Dataset Information

Beta-amyloid Deposition in Biliary Atresia Reduces Liver Regeneration by Inhibiting Energy Metabolism and Mammalian Target of Rapamycin Signaling.

ABSTRACT:

Introduction

Biliary atresia (BA) is a devastating obstructive bile duct disease found in newborns. This study aims to investigate the roles and involved mechanisms of beta-amyloid (Aβ) in the pathogenesis of BA.

Methods

We examined the distribution of Aβ protein and its precursor in the livers of patients with BA. A murine liver organoid and a zebrafish model were established to investigate the exact roles of Aβ in liver regeneration for BA.

Results

Both Aβ mRNA and protein significantly increased in livers of infants with BA and deposited around the central vein. In the plasma, Aβ elevated significantly in patients with BA and positively correlated with liver injury progression. In vitro , Aβ treatment induced abnormal morphology and caused impaired growth in liver organoids. Energy metabolism analysis demonstrated Aβ increased aerobic glycolysis and reduced ATP synthase in organoids, in which the mammalian target of rapamycin signaling was suppressed. In vivo , Aβ42 exposure caused liver degeneration in zebrafish larvae.

Discussion

Aβ depositing in livers of infants with BA reduced the liver regeneration through attenuating mitochondrial respiration and mammalian target of rapamycin signaling.

SUBMITTER: Tian X

PROVIDER: S-EPMC10476755 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Beta-amyloid Deposition in Biliary Atresia Reduces Liver Regeneration by Inhibiting Energy Metabolism and Mammalian Target of Rapamycin Signaling.

Tian Xinbei X Wang Ying Y Zhou Ying Y Wu Bo B Lu Ying Y Du Jun J Wang Weipeng W Cai Wei W Xiao Yongtao Y

Clinical and translational gastroenterology 20221101 11

<h4>Introduction</h4>Biliary atresia (BA) is a devastating obstructive bile duct disease found in newborns. This study aims to investigate the roles and involved mechanisms of beta-amyloid (Aβ) in the pathogenesis of BA.<h4>Methods</h4>We examined the distribution of Aβ protein and its precursor in the livers of patients with BA. A murine liver organoid and a zebrafish model were established to investigate the exact roles of Aβ in liver regeneration for BA.<h4>Results</h4>Both Aβ mRNA and protei ...[more]

PMID: 36137184

Similar Datasets

Project description:BackgroundThe progression of Biliary Atresia (BA) is associated with the number of reactive ductular cells (RDCs) whose heterogeneity in origin and evolution in humans remains unknown. SOX9-positive liver progenitor-like cells (LPLCs) have been shown to participate in RDCs and new hepatocyte formation during cholestatic liver regeneration in an animal model, which implies the possibility that hepatocyte-reprogrammed LPLCs could be a source of RDCs in BA. The present study aimed to elucidate the characteristics of SOX9-positive LPLCs in BA for exploring new possible therapeutic targets by manipulating the bi-differentiation process of LPLCs to prevent disease progression.MethodsTwenty-eight patients, including 24 patients with BA and 4 patients with Congenital Choledochal Cyst as the control group, were retrospectively recruited. Liver biopsy samples were classified histologically using a 4-point scale based on fibrosis severity. LPLCs were detected by SOX9 and HNF4A double positive staining. Single immunohistochemistry, double immunohistochemistry, and multiple immunofluorescence staining were used to determine the different cell types and characteristics of LPLCs.ResultsThe prognostic predictors of BA, namely total bile acid (TBA), RDCs, and fibrosis, were correlated to the emergence of LPLCs. SOX9 and HNF4A double-positive LPLCs co-stained rarely with relevant markers of portal hepatic progenitor cells (portal-HPCs), including CK19, CK7, EPCAM, PROM1 (CD133), TROP2, and AFP. Under cholestasis conditions, LPLCs acquired superior proliferation and anti-senescence ability among hepatocytes. Moreover, LPLCs arranged as a pseudo-rosette structure appeared from the periportal parenchyma to the portal region, which implied the differentiation from hepatocyte-reprogrammed LPLCs to RDCs with the progression of cholestasis.ConclusionsLPLCs are associated with disease progression and prognostic factors of BA. The bipotent characteristics of LPLCs are different from those of portal-HPCs. As cholestasis progresses, LPLCs appear to gain superior proliferation and anti-senescence ability and continually differentiate to RDCs.

Project description:UnlabelledMalaria is an infectious disease caused by parasites of several Plasmodium spp. Cerebral malaria (CM) is a common form of severe malaria resulting in nearly 700,000 deaths each year in Africa alone. At present, there is no adjunctive therapy for CM. Although the mechanisms underlying the pathogenesis of CM are incompletely understood, it is likely that both intrinsic features of the parasite and the human host's immune response contribute to disease. The kinase mammalian target of rapamycin (mTOR) is a central regulator of immune responses, and drugs that inhibit the mTOR pathway have been shown to be antiparasitic. In a mouse model of CM, experimental CM (ECM), we show that the mTOR inhibitor rapamycin protects against ECM when administered within the first 4 days of infection. Treatment with rapamycin increased survival, blocked breakdown of the blood-brain barrier and brain hemorrhaging, decreased the influx of both CD4(+) and CD8(+) T cells into the brain and the accumulation of parasitized red blood cells in the brain. Rapamycin induced marked transcriptional changes in the brains of infected mice, and analysis of transcription profiles predicted that rapamycin blocked leukocyte trafficking to and proliferation in the brain. Remarkably, animals were protected against ECM even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen. These results open a new avenue for the development of highly selective adjunctive therapies for CM by targeting pathways that regulate host and parasite metabolism.ImportanceMalaria is a highly prevalent infectious disease caused by parasites of several Plasmodium spp. Malaria is usually uncomplicated and resolves with time; however, in about 1% of cases, almost exclusively among young children, malaria becomes severe and life threatening, resulting in nearly 700,000 deaths each year in Africa alone. Among the most severe complications of Plasmodium falciparum infection is cerebral malaria with a fatality rate of 15 to 20%, despite treatment with antimalarial drugs. Cerebral malaria takes a second toll on African children, leaving survivors at high risk of debilitating neurological defects. At present, we have no effective adjunctive therapies for cerebral malaria, and developing such therapies would have a large impact on saving young lives in Africa. Here we report results that open a new avenue for the development of highly selective adjunctive therapies for cerebral malaria by targeting pathways that regulate host and parasite metabolism.

Dataset Information

Beta-amyloid Deposition in Biliary Atresia Reduces Liver Regeneration by Inhibiting Energy Metabolism and Mammalian Target of Rapamycin Signaling.

Introduction

Methods

Results

Discussion

Publications

Beta-amyloid Deposition in Biliary Atresia Reduces Liver Regeneration by Inhibiting Energy Metabolism and Mammalian Target of Rapamycin Signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets