Secukinumab demonstrates high efficacy and a favorable safety profile over 52 weeks in Chinese patients with moderate to severe plaque psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease, affecting about 0.6% of the Chinese population. Many patients are not well controlled by conventional treatments, thus there is need for new treatment regimens. In this study, we assessed the efficacy and safety of secukinumab in Chinese patients with moderate to severe plaque psoriasis. METHODS: This study was a 52-week, multicentre, randomized, double-blind, placebo-controlled, parallel-group, Phase 3 trial. A sub-population of study participants (≥18 years) of Chinese ethnicity were randomized to receive subcutaneous injections of 300 or 150 mg secukinumab, or placebo. The co-primary endpoints were psoriasis area severity index (PASI) 75 and Investigator's Global Assessment (IGA) 0/1 at Week 12. RESULTS: A total of 441 Chinese patients were enrolled in this study. Co-primary outcomes were achieved; 300 and 150 mg secukinumab were superior to placebo as shown in the proportion of patients that achieved PASI 75 (97.7% and 87.2% vs. 3.7%, respectively; P < 0.001), and IGA 0/1 (82.3% and 69.7% vs. 2.7%; P < 0.001) at Week 12. Treatment efficacy was maintained until Week 52. There was no increase in overall adverse events with secukinumab relative to placebo throughout the 52-week period. CONCLUSION: Secukinumab is highly effective and well tolerated in Chinese patients with moderate to severe plaque psoriasis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03066609; https://clinicaltrials.gov/ct2/show/record/NCT03066609.

PRAS40 alleviates neurotoxic prion peptide-induced apoptosis via mTOR-AKT signaling.

AIMS: The proline-rich Akt substrate of 40-kDa (PRAS40) protein is a direct inhibitor of mTORC1 and an interactive linker between the Akt and mTOR pathways. The mammalian target of rapamycin (mTOR) is considered to be a central regulator of cell growth and metabolism. Several investigations have demonstrated that abnormal mTOR activity may contribute to the pathogenesis of several neurodegenerative disorders and lead to cognitive deficits. METHODS: Here, we used the PrP peptide 106-126 (PrP106-126 ) in a cell model of prion diseases (also known as transmissible spongiform encephalopathies, TSEs) to investigate the mechanisms of mTOR-mediated cell death in prion diseases. RESULTS: We have shown that, upon stress caused by PrP106-126 , the mTOR pathway activates and contributes to cellular apoptosis. Moreover, we demonstrated that PRAS40 down-regulates mTOR hyperactivity under stress conditions and alleviates neurotoxic prion peptide-induced apoptosis. The effect of PRAS40 on apoptosis is likely due to an mTOR/Akt signaling. CONCLUSION: PRAS40 inhibits mTORC1 hyperactivation and plays a key role in protecting cells against neurotoxic prion peptide-induced apoptosis. Thus, PRAS40 is a potential therapeutic target for prion disease.

Overexpression of BAT3 alleviates prion protein fragment PrP106-126-induced neuronal apoptosis.

BACKGROUNDS AND AIMS: Prion diseases are a group of infectious neurodegenerative diseases characterized by neuronal death and degeneration. Human leukocyte antigen-B-associated transcript 3 (BAT3) is an important apoptosis regulator. We therefore investigated the interactions between BAT3 and prion protein and the potential role of BAT3 in PrP106-126-induced apoptosis. METHODS: BAT3 and prion protein were overexpressed in Hela, Neuro2A, or primary neuronal cells by transfection with BAT3-HA or PRNP-EGFP expression plasmids and their relationship studied by immunofluorescence and Western blotting. The effect of BAT3 on PrP106-126-induced cytotoxicity and apoptosis was detected by the CCK-8 assay and terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. The expression of cytochrome c and Bcl-2 was examined by Western blotting. RESULTS: BAT3 interacted with prion protein and enhanced PrP expression. After PrP106-126 peptide treated, BAT3 was transported from the nucleus to cytoplasm, increased cell viability, and protected neurons from PrP106-126-induced apoptosis through stabilizing the level of Bcl-2 protein and inhibiting the release of cytochrome c to cytoplasm. CONCLUSIONS: Our present data showed a novel molecular mechanism of PrP106-126-induced apoptotic process regulation through the overexpression of BAT3, which may be important for the basic regulatory mechanism of neuron survival in prion diseases and associated neurodegenerative diseases in vivo.