ABSTRACT
Metabolic reprogramming is a phenomenon in which cancer cells alter their metabolic pathways to support their uncontrolled growth and survival. Platinum-based chemotherapy resistance is associated with changes in glucose metabolism, amino acid metabolism, fatty acid metabolism, and tricarboxylic acid cycle. These changes lead to the creation of metabolic intermediates that can provide precursors for the biosynthesis of cellular components and help maintain cellular energy homeostasis. This article reviews the research progress of the metabolic reprogramming mechanism of platinumbased chemotherapy resistance caused by three major nutrients in ovarian cancer.
ABSTRACT
Logical reasoning task involves diverse types of complex reasoning over text, based on the form of multiple-choice question answering (MCQA). Given the context, question and a set of options as the input, previous methods achieve superior performances on the full-data setting. However, the current benchmark dataset has the ideal assumption that the reasoning type distribution on the train split is close to the test split, which is inconsistent with many real application scenarios. To address it, there remain two problems to be studied: 1) how is the zero-shot capability of the models (train on seen types and test on unseen types)? and 2) how to enhance the perception of reasoning types for the models? For problem 1, we propose a new benchmark for generalized zero-shot logical reasoning, named ZsLR. It includes six splits based on the three type sampling strategies. For problem 2, a type-aware model TaCo is proposed. It utilizes the heuristic input reconstruction and builds a text graph with a global node. Incorporating graph reasoning and contrastive learning, TaCo can improve the type perception in the global representation. Extensive experiments on both the zero-shot and full-data settings prove the superiority of TaCo over the state-of-the-art (SOTA) methods. Also, we experiment and verify the generalization capability of TaCo on other logical reasoning dataset.
ABSTRACT
Background: Research on exosomes in metabolic diseases has been gaining attention, but a comprehensive and objective report on the current state of research is lacking. This study aimed to conduct a bibliometric analysis of publications on "exosomes in metabolic diseases" to analyze the current status and trends of research using visualization methods. Methods: The web of science core collection was searched for publications on exosomes in metabolic diseases from 2007 to 2022. Three software packages, VOSviewer, CiteSpace, and R package "bibliometrix" were used for the bibliometric analysis. Results: A total of 532 papers were analyzed, authored by 29,705 researchers from 46 countries/regions and 923 institutions, published in 310 academic journals. The number of publications related to exosomes in metabolic diseases is gradually increasing. China and the United States were the most productive countries, while Ciber Centro de Investigacion Biomedica en Red was the most active institution. The International Journal of Molecular Sciences published the most relevant studies, and Plos One received the most citations. Khalyfa, Abdelnaby published the most papers and Thery, C was the most cited. The ten most co-cited references were considered as the knowledge base. After analysis, the most common keywords were microRNAs, biomarkers, insulin resistance, expression, and obesity. Applying basic research related on exosomes in metabolic diseases to clinical diagnosis and treatment is a research hotspot and trend. Conclusion: This study provides a comprehensive summary of research trends and developments in exosomes in metabolic diseases through bibliometrics. The information points out the research frontiers and hot directions in recent years and will provide a reference for researchers in this field.
Subject(s)
Exosomes , Insulin Resistance , Metabolic Diseases , Humans , Metabolic Diseases/epidemiology , Bibliometrics , ChinaABSTRACT
Lysophosphatidylcholine (LPC), the active metabolite of palmitate, triggers hepatocyte death by activating endoplasmic reticulum stress and JNK signalling-mediated lipoapoptosis. However, LPC-induced cytotoxicity in hepatocytes is not well understood. Here, we found for the first time that LPC-induced cell rounding occurred prior to apoptosis. LPC-induced rounding of cells reduced both cell-extracellular matrix (ECM) adhesion and cell-cell junctions, which promoted detachment-induced apoptosis (defined as anoikis) in hepatocytes. Further study revealed that LPC altered cellular morphology and cell adhesion by inhibiting integrin and cadherin signalling-mediated microfilament polymerization. We also found that ECM supplementation and microfilament cytoskeletal stabilization inhibited LPC-induced hepatocyte death by attenuating anoikis. Our data indicate a novel cytotoxic process and signalling pathway induced by LPC.
Subject(s)
Anoikis/drug effects , Cadherins/genetics , Cell Adhesion/drug effects , Integrins/genetics , Intercellular Junctions/drug effects , Lysophosphatidylcholines/pharmacology , Actin Cytoskeleton/drug effects , Actin Cytoskeleton/metabolism , Actin Cytoskeleton/ultrastructure , Anoikis/genetics , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Cadherins/metabolism , Caspase 8/genetics , Caspase 8/metabolism , Cell Line, Tumor , Endoplasmic Reticulum Stress/drug effects , Endoplasmic Reticulum Stress/genetics , Extracellular Matrix/drug effects , Extracellular Matrix/metabolism , Extracellular Matrix/ultrastructure , Gene Expression Regulation , Hep G2 Cells , Hepatocytes/drug effects , Hepatocytes/metabolism , Hepatocytes/ultrastructure , Humans , Integrins/metabolism , Intercellular Junctions/metabolism , Intercellular Junctions/ultrastructure , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Signal Transduction , Vinculin/genetics , Vinculin/metabolismABSTRACT
Acetaminophen (APAP) is a widely used over-the-counter drug for antipyretic and analgesic, but an overdose will induce acute liver injury. APAP hepatotoxicity has been the most common cause of acute liver failure in western countries with high morbidity and mortality. Geniposide (GP), an iridoid glycoside extracted from the fruit of Gardenia jasminoides, has been reported to exert a profound anti-inflammatory activity on acute and chronic diseases. However, it is never demonstrated whether GP can protect hepatocytes from APAP hepatotoxicity. In this study, we investigated the protective effect and underlying mechanism of GP against AILI. The results showed that GP pretreatment reduced the levels of ALT and AST in a dose-dependent manner and alleviated hepatocyte necrosis and apoptosis in mice exposed at APAP. Moreover, it suppressed the expression of CYP 2E1 and attenuated the exhaustion of GSH and accumulation of MDA in the liver. Furthermore, GP remarkably inhibited inflammatory cells infiltration and mitigated the release of IL-1ß and TNF-α, and inhibited Toll-like receptor 4 (TLR4) expression and nuclear factor kappa (NF-κB) activation. These data suggested that GP could effectively protect hepatocytes from APAP hepatotoxicity through the down-regulation of CYP 2E1 expression and the inhibition of TLR4/NF-κB signaling pathway.
Subject(s)
Hepatocytes/drug effects , Iridoids/pharmacology , NF-kappa B/metabolism , Protective Agents/pharmacology , Toll-Like Receptor 4/metabolism , Acetaminophen , Animals , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/immunology , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Cytochrome P-450 CYP2E1/genetics , Cytochrome P-450 CYP2E1/metabolism , Down-Regulation/drug effects , Glutathione/metabolism , Hepatocytes/metabolism , Hepatocytes/pathology , Interleukin-1beta/blood , Iridoids/therapeutic use , Liver/drug effects , Liver/metabolism , Liver/pathology , Macrophages/drug effects , Macrophages/immunology , Male , Malondialdehyde/metabolism , Mice, Inbred C57BL , Neutrophils/drug effects , Neutrophils/immunology , Protective Agents/therapeutic use , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/bloodABSTRACT
Objective: Paeonol is a natural phenolic component isolated from the root bark of peony with multiple pharmacological activities. We investigated the anti-fibrotic effect and underlying mechanism of paeonol. Methods: Twenty-four male C57BL/6J mice were divided into 4 groups (n = 6 in each group), injected with CCl4 to induce liver fibrosis and administrated with paeonol according to the regimen. The serum activity of ALT and AST, and H&E staining were to assess liver injury. Sirius and Masson staining, and hydroxyproline content were to evaluate the degree of liver fibrosis. TNF-α, IL-6, TGF-ß, MDA, GSH-PX, SOD, and CAT were detected to reflect inflammation and oxidative stress. RT-qPCR and Western blot analysis to assess the activation of HSCs and TGF-ß/Smad3 signaling. Results: Paeonol ameliorated liver injury and liver fibrosis, reflected by the decrease of ALT, AST, less lesion in H&E staining, mitigated fibrosis in Sirius and Masson staining, lessened content of hydroxyproline. Paeonol attenuated the level of IL-6 and TNF-α, and elevated the activity of GSH-PX, SOD, and CAT with reducing the level of MDA. The expression of col 1a, α-SMA, vimentin, and desmin were down-regulated and TGF-ß/Smad3 signaling pathway was inhibited. Conclusion: These data demonstrated that paeonol could alleviate CCl4-induced liver fibrosis through suppression of hepatic stellate cells activation via inhibiting the TGF-ß/Smad3 signaling.