ABSTRACT
Introduction: Diabetes mellitus (DM) is characterized by chronic hyperglycemia and diabetic complications. Exacerbated cortical neuronal degeneration was observed in Alzheimer's disease (AD) patients with DM. In fact, DM is now considered a risk factor of AD, as DM-induced activation of stress responses in the central nervous system (CNS) such as oxidative stress and neuroinflammation may lead to various neurodegenerative disorders. Methylglyoxal (MG) is one of the most reactive advanced glycation end-product (AGE) precursors. Abnormal accumulation of MG is observed in the serum of diabetic patients. As MG is reported to promote brain cells impairment in the CNS, and it is found that AGEs are abnormally increased in the brains of AD patients. Therefore, the effect of MG causing subsequent symptoms of AD was investigated. Methods: 5-week-old C57BL/6 mice were intraperitoneally injected with MG solution for 11 weeks. The Morris water maze (MWM) was used to examine the spatial learning ability and cognition of mice. After MG treatment, MTT assay, real-time PCR analyses, and Western blot were performed to assess the harvested astrocytes and hippocampi. Results: Significantly longer escape latency and reduced percentage time spent in the target quadrant were observed in the 9-week-MG-treated mice. We have found in both in vitro and in vivo models that MG induced astrogliosis, pro-inflammatory cytokines, AD-related markers, and ERK activation. Further, trend of normalization of the tested markers mRNA expressions were observed after ERK inhibition. Conclusion: Our in vivo results suggested that MG could induce AD symptoms and in vitro results implied that ERK may regulate the promotion of inflammation and Aß formation in MG-induced reactive astrocytes. Taken together, MG may participate in the dysfunction of brain cells resulting in possible diabetes-related neurodegeneration by promoting astrogliosis, Aß production, and neuroinflammation through the ERK pathway. Our findings provide insight of targeting ERK as a therapeutic application for diabetes-induced AD.
ABSTRACT
BACKGROUND & AIMS: In cirrhosis, superimposed inflammation often culminates in acute-on-chronic liver failure (ACLF) but the mechanism underlying this increased sensitivity is not clear. Cx43 is a ubiquitous gap junction protein that allows transmission of signals between cells at a much higher rate than the constitutively expressed gap junctions. The aims of the study were to test the hypothesis that inflammation drives the increased expression of hepatic Cx43 and to determine its role by Cx43 inhibition. METHODS: Four weeks after bile-duct ligation (BDL) or sham operation, rats were treated with an anti-TNF antibody, or saline; with or without LPS (1mg/kg); given 3h prior to termination. Biochemistry and cytokines were measured in the plasma and hepatic protein expression (NFkB, TNFα, iNOS, 4HNE, Cx26, 32, and 43) and confocal microscopy (Cx26, 32, and 43) were performed. The effect of a Cx43-specific inhibitory peptide was studied in a mouse BDL model. RESULTS: BDL animals administered LPS developed typical features of ACLF but animals administered infliximab were relatively protected. Cx26/32 expression was significantly decreased in BDL animals while Cx43 was significantly increased and increased further following LPS. Infliximab treatment prevented this increase. However, inhibiting Cx43 in BDL mice produced detrimental effects with markedly greater hepatocellular necrosis. CONCLUSIONS: The results of this study show for the first time an increased expression of hepatic Cx43 in cirrhosis and ACLF, which was related to the severity of inflammation. This increased Cx43 expression is likely to be an adaptive protective response of the liver to allow better cell-to-cell communication.
