for the Genotyping of Racing Performance-Associated Single Nucleotide Polymorphisms in Pigeons.

Pigeon racing's recent upturn in popularity can be attributed in part to the huge prize money involved in these competitions. As such, methods to select pigeons with desirable genetic characteristics for racing or for selective breeding have also been gaining more interest. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for genotyping-specific genes is one of the most commonly used molecular techniques, which can be costly, laborious and time consuming. The present study reports the development of an alternative genotyping method that employs Kompetitive Allele Specific Polymerase Chain Reaction (KASP) technology with specifically designed primers to detect previously reported racing performance-associated polymorphisms within the LDHA, MTYCB, and DRD4 genes. To validate, KASP assays and PCR-RFLP assays results from 107 samples genotyped for each of the genes were compared and the results showed perfect (100%) agreement of both methods. The developed KASP assays present an alternative rapid, reliable, and cost-effective method to identify polymorphisms in pigeons.

miR-302 Attenuates Mutant Huntingtin-Induced Cytotoxicity through Restoration of Autophagy and Insulin Sensitivity.

Huntington's disease (HD) is an autosomal-dominant brain disorder caused by mutant huntingtin (mHtt). Although the detailed mechanisms remain unclear, the mutational expansion of polyglutamine in mHtt is proposed to induce protein aggregates and neuronal toxicity. Previous studies have shown that the decreased insulin sensitivity is closely related to mHtt-associated impairments in HD patients. However, how mHtt interferes with insulin signaling in neurons is still unknown. In the present study, we used a HD cell model to demonstrate that the miR-302 cluster, an embryonic stem cell-specific polycistronic miRNA, is significantly downregulated in mHtt-Q74-overexpressing neuronal cells. On the contrary, restoration of miR-302 cluster was shown to attenuate mHtt-induced cytotoxicity by improving insulin sensitivity, leading to a reduction of mHtt aggregates through the enhancement of autophagy. In addition, miR-302 also promoted mitophagy and stimulated Sirt1/AMPK-PGC1α pathway thereby preserving mitochondrial function. Taken together, these results highlight the potential role of miR-302 cluster in neuronal cells, and provide a novel mechanism for mHtt-impaired insulin signaling in the pathogenesis of HD.

The Pluripotency Factor Nanog Protects against Neuronal Amyloid ß-Induced Toxicity and Oxidative Stress through Insulin Sensitivity Restoration.

Amyloid ß (Aß) is a peptide fragment of the amyloid precursor protein that triggers the progression of Alzheimer's Disease (AD). It is believed that Aß contributes to neurodegeneration in several ways, including mitochondria dysfunction, oxidative stress and brain insulin resistance. Therefore, protecting neurons from Aß-induced neurotoxicity is an effective strategy for attenuating AD pathogenesis. Recently, applications of stem cell-based therapies have demonstrated the ability to reduce the progression and outcome of neurodegenerative diseases. Particularly, Nanog is recognized as a stem cell-related pluripotency factor that enhances self-renewing capacities and helps reduce the senescent phenotypes of aged neuronal cells. However, whether the upregulation of Nanog can be an effective approach to alleviate Aß-induced neurotoxicity and senescence is not yet understood. In the present study, we transiently overexpressed Nanog-both in vitro and in vivo-and investigated the protective effects and underlying mechanisms against Aß. We found that overexpression of Nanog is responsible for attenuating Aß-triggered neuronal insulin resistance, which restores cell survival through reducing intracellular mitochondrial superoxide accumulation and cellular senescence. In addition, upregulation of Nanog expression appears to increase secretion of neurotrophic factors through activation of the Nrf2 antioxidant defense pathway. Furthermore, improvement of memory and learning were also observed in rat model of Aß neurotoxicity mediated by upregulation of Nanog in the brain. Taken together, our study suggests a potential role for Nanog in attenuating the neurotoxic effects of Aß, which in turn, suggests that strategies to enhance Nanog expression may be used as a novel intervention for reducing Aß neurotoxicity in the AD brain.

GLP-1 Analogue Liraglutide Attenuates Mutant Huntingtin-Induced Neurotoxicity by Restoration of Neuronal Insulin Signaling.

Huntington's disease (HD) is a progressive and fatal neurodegenerative disease caused by CAG repeat expansion in the coding region of huntingtin (HTT) protein. The accumulation of mutant HTT (mHTT) contributes to neurotoxicity by causing autophagy defects and oxidative stress that ultimately lead to neuronal death. Interestingly, epidemiologic studies have demonstrated that the prevalence of type-2 diabetes, a metabolic disease mainly caused by defective insulin signaling, is higher in patients with HD than in healthy controls. Although the precise mechanisms of mHTT-mediated toxicity remain unclear, the blockade of brain insulin signaling may initiate or exacerbate mHTT-induced neurodegeneration. In this study, we used an in vitro HD model to investigate whether neuronal insulin signaling is involved in mHTT-mediated neurotoxicity. Our results demonstrated that mHTT overexpression significantly impairs insulin signaling and causes apoptosis in neuronal cells. However, treatment with liraglutide, a GLP-1 analogue, markedly restores insulin sensitivity and enhances cell viability. This neuroprotective effect may be attributed to the contribution of the upregulated expression of genes associated with endogenous antioxidant pathways to oxidative stress reduction. In addition, liraglutide stimulates autophagy through AMPK activation, which attenuates the accumulation of HTT aggregates within neuronal cells. Our findings collectively suggest that liraglutide can rescue impaired insulin signaling caused by mHTT and that GLP-1 may potentially reduce mHTT-induced neurotoxicity in the pathogenesis of HD.

Aß exacerbates α-synuclein-induced neurotoxicity through impaired insulin signaling in α-synuclein-overexpressed human SK-N-MC neuronal cells.

AIM: α-Synuclein (αSyn) is known as a small soluble protein abundantly expressed in neuronal cells. Although its physiological role is still unclear, the aggregation of αSyn has been recognized as responsible for some neurodegenerative disorders such as dementia with Lewy bodies (DLB). In most cases, intracellular abnormal aggregates are caused by protein-coding mutations that alter primary structure and therefore increase propensity toward aggregation. However, no pathogenic alterations or polymorphisms in αSyn are found in DLB patients so far, suggesting genetic mutations may not play a major role in DLB pathogenesis. In contrast, emerging evidence reveals that amyloid ß (Aß) may contribute to aggregate formation and exacerbate neurotoxicity of αSyn. However, the underlying mechanism of action has remained unclear. METHODS: To investigate molecular pathways involved in Aß-mediated αSyn pathology, we established an in vitro model for inducible αSyn overexpression in SK-N-MC human neuronal cells. RESULTS: Our results demonstrated that Aß treatment in αSyn-overexpressed neuronal cells significantly increases αSyn intracellular aggregation and cytotoxicity. Moreover, Aß also caused AMP-activated protein kinase (AMPK) inhibition and impaired insulin sensitivity, which leads to significant downregulation of nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1) antioxidant signaling to elicit αSyn aggregation. CONCLUSIONS: This raised the possibility that insulin resistance could be one of the causative factors of αSyn toxicity, and the strategies for insulin sensitization may have therapeutic potential for synucleinopathies including DLB.

Depression and family support in breast cancer patients.

BACKGROUND: Breast cancer is the most common cancer in women. Among the survivors, depression is one of the most common psychiatric comorbidities. This paper reports the point prevalence of major depressive disorder among breast cancer patients and the association between family support and major depressive disorder. METHODS: Clinical data were collected from a breast cancer clinic of a general hospital in central Taiwan. Participants included 300 patients who were older than 18 years and diagnosed with breast cancer. Among these individuals, we used Mini International Neuropsychiatric Interview (a structural diagnostic tool for psychiatric disorders) to ascertain if they had major depressive disorder. We also used the Family Adaptability, Partnership, Growth, Affection, and Resolve score to assess the family support. RESULTS: The point prevalence of major depressive disorder among breast cancer patients was 8.33%, and this was positively associated with insomnia, psychiatric family history, pain severity, and radiotherapy and negatively associated with menopause, cancer duration, hormone therapy, and family support. Family support (adjusted odds ratio =0.87, 95% CI: 0.78-0.98) was found to be an associated factor for major depressive disorder in breast cancer patients after controlling for potential risk factors. CONCLUSION: Major depressive disorder is a common comorbidity among breast cancer patients. Family support is an important associated factor for these patients. Health care professionals should evaluate mood problems and family support while treating these patients.

Voluntary attendance of small-group brainstorming tutoring courses intensify new clerk's "excellence in clinical care": a pilot study.

BACKGROUND: Clerkship provides a unique way of transferring the knowledge and skills gathered during medical school's curriculum into real-ward clinical care environment. The annual program evaluation has indicated that the training of clerks in diagnostic and clinical reasoning skills needed to be enhanced. Recently, "clinical excellence" program have been promoted in our institution to augment the excellence in clinical care of new clerks. Current study aims to evaluate whether this pilot program improve the "clinical excellence" of new clerks. METHODS: In a pilot study, groups of new clerks in years 2013 and 2014 voluntarily attended either a small-group brainstorming course or a didactic classroom tutoring courses as part of their 3-month internal medicine clinical rotation block. A third group of new clerks did not join either of the above courses and this group served as the control group. Pre-block/post-block self-assessment and post-block 5-station mini-Objective Subjective Clinical Examinations (OSCEs) were used to evaluate the effectiveness of these two additional courses that trained diagnostic and clinical reasoning skills. RESULTS: Overtime, the percentages of new clerks that attended voluntarily either the small-group brainstorming or classroom tutoring courses were increased. Higher post-block self-assessed diagnostic and clinical reasoning skill scores were found among individuals who attended the small-group brainstorming courses compared to either the didactic group or the control group. In a corresponding manner, the small-group brainstorming group obtained higher summary OSCEdiag and OSCEreason scores than either the didactic group or control group. For all basic images/laboratory OSCE stations, the individual diagnostic skill (OSCEdiag) scores of the small-group brainstorming group were higher than those of the didactic group. By way of contrast, only the clinical reasoning skill (OSCEreason) scores of the basic electrocardiogram and complete blood count + biochemistry OSCE station of thesmall-group brainstorming group were higher than those of the didactic group. Among the small-group brainstorming group, clerks with higher cumulative learning hours (>30-h) had significant higher OSCEdiag and OSCEreason scores (>400) than those with less cumulative learning hours. CONCLUSION: Our pilot study provides a successful example of the use of a small-group tutoring courses for augmenting the diagnostic and clinical reasoning skills of new clerks. The positive results obtained during the initial 2-year long pilot "clinical excellence" program have encouraged the formal implementation of this course as part of the clerkship curriculum.

A model of four hierarchical levels to train Chinese residents' teaching skills for "practice-based learning and improvement" competency.

OBJECTIVES: The current study focused on validating a protocol for training and auditing the resident's practice-based learning and improvement (PBLI) and quality improvement (QI) competencies for primary care. METHODS: Twelve second-year (R2), 12 first-year (R1) and 12 postgraduate year-1 residents were enrolled into group A, B and C, respectively, as trainees. After three training protocols had been completed, a writing test, self-assessed questionnaire and mini-OSTE and end-of-rotation assessment were used in auditing the PBLI competency, performance and teaching ability of trainees. RESULTS: Baseline expert-assessed PBLI and QI knowledge application tool writing scores were low for the R1 and R2 residents. After three training protocols, PBLI and QI proficiencies, performance and teaching abilities were improved to similar levels cross the three training levels of residents based on the expert-assessed writing test-audited assessments and on the faculty and standardized clerk-assessed end-of-rotation-/mini-OSTE-audited assessments. CONCLUSION: The different four-level hierarchical protocols used to teach group A, B and C were equally beneficial and fitted their needs; namely the different levels of the trainees. Specifically, each level was able to augment their PBLI and QI proficiency. This educational intervention helps medical institutions to train residents as PBLI instructors.

Quality of life of individuals with schizophrenia living in the community: relationship to socio-demographic, clinical and psychosocial characteristics.

AIMS AND OBJECTIVES: To examine the level of quality of life in individuals with schizophrenia and to test its association with socio-demographic, clinical and psychosocial characteristics. BACKGROUND: Quality of life has been a focus of concern in mental health care, yet the level of quality of life and its determinants for individuals with schizophrenia are not well known. DESIGN: Cross-sectional, descriptive design. METHODS: A total of 148 individuals with schizophrenia participated in the study. A demographic information sheet, the 18-item Brief Psychiatric Rating Scale, the Chinese Health Questionnaires, the Mutuality Scale and the World Health Organization Quality of Life Scale, brief version, were used to collect data. Data were analysed with descriptive statistics, Pearson product-moment correlation and stepwise multiple linear regression. RESULTS: Most of participants were single, unemployed, had a low education level and were supported financially by family. Quality of life was positively correlated with age of mental illness onset, mutuality, employment status and monthly household income, whereas it was negatively associated with the length of mental illness, symptom severity and health status. Health status, mutuality, symptom severity, monthly household income and employment status were found to be key significant predictors with mutuality having the greatest effect on quality of life. CONCLUSIONS: The findings increase our understanding of socio-demographic, clinical and psychosocial characteristics influencing the degree of quality of life in individuals with schizophrenia. Incorporation of families and communities into the treatment programmes would enhance patients' capabilities of social integration and satisfaction with their lives. RELEVANCE TO CLINICAL PRACTICE: Health care providers should make use of community-oriented intervention programmes that aim to strengthen psychosocial functioning. Particularly, programmes that enhance health status and mutuality should be identified and developed for both individuals with schizophrenia and their families.