L-Alaninamide

Objective: To investigate the molecular mechanism of hypoxia-induced rheumatoid arthritis synovial fibroblast (RASF) activation via Notch-1 and Notch-3 signaling, and to evaluate its potential as a therapeutic target. Methods: Expression of Notch-1 intracellular domain (N1ICD), N3ICD, and hypoxia-inducible factor 1α (HIF-1α) was assessed by immunhistology in synovial tissue from patients with RA. RASFs were cultured under hypoxic conditions and normoxic conditions with or without small interfering RNAs (siRNAs), and N1ICD and N3ICD were overexpressed under normoxic conditions. Rats with collagen-induced arthritis (CIA) were administered LY411575 (inhibitor of N1ICD and N3ICD) for 15 days and 28 days, and its therapeutic efficacy was assessed by histologic and radiologic evaluation of the rat synovial tissue, and by analysis of inflammatory cytokine production in the serum of rats. Results: N1ICD, N3ICD, and HIF-1α were expressed abundantly in the synovial tissue of RA patients. HIF-1α was shown to directly regulate the expression of Notch-1 and Notch-3 genes under hypoxic conditions. Moreover, hypoxia-induced N1ICD and N3ICD expression in RASFs was blocked by HIF-1α siRNA. Notch-1 siRNA and Notch-3 siRNA inhibited hypoxia-induced RASF invasion and angiogenesis in vitro, whereas overexpression of N1ICD and N3ICD promoted these processes. In addition, Notch-1 was shown to regulate RASF migration and epithelial-mesenchymal transition under hypoxic conditions, whereas Notch-3 was shown to regulate the processes of anti-apoptosis and autophagy. Furthermore, in vivo studies in rats with CIA showed that the N1ICD and N3ICD inhibitor LY411575 had a therapeutic effect in terms of ameliorating the symptoms and severity of the disease. Conclusion: This study identified a functional link between HIF-1α, Notch-1, and Notch-3 signaling in regulating activation of RASFs and the processes involved in the pathogenesis of RA.

Development of γ-secretase inhibitors (GSIs) and modulators (GSMs) represents an attractive therapeutic opportunity for Alzheimer's disease (AD) and cancers. However, how these GSIs and GSMs target γ-secretase has remained largely unknown. Here, we report the cryoelectron microscopy (cryo-EM) structures of human γ-secretase bound individually to two GSI clinical candidates, Semagacestat and Avagacestat, a transition state analog GSI L685,458, and a classic GSM E2012, at overall resolutions of 2.6-3.1 Å. Remarkably, each of the GSIs occupies the same general location on presenilin 1 (PS1) that accommodates the β strand from amyloid precursor protein or Notch, interfering with substrate recruitment. L685,458 directly coordinates the two catalytic aspartate residues of PS1. E2012 binds to an allosteric site of γ-secretase on the extracellular side, potentially explaining its modulating activity. Structural analysis reveals a set of shared themes and variations for inhibitor and modulator recognition that will guide development of the next-generation substrate-selective inhibitors.

Objective: To assess the efficacy and safety of Aβ-targeting agents for mild to moderate Alzheimer's disease. Methods: The MEDLINE, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform search portal were searched from their inception to April 2020. We generated pooled estimates using random effects meta-analyses. Results: Nineteen randomised controlled trials, of which 17 had a low risk of bias, included 12 903 participants. The meta-analysis showed no difference in the cognitive subscale of Alzheimer's Disease Assessment Scale (ADAS-Cog) between anti-Aβ drugs and placebo (mean difference (MD): 0.20, 95% CI -0.40 to 0.81; I 2=99.8%; minimal important difference 3.1-3.8 points, moderate-certainty evidence). For ADAS-Cog, results suggested that one drug that increases Aβ clearance may differ in effect (MD: -0.96, 95% CI -0.99 to -0.92) from drugs that reduce Aβ production (MD: 0.78, 95% CI 0.25 to 1.32) (interaction p<0.000001); this difference also existed in the outcome of MMSE and CDR-SOB. Compared with placebo, anti-Aβ drug-related adverse events were as follows: anxiety, depression, diarrhoea, fatigue, rash, syncope and vomit. Discussion: From current evidence, anti-Aβ interventions are unlikely to have an important impact on slowing cognitive or functional decline. Although the subgroup analysis suggested possible benefits from Aβ clearance drugs, the analysis has limited credibility, and a benefit from drugs that increase clearance, if real, is very small. Trial registration number: PROSPERO registration number CRD42019126272.