Summary The cause of elevated level of amyloid β-peptide (Aβ42) in common late-onset sporadic (AD) has not been established. Here we show that the membrane lipid peroxidation product 4-hydroxynonenal (HNE) is associated with amyloid and neurodegenerative pathologies in AD, and that it enhances γ-secretase activity and Aβ42 production in neurons. The γ-secretase substrate receptor, nicastrin was found to be modified by HNE in cultured neurons and in brain specimens from AD patients, in which HNE-nicastrin levels were found to be correlated with increased γ-secretase activity and Aβ plaque burden. Furthermore, HNE modification of nicastrin enhanced its binding to the γ-secretase substrate, amyloid precursor protein (APP) C99. In addition, the stimulation of γ-secretase activity and Aβ42 production by HNE were blocked by an HNE-scavenging histidine analog in a 3xTgAD mouse model of AD. These findings suggest a specific molecular mechanism by which oxidative stress increases Aβ42 production in AD, and identify HNE as a novel therapeutic target upstream of the γ-secretase cleavage of APP.

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ObjectiveTo test the hypothesis that Notch signalling plays a role in the pathogenesis of rheumatoid arthritis (RA) and to determine whether pharmacological inhibition of Notch signalling with γ-secretase inhibitors can ameliorate the RA disease process in an animal model.MethodsCollagen-induced arthritis was induced in C57BL/6 or Notch antisense transgenic mice by immunisation with chicken type II collagen (CII). C57BL/6 mice were administered with different doses of inhibitors of γ-secretase, an enzyme required for Notch activation, at disease onset or after onset of symptoms. Severity of arthritis was monitored by clinical and histological scores, and in vivo non-invasive near-infrared fluorescence (NIRF) images. Micro-CT was used to confirm joint destruction. The levels of CII antibodies and cytokines in serum were determined by ELISA and bead-based cytokine assay. The expression levels of cytokines were studied by quantitative PCR in rheumatoid synovial fibroblasts.ResultsThe data show that Notch signalling stimulates synoviocytes and accelerates their production of proinflammatory cytokines and immune responses involving the upregulation of IgG1 and IgG2a. Pharmacological inhibition of γ-secretase and antisense-mediated knockdown of Notch attenuates the severity of inflammatory arthritis, including arthritis indices, paw thickness, tissue damage and neutrophil infiltration, and reduces the levels of active NF-κB, ICAM-1, proinflammatory cytokines and matrix metalloproteinase-3 activity in the mouse model of RA.ConclusionsThese results suggest that Notch is involved in the pathogenesis of RA and that inhibition of Notch signalling is a novel approach for treating RA.

Abstractβ-secretase (BACE1), an enzyme responsible for the production of amyloid β-peptide (Aβ), is increased by oxidative stress and is elevated in the brains of patients with sporadic Alzheimer's disease (AD). Here we show that oxidative stress fails to induce BACE1 expression in presenilin-1 (γ-secretase)-deficient cells and in normal cells treated with γ-secretase inhibitors. Oxidative stress-induced β-secretase activity and sAPPβ levels were suppressed by γ-secretase inhibitors. Levels of γ-and β-secretase activities were greater in brain tissue samples from AD patients compared to non-demented control subjects, and the elevated BACE1 level in the brains of 3xTgAD mice was reduced by treatment with a γ-secretase inhibitor. Our findings suggest that γ-secretase mediates oxidative stress-induced expression of BACE1 resulting in excessive Aβ production in AD. The authors declare that they have no actual or potential conflicts of interest to disclose. Appropriate approval and procedures were used concerning human subjects and animals.

This study aimed to demonstrate that curcumin (Cur)-containing graphene composites have high anticancer activity. Specifically, graphene-derivatives were used as nanovectors for the delivery of the hydrophobic anticancer drug Cur based on pH dependence. Different Cur-graphene composites were prepared based on polar interactions between Cur and the number of oxygen-containing functional groups of respective starting materials. The degree of drug-loading was found to be increased by increasing the number of oxygen-containing functional groups in graphene-derivatives. We demonstrated a synergistic effect of Cur-graphene composites on cancer cell death (HCT 116) both in vitro and in vivo. As-prepared graphene quantum dot (GQD)-Cur composites contained the highest amount of Cur nano-particles and exhibited the best anticancer activity compared to the other composites including Cur alone at the same dose. This is the first example of synergistic chemotherapy using GQD-Cur composites simultaneous with superficial bioprobes for tumor imaging.