Highlights d Ab induces metabolic reprogramming of microglia from OXPHOS to glycolysis d Metabolic reprogramming of microglia is dependent on the mTOR-HIF-1a pathway d Chronic exposure to Ab induces metabolic defects of microglia d Metabolic boosting with IFN-g restores immunological function of microglia
ObjectiveCerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive.DesignUsing a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis.ResultsComposition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice.ConclusionThese results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.
Activation of protein kinase C (PKC) has been implicated in gastric carcinogenesis. Enzastaurin is an oral ATP-competitive inhibitor of the PKCB isozyme. Although enzastaurin was initially advanced to the clinic based on its antiangiogenic activity, it is also known to have a direct effect on a variety of human cancer cells, inducing apoptosis by inhibiting the Akt signal pathway. However, data on enzastaurin for gastric cancer are limited. Therefore, this study was performed to assess the antitumor activity of enzastaurin on gastric cancer cells and to investigate the underlying antitumor mechanisms. Enzastaurin suppressed the proliferation of cultured gastric cancer cells and the growth of gastric carcinoma xenografts. Enzastaurin did not have an effect on gastric cancer cell cycle progression; however, it had a direct apoptosis-inducing effect through the caspase-mediated mitochondrial pathway. Glycogen synthase kinase 3B phosphorylation, a reliable pharmacodynamic marker of enzastaurin activity, and Akt phosphorylation were both decreased after treatment with enzastaurin. Although the p90 ribosomal S6 kinase (Rsk) was also dephosphorylated, Erk phosphorylation was not affected in the enzastaurin-treated gastric cancer cells. Enzastaurin activated Bad, one of the Bcl-2 proapoptotic proteins, through dephosphorylation at Ser 112 , and depletion of Bad activity resulted in resistance to enzastaurin-induced apoptosis and cytotoxicity in gastric cancer cells. These data suggest that enzastaurin induces apoptosis through Rsk-mediated and Badmediated pathways, besides inhibiting the Akt signal cascade. Furthermore, enzastaurin had synergistic or additive effects when combined with 5-fluorouracil, cisplatin, paclitaxel, or irinotecan. These results warrant further clinical investigation of enzastaurin for gastric cancer treatment. [Cancer Res 2008;68(6):1916-26]
The aggregation of amyloid beta (Ab)p roteins in senile plaques is ac ritical event during the development of Alzheimersdisease,and the postmortem detection of Ab-rich proteinaceous deposits through fluorescent staining remains one of the most robust diagnostic tools.I na nimal models, fluorescence imaging can be employed to follow the progression of the disease,and among the different imaging methods, two-photon microscopy(TPM) has emerged as one of the most powerful. To date,s everal near-infrared-emissive two-photon dyes with ahigh affinity for Ab fibrils have been developed, but there has often been at radeoff between excellent two-photon cross-sections and large fluorescence signal-to-background ratios.I nt he current work, we introduced at wisted intramolecular charge state (TICT)-based de-excitation pathway, which results in aremarkable fluorescence increase of around 167-fold in the presence of Ab fibrils,w hile maintaining an excellent two-photon cross section, thereby enabling highcontrast ex vivo and in vivo TPM imaging. Overall, the results suggest that adopting TICT de-excitation in two-photon fluorophores may represent ag eneral method to overcome the tradeoff between probe brightness and signal-to-background ratio.
A novel fluorescent sensor based on the Zn2+-DPA complex shows selective detection of flavin adenine dinucleotide (FAD) from among other flavins in water, and it was used to detect FAD in eosinophils by fluorescence microscopy and FACS.
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