Serum interleukin- (IL-) 27 level has been reported to increase in patients with several autoimmune diseases; however, its significance in patients with antineutrophil cytoplasmic antibody- (ANCA-) as Show more
Serum interleukin- (IL-) 27 level has been reported to increase in patients with several autoimmune diseases; however, its significance in patients with antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitis (AAV) is unknown. In this study, we investigated the associations between serum IL-27, laboratory features, and activity of AAV and evaluate the predictive ability of serum IL-27 level for disease activity. This study included 77 AAV patients, and we collected clinical and laboratory data at blood sampling. Inflammation-related variables included white blood cell, neutrophil, lymphocyte and platelet counts, serum albumin, erythrocyte sedimentation rate, and C-reactive protein levels. Serum IL-27 and IL-18 levels were measured from stored sera using Human Magnetic Luminex® assay. High disease activity of AAV was defined as the highest tertile of Birmingham vasculitis activity score (BVAS) (≥11). The mean age of the enrolled patients was 59.9 years, and 38 (49.4%) were diagnosed as microscopic polyangiitis. In the multivariable analysis, serum albumin ( Show less
Impaired nutrient sensing and dysregulated glucose homeostasis are common in diabetes. However, how nutrient-sensitive signaling components control glucose homeostasis and β cell survival under diabet Show more
Impaired nutrient sensing and dysregulated glucose homeostasis are common in diabetes. However, how nutrient-sensitive signaling components control glucose homeostasis and β cell survival under diabetic stress is not well understood. Here, we show that mice lacking the core nutrient-sensitive signaling component mammalian target of rapamycin (mTOR) in β cells exhibit reduced β cell mass and smaller islets. mTOR deficiency leads to a severe reduction in β cell survival and increased mitochondrial oxidative stress in chemical-induced diabetes. Mechanistically, we find that mTOR associates with the carbohydrate-response element-binding protein (ChREBP)-Max-like protein complex and inhibits its transcriptional activity, leading to decreased expression of thioredoxin-interacting protein (TXNIP), a potent inducer of β cell death and oxidative stress. Consistent with this, the levels of TXNIP and ChREBP were highly elevated in human diabetic islets and Show less
Prion protein (PRNP) has been implicated in various types of neurodegenerative diseases. Although much is known about prion diseases, the function of cellular PRNP remains cryptic. Here, we show that Show more
Prion protein (PRNP) has been implicated in various types of neurodegenerative diseases. Although much is known about prion diseases, the function of cellular PRNP remains cryptic. Here, we show that PRNP mediates amyloid β1–42 (Aβ42)-induced autophagy activation through its interaction with BECN1. Treatment with Aβ42 enhanced autophagy flux in neuronal cells. Aβ42-induced autophagy activation, however, was impaired in prnp-knockout primary cortical neurons and Prnp-knockdown or prnp-knockout neuronal cells. Immunoprecipitation assays revealed that PRNP interacted with BECN1 via the BCL2-binding domain of BECN1. This interaction promoted the subcellular localization of BECN1 into lipid rafts of the plasma membrane and enhanced activity of PtdIns3K (whose catalytic subunit is termed PIK3C3, mammalian ortholog of yeast VPS34) in lipid rafts by generating PtdIns3P in response to Aβ42. Further, the levels of lipid rafts that colocalized with BECN1, decreased in the brains of aged C57BL/6 mice, as did PRNP. These results suggested that PRNP interacts with BECN1 to recruit the PIK3C3 complex into lipid rafts and thus activates autophagy in response to Aβ42, defining a novel role of PRNP in the regulation of autophagy. Show less