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Isolated hepatocytes undergo lipoapoptosis, a feature of hepatic lipotoxicity, on treatment with saturated free fatty acids (FFA) such as palmitate (PA). However, it is unknown if palmitate is directly toxic to hepatocytes or if its toxicity is indirect via the generation of lipid metabolites such as lysophosphatidylcholine (LPC). PA-mediated hepatocyte lipoapoptosis is associated with endoplasmic reticulum (ER) stress, c-Jun NH(2)-terminal kinase (JNK) activation, and a JNK-dependent upregulation of the potent proapoptotic BH3-only protein PUMA (p53 upregulated modulator of apoptosis). Our aim was to determine which of these mechanisms of lipotoxicity are activated by PA-derived LPC. We employed Huh-7 cells and isolated murine and human primary hepatocytes. Intracellular LPC concentrations increase linearly as a function of the exogenous, extracellular PA, stearate, or LPC concentration. Incubation of Huh-7 cells or primary hepatocytes with LPC induced cell death by apoptosis in a concentration-dependent manner. Substituting LPC for PA resulted in caspase-dependent cell death that was accompanied by activating phosphorylation of JNK with c-Jun phosphorylation and an increase in PUMA expression. LPC also induced ER stress as manifest by eIF2α phosphorylation and CAAT/enhancer binding homologous protein (CHOP) induction. LPC cytotoxicity was attenuated by pharmacological inhibition of JNK or glycogen synthase kinase-3 (GSK-3). Similarly, short-hairpin RNA (shRNA)-targeted knockdown of CHOP protected Huh-7 cells against LPC-induced toxicity. The LPC-induced PUMA upregulation was prevented by JNK inhibition or shRNA-targeted knockdown of CHOP. Finally, genetic deficiency of PUMA rendered murine hepatocytes resistant to LPC-induced apoptosis. We concluded that LPC-induced lipoapoptosis is dependent on mechanisms largely indistinguishable from PA. These data suggest that FFA-mediated cytotoxicity is indirect via the generation of the toxic metabolite, LPC.
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http://dx.doi.org/10.1152/ajpgi.00301.2011 | DOI Listing |
Toxicol Appl Pharmacol
December 2024
Department of Infectious Diseases, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, People's Republic of China. Electronic address:
Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease. The present work aimed to explore the function of regulator of Calcineurin 2 (RCAN2) in NAFLD and its related mechanisms. Mice were fed with high-fat diet (HFD) to construct NAFLD model.
View Article and Find Full Text PDFPhytochemistry
December 2024
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China. Electronic address:
Two unprecedented sesquiterpene and monoterpene heterodimers and ten previously undescribed sesquiterpenoids, artemordosins A-L (1-12), as well as ten known sesquiterpenoids (13-22), were obtained from Artemisia ordosica. Their structures were elucidated based on comprehensive analyses of NMR, IR, HRESIMS, GIAO NMR calculations with DP4+ probability analysis, and ECD calculations. Notably, artemordosins A and B (1 and 2) were the first examples of cadinane-monoterpene dimers, and artemordosin A (1) was a cadinane-myrceane heterodimer with a 6/6/6/6 ring system formed by [4 + 2] cycloaddition, while artemordosin B (2) was a 4,5-seco-cadinane-artemisane dimer connected through a C-5-O-C-4' linkage.
View Article and Find Full Text PDFArch Virol
December 2024
Department of Medical Entomology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.
Most members of the genus Orthonairovirus, represented by Crimean-Congo hemorrhagic fever virus and Nairobi sheep disease virus, are tick-borne, and some have become a public health concern in recent years. Here, we report the isolation and genetic and biological characterization of a new orthonairovirus, designated as "Iwanai Valley virus" (IWVV), from Ixodes ovatus ticks in Hokkaido, Japan. The amino acid sequence of the viral nucleoprotein (NP) was found to be 34-45% identical to those of known orthonairoviruses.
View Article and Find Full Text PDFAm J Transl Res
November 2024
Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University Shanghai 200438, The People's Republic of China.
Background: The mechanism of ferroptosis is primarily driven by the iron-dependent lethal accumulation of membrane lipid peroxidation. Bavachin has been found to exacerbate lipid peroxidation in cancer cells; however, whether it hinders hepatocellular carcinoma (HCC) progression by way of ferroptosis remains unknown.
Methods: Cell counting kit-8 (CCK-8) assay was used to measure the effect of Bavachin on the viability of HCC cells, so as to determine the appropriate drug concentration for subsequent experiments.
J Endod
December 2024
Division of Endodontics, Department of Conservative Dental Sciences, College of Dentistry, Qassim University, Qassim, Saudi Arabia.
Introduction: The objective of this study was to assess the calcium ions (Ca) release, pH shift, bioactivity, and cytotoxicity of both forms of EndoSequence Root Repair Material: regular set (ES) and fast set (ESF).
Methods: ES (n = 10) and ESF (n = 10) forms were tested for their bioactivity. Elemental analysis was done on the fresh material and material immersed in phosphate-buffered saline (PBS) for 30 days.
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