BackgroundExtracellular accumulation of amyloid β-peptide (Aβ) is one of pathological hallmarks of Alzheimer’s disease (AD) and contributes to the neuronal loss. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress-inducible neurotrophic factor. Many groups, including ours, have proved that MANF rescues neuronal loss in several neurological disorders, such as Parkinson’s disease and cerebral ischemia. However, whether MANF exerts its protective effect against Aβ neurotoxicity in AD remains unknown.MethodsIn the present study, the characteristic expressions of MANF in Aβ1–42-treated neuronal cells as well as in the brains of APP/PS1 transgenic mice were analyzed by immunofluorescence staining, qPCR, and Western blot. The effects of MANF overexpression, MANF knockdown, or recombination human MANF protein (rhMANF) on neuron viability, apoptosis, and the expression of ER stress-related proteins following Aβ1–42 exposure were also investigated.ResultsThe results showed the increased expressions of MANF, as well as ER stress markers immunoglobulin-binding protein (BiP) and C/EBP homologous protein (CHOP), in the brains of the APP/PS1 transgenic mice and Aβ1–42-treated neuronal cells. MANF overexpression or rhMANF treatment partially protected against Aβ1–42-induced neuronal cell death, associated with marked decrease of cleaved caspase-3, whereas MANF knockdown with siRNA aggravated Aβ1–42 cytotoxicity including caspase-3 activation. Further study demonstrated that the expressions of BiP, ATF6, phosphorylated-IRE1, XBP1s, phosphorylated-eIF2α, ATF4, and CHOP were significantly downregulated by MANF overexpression or rhMANF treatment in neuronal cells following Aβ1–42 exposure, whereas knockdown of MANF has the opposite effect.ConclusionsThese findings demonstrate that MANF may exert neuroprotective effects against Aβ-induced neurotoxicity through attenuating ER stress, suggesting that an applicability of MANF as a therapeutic candidate for AD.Electronic supplementary materialThe online version of this article (10.1186/s12974-019-1429-0) contains supplementary material, which is available to authorized users.

Accumulating evidence for overexpression of FOXC1 in various types of human cancer suggests that it plays a key role in tumor biology. However, little is known about the function of FOXC1 in pancreatic ductal adenocarcinoma (PDA). This study was to investigate the expression profile of FOXC1 in PDA and its clinical significance. We detected the expression profile of FOXC1 mRNA and protein in PDA tissue and in corresponding normal tissue by quantitative reverse-transcriptase polymerase chain reaction and western blotting. Immunohistochemistry was also used in the detection of FOXC1 protein expression. The clinicopathological implications of these proteins were analyzed statistically. Survival analysis was performed to assess prognostic significance. FOXC1 mRNA was overexpressed in PDA tissue when compared with corresponding normal tissue, so was FOXC1 protein. The overexpression of FOXC1 was significantly associated with the degree of clinical stage (p < 0.001), histological differentiation (p = 0.002), and lymph node metastases (p < 0.001). Survival analysis revealed that overexpression of FOXC1 is associated with a poorer prognosis. These observations suggest that FOXC1 plays a key role in PDA and therefore may provide an opportunity for developing a novel therapeutic target as well as a prognostic marker in PDA.

The breast cancer gene 1 (BRCA1) is a tumor suppressor, and mutations or epigenetic inactivation will increase the risk of breast cancer oncogenesis. The current research aimed to explore the relationship between BRCA1 expression, prognosis, and tumor immunity in hepatocellular carcinoma (HCC). In this study, BRCA1 expression was analyzed via multiple online databases and its association with clinical characteristics, prognosis and genetic alterations was identified using the original The Cancer Genome Atlas-liver hepatocellular carcinoma cohorts. DNA methylation sites and their prognostic values were analyzed using MethSurv. The correlations between BRCA1 and immune infiltration were investigated via Tumor Immune Estimation Resource. As results, BRCA1 was significantly upregulated in tumor tissues in multiple HCC cohorts. Besides, high BRCA1 expression was correlated with race, advanced T stage, clinical stage, poor tumor grade, MSI status, and worse prognosis. Notably, BRCA1 expression was positively correlated with infiltration levels of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. The current findings imply that BRCA1 is associated with prognosis and immune infiltration, laying foundations for in-depth research on the role of BRCA1 in HCC.