zearalenone and Disease-Models--Animal

This review summarizes the information regarding the in vivo studies of Fusarium mycotoxins in the last decade. The most common studies are classified as subacute toxicity, subchronic toxicity, acute toxicity, toxicokinetic studies and teratogenicity in order of importance. The most used animals in in vivo studies are pigs, rats, chickens and mice. Fumonisin B1, deoxynivalenol, zearalenone, nivalenol and T-2 toxin are the most studied fusarotoxins. Studies with combinations of mycotoxins are also frequent, deoxynivalenol generally being one of them. The predominant route of administration is oral, administered mostly in the form of naturally contaminated feed. Other administration routes also used are intraperitoneal, intravenous and subcutaneous. In vivo research on Fusarium mycotoxins has increased since 2010 highlighting the need for such studies in the field of food and feed safety.

Topics: Animal Feed; Animals; Chickens; Consumer Product Safety; Disease Models, Animal; Food Contamination; Food Microbiology; Fumonisins; Fusarium; Mice; Mycotoxins; Rats; Swine; T-2 Toxin; Trichothecenes; Zearalenone

Zearalenone (ZEN) is a non-steroidal mycoestrogen that widely contaminates agricultural products. ZEN and its derivatives share similar molecular mechanisms and activity with estrogens and interact with ERα and ERβ leading to changes in the reproductive system in both animals and humans. The reduced form of ZEN, α-ZEA ralenol, has been used as an anabolic agent for animals and also proposed as hormonal replacement therapy in postmenopausal women. Furthermore, both zearelanol ZEN and derivatives have been patented as oral contraceptives. ZEN has been widely used in the United States since 1969 to improve fattening rates in cattle by increasing growth rate and feed conversion efficiency. Evidence of human harm from this practice is provided by observations of central precocious puberty. As a result, this practice has been banned by the European Union. As ZEN has been associated with breast enlargement in humans, it has been included in many bust-enhancing dietary supplements but epidemiological evidence is lacking with regard to breast cancer risk. Extensive work with human breast cancer cell lines has shown estrogenic stimulation in those possessing ER but a reduction in DMBA-induced breast cancers in rodents given ZEN. Protein disulfide isomerase provides a molecular biomarker of dietary exposure to ZEN and its derivatives allowing the detection and control of harmful food intake. The interaction of ZEN with anti-estrogens, anticancer agents and antioxidants requires further investigation.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Breast Neoplasms; Cattle; Cell Line, Tumor; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Estrogens, Non-Steroidal; Female; Food Contamination; Growth Substances; Hormone Replacement Therapy; Humans; Inactivation, Metabolic; Puberty, Precocious; Receptors, Estrogen; Zearalenone; Zeranol

The high prevalence of colorectal cancer (CRC) and its leading death causing rate have placed a considerable burden on patients and healthcare providers. There is a need for a therapy that has fewer adverse effects and greater efficiency. Zearalenone (ZEA), an estrogenic mycotoxin, has been demonstrated to exert apoptotic properties when administrated in higher doses. However, it is unclear whether such apoptotic effect remains valid in an in vivo setting. The current study aimed to investigate the effect of ZEA on CRC and its underlying mechanisms in the azoxymethane/ dextran sodium sulfate (AOM/DSS) model. Our results revealed that ZEA significantly lowered the total number of tumours, colon weight, colonic crypt depth, collagen fibrosis and spleen weight. ZEA suppressed Ras/Raf/ERK/cyclin D1 pathway, increasing the expression of apoptosis parker, cleaved caspase 3, while decreasing the expression of proliferative marker, Ki67 and cyclin D1. The gut microbiota composition in ZEA group showed higher stability and lower vulnerability in the microbial community when compared to AOM/DSS group. ZEA increased the abundance of short chain fatty acids (SCFAs) producing bacteria unidentified Ruminococcaceae, Parabacteroidies and Blautia, as well as the faecal acetate content. Notably, unidentified Ruminococcaceae and Parabacteroidies were substantially correlated with the decrease in tumour count. Overall, ZEA demonstrated a promising inhibitory effect on colorectal tumorigenesis and exhibited the potential for further development as a CRC treatment.

Topics: Animals; Azoxymethane; Bacteria; Carcinogenesis; Cell Transformation, Neoplastic; Colitis; Colorectal Neoplasms; Cyclin D1; Dextran Sulfate; Disease Models, Animal; Humans; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Zearalenone

Topics: Animals; Apoptosis; Autophagy; Cell Survival; Cells, Cultured; Disease Models, Animal; Humans; Male; Mice; Spermatogonia; Zearalenone

Zearalenone (ZEA) is a secondary metabolite produced by fungi such as Fusarium and Fusarium flavum, which is classified as a mycotoxin. Crops and feed in a humid surrounding are widely polluted by ZEA, which further endangering the healthful aquaculture of poultry and even human health. Up to now, prevention and cure of mycotoxicosis is still a crucial subject of poultry husbandry. Baicalin (BAI) is a flavonoid refined from dried roots of Scutellaria baicalensis possessing the function of hepatoprotective, anti-inflammatory, anti-oxidant, and anti-atherosclerotic efficacies.etc. But whether Baicalin also has a protective effect against ZEA intoxication is unclear. Therefore, the aim of this study was to establish a model of ZEA-induced toxic injury in chicks, and then to investigate the way in which Baicalin plays a protective role in the mechanism of ZEA-induced liver and kidney injury in chicks. The results exhibit that Baicalin could not only significantly decrease aspartate aminotransferase (AST) , alanine aminotransferase (ALT) and creatinine (Cre) levels in serum, but also ameliorate ZEA-induced pathologic changes of liver and kidney. Baicalin could also significantly regulate ZEA-induced the changes of catalase (CAT) , malondialdehyde (MDA) , total sulfhydryl group , except for glutathione peroxidase (GSH-px) , and inhibit the mRNA levels of inflammatory cytokines tumor necrosis factor-α (TNF-α) , interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2) with caspase-3 and caspase-11 in the caspase signaling pathway , meanwhile inhibit the cell apoptosis in immunohistochemistry. In summary, we successfully established a model of ZEA-induced liver injury in chicks, and confirm that Baicalin can reduce ZEA-induced liver and kidney injury in chicks. The mechanism of these effects is via inhibiting inflammation, oxidative stress and apoptosis, which also indicates the potential applicability of Baicalin for the prevention and treatment of ZEA-induced toxicity in chicks.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Caspases; Chemical and Drug Induced Liver Injury; Chickens; Cytokines; Disease Models, Animal; Flavonoids; Inflammation Mediators; Kidney; Liver; Oxidative Stress; Signal Transduction; Zearalenone

Zearalenone (ZEA) is a mycotoxin that has several adverse effects on most mammalian species. However, the effects of ZEA on macrophage-mediated innate immunity during infection have not been examined. In the present study, bacterial lipopolysaccharides (LPS) were used to induce the activation of macrophages and evaluate the effects of ZEA on the inflammatory responses and inflammation-associated signaling pathways. The experimental results indicated that ZEA suppressed LPS-activated inflammatory responses by macrophages including attenuating the production of proinflammatory mediators (nitric oxide (NO) and prostaglandin E

Topics: Animals; Cell Survival; Cells, Cultured; Disease Models, Animal; Female; Humans; Immunity, Innate; Inflammasomes; Lipopolysaccharides; Macrophages; Mice; Mycotoxins; Zearalenone

The immunotoxicity of zearalenone (ZEA) and deoxynivalenol (DON), two of the most common environmental mycotoxins, has been well investigated. However, due to the complexity of the immune system, especially during bacterial infection, many types of immune cells are involved in invasion resistance and bacterial clearance. Of these, T helper 2 (Th2) cells, which are members of the helper T cell family, assist B cells to activate and differentiate into antibody-secreting cells, participate in humoral immune response, and, ultimately, eliminate pathogens. Thus, it is important to identify the stage at which these toxins affect the immune function, and to clarity the underlying mechanisms. In this study, mice infected with Listeria monocytogenes (Listeria) were used to study the effects of ZEA, DON, and ZEA + DON on Th2 differentiation, Interleukin-4 Receptor (IL-4R) expression, costimulatory molecules expression and cytokine secretion after Listeria infection. Naive CD4

Topics: Animals; CD40 Ligand; Cell Differentiation; Cells, Cultured; Cytokines; Disease Models, Animal; Female; Host-Pathogen Interactions; Inducible T-Cell Co-Stimulator Protein; Listeria monocytogenes; Listeriosis; Lymphocyte Activation; Mice, Inbred BALB C; Mice, Inbred C57BL; Receptors, Interleukin-4; Signal Transduction; Spleen; Th2 Cells; Trichothecenes; Zearalenone

Endophyte is considered a source of natural bioactive secondary metabolites that provides an array of bioactive lead compounds. The present study was aimed to determine the antimicrobial and anti-inflammatory potential of fungal endophytes isolated from Catharanthus roseus.. A total of seven fungal endophytes crude extract were screened against bacterial pathogens. Of these, Curvularia geniculata CATDLF7 crude extract exhibited the most potent inhibitory activity against bacterial pathogens. Hence, CATDLF7 crude extract was subjected to chromatographic separation. This purification leads to the isolation of six pure compounds (1PS - 6PS). Of these, 3PS was found to be a major constituent and most effective against clinical isolates of methicillin- resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentration (MIC) values ranging from 100 to 200 μg/ml. Based on the spectroscopic data, 3PS was characterized as α,β- dehydrocurvularin. This compound also showed synergistic interaction with norfloxacin and reduced its MIC up to 32-folds with a fractional inhibitory concentration index (FICI) of 0.09.. To understand the possible antibacterial mechanism of action, α,β-dehydrocurvularin alone (100 μg/ml) exhibited efflux pump inhibitory potential by 0.84 fold decreasing in ethidium bromide (EtBr) fluorescence. In addition, α,β-dehydrocurvularin inhibited inflammatory cytokines TNF-α and IL-6 production, which is further validated by molecular docking scores -4.921 and -5.641, respectively, for understanding orientation and binding affinity.. Overall, the results highlighted identifying bioactive compound α,β-dehydrocurvularin, which could be used as an antimicrobial and anti-inflammatory agent.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Catharanthus; Cytokines; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Endophytes; Female; Humans; Interleukin-6; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Molecular Docking Simulation; Norfloxacin; Plant Extracts; Plant Leaves; Protein Binding; Signal Transduction; Structure-Activity Relationship; Zearalenone

The ingestion of mycotoxins can cause adverse health effects and represents a severe health risk to humans and livestock. Even though several acute and chronic effects have been described, the effect on the gut metaproteome is scarcely known. For that reason, we used metaproteomics to evaluate the effect of the mycotoxins deoxynivalenol (DON) and zearalenone (ZEN) on the gut microbiome of 15 weaned piglets. Animals were fed for 28 days with feed contaminated with different concentrations of DON (DONlow: 870 μg DON/kg feed, DONhigh: 2493 μg DON/kg feed) or ZEN (ZENlow: 679 μg ZEN/kg feed, ZENhigh: 1623 μg ZEN/kg feed). Animals in the control group received uncontaminated feed. The gut metaproteome composition in the high toxin groups shifted compared to the control and low mycotoxin groups, and it was also more similar among high toxin groups. These changes were accompanied by the increase in peptides belonging to Actinobacteria and a decrease in peptides belonging to Firmicutes. Additionally, DONhigh and ZENhigh increased the abundance of proteins associated with the ribosomes and pentose-phosphate pathways, while decreasing glycolysis and other carbohydrate metabolism pathways. Moreover, DONhigh and ZENhigh increased the abundance of the antioxidant enzyme thioredoxin-dependent peroxiredoxin. In summary, the ingestion of DON and ZEN altered the abundance of different proteins associated with microbial metabolism, genetic processing, and oxidative stress response, triggering a disruption in the gut microbiome structure.

Topics: Animals; Disease Models, Animal; Female; Gastrointestinal Microbiome; Humans; Mycotoxins; Proteomics; Swine; Therapy Animals; Trichothecenes; Weaning; Zearalenone

Endocrine disruptor zearalenone (ZEA) has been found to damage the reproductive system especially spermatogenesis. In our previous report, we have found that low dose (lower than No-Observed Effect Level, NOEL) ZEA exposure disturbed mouse spermatogenesis and diminished mouse semen quality. The purpose of current investigation was to explore the underlying mechanisms of pubertal low dose ZEA exposure upsetting spermatogenesis. And it was demonstrated that pubertal low dose ZEA exposure disrupted the meiosis process and the important genetic pathways to inhibit the spermatogenesis and even to diminish the semen quality with the decrease in spermatozoa motility and concentration. The DNA methylation markers 5mC and 5hmC were decreased, the histone methylation marker H3K27 was increased, at the same time estrogen receptor alpha was diminished in mouse testis after pubertal low dose ZEA exposure. The data indicate that the disruption in spermatogenesis by pubertal low dose ZEA exposure may be through the alterations in genetic and epigenetic pathways, and the interactions with estrogen receptor signaling pathway. Therefore, we should pay great attention on ZEA exposure to reduce its adverse impacts on male reproductive health.

Topics: Adolescent; Animals; Cell Division; Disease Models, Animal; Epigenesis, Genetic; Estrogen Receptor alpha; Humans; Male; Mice; Signal Transduction; Sperm Motility; Spermatogenesis; Zearalenone

Zearalenone (ZEA), a F-2 mycotoxin produced by Fusarium, has been found to be an endocrine disruptor through oestrogen receptor signalling pathway to impair spermatogenesis. The disruption on reproductive systems by ZEA exposure might be transgenerational. In our previous report, we have found that low dose (lower than no-observed effect level, NOEL) of ZEA impaired mouse spermatogenesis and decreased mouse semen quality. The purpose of the current investigation was to explore the impacts of low-dose ZEA on spermatogenesis in the offspring after prenatal exposure and the underlying mechanisms. And it demonstrated that prenatal low-dose ZEA exposure disrupted the meiosis process to inhibit the spermatogenesis in offspring and even to diminish the semen quality by the decrease in spermatozoa motility and concentration. The DNA methylation marker 5hmC was decreased, the histone methylation markers H3K9 and H3K27 were elevated, and oestrogen receptor alpha was reduced in the offspring testis after prenatal low-dose ZEA exposure. The data suggest that the disruption in spermatogenesis by prenatal low-dose ZEA exposure may be through the modifications on epigenetic pathways (DNA methylation and histone methylation) and the interactions with oestrogen receptor signalling pathway. Moreover, in the current study, the male offspring were indirectly exposed to low-dose ZEA through placenta and the spermatogenesis in offspring was disrupted which suggested that the toxicity of ZEA on reproductive systems was very severe. Therefore, we strongly recommend that greater attention should be paid to this mycotoxin to minimize its adverse impact on human spermatogenesis.

Topics: Animals; Animals, Newborn; Disease Models, Animal; DNA Methylation; Dose-Response Relationship, Drug; Endocrine Disruptors; Epigenesis, Genetic; Female; Histone Code; Humans; Infertility, Male; Male; Maternal Exposure; Maternal-Fetal Exchange; Mice; Mice, Inbred ICR; No-Observed-Adverse-Effect Level; Pregnancy; Prenatal Exposure Delayed Effects; Semen Analysis; Signal Transduction; Sperm Motility; Spermatogenesis; Testis; Zearalenone

Zearalenone (ZEN), one of the more virulent mycotoxins occurred in various cereals and feed during recent decades and made serious health hazards to plants, animals and humans. Vitamin C (Vc) has been shown to be an effective antidote to zearalenone. In this paper, the effects of diets containing zearalenone on the growth performance, genital organ and immunoglobulin of weaning piglets and the toxicity alleviation of vitamin C were studied. Piglets were weaned at 21 days of age and 32 healthy female hybrid weaning piglets (Duroc × Landrace × Large white) with a mean weight of 12.27 ± 0.30 kg were randomly selected. The thirty-two female weaning piglets were divided into four treatment groups according to body weight: control; basal diet + vitamin C (150 mg/kg); basal diet + 1.0 mg/kg ZEN; basal diet + 1 mg/kg ZEN+vitamin C (150 mg/kg). There were eight replicates in each group. The test period was twenty-eight days. The results demonstrated that dietary zearalenone could significantly increase the length, width and area of vulva (P < 0.05), the genital organ coefficient (P < 0.05), the level of IgA, IgG and IgM (P < 0.05), the level of BUN, CRE, AST and TBIL (P < 0.05), and significantly decrease the level of E2, PROG, LH and FSH (P < 0.05). However, the addition of 150 mg/kg vitamin C to dietary zearalenone prevented deformities in the vulva, decrease in immune response capacity, changes in serum biochemical indicators and disorders in hormones level of the piglets that received the diet containing only zearalenone. In conclusion, feeding ZEN of 1.0 mg/kg can result in a deleterious effect on piglets, which was totally or partly ameliorated by dietary supplementation of vitamin C at concentrations about 150 mg/kg diet. This study systematically investigated the inhibition mechanism of vitamin C on ZEN-induced reproductive toxicity, immunotoxicity and hematological toxicity of piglets, and which provided new ideas for reducing the harm of mycotoxins to the animals through means of nutrition regulation.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Ascorbic Acid; Aspartate Aminotransferases; Biomarkers; Cholesterol; Creatinine; Disease Models, Animal; Estradiol; Female; Follicle Stimulating Hormone; Immunoglobulins; Kidney; Luteinizing Hormone; Progesterone; Reproduction; Serum Albumin; Swine; Triglycerides; Weaning; Zearalenone

Recently, more and more studies support that inflammation is involved in the pathogenesis of epilepsy. Although TGFβ signaling is involved in epileptogenesis, whether TGFβ-associated neuroinflammation is sufficient to regulate epilepsy remains unknown to date. Furthermore, tumor necrosis factor-α receptor-associated factor-6 (TRAF6), transforming growth factor beta-activated kinase 1 (TAK1), which are the key elements of TGFβ-associated inflammation, is still unclear in epilepsy. Therefore, the present study aimed to explore the role of TRAF6 and TAK1 in pilocarpine-induced epileptic rat model. Firstly, the gene levels and protein expression of TRAF6 and TAK1 were detected in different time points after pilocarpine-induced status epilepticus (SE). 5z-7-oxozeaenol treatment (TAK1 antagonist) was then performed; the changes in TRAF6, TAK1, phosphorylated-TAK1 (P-TAK1), interleukin-1β (IL-1β) levels, neuronal survival and apoptosis, and seizure activity were detected. Our results showed that expressions of TRAF6 were increased after SE, reached the peak in 7day, maintained at the high level to 30days, and the TAK1, P-TAK1 levels were increased after SE following time. After 5z-7-oxozeaenol treatment in epileptic rats, TRAF6-TAK1-P-TAK1 signaling protein expressions were reduced, inflammatory cytokine IL-1β expression was decreased, neuron survival index was improved, the neuron apoptosis index was decreased and seizure durations were alleviated. In conclusion, the expression of TRAF6 and TAK1 are related to the progression of epilepsy. TAK1 might be a potential intervention target for the treatment of epilepsy via neuroprotection.

Topics: Animals; Cell Survival; Cerebral Cortex; Disease Models, Animal; Encephalitis; Hippocampus; Interleukin-1beta; Male; MAP Kinase Kinase Kinases; Neurons; Neuroprotection; Pilocarpine; Rats; Rats, Sprague-Dawley; Status Epilepticus; TNF Receptor-Associated Factor 6; Zearalenone

Zearalenone (ZEA) is a secondary metabolite produced by Fusarium species. ZEA was proved to exert a wide range of unwanted side effects, but its mechanism of action, particularly at duodenum levels, remains unclear. In our study based on the microarray technology we assessed the alteration of gene expression pattern Sus scrofa duodenum which has been previously exposed to ZEA. Gene expression data was validated by qRT-PCR and ELISA. The gene expression data were further extrapolated the results to their human orthologues and analyzed the data in the context of human health using IPA (Ingenuity Pathways Analysis).. Using Agilent microarray technology, we found that gene expression pattern was significantly affected by ZEA exposure, considering a 2-fold expression difference as a cut-off level and a p-value < 0.05. In total, we found 1576 upregulated and 2446 downregulated transcripts. About 1084 genes (764 downregulated and 751 overexpressed) were extrapolated to their human orthologues. IPA analysis showed various altered key cellular and molecular pathways. As expected, we observed a significant alteration of immune response related genes, MAPK (mitogen activate protein kinases) pathways or Toll-Like Receptors (TLRs). What captured our attention was the modulation of pathways related to the activation of early carcinogenesis.. Our data demonstrate that ZEA has a complex effect at duodenum level. ZEA is able to activate not only the immune response related genes, but also those relate to colorectal carcinogenesis. The effects can be more dramatic when connected with the exposure to other environmental toxic agents or co-occurrence with different microorganisms.

Topics: Animals; Cytokines; Disease Models, Animal; Duodenum; Estrogens, Non-Steroidal; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Humans; Reproducibility of Results; Sus scrofa; Transcriptome; Zearalenone

Intrauterine inflammation (IUI) associated with infection is the major cause of preterm birth (PTB) at <32 weeks' gestation and accounts for ∼40% of all spontaneous PTBs. Pharmacological strategies to prevent PTB and improve fetal outcomes will likely require both antimicrobial and anti-inflammatory therapies. Here we investigated the effects of two cytokine-suppressive anti-inflammatory drugs (CSAIDs), compounds that specifically target inflammatory signalling pathways, in an ovine model of lipopolysaccharide (LPS)-induced chorioamnionitis. Chronically catheterized ewes at 116 days gestation (n = 7/group) received an intra-amniotic (IA) bolus of LPS (10 mg) plus vehicle or CSAIDS: TPCA-1 (1.2 mg/kg fetal weight) or 5z-7-oxozeaenol (OxZnl; 0.4 mg/kg fetal weight); controls received vehicle (dimethylsulphoxide). Amniotic fluid (AF), fetal and maternal blood samples were taken 0, 2, 6, 12, 24 and 48 h later; tissues were taken at autopsy (48 h). Administration of TPCA-1 or OxZnl abrogated the stimulatory effects of LPS (P < 0.01 versus vehicle control) on production of PGE2 in AF, with lesser (non-significant) effects on IL-6 production. Fetal membrane polymorphonuclear cell infiltration score was significantly higher in LPS versus vehicle control animals (P < 0.01), and this difference was absent with TPCA-1 and OxZnl treatment. LPS-induced systemic fetal inflammation was highly variable, with no significant effects of CSAIDs observed. Lung inflammation was evident with LPS exposure, but unaffected by CSAID treatment. We have shown in a large animal model that IA administration of a single dose of CSAIDs can suppress LPS-induced IA inflammatory responses, while fetal effects were minimal. Further development and investigation of these compounds in infectious models is warranted.

Topics: Amniotic Fluid; Animals; Anti-Inflammatory Agents; Biomarkers; Catheters, Indwelling; Chorioamnionitis; Disease Models, Animal; Female; Fetal Blood; I-kappa B Kinase; Lipopolysaccharides; Lung; MAP Kinase Kinase Kinases; Phenylurea Compounds; Pregnancy; Premature Birth; Protein Kinase Inhibitors; Sheep, Domestic; Signal Transduction; Thiophenes; Western Australia; Zearalenone

Accumulating evidence suggests that activation of mitogen-activated protein kinases (MAPKs) and nuclear factor NF-κB exacerbates early brain injury (EBI) following subarachnoid hemorrhage (SAH) by provoking proapoptotic and proinflammatory cellular signaling. Here we evaluate the role of TGFβ-activated kinase 1 (TAK1), a critical regulator of the NF-κB and MAPK pathways, in early brain injury following SAH. Although the expression level of TAK1 did not present significant alternation in the basal temporal lobe after SAH, the expression of phosphorylated TAK1 (Thr-187, p-TAK1) showed a substantial increase 24 h post-SAH. Intracerebroventricular injection of a selective TAK1 inhibitor (10 min post-SAH), 5Z-7-oxozeaenol (OZ), significantly reduced the levels of TAK1 and p-TAK1 at 24 h post-SAH. Involvement of MAPKs and NF-κB signaling pathways was revealed that OZ inhibited SAH-induced phosphorylation of p38 and JNK, the nuclear translocation of NF-κB p65, and degradation of IκBα. Furthermore, OZ administration diminished the SAH-induced apoptosis and EBI. As a result, neurological deficits caused by SAH were reversed. Our findings suggest that TAK1 inhibition confers marked neuroprotection against EBI following SAH. Therefore, TAK1 might be a promising new molecular target for the treatment of SAH.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Cerebrovascular Trauma; Disease Models, Animal; Gene Expression Regulation; I-kappa B Proteins; Injections, Intraventricular; Male; MAP Kinase Kinase 4; MAP Kinase Kinase Kinases; Neurons; Neuroprotective Agents; NF-KappaB Inhibitor alpha; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Signal Transduction; Stereotaxic Techniques; Subarachnoid Hemorrhage; Transcription Factor RelA; Zearalenone

Zearalenone (ZEA) is a non-steroidal estrogenic mycotoxin produced by several species of Fusarium, commonly found in the soil in temperate and warm countries and is a frequent contaminant of cereal crops worldwide. Accordingly, it has been implicated in several mycotoxicosis in farm animals and in humans, but the underlying mechanisms remain largely unknown. Therefore, the current study was aimed to investigate the effect of an acute dose of ZEA (40 mg/kg, p.o.) on reproductive and hematological parameters, as well as on markers of oxidative stress in liver, kidney and testes in mice. Adult Swiss albino male mice were exposed to a single oral administration of ZEA, and 48 h thereafter behavioral and biochemical tests were performed. No differences in locomotor or exploratory activity were observed in the open-field test. On the other hand, ZEA increased the number of leukocytes, segmented neutrophils, sticks, eosinophils, monocytes and decreased platelets and lymphocytes number. Moreover, ZEA drastically reduced the number and motility of live spermatozoa. Additionally, while levels of thiobarbituric acid reactive substances (TBARS), non-protein thiols (NPSH) and ascorbic acid in liver, kidney and testes were not altered by ZEA administration, superoxide dismutase activity increased in all tissues evaluated, catalase activity increased in the kidney, and glutathione-S-transferase activity decreased in kidney and testes. In summary, we showed that ZEA have acute toxic effects mainly in reproductive system of adult male Swiss albino mice and its effect probably is related to a reduced activity of GST and increased in SOD activity in testes.

Topics: Animals; Catalase; Disease Models, Animal; Down-Regulation; Estrogens, Non-Steroidal; Fusarium; Glutathione Transferase; Kidney; Liver; Male; Mice; Mycotoxicosis; Oligospermia; Organ Specificity; Oxidative Stress; Random Allocation; Superoxide Dismutase; Testis; Up-Regulation; Zearalenone

Transforming growth factor-β-activated kinase (TAK1) is a member of the mitogen-activated protein kinase family that plays important roles in apoptosis and inflammatory signaling, both of which are critical components of stroke pathology. TAK1 has recently been identified as a major upstream kinase that phosphorylates and activates adenosine monophosphate-activated protein kinase (AMPK), a major mediator of neuronal injury after experimental cerebral ischemia. We studied the functional role of TAK1 and its mechanistic link with AMPK after stroke.. Male mice were subjected to transient middle cerebral artery occlusion (MCAO). The TAK1 inhibitor 5Z-7-oxozeaenol was injected either intracerebroventricularly or intraperitoneally at various doses and infarct size and functional outcome after long term survival was assessed. Mice with deletion of the AMPK α2 isoform were utilized to assess the contribution of downstream AMPK signaling to stroke outcomes. Levels of pTAK1, pAMPK, and other TAK1 targets including the pro-apoptotic molecule c-Jun-N-terminal kinase (JNK)/c-Jun and the pro-inflammatory protein cyclooxygenase-2 were also examined.. TAK1 is critical in stroke pathology. Delayed treatment with a TAK1 inhibitor reduced infarct size and improved behavioral outcome even when given several hours after stroke onset. This protective effect may be independent of AMPK activation but was associated with a reduction in JNK and c-Jun signaling.. Enhanced TAK1 signaling, via activation of JNK, contributes to cell death in ischemic stroke. TAK1 inhibition is a novel therapeutic approach for stroke as it is neuroprotective with systemic administration, has a delayed therapeutic window, and demonstrates sustained neuroprotective effects.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Apoptosis; Brain Ischemia; Disease Models, Animal; Male; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Protein Kinases; Random Allocation; Signal Transduction; Zearalenone

In previous studies, we identified the fungal macrocyclic lactone (S)-curvularin (SC) as an anti-inflammatory agent using a screening system detecting inhibitors of the Janus kinase/signal transducer and activator of transcription pathway. The objective of the present study was to investigate whether SC is able to decrease proinflammatory gene expression in an in vivo model of a chronic inflammatory disease. Therefore, the effects of SC and dexamethasone were compared in the model of collagen-induced arthritis (CIA) in mice. Total genomic microarray analyses were performed to identify SC target genes. In addition, in human C28/I2 chondrocytes and MonoMac6 monocytes, the effect of SC on proinflammatory gene expression was tested at the mRNA and protein level. In the CIA model, SC markedly reduced the expression of a number of proinflammatory cytokines and chemokines involved in the pathogenesis of CIA as well as human rheumatoid arthritis (RA). In almost all cases, the effects of SC were comparable with those of dexamethasone. In microarray analyses, we identified additional new therapeutic targets of SC. Some of them, such as S100A8, myeloperoxidase, or cathelicidin, an antimicrobial peptide, are known to be implicated in pathophysiological processes in RA. Similar anti-inflammatory effects of SC were also observed in human C28/I2 chondrocyte cells, which are resistant to glucocorticoid treatment. These data indicate that SC and glucocorticoid effects are mediated via independent signal transduction pathways. In summary, we demonstrate that SC is a new effective anti-inflammatory compound that may serve as a lead compound for the development of new drugs for the therapy of chronic inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Cell Line, Transformed; Cells, Cultured; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation Mediators; Mice; Mice, Inbred DBA; Mice, Transgenic; Zearalenone

Female guinea pigs were tested to determine whether they could serve as a model of zearalenone (ZEN) toxicosis during early pregnancy, as observed in domestic swine. Only 1 of 4 female guinea pigs that were given 21 mg of ZEN/kg of body weight orally during the first 8 days after mating was pregnant when examined 22 days after mating. Guinea pigs that were given 7 or 14 mg of ZEN/kg had normal fetal development. Serum concentrations of progesterone were less than 12 ng/ml in all guinea pigs 8 and 15 days after mating. Serum concentrations of progesterone were greater than 100 ng/ml in pregnant guinea pigs on day 22, but remained less than 12 ng/ml in nonpregnant guinea pigs. Three of 5 guinea pigs treated with 20 mg of ZEN/kg and only 1 of 4 guinea pigs given 30 mg of ZEN/kg on days 1 to 3 after mating were pregnant 22 days after mating. Female guinea pigs treated with 20 or 30 mg of ZEN/kg on days 4 to 5 or 6 to 8 after mating and female guinea pigs treated with 60 or 90 mg of ZEN/kg on days 4 and 5 after mating had normal pregnancies. Serum concentrations of progesterone were less than 10 ng/ml in all guinea pigs on day 15 and remained low on day 22 only in nonpregnant guinea pigs.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Animals; Copulation; Corpus Luteum; Disease Models, Animal; Embryonic and Fetal Development; Female; Fetus; Guinea Pigs; Pregnancy; Pregnancy, Animal; Progesterone; Resorcinols; Zearalenone