ABSTRACT
Acute liver injury (ALI) is a common life-threatening condition with a high mortality rate due to liver disease-related death. However, current therapeutic interventions for ALI remain ineffective, and the development of effective novel therapies is urgently needed. Liver samples from patients with drug-induced ALI were collected to detect adenosine kinase (ADK) expression. Male C57BL/6 J mice, hepatocyte-specific ADK knockout (ADKHKO) mice, and their controls (ADKf/f) were exposed to acetaminophen (APAP) and other treatments to investigate the mechanisms of APAP-related ALI. ADK expression was significantly decreased in APAP-injured livers. Hepatocyte-specific ADK deficiency exacerbated APAP-induced ALI, while a gain-of-function approach delivering AAV-ADK, markedly alleviated APAP-induced ALI, as indicated by changes in alanine aminotransferases (ALT) levels, aspartate aminotransferase (AST) levels, neutrophil infiltration and hepatocyte death. This study showed that ADK played a critical role in ALI by activating autophagy through two signaling pathways, the adenosine monophosphate-activated protein kinase (AMPK)-mTOR pathway and the adenosine receptor A1 (ADORA1)-Akt-mTOR pathway. Furthermore, we found that metformin upregulated ADK expression in hepatocytes and protected against APAP-induced ALI. These results demonstrate that ADK is critical in protecting against APAP-induced ALI and that developing therapeutics targeting ADK-adenosine-ADORA1 is a new approach for ALI treatment. Metformin is a potential candidate for preventing ALI by upregulating ADK.
Subject(s)
Acetaminophen , Adenosine Kinase , Autophagy , Chemical and Drug Induced Liver Injury , Hepatocytes , Signal Transduction , Animals , Humans , Male , Mice , Acetaminophen/adverse effects , Adenosine Kinase/metabolism , Adenosine Kinase/genetics , AMP-Activated Protein Kinases/metabolism , Autophagy/drug effects , Chemical and Drug Induced Liver Injury/metabolism , Hepatocytes/metabolism , Hepatocytes/drug effects , Liver/drug effects , Liver/metabolism , Liver/pathology , Mice, Inbred C57BL , Mice, Knockout , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolismABSTRACT
A SERS substrate with high sensitivity and reusability was proposed. The chip consists of multiple ZnO microcavities loaded with silver particles. Based on structural characteristics, this coupling between cavity modes and localized surface plasmon modes can highly localize the electric field, where experimental results revealed a detection limit of 10-11 M for R6G. In addition, during carrier control in semiconductors with localized electromagnetic fields, our substrate also exhibits high self-cleaning efficiency and in situ detection stability. Even in a dry environment, it exhibits excellent light-mediated cleaning ability across multiple reuse test cycles. The convenient, rinse-free substrate, with its cost-effective and sustainable features, shows great promise for the study on detection and degradation of active materials.