Transcription factors play a significant role during the symptomatic onset and progression of prion diseases. We previously showed the immunomodulatory and nuclear factor of activated T cells' (NFAT) suppressive effects of an immunosuppressant, FK506, in the symptomatic stage and an antibiotic, minocycline, in the pre-symptomatic stage of prion infection in hamsters. Here we used for the first time, a combinatory FK506+minocycline treatment to test its transcriptional modulating effects in the symptomatic stage of prion infection. Our results indicate that prolonged treatment with FK506+minocycline was effective in alleviating astrogliosis and neuronal death triggered by misfolded prions. Specifically, the combinatory therapy with FK506+minocycline lowered the expression of the astrocytes activation marker GFAP and of the microglial activation marker IBA-1, subsequently reducing the level of pro-inflammatory cytokines interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), and increasing the levels of anti-inflammatory cytokines IL-10 and IL-27. We further found that FK506+minocycline treatment inhibited mitogen-activated protein kinase (MAPK) p38 phosphorylation, NF-kB nuclear translocation, caspase expression, and enhanced phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated Bcl2-associated death promoter (pBAD) levels to reduce cognitive impairment and apoptosis. Interestingly, FK506+minocycline reduced mitochondrial fragmentation and promoted nuclear factor⁻erythroid2-related factor-2 (NRF2)-heme oxygenase 1 (HO-1) pathway to enhance survival. Taken together, our results show that a therapeutic cocktail of FK506+minocycline is an attractive candidate for prolonged use in prion diseases and we encourage its further clinical development as a possible treatment for this disease.
Abstract Aims : To explore the therapeutic characteristics of gestational diabetes mellitus (GDM) patients receiving insulin therapy during pregnancy. Methods : In this retrospective study, 790 GDM patients from Shanghai General Hospital were enrolled. Information consisting of demographic and laboratory data, the insulin treatment protocol, and daily insulin dosage before delivery were collected. Results : A total of 236 (29.87%) GDM patients received insulin treatment. Fasting plasma glucose (FPG), 1-hour plasma glucose (1hPG), HbA1c, and gestational week at diagnosis were associated with insulin treatment. The average daily insulin dosages were 0.15, 0.27, 0.29, and 0.50 U/kg, from once daily to four daily injections, while insulin pump users received 0.62 U/kg ( P for trend<0.001). FPG, 1hPG, and HbA1c at diagnosis showed significant value for predicting the need for four daily insulin injectionsbefore delivery in ROC analysis (all P <0.001), and the cut-off values were 5.6 mmol/L, 10.4 mmol/L, and 5.7%. The AUC for the model considering FPG, 1hPG, and HbA1c together was larger than that of any single variable (all P <0.05). Conclusion : The average daily insulin dosage before delivery increased with the frequency of insulin injections. Patients with FPG ³5.6 mmol/L, 1hPG ³10.4 mmol/L, and HbA1c ³5.7% at diagnosis required intensive insulin therapy before delivery.
Diabetic retinopathy (DR) is the leading cause of blindness among the working-age population. Although controlling blood glucose levels effectively reduces the incidence and development of DR to less than 50%, there are currently no diagnostic biomarkers or effective treatments for DR development in glucose-well-controlled diabetic patients (GW-DR). In this study, we established a prospective GW-DR cohort by strictly adhering to glycemic control guidelines and maintaining regular retinal examinations over a median 2-year follow-up period. The discovery cohort encompassed 71 individuals selected from a pool of 292 recruited diabetic patients at baseline, all of whom consistently maintained hemoglobin A1c (HbA1c) levels below 7% without experiencing hypoglycemia. Within this cohort of 71 individuals, 21 subsequently experienced new-onset GW-DR, resulting in an incidence rate of 29.6%. In the validation cohort, we also observed a significant GW-DR incidence rate of 17.9%. Employing targeted metabolomics, we investigated the metabolic characteristics of serum in GW-DR, revealing a significant association between lower levels of ethanolamine and GW-DR risk. This association was corroborated in the validation cohort, exhibiting superior diagnostic performance in distinguishing GW-DR from diabetes compared to the conventional risk factor HbA1c, with AUCs of 0.954 versus 0.506 and 0.906 versus 0.521 in the discovery and validation cohorts, respectively. Furthermore, in a streptozotocin (STZ)-induced diabetic rat model, ethanolamine attenuated diabetic retinal inflammation, accompanied by suppression of microglial diacylglycerol (DAG)-dependent protein kinase C (PKC) pathway activation. In conclusion, we propose that ethanolamine is a potential biomarker and represents a viable biomarker-based therapeutic option for GW-DR.
This thesis explores the correlation between changes in Taiwanese identity and presentations of the performing arts at Taiwan’s National Performing Arts Centre, formerly the National Chiang Kai-shek Cultural Centre, an institution that operates at arm’s-length from the Government. It also investigates the way the Centre operates in relation to national cultural policy. The evolution of Taiwanese identity and government cultural policy between 1949 and 2017 is analysed with a special focus on 1987-2017 to see whether any changes are reflected in the Centre’s programmes. Senior politicians, artists and arts administrators were interviewed about the way government cultural policy is formulated and how programming at the Centre has responded. All confirm that changes in cultural policy are only related to the work of the Centre through a general understanding of the zeitgeist, rather than ministerial demands. Government policy is worded so generally that it does not dictate how the Centre should operate, so although programming has changed along with cultural policy, it is not because of it. Analysis of the Centre’s programming shows that it reflects the way the performing arts in Taiwan have developed along with its identity from traditional Chinese to multicultural Taiwanese. The Centre responds to national identity and also helps to create it. Thus, programming mirrors the development of the way both cultural policy and Taiwanese identity has changed. The Centre is responsible to a government-appointed Board, rather than to the Government itself, but this does not mean that it is free of government control. The Centre values its freedom of operation but is sensitive to the unwritten limits to its activity and to its dependency on continued government subsidy.
Prion diseases are neurodegenerative diseases associated with neuron damage and behavioral disorders in animals and humans.Melatonin is a potent antioxidant and is used to treat a variety of diseases.We investigated the neuroprotective effect of melatonin on prion-induced damage in N2a cells.N2a cells were pretreated with 10 μM melatonin for 1 hour followed by incubation with 100 μM PrP 106-126 for 24 hours.Melatonin markedly alleviated PrP 106-126 -induced apoptosis of N2a cells, and inhibited PrP 106-126 -induced mitochondrial abnormality and dysfunction, including mitochondrial fragmentation and overproduction of reactive oxygen species (ROS), suppression of ATP, reduced mitochondrial membrane potential (MMP), and altered mitochondrial dynamic proteins dynamin-related protein 1 (DRP1) and optic atrophy protein 1 (OPA1).Our findings identify that pretreatment with melatonin prevents the deleterious effects of PrPSc on mitochondrial function and dynamics, protects synapses and alleviates neuron damage.Melatonin could be a novel and effective medication in the therapy of prion diseases.
Humanin (MT-RNR2) is an endogenous polypeptide that is involved in many diseases, including T2DM. Gestational diabetes mellitus (GDM) is defined as hyperglycemia during pregnancy. The aim of this study was to evaluate serum humanin levels in women with or without GDM and to elucidate possible correlations with anthropometric parameters, metabolic parameters and the incidence of GDM. Eighty-four women with GDM and 73 control women were enrolled in this study. The clinical and biochemical parameters of all subjects were determined. Serum humanin levels were measured by an ELISA. Serum humanin levels were significantly lower in women with GDM than in control women. Moreover, humanin levels were significantly negatively correlated with the presence of GDM, body weight, BMI at 24 weeks of gestation, TG, FPG, 1 hPG, 2 hPG, FINS, and HOMA-IR. In contrast, humanin levels were significantly positively correlated with FT3 and FT4. A binary logistic analysis showed that humanin levels were associated with the incidence of GDM. Additional follow-up studies are needed to highlight whether and how decreased humanin levels play an important role in GDM.摘要 Humanin (MT-RNR2)是一种内源性多肽, 与很多疾病相关, 包括2 型糖尿病。 妊娠期糖尿病（GDM）是指在妊娠期的血糖异常升高。本研究的目的就是比较血清humanin多肽在患和不患妊娠期糖尿病女性之间的差别, 并阐明humanin多肽与人体某些参数, 代谢指标及GDM发生率之间可能存在的相关性。84名GDM女性与73名正常妊娠女性纳入该研究。记录所有患者的临床及生物代谢指标, 血清humanin多肽水平用ELISA方法检测。结果显示, GDM患者中humanin多肽的水平显著低于对照组, humanin多肽的水平与GDM发生率、体重及妊娠24周时BMI、甘油三酯、空腹血糖、1小时空腹血糖, 2小时空腹血糖、胰岛素及胰岛素抵抗指数之间存在显著的负相关。相反, humanin多肽的水平与FT3和 FT4呈显著的正相关。二元的Logistic回归分析显示humanin多肽水平与GDM的发生率相关。尚需要进一步的研究来证实humanin多肽水平的降低是否在GDM的发生中起着重要的作用, 又是如何起作用的。.
Prion diseases are neurodegenerative disorders characterized by the accumulation of misfolded prion protein, spongiform changes in the brain, and brain inflammation as a result of the wide-spread activation of microglia. Autophagy is a highly conserved catabolic process for the clearance of cytoplasmic components, including protein aggregates and damaged organelles; this process also eliminates pathological PrPSc as it accumulates during prion infection. The NALP3 inflammasome is a multiprotein complex that is a component of the innate immune system and is responsible for the release of pro-inflammatory cytokines. Our previous study showed that the neurotoxic prion peptide PrP106-126 induces NALP3 inflammasome activation and subsequent IL-1β release in microglia. Autophagy is involved in the regulation of the immune responses and inflammation in many diseases including neurodegenerative diseases. However, the relationship between autophagy and NALP3 inflammasome in prion diseases has not been investigated. In this study, we demonstrated that the processing and release of mature IL-1β is significantly enhanced by the inhibition of autophagy. Conversely, gene-silencing of the NALP3 inflammasome promotes autophagy. Suppression of TRIF or TLR4 by siRNA attenuated PrP106-126-induced autophagy, which is indicating that the TLR4-TRIF signaling pathway is involved in PrP106-26-induced autophagy. Caspase 1 directly cleaved TRIF to diminish TLR-4-TRIF mediated autophagy, Our findings suggest that the inhibition of autophagy by NALP3 inflammasome is probably mediated by activated Caspase-1-induced TRIF cleavage. This is the first study reporting that the NALP3 inflammasome complex negatively regulates autophagy in response to PrP106-126 stimulation in microglia, and partly explain the mechanism of autophagy inhibition by Caspase-1 in PrP106-126-induced BV2 cell activation. Our findings suggest that autophagy up-regulation and inhibition of Caspase-1 may protect against prion-induced neuroinflammation and accelerate misfolded protein degradation and are potential therapeutic approaches for prion diseases.
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