Dataset Information

Skin Mast Cell-Driven Ceramides Drive Early Apoptosis in Pre-Symptomatic Eczema in Mice.

ABSTRACT: Atopic dermatitis (AD or eczema) is the most common chronic inflammatory skin disorder worldwide. Ceramides (Cer) maintain skin barrier functions, which are disrupted in lesional skin of AD patients. However, Cer status during the pre-lesional phase of AD is not well defined. Using a variation of human AD-like preclinical model consisting of a 7-day topical exposure to ovalbumin (OVA), or control, we observed elevation of Cer C16 and C24. Skin mRNA quantification of enzymes involved in Cer metabolism [Cer synthases (CerS) and ceramidases (Asah1/Asah2)], which revealed augmented CerS 4, 5 and 6 and Asah1. Given the overall pro-apoptotic nature of Cer, local apoptosis was assessed, then quantified using novel morphometric measurements of cleaved caspase (Casp)-3-restricted immunofluorescence signal in skin samples. Apoptosis was induced in response to OVA. Because apoptosis may occur downstream of endoplasmic reticulum (ER) stress, we measured markers of ER stress-induced apoptosis and found elevated skin-associated CHOP protein upon OVA treatment. We previously substantiated the importance of mast cells (MC) in initiating early skin inflammation. OVA-induced Cer increase and local apoptosis were prevented in MC-deficient mice; however, they were restored following MC reconstitution. We propose that the MC/Cer axis is an essential pathogenic feature of pre-lesional AD, whose targeting may prevent disease development.

SUBMITTER: Robida PA

PROVIDER: S-EPMC8346072 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:IntroductionAlzheimer's disease (AD) is highly heterogeneous, with substantial individual variabilities in clinical progression and neurobiology. Amyloid deposition has been thought to drive cognitive decline and thus a major contributor to the variations in cognitive deterioration in AD. However, the clinical heterogeneity of patients with early symptomatic AD (mild cognitive impairment or mild dementia due to AD) already with evidence of amyloid abnormality in the brain is still unknown.MethodsParticipants with a baseline diagnosis of mild cognitive impairment or mild dementia, a positive amyloid-PET scan, and more than one follow-up Alzheimer's Disease Assessment Scale-Cognitive Subscale-13 (ADAS-Cog-13) administration within a period of 5-year follow-up were selected from the Alzheimer's Disease Neuroimaging Initiative database (n = 421; age = 73±7; years of education = 16 ± 3; percentage of female gender = 43%; distribution of APOE4 carriers = 68%). A non-parametric k-means longitudinal clustering analysis in the context of the ADAS-Cog-13 data was performed to identify cognitive subtypes.ResultsWe found a highly variable profile of cognitive decline among patients with early AD and identified 4 clusters characterized by distinct rates of cognitive progression. Among the groups there were significant differences in the magnitude of rates of changes in other cognitive and functional outcomes, clinical progression from mild cognitive impairment to dementia, and changes in markers presumed to reflect neurodegeneration and neuronal injury. A nomogram based on a simplified logistic regression model predicted steep cognitive trajectory with an AUC of 0.912 (95% CI: 0.88 - 0.94). Simulation of clinical trials suggested that the incorporation of the nomogram into enrichment strategies would reduce the required sample sizes from 926.8 (95% CI: 822.6 - 1057.5) to 400.9 (95% CI: 306.9 - 516.8).DiscussionOur findings show usefulness in the stratification of patients in early AD and may thus increase the chances of finding a treatment for future AD clinical trials.

Project description:Cognitive decline accompanying the clinically more salient motor symptoms of Huntington's disease (HD) has been widely noted and can precede motor symptoms onset. Less clear is how such decline bears on language functions in everyday life, though a small number of experimental studies have revealed difficulties with the application of rule-based aspects of language in early stages of the disease. Here we aimed to determine whether there is a systematic linguistic profile that characterizes spontaneous narrative speech in both pre-manifest and/or early manifest HD, and how it is related to striatal degeneration and neuropsychological profiles. Twenty-eight early-stage patients (19 manifest and 9 gene-carriers in the pre-manifest stage), matched with 28 controls, participated in a story-telling task. Speech was blindly scored by independent raters according to fine-grained linguistic variables distributed over 5 domains for which composite scores were computed (Quantitative, Fluency, Reference, Connectivity, and Concordance). Voxel-based morphometry (VBM) was used to link specific brain degeneration patterns to loci of linguistic decline. In all of these domains, significant differences were observed between groups. Deficits in Reference and Connectivity were seen in the pre-manifest stage, where no other neuropsychological impairment was detected. Among HD patients, there was a significant positive correlation only between the values in the Quantitative domain and gray matter volume bilaterally in the putamen and pallidum. These results fill the gap of qualitative data of spontaneous narrative speech in HD and reveal that HD is characterized by systematic linguistic impairments leading to dysfluencies and disorganization in core domains of grammatical organization. This includes the referential use of noun phrases and the embedding of clauses, which mediate crucial dimensions of meaning in language in its normal social use. Moreover, such impairment is seen prior to motor symptoms onset and when standardized neuropsychological test profiles are otherwise normal.

Dataset Information

Skin Mast Cell-Driven Ceramides Drive Early Apoptosis in Pre-Symptomatic Eczema in Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets