Project description:In this study, female DO mice were administered zileuton or vehicle i.g. daily for seven days, and assessed for the toxic outcomes in the livers. In addition to the clinical and histopathological assessment, RNA-seq analysis was performed to identify the differentially expressed genes in animals susceptible to the zileuton toxicity. Pathway analysis on the differentially expressed genes was performed to investigate the molecular mechanisms underlying the sensitivity to the liver toxicity.
Project description:Clinical use of triptolide (TP) is restricted due to severe toxicity. This study assessed the protective effect of crocin (CR) as a natural antioxidant against TP-induced toxicity. Mouse Liver tissues were selected from the Control, MTP, and MTP+CR groups for transcriptome studies.
Project description:The goal of the study is to compare transcriptome profile of mouse liver with acetaminophen toxicity to potentially therapeutic healthy blood serum exosome or cytokine treatments along with acetaminophen Studies also included sequencing of miRNA from exosomes isolated from pooled serum of several healthy anonimous human donors and livers of mice that received the exosome treatment along with acetominophen.
Project description:Immunotherapy is revolutionizing cancer treatment, but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions remains poorly understood. Here, using anti-CD40-treatment in mice as a model of Th1-promoting immunotherapy, we show liver macrophages’ vulnerability to promote local adverse events. Mechanistically, tissue-resident Kupffer cells mediate liver toxicity by sensing lymphocyte-derived IFN-g and producing IL-12. Conversely, dendritic cells are dispensable for toxicity but drive tumor control. Though macrophages, IL-12, and IFN-g are not necessarily toxic themselves, we find that they prompt a neutrophil response that determines the severity of tissue damage. We further show that similar inflammatory pathways characterize adverse events across tissues, following anti-PD-1 and anti-CTLA4 immunotherapies, and in humans. These findings implicate macrophages and neutrophils as mediators and effectors of aberrant inflammation in Th1-promoting immunotherapy, and suggest distinct mechanisms of toxicity and antitumor immunity.
Project description:Agonistic CD40 monoclonal antibodies have emerged as promising immunotherapeutic compounds with impressive anti-tumoral effects. However, one of the main limitations of their use in patients is the severe liver necro-hepatitis they can induce. Up to this point, no effective treatment for anti-CD40 liver toxicity that does not hinder anti-tumor efficacy has been found. In the present study , we show that anti-CD40 liver toxicity is dependent on liver macrophages and recruitment of monocytes and neutrophils. We specifically reprogrammed the phenotype of liver macrophages to anti-inflammatory erythrophagocytes by using repeated injection of anti-erythrocyte murine Ter119 (mTer119) antibody. mTer119 administration induced phagocytosis of erythrocytes by liver macrophages and their transformation to Hmoxhigh/Marcohigh/MHC-IIlow erythrophagocytes. mTer119 treatment prevented anti-CD40 induced liver toxic side-effect, with significantly reduced elevation of plasma transaminases level and area of liver necrosis on histology, while preserving the anti-tumoral efficiency of anti-CD40. Our study offers a novel targeted therapeutic approach to treat immune-related liver adverse side effects of immunotherapies.
Project description:Dichloroacetyl chloride (DCAC) is a metabolic intermediate of trichloroethene (TCE), an industrial chemical and ubiquitous environmental contaminant. TCE and its metabolites have been implicated in the induction of organ-specific and systemic autoimmunity, in the acceleration of autoimmune responses, and in the development of liver toxicity. In humans, effects of environmental toxicants are often multifactorial and detected only after long-term exposure. Therefore, we developed a small-animal model to determine mechanisms by which DCAC and related acylating agents affect liver disease. Autoimmune-prone female MRL +/+ mice were injected i.p. with 0.2 mmole/kg of DCAC or the acylating agent dichloroacetic anhydride (DCAA) in corn oil twice weekly for six weeks. We then determined changes in the liver transcriptome using microarray gene expression analysis. After exposure to DCAC or DCAA, we observed changes in liver gene expression consistent with inflammatory processes. Both toxicants up-regulated expression of acute phase response and inflammatory genes. Further, metallothionein genes were strongly up-regulated, indicating effects of the toxicants on zinc ion homeostasis and stress responses. In addition, DCAC and DCAA induced up-regulation of several genes indicative of tumorogenesis. Microarray gene expression analysis using a restricted set of genes could be a valuable tool to screen for early changes in liver function following suspected exposure to environmental toxicants. Keywords: Response to acylating agents; inflammatory response; disease state analysis.
Project description:Agonistic CD40 monoclonal antibodies have emerged as promising immunotherapeutic compounds with impressive anti-tumoral effects. However, one of the main limitations of their use in patients is the severe liver necro-hepatitis they can induce. Up to this point, no effective treatment for anti-CD40 liver toxicity that does not hinder anti-tumor efficacy has been found. In the present study , we show that anti-CD40 liver toxicity is dependent on liver macrophages and recruitment of monocytes and neutrophils. We specifically reprogrammed the phenotype of liver macrophages to anti-inflammatory erythrophagocytes by using repeated injection of anti-erythrocyte murine Ter119 (mTer119) antibody. mTer119 administration induced phagocytosis of erythrocytes by liver macrophages and their transformation to Hmoxhigh/Marcohigh/MHC-IIlow erythrophagocytes. mTer119 treatment prevented anti-CD40 induced liver toxic side-effect, with significantly reduced elevation of plasma transaminases level and area of liver necrosis on histology, while preserving the anti-tumoral efficiency of anti-CD40. Our study offers a novel targeted therapeutic approach to treat immune-related liver adverse side effects of immunotherapies.
Project description:we report an assessment of macrolides related liver toxicity by using ADMET prediction, molecular docking, structure-toxicity relationship and experimental verification via detecting the c-fos gene expression in liver cells.We employed the model to virtual screening of azithromycin impurities with high hepatotoxicity, and then experimental confirmed by liver toxicity in zebrafish, and c-fos gene expression.
Project description:In this study, we aim to identify candidate biomarkers which may be useful as surrogate indicators of toxicity for pre-clinical development of panPPAR-agonist drug candidates. Gene expression microarray, histopathology and clinical chemistry data were generated from liver, heart, kidney and skeletal muscles of three groups of mice administered with three different dosages of an experimental pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist, PPM-201, for 14 days. The histopathology and clinical chemistry data were compared with the gene expression analysis and candidate biomarker genes were identified.