Pancreatitis is a common gastrointestinal disorder that causes hospitalization with significant morbidity and mortality.The mechanistic pathophysiology of pancreatitis is complicated,limiting the discovery of pharmacological intervention methods.Here,we show that the administration of ATN-161,an antagonist of Integrin-a5,significantly mitigates the pathological condition of acute pancreatitis induced by caerulein.We find that CK19-positive pancreatic ductal cells align parallel to blood vessels in the pancreas.In the caerulein-induced acute pancreatitis model,the newly emergent CK19-positive cells are highly vascularized,with a significant increase in vascular density and endothelial cell number.Single-cell RNA sequencing analysis shows that ductal and endothelial cells are intimate interacting partners,suggesting the existence of a ductal-endothelial interface in the pancreas.Pancreatitis dramatically reduces the crosstalk in the ductal-endothelial interface but promotes the Spp-1/Integrin-a5 signaling.Blocking this signaling with ATN-161 significantly reduces acinar-to-ductal metaplasia,pathological angiogenesis,and restores other abnormal defects induced by caerulein.Our work reveals the therapeutic potential of ATN-161 as an uncharacterized pharmacological method to alleviate the symptoms of pancreatitis.
Background Gaining more information about the reciprocal associations between different biomarkers within the ATN(Amyloid/Tau/Neurodegeneration)framework across the Alzheimer’s disease(AD)spectrum is clinically relevant.We aimed to conduct a comprehensive head-to-head comparison of plasma and positron emission tomography(PET)ATN biomarkers in subjects with cognitive complaints.Methods A hospital-based cohort of subjects with cognitive complaints with a concurrent blood draw and ATN PET imaging(18F-florbetapir for A,18F-Florzolotau for T,and 18F-fluorodeoxyglucose[18F-FDG]for N)was enrolled(n=137).Theβ-amyloid(Aβ)status(positive versus negative)and the severity of cognitive impairment served as the main outcome measures for assessing biomarker performances.Results Plasma phosphorylated tau 181(p-tau181)level was found to be associated with PET imaging of ATN biomarkers in the entire cohort.Plasma p-tau181 level and PET standardized uptake value ratios of AT biomarkers showed a similarly excellent diagnostic performance for distinguishing between Aβ+and Aβ−subjects.An increased tau burden and glucose hypometabolism were significantly associated with the severity of cognitive impairment in Aβ+subjects.Additionally,glucose hypometabolism-along with elevated plasma neurofilament light chain level-was related to more severe cognitive impairment in Aβ−subjects.Conclusion Plasma p-tau181,as well as 18F-florbetapir and 18F-Florzolotau PET imaging can be considered as interchangeable biomarkers in the assessment of Aβstatus in symptomatic stages of AD.18F-Florzolotau and 18F-FDG PET imaging could serve as biomarkers for the severity of cognitive impairment.Our findings have implications for establishing a roadmap to identifying the most suitable ATN biomarkers for clinical use.
Tau proteins accumulation and their spreading pattern were afected by gender in cognitive impairment patients,especially in the progression of Alzheimer’s disease(AD).However,it was unclear whether the gender efects for tau deposition infuenced by amyloid deposition.The aim of this study was to investigate gender diferences for tau depositions in Aβpositive(A^(+))subjects.In this study,tau and amyloid positron emission tomography images,structural magnetic resonance imaging images,and demographic information were collected from 179 subjects in Alzheimer’s Disease Neuroimaging Initiative(ADNI)database and 63 subjects from Huashan Hospital.Subjects were classifed as T^(+)or T^(-)according to the presence or absence of tau(T)biomarkers.We used two-sample t test and one-way analysis of variance test to analyze the efect of gender with adjusting for age,years of education,and Minimum Mental State Examination.In the ADNI cohort,we found diferences in Tau deposition in fusiform gyrus,inferior temporal gyrus,middle temporal gyrus and parahippocampal gyrus between the female T^(+)(FT^(+))and male T^(+)(MT^(+))groups(p<0.05).Tau deposition did not difer signifcantly between female T^(-)(FT^(-))and male T^(-)(MT^(-))subjects(p>0.05).In the Huashan Hospital cohort,there was no diference in Tau deposition between FT^(+)and MT^(+)(p>0.05).The results show that tau depositions signifcantly increased in females in above brain regions.Our fndings suggest that tau deposition is infuenced by gender in the A+subjects.This result has important clinical implications for the development of gender-guided early interventions for patients with both Tau and Amyloid depositions.