4 research outputs found
Melanocortin peptides inhibit urate crystal-induced activation of phagocytic cells
Introduction The melanocortin peptides have marked antiinflammatory
potential, primarily through inhibition of
proinflammatory cytokine production and action on phagocytic
cell functions. Gout is an acute form of arthritis caused by the
deposition of urate crystals, in which phagocytic cells and
cytokines play a major pathogenic role. We examined whether
alpha-melanocyte-stimulating hormone (\u3b1-MSH) and its
synthetic derivative (CKPV)2 influence urate crystal-induced
monocyte (Mo) activation and neutrophil responses in vitro.
Methods Purified Mos were stimulated with monosodium urate
(MSU) crystals in the presence or absence of melanocortin
peptides. The supernatants were tested for their ability to induce
neutrophil activation in terms of chemotaxis, production of
reactive oxygen intermediates (ROIs), and membrane
expression of CD11b, Toll-like receptor-2 (TLR2) and TLR4. The
proinflammatory cytokines interleukin (IL)-1\u3b2, IL-8, and tumor
necrosis factor-alpha (TNF-\u3b1) and caspase-1 were determined
in the cell-free supernatants. In parallel experiments, purified
neutrophils were preincubated overnight with or without
melanocortin peptides before the functional assays.
Results The supernatants from MSU crystal-stimulated Mos
exerted chemoattractant and priming activity on neutrophils,
estimated as ROI production and CD11b membrane
expression. The supernatants of Mos stimulated with MSU in the
presence of melanocortin peptides had less chemoattractant
activity for neutrophils and less ability to prime neutrophils for
CD11b membrane expression and oxidative burst. MSU crystalstimulated
Mos produced significant levels of IL-1\u3b2, IL-8, TNF-\u3b1,
and caspase-1. The concentrations of proinflammatory
cytokines, but not of caspase-1, were reduced in the
supernatants from Mos stimulated by MSU crystals in the
presence of melanocortin peptides. Overnight incubation of
neutrophils with the peptides significantly inhibited their ability to
migrate toward chemotactic supernatants and their capacity to
be primed in terms of ROI production.
Conclusions \u3b1-MSH and (CKPV)2 have a dual effect on MSU
crystal-induced inflammation, inhibiting the Mos' ability to
produce neutrophil chemoattractants and activating
compounds and preventing the neutrophil responses to these
proinflammatory substances. These findings reinforce previous
observations on the potential role of \u3b1-MSH and related
peptides as a new class of drugs for treatment of inflammatory
arthritis
α-Melanocyte-stimulating-hormone (α-MSH) modulates human chondrocyte activation induced by proinflammatory cytokines
Development of Phagocytic Function of Cultured Human Monocytes Is Regulated by Cell Surface IL-10
Ambroxol as a disease-modifying treatment to reduce the risk of cognitive impairment in GBA-associated Parkinson’s disease: a multicentre, randomised, double-blind, placebo-controlled, phase II trial. The AMBITIOUS study protocol
Background Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme β-glucocerebrosidase (GCase), are the most frequent genetic risk factor for Parkinson’s disease (PD). GBA-related PD (GBA-PD) patients have higher risk of dementia and reduced survival than non-carriers. Preclinical studies and one open-label trial in humans demonstrated that the chaperone ambroxol (ABX) increases GCase levels and modulates α-synuclein levels in the blood and cerebrospinal fluid (CSF).Methods and analysis In this multicentre, double-blind, placebo-controlled, phase II clinical trial, we randomise patients with GBA-PD in a 1:1 ratio to either oral ABX 1.2 g/day or placebo. The duration of treatment is 52 weeks. Each participant is assessed at baseline and weeks 12, 26, 38, 52 and 78. Changes in the Montreal Cognitive Assessment score and the frequency of mild cognitive impairment and dementia between baseline and weeks 52 are the primary outcome measures. Secondary outcome measures include changes in validated scales/questionnaires assessing motor and non-motor symptoms. Neuroimaging features and CSF neurodegeneration markers are used as surrogate markers of disease progression. GCase activity, ABX and α-synuclein levels are also analysed in blood and CSF. A repeated-measures analysis of variance will be used for elaborating results. The primary analysis will be by intention to treat.Ethics and dissemination The study and protocols have been approved by the ethics committee of centres. The study is conducted according to good clinical practice and the Declaration of Helsinki. The trial findings will be published in peer-reviewed journals and presented at conferences.Trial registration numbers NCT05287503, EudraCT 2021-004565-13