Inflammatory Cytokine-Induced Muscle Atrophy and Weakness Can Be Ameliorated by an Inhibition of TGF-ß-Activated Kinase-1.

Chronic inflammation causes muscle wasting. Because most inflammatory cytokine signals are mediated via TGF-ß-activated kinase-1 (TAK1) activation, inflammatory cytokine-induced muscle wasting may be ameliorated by the inhibition of TAK1 activity. The present study was undertaken to clarify whether TAK1 inhibition can ameliorate inflammation-induced muscle wasting. SKG/Jcl mice as an autoimmune arthritis animal model were treated with a small amount of mannan as an adjuvant to enhance the production of TNF-α and IL-1ß. The increase in these inflammatory cytokines caused a reduction in muscle mass and strength along with an induction of arthritis in SKG/Jcl mice. Those changes in muscle fibers were mediated via the phosphorylation of TAK1, which activated the downstream signaling cascade via NF-κB, p38 MAPK, and ERK pathways, resulting in an increase in myostatin expression. Myostatin then reduced the expression of muscle proteins not only via a reduction in MyoD1 expression but also via an enhancement of Atrogin-1 and Murf1 expression. TAK1 inhibitor, LL-Z1640-2, prevented all the cytokine-induced changes in muscle wasting. Thus, TAK1 inhibition can be a new therapeutic target of not only joint destruction but also muscle wasting induced by inflammatory cytokines.

FOXO3a/PI3K/Akt pathway participates in the ROS- induced apoptosis triggered by α-ZEL and ß-ZEL.

Zearalenone (ZEN), an estrogenic mycotoxin, is one of the most common food and feed contaminants. Also, its metabolites α-zearalenol (α-ZEL) and ß-zearalenol (ß-ZEL) are considered to induce oxidative stress, however its effect in prostate cells is not known yet. Our previous observations showed that forehead box transcription factor 3a (FOXO3a) expression is modified in hormone- sensitive cells in the response to mycotoxins, similar to the phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) pathway. Thus, this study evaluated the direct molecular effect of α-ZEL and ß-ZEL in a dose of 30 µM in hormone-dependent human prostate cancer (PCa) cells with the focus of the involvement of FOXO3a and PI3K/Akt signaling pathway in that effect. We observed that both active metabolites of ZEN reduced cell viability, induced oxidative stress, cell cycle arrest and apoptosis in PCa cells. Furthermore, we observed that FOXO3a as well as PI3K/Akt signaling pathway participate in ZELs induced toxicity in PCa cells, indicating that this signaling pathway might be a regulator of mycotoxin-induced toxicity generally.

Zearalenone modulates the function of goat endometrial cells via the mitochondrial quality control system.

Zearalenone (ZEN) is a mycotoxin known for its estrogen-like effects, which can disrupt the normal physiological function of endometrial cells and potentially lead to abortion in female animals. However, the precise mechanism by which ZEN regulates endometrial function remains unclear. In this study, we found that the binding receptor estrogen receptors for ZEN is extensively expressed across various segments of the uterus and within endometrial cells, and a certain concentration of ZEN treatment reduced the proliferation capacity of goat endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs). Meanwhile, cell cycle analysis revealed that ZEN treatment leaded to cell cycle arrest in goat EECs and ESCs. To explore the underlying mechanism, we investigated the mitochondrial quality control systems and observed that ZEN triggered excessive mitochondrial fission and disturbed the balance of mitochondrial fusion-fission dynamics, impaired mitochondrial biogenesis, increased mitochondrial unfolded protein response and mitophagy in goat EECs and ESCs. Additionally, ZEN treatment reduced the activities of mitochondrial respiratory chain complexes, heightened the production of hydrogen peroxide and reactive oxygen species, and caused cellular oxidative stress and mitochondrial dysfunction. These results suggest that ZEN has adverse effects on goat endometrium cells by disrupting the mitochondrial quality control system and affecting cell cycle and proliferation. Understanding the underlying molecular pathways involved in ZEN-induced mitochondrial dysfunction and its consequences on cell function will provide critical insights into the reproductive toxicity of ZEN and contribute to safeguarding the health and wellbeing of animals and humans exposed to this mycotoxin.

Disruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis.

Macrophage-orchestrated inflammation contributes to multiple diseases including sepsis. However, the underlying mechanisms remain to be defined clearly. Here, we show that macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is up-regulated in murine sepsis models. When myeloid Tigar is ablated, sepsis induced by either lipopolysaccharide treatment or cecal ligation puncture in male mice is attenuated via inflammation inhibition. Mechanistic characterizations indicate that TIGAR directly binds to transforming growth factor ß-activated kinase (TAK1) and promotes tumor necrosis factor receptor-associated factor 6-mediated ubiquitination and auto-phosphorylation of TAK1, in which residues 152-161 of TIGAR constitute crucial motif independent of its phosphatase activity. Interference with the binding of TIGAR to TAK1 by 5Z-7-oxozeaenol exhibits therapeutic effects in male murine model of sepsis. These findings demonstrate a non-canonical function of macrophage TIGAR in promoting inflammation, and confer a potential therapeutic target for sepsis by disruption of TIGAR-TAK1 interaction.

5Z-7-Oxozaenol attenuates cuprizone-induced demyelination in mice through microglia polarization regulation.

INTRODUCTION: Demyelination is a key factor in axonal degeneration and neural loss, leading to disability in multiple sclerosis (MS) patients. Transforming growth factor beta activated kinase 1 (TAK1) is a critical molecule involved in immune and inflammatory signaling pathways. Knockout of microglia TAK1 can inhibit autoimmune inflammation of the brain and spinal cord and improve the outcome of MS. However, it is unclear whether inhibiting TAK1 can alleviate demyelination. METHODS: Eight-week-old male c57bl/6j mice were randomly divided into five groups: (a) the control group, (b) the group treated with cuprizone (CPZ) only, (c) the group treated with 5Z-7-Oxozaenol (OZ) only, and (d) the group treated with both cuprizone and 15 µg/30 µg OZ. Demyelination in the mice of this study was induced by administration of CPZ (ig) at a daily dose of 400 mg/kg for consecutive 5 weeks. OZ was intraperitoneally administered at mentioned doses twice a week, starting from week 3 after beginning cuprizone treatment. Histology, rotarod test, grasping test, pole test, Western blot, RT-PCR, and ELISA were used to evaluate corpus callosum demyelination, behavioral impairment, oligodendrocyte differentiation, TAK1 signaling pathway expression, microglia, and related cytokines. RESULTS: Our results demonstrated that OZ protected against myelin loss and behavior impairment caused by CPZ. Additionally, OZ rescued the loss of oligodendrocytes in CPZ-induced mice. OZ inhibited the activation of JNK, p65, and p38 pathways, transformed M1 polarized microglia into M2 phenotype, and increased brain-derived neurotrophic factor (BDNF) expression to attenuate demyelination in CPZ-treated mice. Furthermore, OZ reduced the expression of proinflammatory cytokines and increases anti-inflammatory cytokines in CPZ-treated mice. CONCLUSION: These findings suggest that inhibiting TAK1 may be an effective approach for treating demyelinating diseases.

The Reaction of the Yeast Saccharomyces cerevisiae to Contamination of the Medium with Aflatoxins B2 and G1, Ochratoxin A and Zearalenone in Aerobic Cultures.

The mechanisms by which yeast cells respond to environmental stress include the production of heat shock proteins (HSPs) and the reduction of oxidative stress. The response of yeast exposed to aflatoxins B2+G1 (AFB2+G1), ochratoxin A (OTA), and zearalenone (ZEA) in aerobic conditions was studied. After 72 h of yeast cultivation in media contaminated with mycotoxins, the growth of yeast biomass, the level of malondialdehyde, and the activity of superoxide dismutase, glutathione S-transferase and glutathione peroxidase were examined; the expression profile of the following heat shock proteins was also determined: HSP31, HSP40, HSP60, HSP70, and HSP104. It was demonstrated that at the tested concentrations, both AFB2+G1 and ZEA inhibited yeast biomass growth. OTA at a concentration of 8.4 [µg/L] raised the MDA level. Intensified lipoperoxidation and increased activity of SOD and GPx were observed, regardless of the level of contamination with ZEA (300 µg/L or 900 µg/L). Increased contamination with AFB2+G1 and OTA caused an increase in the production of most HSPs tested (HSP31, HSP40, HSP70, HSP104). ZEA contamination in the used concentration ranges reduced the production of HSP31. The response of yeast cells to the presence of mycotoxin as a stressor resulted in the expression of certain HSPs, but the response was not systematic, which was manifested in different profiles of protein expression depending on the mycotoxin used. The tested mycotoxins influenced the induction of oxidative stress in yeast cells to varying degrees, which resulted in the activation of mainly SOD without GST mobilization or with a small involvement of GPx.

chi-miR-130b-3p regulates the ZEA-induced oxidative stress damage through the KEAP1/NRF2 signaling pathway by targeting SESN2 in goat GCs.

As a dominant mycotoxin, zearalenone (ZEA) has attracted extensive attention due to its estrogen-like effect and oxidative stress damage in cells. In order to find a way to relieve cell oxidative stress damage caused by ZEA, we treated goat granulosa cells (GCs) with ZEA and did a whole transcriptome sequencing. The results showed that the expression level of Sesterin2 (SESN2) was promoted extremely significantly in the ZEA group (p < .01). In addition, our research demonstrated that SESN2 could regulate oxidative stress level in GCs through Recombinant Kelch Like ECH Associated Protein 1 (KEAP1)/Nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway. The overexpression of SESN2 could reduce the oxidative damage, whereas knockdown of SESN2 would aggravate the oxidative damage caused by ZEA. What's more, microRNA (miRNA) chi-miR-130b-3p can bind to SESN2 3'-untranslated region (3'UTR) to regulate the expression of SESN2. The mimics/inhibition of chi-miR-130b-3p would have an effect on oxidative damage triggered by ZEA in GCs as well. In summary, these results elucidate a new pathway by which chi-miR-130b-3p affects the KEAP1/NRF2 pathway in GCs by modulating SESN2 expression in response to ZEA-induced oxidative stress damage.

Zearalenone attenuates colitis associated colorectal tumorigenesis through Ras/Raf/ERK pathway suppression and SCFA-producing bacteria promotion.

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.

Relationship Between Mycotoxin Production and Gene Expression in Fusarium graminearum Species Complex Strains Under Various Environmental Conditions.

The Fusarium graminearum species complex (FGSC) can produce various mycotoxins and is a major concern for food quantity and quality worldwide. In this study, we determined the effects of water activity (aw), temperature, incubation time and their interactions on mycotoxin accumulation and the expression levels of biosynthetic genes in FGSC strains from maize samples in China. The highest deoxynivalenol (DON), 3-acetyldeoxynivalenol(3ADON) and 15-acetyldeoxynivalenol (15ADON) levels of the F. boothii and F. graminearum strains were observed at 0.98 aw/30 °C or 0.99 aw/25 °C. F. asiaticum and F. meridionale reached maximum nivalenol (NIV) and 4-acetylnivalenol (4ANIV) contents at 0.99 aw and 30 °C. With the extension of the incubation time, the concentrations of DON and NIV gradually increased, while those of their derivatives decreased. F. boothii, F. meridionale and one F. asiaticum strain had the highest zearalenone (ZEN) values at 0.95 aw and 25 °C, while the optimum conditions for the other F. asiaticum strain and F. graminearum were 0.99 aw and 30 °C. Four genes associated with trichothecene and zearalenone synthesis were significantly induced under higher water stress in the early stage of production. The results indicated independence of mycotoxin production and gene expression, as maximum amounts of these toxic metabolites were observed at higher aw in most cases. This study provides useful information for the monitoring and prevention of such toxins entering the maize production chain.

In vitro antifungal activity of lasiodiplodin, isolated from endophytic fungus Lasiodiplodia pseudotheobromae J-10 associated with Sarcandra glabra and optimization of culture conditions for lasiodiplodin production.

A macrolide antibiotic, lasiodiplodin was isolated from the endophytic fungus (EF) Lasiodiplodia pseudotheobromae J-10 associated with the medicinal plant Sarcandra glabra. In vitro antifungal assay demonstrated the inhibitory activity of lasiodiplodin against the growth of six phytopathogenic fungi, with the IC50 values ranging between 15.50 and 52.30 µg/mL. The highest antifungal activities were recorded against Exserohilum turcicum, Colletotrichum capsici, and Pestalotiopsis theae, with IC50 values of 15.50, 15.90, and 17.55 µg/mL, respectively. The underlying mechanism of the antifungal activity of lasiodiplodin against E. turcicum included the alteration of its colony morphology and disturbance of its cell membrane integrity. In addition, the optimization of L. pseudotheobromae J-10 culture conditions increased lasiodiplodin yield to 52.33 mg/L from 0.59 mg/L at pre-optimization. This is the first report on the isolation and identification of antifungal compound from the EF L. pseudotheobromae J-10 associated with S. glabra, as well as on the optimization of L. pseudotheobromae J-10 culture conditions to increase lasiodiplodin yield. The results of this study support that lasiodiplodin is a natural compound with high potential bioactivity against phytopathogens, and provide a basis for further study of the EF associated with S. glabra.

In vitro effect of zearalenone on sperm parameters, oocyte maturation and embryonic development in buffalo.

The negative impact of zearalenone (ZEN; potent estrogenic mycotoxin) exposure on buffalo embryo production has not yet been determined. In the current study, buffalo sperm and oocytes were exposed to ZEN at different concentrations during maturation. Sperms (with and without ZEN exposure) were incubated for 2 h and evaluated for motility, viability, acrosome integrity, normality, and ultrastructure. Matured oocytes exposed to ZEN were stained to determine their nuclear maturation. Further, their developmental ability was evaluated after in vitro fertilization. Our results showed the toxic effects of ZEN at high concentrations (2000 ng/mL) on different buffalo sperm parameters. The number of acrosome-intact sperm was reduced at 0 h after exposure to a concentration of ≥ 100 ng/mL. Furthermore, the maturation rate of buffalo oocytes (telophase I + metaphase II) was significantly decreased in ZEN-treated oocytes with a higher degeneration rate. Oocytes matured in 1000 ng/mL ZEN and subsequently exhibited considerable reduction in cleavage rate and blastocyst formation compared with control oocytes (2.6% vs. 13.1%). Moreover, the morula rate was decreased (p < 0.001) in ZEN-treated oocytes at concentrations of ≥ 10 ng/mL. Overall, the adverse effects of in vitro ZEN exposure on buffalo sperm parameters and oocyte meiotic progression with a notable reduction in cleavage, morula, and blastocyst rates were defined by these results. Altogether, buffaloes should be considered sensitive to ZEN exposure with respect to their reproductive function.

A molecular dynamics perspective into estrogen receptor inhibition by selective flavonoids as alternative therapeutic options.

Zearalenone is an estrogenic mycotoxin which is a common food contaminant and has been implicated in increasing the incidence of carcinogenesis and other reproductive health ailments through the estrogen receptor alpha (ERα) pathway. Competitive ERα blockers such as 4-Hydroxytamoxifen (OHT), are synthetic FDA approved drugs which, albeit being an effective anticancer agent, induces life altering side effects. For this reason, there is an increased interest in the use of naturally occurring medicinal plant products such as flavonoids. This study aimed to identity flavonoid ERα inhibitors and provide insights into the mechanism of inhibition using computational techniques. The Molecular Mechanics/Generalized Born Surface Area calculations revealed that quercetrin, hesperidin, epigallocatechin 3-gallate and kaempferol 7-O-glucoside out of 14 flavonoids had higher binding affinity for ERα than OHT. The structural analysis revealed that the binding of the compounds to the receptor lead to dynamic alterations, which induced conformational shift in the structure and orientation of the receptor resulting in stabilised, compact and low energy systems. The results of this study provide imperative information that supports the use of flavonoids in the inhibition of ERα to prevent or ameliorate the consequential adverse effects associated with zearalenone exposure.Communicated by Ramaswamy H. Sarma.

Zearalenone and its metabolite exposure directs oestrogen metabolism towards potentially carcinogenic metabolites in human breast cancer MCF-7 cells.

Zearalenone (ZEN) is produced by Fusarium species contaminating various agriculture crops. In this study, the effects of ZEN and its metabolites α-zearalenol (α-ZEL), and ß-zearalenol (ß-ZEL) on the formation of carcinogenic oestrogen-catechols in MCF-7 cells were investigated. To assess the effects of mycoestrogens on the activity of cytochrome P450 1A1 and CYP1B1, the rate of ethoxyresorufin O-deethylation (EROD-assay) was measured. The effects of mycoestrogens on the expression of CYP 1A1, CYP 1B1, aryl-hydrocarbon receptor (AhR), and oestrogen receptor alpha (ERα) were determined by qPCR. The catechol-O-methyltransferase (COMT) activity was measured as the ratio of the methoxy metabolites of oestradiol. Results show that mycoestrogens inhibited significantly the CYP1-dependent EROD activities. In the presence of selective inhibitors, mycoestrogens reduced CYP 1A1 and enhanced CYP 1B1 activity. Quantitative PCR analyses demonstrated the upregulation of AhR and confirmed the selective effect of mycoestrogens on CYP1 expression levels and the decline of the CYP 1A1/CYP 1B1 ratio. Mycoestrogens increased the ratio of 4-MeOE to 2-MeOE2 formation significantly (P < 0.05). Our results suggest that the tested mycoestrogens increase the production of CYP1B1-mediated oestrogen catechol metabolites, directing the biotransformation of E2 towards 4-OHE2, which has been identified earlier as a crucial factor in oestrogen-induced tumour initiation.

Environment, Grain Development, and Harvesting Strategy Effects on Zearalenone Contamination of Grain from Fusarium Head Blight-Affected Wheat Spikes.

Fusarium head blight (FHB), caused by the fungus Fusarium graminearum, is associated with grain contamination with mycotoxins such as deoxynivalenol (DON) and zearalenone (ZEA). Unlike DON, less is known about factors affecting ZEA production during FHB epidemics. The objective of this study was to quantify ZEA contamination of wheat grain as influenced by temperature, relative humidity, FHB index (IND), grain maturation, simulated late-season rainfall, and harvest timing. Mean ZEA concentrations were low (<1.1 ppm) during the early stages of grain development (25 to 31 days after anthesis [DAA]) but rapidly increased 35 to 51 DAA in field experiments, particularly under rainy conditions. Five or ten consecutive days with simulated rainfall shortly before harvest greatly increased ZEA contamination. Similarly, extremely high levels of ZEA (51.8 to 468.6 ppm) were observed in grain from spikes exposed to 100% relative humidity (RH) at all tested temperatures and mean IND levels under controlled conditions. Interestingly, at RH ≤ 90%, ZEA concentrations were very low (0.1 to 3.6 ppm) at all tested temperatures, even at IND above 90%. At 100% RH, mean ZEA contamination was significantly higher at 20 and 25°C (235.1 and 278.2 ppm) than at 30°C (104.7 ppm). Grain harvested early and not exposed to rainfall had lower mean ZEA than grain harvested late and/or subjected to preharvest rainfall. This study was the first to associate ZEA contamination of grain from FHB-affected wheat spikes with temperature and moisture and show through designed experiments that early harvest could be a useful strategy for reducing ZEA contamination.

Trichoderma versus Fusarium-Inhibition of Pathogen Growth and Mycotoxin Biosynthesis.

This study evaluated the ability of selected strains of Trichoderma viride, T. viridescens, and T. atroviride to inhibit mycelium growth and the biosynthesis of mycotoxins deoxynivalenol (DON), nivalenol (NIV), zearalenone (ZEN), α-(α-ZOL) and ß-zearalenol (ß-ZOL) by selected strains of Fusarium culmorum and F. cerealis. For this purpose, an in vitro experiment was carried out on solid substrates (PDA and rice). After 5 days of co-culture, it was found that all Trichoderma strains used in the experiment significantly inhibited the growth of Fusarium mycelium. Qualitative assessment of pathogen-antagonist interactions showed that Trichoderma colonized 75% to 100% of the medium surface (depending on the species and strain of the antagonist and the pathogen) and was also able to grow over the mycelium of the pathogen and sporulate. The rate of inhibition of Fusarium mycelium growth by Trichoderma ranged from approximately 24% to 66%. When Fusarium and Trichoderma were co-cultured on rice, Trichoderma strains were found to inhibit DON biosynthesis by about 73% to 98%, NIV by about 87% to 100%, and ZEN by about 12% to 100%, depending on the pathogen and antagonist strain. A glycosylated form of DON was detected in the co-culture of F. culmorum and Trichoderma, whereas it was absent in cultures of the pathogen alone, thus suggesting that Trichoderma is able to glycosylate DON. The results also suggest that a strain of T. viride is able to convert ZEN into its hydroxylated derivative, ß-ZOL.

TAK1-inhibitors did not reduce disease burden in a Vκ*MYC model of multiple myeloma.

OBJECTIVE: Multiple myeloma is a haematological malignancy characterized by proliferation of monoclonal plasma cells in the bone marrow. Development of resistance and minimal residual disease remain challenging in the treatment of multiple myeloma. Transforming growth factor-ß activated kinase 1 (TAK1) has recently gained attention as a potential drug target in multiple myeloma. This study aimed at determining the in vivo effects of TAK1-inhibitors in a Vκ*MYC multiple myeloma mouse model. RESULTS: We treated mice carrying Vκ*MYC multiple myeloma cells with the TAK1-inhibitors 5Z-7-oxozeaenol and NG25. There were tendencies towards increased survival for both inhibitors, but only NG25 prolonged survival significantly. However, this effect was limited, and no differences in disease burden were observed for any of the treatments. In conclusion, although TAK1-inhibitors might prolong survival somewhat, they do not prevent disease in the Vκ*MYC mouse model of multiple myeloma.

Sodium selenite attenuates zearalenone-induced apoptosis through inhibition of endoplasmic reticulum stress in goat trophoblast cells.

Zearalenone (ZEL)-induced apoptosis in different cells is mediated by various molecular mechanisms, including endoplasmic reticulum (ER) stress. Selenium, an inorganic micronutrient, has several cytoprotective properties, but its potential protective action against ZEL-induced apoptosis in trophoblast cells and the precise mechanisms remain unclear. In this study, we investigated the effects of sodium selenite, a predominant chemical form of selenium, on cell viability, apoptosis, and progesterone (P4) production in ZEL-treated goat trophoblast cell line and explored the underlying molecular mechanisms. ZEL treatment repressed cell viability and promoted apoptosis, which was accompanied by an enhancement of the activity of caspase 3, a key executioner of apoptosis. ZEL treatment was involved in the upregulation of malonaldehyde (MDA) levels and was implicated in the reduction of the protein expression of selenoprotein S (SELS), thereby triggering protein expression of ER stress biomarkers (glucose-regulated protein 78 (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP)). However, sodium selenite attenuates these adverse effects, including increases in apoptotic rate, caspase 3 activity, MDA, GRP78, and CHOP expression and decreases in SELS expression in cells treated with ZEL or Thapsigargin (Tg, an ER stress agonist). Simultaneously, 4-phenylbutyric acid (4-PBA, an ER stress antagonist) treatment significantly alleviated the ZEL-induced deleterious effects on cells in response to ZEL, similarly to sodium selenite. In addition, sodium selenite supplementation effectively rescued the ZEL-induced decrease in P4 production in ZEL-treated cells. In summary, these findings suggest that ZEL triggers apoptosis in goat trophoblast cells by downregulating SELS expression and activating the ER stress signaling pathway and that sodium selenite protects against these detrimental effects. This study provides novel insights into the benefits of using selenium against ZEL-induced apoptosis and cellular damage.

Targeted Analysis of Sphingolipids in Turkeys Fed Fusariotoxins: First Evidence of Key Changes That Could Help Explain Their Relative Resistance to Fumonisin Toxicity.

The effects of fumonisins on sphingolipids in turkeys are unknown, except for the increased sphinganine to sphingosine ratio (Sa:So) used as a biomarker. Fumonisins fed at 20.2 mg/kg for 14 days were responsible for a 4.4 fold increase in the Sa:So ratio and a decrease of 33% and 36% in C14-C16 ceramides and C14-C16 sphingomyelins, respectively, whereas C18-C26 ceramides and C18-C26 sphingomyelins remained unaffected or were increased. Glucosyl- and lactosyl-ceramides paralleled the concentrations of ceramides. Fumonisins also increased dihydroceramides but had no effect on deoxysphinganine. A partial least squfares discriminant analysis revealed that all changes in sphingolipids were important in explaining the effect of fumonisins. Because deoxynivalenol and zearalenone are often found in feed, their effects on sphingolipids alone and in combination with fumonisins were investigated. Feeding 5.12 mg deoxynivalenol/kg reduced dihydroceramides in the liver. Zearalenone fed at 0.47 mg/kg had no effect on sphingolipids. When fusariotoxins were fed simultaneously, the effects on sphingolipids were similar to those observed in turkeys fed fumonisins alone. The concentration of fumonisin B1 in the liver of turkeys fed fumonisins was 0.06 µmol/kg. Changes in sphingolipid concentrations differed but were consistent with the IC50 of fumonisin B1 measured in mammals; these changes could explain the relative resistance of turkeys to fumonisins.

Zearalenone promotes follicle development through activating the SIRT1/PGC-1α signaling pathway in the ovaries of weaned gilts.

This study aimed to investigate the effect of zearalenone (ZEA) exposure on follicular development in weaned gilts, and its mechanism based on the silent information regulator 1 (SIRT1)/peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) signaling pathway. A total of 32 healthy female weaned piglets (Landrace × Yorkshire × Duroc) with an average body weight of 12.39 ± 0.24 kg were randomly allotted to a basal diet supplemented with 0, 0.15, 1.5, or 3.0 mg/kg ZEA for a 32-d feeding test. Blood and ovarian samples were obtained at the end of the experiment to determine serum toxin concentrations, ovarian histology, and the expressions of proliferating cell nuclear antigen (PCNA) and SIRT1/PGC-1α signaling pathway-related genes. Results showed that the vulva area, serum concentrations of ZEA, α-zearalenol and ß-zearalenol, the thickness of the growing follicular layer, and the diameter of the largest growing follicles, as well as the expressions of SIRT1, PGC-1α, estrogen-related receptor α (ERRα), ATP synthase subunit beta (ATP5B), and PCNA, increased linearly (P < 0.05) with increasing dietary ZEA, whereas the thickness of the primordial follicle layer decreased linearly (P < 0.05). Immunohistochemical analysis showed that the immunoreactive substances of SIRT1 and PGC-1α in the ovaries enhanced with the increasing dietary ZEA (P < 0.05). In addition, the thickness of the growing follicular layer and the diameter of the largest growing follicle were positively correlated with relative mRNA and protein expressions of SIRT1, PGC-1α, ERRα, ATP5B, and PCNA (P < 0.05). However, the thickness of the primordial follicle layer was negatively correlated with the mRNA and protein expression of SIRT1, PGC-1α, ERRα, ATP5B, and PCNA (P < 0.05). Interestingly, the 1.5 mg/kg ZEA treatment had highly hyperplastic follicles, whereas 3.0 mg/kg ZEA resulted in a large number of follicular atresia, which indicated that low-dose ZEA exposure accelerated follicular proliferation, while high-dose ZEA promoted follicular atresia, although the critical value interval needs further confirmation. Results provide a theoretical basis for finding the therapeutic target of ZEA-induced reproductive disorders in weaned gilts.

Zearalenone (ZEA), an estrogenic fusariotoxin, existing in various grains and feedstuffs, could disrupt the endocrine and reproductive systems. However, the underlying mechanisms of ZEA-induced follicular development have not been fully elucidated. This study was to explore the effects and the possible molecular mechanisms of ZEA on follicular development. A total of 32 female weaned piglets were randomly allotted to a basal diet supplemented with 0, 0.15, 1.5, or 3.0 mg/kg ZEA for a 32-d feeding test. The results showed that dietary ZEA increased the vulva area and serum toxin levels, and accelerated follicle development. Moreover, 1.5 and 3.0 mg/kg ZEA changed the expression of proliferating cell nuclear antigen (PCNA) and activated the silent information regulator 1 (SIRT1)/peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) signaling pathway. Meanwhile, ZEA could promote follicle development by regulating PCNA expression through activation of the SIRT1/PGC-1α signaling pathway. The very significant contribution was that the proliferated follicles significantly increased with the increasing ZEA concentration when the ZEA in the diet was less than 1.5 mg/kg; however, atretic follicles significantly increased when the ZEA in the diet was 3.0 mg/kg. This study provides a theoretical basis for finding the therapeutic target of ZEA-induced reproductive disorders in weaned gilts.

(R)-(+)-Lasiodiplodin isolated from the endophytic fungus Sordaria tamaensis exhibits potent antimycobacterial and anti-inflammatory activities in vitro and in vivo: a dual approach for the treatment of severe pulmonary tuberculosis.

OBJECTIVES: This study aimed to evaluate endophytic fungi isolated from Tocoyena bullata and Humiria balsamifera plant species for their antimycobacterial and anti-inflammatory activities, focusing on severe pulmonary tuberculosis cases which are often associated with exacerbated inflammation. METHODS: Mycobacterium suspensions were incubated with the samples for 5 days. RAW 264.7 macrophages stimulated with LPS were also incubated with them for 24 h to assess the inhibition of inflammatory mediator production and cytotoxicity. C57BL/6 mice were infected with Mtb M299 and treated for 15 days with lasiodiplodin (Lasio). KEY FINDINGS: Endophytic fungus Sordaria tamaensis, obtained from T. bullata, was the most promising. Its ethanolic extract impaired mycobacterial growth with MIC50 (µg/ml): 1.5 ± 0.6 (BCG), 66.8 ± 0.1 (H37Rv) and 80.0 ± 0.1 (M299). (R)-(+)-Lasio showed MIC50 92.2 ± 1.8 µg/ml (M299). In addition, Lasio was able to inhibit NO, IL-1ß and TNF-α production and was not cytotoxic for macrophages. M. tuberculosis-infected C57BL/6 animals treated by Lasio reduced the number of acid-fast bacilli, lung pathology, leucocyte influx and proinflammatory cytokine production in the lungs. The class IIa fructose 1,6-bisphosphate aldolase was the predicted hypothetical target of Lasio. CONCLUSIONS: (R)-(+)-Lasio stood out as a promising anti-TB compound, exhibiting anti-inflammatory and antimycobacterial effects, as well as low cytotoxicity.