T-2 toxin is the most toxic trichothecene mycotoxin, and it exerts potent toxic effects, including immunotoxicity, neurotoxicity, and reproductive toxicity. Recently, several novel metabolites, including 3',4'-dihydroxy-T-2 toxin and 4',4'-dihydroxy-T-2 toxin, have been uncovered. The enzymes CYP3A4 and carboxylesterase contribute to T-2 toxin metabolism, with 3'-hydroxy-T-2 toxin and HT-2 toxin as the corresponding primary products. Modified forms of T-2 toxin, including T-2-3-glucoside, exert their immunotoxic effects by signaling through JAK/STAT but not MAPK. T-2-3-glucoside results from hydrolyzation of the corresponding parent mycotoxin and other metabolites by the intestinal microbiota, which leads to enhanced toxicity. Increasing evidence has shown that autophagy, hypoxia-inducible factors, and exosomes are involved in T-2 toxin-induced immunotoxicity. Autophagy promotes the immunosuppression induced by T-2 toxin, and a complex crosstalk between apoptosis and autophagy exists. Very recently, "immune evasion" activity was reported to be associated with this toxin; this activity is initiated inside cells and allows pathogens to escape the host immune response. Moreover, T-2 toxin has the potential to trigger hypoxia in cells, which is related to activation of hypoxia-inducible factor and the release of exosomes, leading to immunotoxicity. Based on the data from a series of human exposure studies, free T-2 toxin, HT-2 toxin, and HT-2-4-glucuronide should be considered human T-2 toxin biomarkers in the urine. The present review focuses on novel findings related to the metabolism, immunotoxicity, and human exposure assessment of T-2 toxin and its modified forms. In particular, the immunotoxicity mechanisms of T-2 toxin and the toxicity mechanism of its modified form, as well as human T-2 toxin biomarkers, are discussed. This work will contribute to an improved understanding of the immunotoxicity mechanism of T-2 toxin and its modified forms.

• MeSH
• Apoptosis MeSH
• Autophagy MeSH
• Biomarkers MeSH
• Cell Hypoxia MeSH
• Humans MeSH
• Signal Transduction MeSH
• T-2 Toxin analogs & derivatives   metabolism   toxicity   MeSH
• Environmental Exposure analysis   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Deoxynivalenol (DON) is an unavoidable contaminant in human food, animal feeds, and agricultural products. Growth retardation in children caused by extensive DON pollution has become a global problem that cannot be ignored. Previous studies have shown that DON causes stunting in children through intestinal dysfunction, insulin-like growth factor-1 (IGF-1) axis disorder and peptide YY (PYY). Galanin-like peptide (GALP) is an important growth regulator, but its role in DON-induced growth retardation is unclear. In this study, we report the important role of GALP during DON-induced growth inhibition in the rat pituitary tumour cell line GH3. DON was found to increase the expression of GALP through hypomethylationin the promoter region of the GALP gene and upregulate the expression of proinflammatory factors, while downregulate the expression of growth hormone (GH). Furthermore, GALP overexpression promoted proinflammatory cytokines, including TNF-α, IL-1β, IL-11 and IL-6, and further reduced cell viability and cell proliferation, while the inhibitory effect of GALP was the opposite. The expression of GALP and insulin like growth factor binding protein acid labile subunit (IGFALS) showed the opposite trend, which was the potential reason for the regulation of cell proliferation by GALP. In addition, GALP has anti-apoptotic effects, which could not eliminate the inflammatory damage of cells, thus aggravating cell growth inhibition. The present findings provide new mechanistic insights into the toxicity of DON-induced growth retardation and suggest a therapeutic potential of GALP in DON-related diseases.

• MeSH
• Apoptosis MeSH
• Epigenesis, Genetic drug effects   MeSH
• Galanin genetics   metabolism   MeSH
• Glycoproteins genetics   metabolism   MeSH
• Pituitary Gland cytology   MeSH
• Rats MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation MeSH
• Carrier Proteins genetics   metabolism   MeSH
• Trichothecenes pharmacology   MeSH
• Gene Silencing MeSH
• Up-Regulation drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The cancer mortality rate of hepatocellular carcinoma (HCC) is the second highest in the world and the therapeutic options are limited. The incidence of this deadly cancer is rising at an alarming rate because of the high degree of resistance to chemo- and radiotherapy, lack of proper, and adequate vaccination to hepatitis B, and lack of consciousness and knowledge about the disease itself and the lifestyle of the people. DNA methylation and DNA methylation-induced epigenetic alterations, due to their potential reversibility, open the access to develop novel biomarkers and therapeutics for HCC. The contribution to these epigenetic changes in HCC development still has not been thoroughly summarized. Thus, it is necessary to better understand the new molecular targets of HCC epigenetics in HCC diagnosis, prevention, and treatment. This review elaborates on recent key findings regarding molecular biomarkers for HCC early diagnosis, prognosis, and treatment. Currently emerging epigenetic drugs for the treatment of HCC are summarized. In addition, combining epigenetic drugs with nonepigenetic drugs for HCC treatment is also mentioned. The molecular mechanisms of DNA methylation-mediated HCC resistance are reviewed, providing some insights into the difficulty of treating liver cancer and anticancer drug development.

• MeSH
• Drug Resistance, Neoplasm MeSH
• Carcinoma, Hepatocellular * diagnosis   drug therapy   genetics   MeSH
• Humans MeSH
• DNA Methylation MeSH
• Liver Neoplasms * diagnosis   drug therapy   genetics   MeSH
• Prognosis MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are currently the most effective lipid-lowering drugs, effectively reducing the plasma total cholesterol and low-density lipoprotein, while also decreasing three triacylglycerols and increasing plasma high-density lipoprotein to a certain extent. However, the excessive or long-term use of statins can cause in vitro cytotoxicity, in vivo liver injury, liver necrosis, kidney damage, and myopathy in both human beings and animals. Many studies indicate that oxidative stress is involved in the various toxicities associated with statins, and various antioxidants have been evaluated to investigate their protective roles against statin-induced liver, kidney, and muscle toxicities. Widespread attention has been given to statin-induced oxidative stress, with and without the use of other drugs. Much of the information about the mechanism for this reduction comes from cell culture and in experimental animal studies. The primary focus of this article is to summarize the research progress associated with oxidative stress as a plausible mechanism for statin-induced toxicity, as well as its metabolic interactions. This review summarizes the research conducted over the past five years into the production of reactive oxygen species, oxidative stress as a result of statin treatments, and their correlation with statin-induced toxicity and metabolism. Statin-induced metabolism involves various CYP450 enzymes, which provide potential sites for statin-induced oxidative stress, and these metabolic factors are also reviewed. The therapeutics of a variety of compounds against statin-induced organ damage based on their anti-oxidative effects is also discussed to further understand the role of oxidative stress in statin-induced toxicity. This review sheds new light on the critical roles of oxidative stress in statin-induced toxicity and prevention of this oxidative damage, as well as on the contradictions and unknowns that still exist regarding statin toxicity and the cellular effects in terms of organ injury and cell signaling pathways.

• MeSH
• Drug Interactions MeSH
• Humans MeSH
• Oxidative Stress drug effects   MeSH
• Drug Overdose MeSH
• Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects   pharmacokinetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

T-2 toxin is a secondary metabolite produced by Fusarium species and commonly contaminates food and animal feed. T-2 toxin can induce hepatotoxicity through apoptosis and oxidative stress; however, the underlying mechanism is not clear. Recent studies indicated that RASSF4, a member of the RASSF family, participates in cell apoptosis and some cancers due to its inactivation via DNA hypermethylation. However, its role in T-2 toxin-induced liver toxicity is poorly understood. Therefore, in this study, female Wistar rats were given a single dose of T-2 toxin at 2 mg/kg b.w. and were sacrificed at 1, 3 and 7 days post-exposure. A normal rat liver cell line (BRL) was exposed to different concentrations of T-2 toxin (10, 20, 40 nM) for 4, 8, 12 h, respectively. Histopathological analysis revealed with apoptosis in some liver cells and clear proliferation under T-2 toxin exposure. Expression analysis by immunohistochemical assays, quantitative real-time PCR (qPCR) and western blot demonstrated that T-2 toxin activated PI3K-Akt/Caspase/NF-κB signaling pathways. Additionally, DNA methylation assays revealed that the expression of RASSF4 was silenced by promoter hypermethylation after exposure to T-2 toxin for 1 and 3 days as compared to the control group. Moreover, joint treatment of 5-Aza-2'-deoxycytidine (DAC) (5 μM) and T-2 toxin (40 nM) increased expression of RASSF4 and PI3K-Akt/caspase/NF-κB signaling pathways-related genes, inducing cell apoptosis. These findings for the first time demonstrated that DNA methylation regulated the RASSF4 expression under T-2 toxin, along with the activation of its downstream pathways, resulting in apoptosis.

• MeSH
• Apoptosis drug effects   MeSH
• Cell Line MeSH
• Intracellular Signaling Peptides and Proteins metabolism   MeSH
• Liver drug effects   metabolism   MeSH
• Rats MeSH
• Real-Time Polymerase Chain Reaction MeSH
• DNA Methylation * drug effects   MeSH
• Tumor Suppressor Proteins metabolism   MeSH
• Rats, Wistar MeSH
• Flow Cytometry MeSH
• T-2 Toxin toxicity   MeSH
• Dose-Response Relationship, Drug MeSH
• Blotting, Western MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Currently, T-2 toxin has been reported to cause liver toxicity with the effects of oxidative stress and inflammation; however, the underlying mechanism of T-2 toxin-induced liver injury is not fully understood. Increasing lines of evidence show that DNA methylation affects the expression of inflammatory cytokine, and plays a crucial role in autoimmune diseases. Nevertheless, the potential role of DNA methylation in the hepatotoxicity of T-2 toxin has not been explored. In this study, female Wistar rats were given a single dose of T-2 toxin at 2 mg/kg b.w. and were sacrificed at 1, 3 and 7 days post-exposure. In vitro, a normal rat liver cell line (BRL) was exposed to different concentrations of T-2 toxin. Histopathological analysis was used to investigate damage to the liver, which was detected at the molecular level by RT-PCR, Western blot and immunohistochemical assays, methylation-specific PCR (MSP), bisulfite sequencing (BSP), and flow cytometry. The results showed that T-2 toxin significantly increased the levels of DNA methyltransferases (DNMT1, DNMT3A), which were mainly concentrated at the site of liver injury. The 5-methylcytosine (5-mC) level of genomic DNA was also raised in T-2 toxin-treated rat livers. The expression of inflammatory cytokines (IL-6, IL-1β, IL-11, IL-1α, and TNF-α) increased both in vivo and in vitro under T-2 toxin treatment. Notably, DNA demethylation directly increased the expression of cytokines IL-11, IL-6, IL-α, and TNF-α under T-2 toxin exposure. DNA methylation inhibitors combined with T-2 toxin directly or indirectly induced the production of inflammatory cytokines and aggravate cell apoptosis. Our study uncovered for the first time that DNA methylation is related to the expression of inflammatory cytokines in T-2 toxin-induced liver injury. These findings suggested that DNA methylation is a potential mechanism of T-2 toxin-induced hepatotoxicity.

• MeSH
• CpG Islands MeSH
• Cytokines genetics   metabolism   MeSH
• Liver drug effects   metabolism   pathology   MeSH
• Rats MeSH
• Inflammation Mediators metabolism   MeSH
• DNA Methylation * MeSH
• Rats, Wistar MeSH
• Promoter Regions, Genetic MeSH
• T-2 Toxin toxicity   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Mequindox (MEQ), belonging to quinoxaline-di-N-oxides (QdNOs), is a synthetic antimicrobial agent widely used in China. Previous studies found that the kidney was one of the main toxic target organs of the QdNOs. However, the mechanisms underlying the kidney toxicity caused by QdNOs in vivo still remains unclear. The present study aimed to explore the molecular mechanism of kidney toxicity in mice after chronic exposure to MEQ. MEQ led to the oxidative stress, apoptosis, and mitochondrial damage in the kidney of mice. Meanwhile, MEQ upregulated Bax/Bcl-2 ratio, disrupted mitochondrial permeability transition pores, caused cytochrome c release, and a cascade activation of caspase, eventually induced apoptosis. The oxidative stress mediated by MEQ might led to mitochondria damage and apoptosis in a mitochondrial-dependent apoptotic pathway. Furthermore, upregulation of the Nrf2-Keap1 signaling pathway was also observed. Our findings revealed that the oxidative stress, mitochondrial dysfunction, and the Nrf2-Keap1 signaling pathway were associated with the kidney apoptosis induced by MEQ in vivo.

• Publication type
• Journal Article MeSH

T-2 toxin, a trichothecene mycotoxin, is a common contaminant in food and animal feed, and is also present in processed cereal products. The most common route of T-2 toxin exposure in humans is through dietary ingestion. The cytotoxic effects of T-2 toxin include modifications to feeding behavior, nervous disorders, cardiovascular alterations, immunosuppression, and hemostatic derangements. However, to date, effects on the central nervous system (CNS) have rarely been reported. In the present study, female Wistar rat were given a single dose of T-2 toxin at 2 mg/kg b.w. and were sacrificed at one, three, and seven days post-exposure. Histopathological analysis and transmission electron microscope (TEM) observations were used to investigate injury to the brain and pituitary gland. Damage to the brain and pituitary at the molecular level was detected by real time-polymerase chain reaction (RT-PCR), western blot, and immunohistochemical assays. Liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS) was used to investigate T-2 concentration in the brain. The results showed that pathological lesions were obvious in the brain at three days post-exposure; lesions in the pituitary were not observed until seven days post-exposure. Autophagy in the brain and apoptosis in the pituitary suggest that T-2 toxin may induce different acute reactions in different tissues. Importantly, low concentrations of T-2 toxin in the brain were observed in only one rat. Responsible for the above mentioned, we hypothesize that brain damage caused by this toxin may be due to the ability of the toxin to directly cross the blood-brain barrier (BBB). Therefore, given its widespread pollution in food, we should pay more attention to the neurotoxic effects of the T-2 toxin, which may have widespread implications for human health.

• MeSH
• Apoptosis drug effects   MeSH
• Autophagy drug effects   MeSH
• Time Factors MeSH
• Behavior, Animal drug effects   MeSH
• Chromatography, Liquid MeSH
• Blood-Brain Barrier metabolism   MeSH
• Risk Assessment MeSH
• Pituitary Gland drug effects   metabolism   ultrastructure   MeSH
• Immunohistochemistry MeSH
• Capillary Permeability MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Brain drug effects   metabolism   ultrastructure   MeSH
• Neurotoxicity Syndromes etiology   metabolism   pathology   psychology   MeSH
• Rats, Wistar MeSH
• Gene Expression Regulation MeSH
• T-2 Toxin metabolism   toxicity   MeSH
• Tandem Mass Spectrometry MeSH
• Microscopy, Electron, Transmission MeSH
• Blotting, Western MeSH
• Animals MeSH
• Check Tag
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Paracetamol (APAP) is one of the most widely used and popular over-the-counter analgesic and antipyretic drugs in the world when used at therapeutic doses. APAP overdose can cause severe liver injury, liver necrosis and kidney damage in human beings and animals. Many studies indicate that oxidative stress is involved in the various toxicities associated with APAP, and various antioxidants were evaluated to investigate their protective roles against APAP-induced liver and kidney toxicities. To date, almost no review has addressed the APAP toxicity in relation to oxidative stress. This review updates the research conducted over the past decades into the production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and oxidative stress as a result of APAP treatments, and ultimately their correlation with the toxicity and metabolism of APAP. The metabolism of APAP involves various CYP450 enzymes, through which oxidative stress might occur, and such metabolic factors are reviewed within. The therapeutics of a variety of compounds against APAP-induced organ damage based on their anti-oxidative effects is also discussed, in order to further understand the role of oxidative stress in APAP-induced toxicity. This review will throw new light on the critical roles of oxidative stress in APAP-induced toxicity, as well as on the contradictions and blind spots that still exist in the understanding of APAP toxicity, the cellular effects in terms of organ injury and cell signaling pathways, and finally strategies to help remedy such against oxidative damage.

• MeSH
• Antioxidants pharmacology   MeSH
• Antipyretics toxicity   MeSH
• Humans MeSH
• Analgesics, Non-Narcotic toxicity   MeSH
• Oxidative Stress drug effects   MeSH
• Acetaminophen toxicity   MeSH
• Drug Overdose MeSH
• Reactive Oxygen Species metabolism   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

T-2 toxin, a major compound of trichothecenes, induces cell apoptosis and growth hormone (GH) deficiency and causes considerable growth retardation in animals and human cells. However, the mechanism underlying its growth suppression still remains unclear. Recent studies have suggested that ROS induced cell apoptosis and animal feed intake reduction, but there are limited reports on the role of RNS in T-2 toxin-mediated mitochondrial damage, cell apoptosis and growth retardation. Herein, T-2 toxin-induced GH3 cell damage and apoptosis were tested by MTT assay, LDH leakage and flow cytometry, respectively. Intracellular NO and antioxidant enzyme activity, ΔΨm, morphometric changes of mitochondria, the caspase pathway, and inflammatory factors were investigated. Free radical scavengers NAC, SOD and NO scavenger haemoglobin were used to explore the role of oxidative stress and the relationship between NO production and caspase pathway. The results clearly revealed that T-2 toxin caused significant increases in NO generation, cell apoptosis, GH deficiency, increased iNOS activity, upregulation of inflammatory factors and caspase pathway, decreases in ΔΨm and morphosis damage. These data suggest that mitochondria are a primary target of T-2 toxin-induced NO, and NO is a key mediator of T-2 toxin-induced cell apoptosis and GH deficiency via the mitochondria-dependent pathway in cells.

• MeSH
• Pituitary Gland, Anterior cytology   MeSH
• Apoptosis drug effects   MeSH
• Caspases metabolism   MeSH
• Rats MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• Mitochondria drug effects   metabolism   MeSH
• Nitric Oxide metabolism   MeSH
• Oxidative Stress drug effects   MeSH
• Growth Hormone deficiency   MeSH
• Signal Transduction drug effects   MeSH
• Somatotrophs drug effects   metabolism   pathology   MeSH
• Nitric Oxide Synthase Type II metabolism   MeSH
• T-2 Toxin toxicity   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH