Search

Positive-sense RNA viruses modify intracellular calcium stores, endoplasmic reticulum and Golgi apparatus (Golgi) to generate membranous replication organelles known as viral factories. Viral factories provide a conducive and substantial enclave for essential virus replication via concentrating necessary cellular factors and viral proteins in proximity. Here, we identified the vital role of a broad-spectrum antiviral, peruvoside in limiting the formation of viral factories. Mechanistically, we revealed the pleiotropic cellular effect of Src and PLC kinase signaling via cyclin-dependent kinase 1 signaling leads to Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1) phosphorylation and Golgi vesiculation by peruvoside treatment. The ramification of GBF1 phosphorylation fosters GBF1 deprivation consequentially activating downstream antiviral signaling by dampening viral factories formation. Further investigation showed signaling of ERK1/2 pathway via cyclin-dependent kinase 1 activation leading to GBF1 phosphorylation at Threonine 1337 (T1337). We also showed 100% of protection in peruvoside-treated mouse model with a significant reduction in viral titre and without measurable cytotoxicity in serum. These findings highlight the importance of dissecting the broad-spectrum antiviral therapeutics mechanism and pave the way for consideration of peruvoside, host-directed antivirals for positive-sense RNA virus-mediated disease, in the interim where no vaccine is available. Peruvoside inhibits viral replication via Src/ERK kinase cascade activation of CDK1 and GBF1 phosphorylation. Phosphorylated GFB1 successively causes direct/indirect Golgi vesiculation which curtails viral replication. [Display omitted] [ABSTRACT FROM AUTHOR]

Mycotoxins are toxic, fungal secondary metabolites that contaminate agricultural commodities, food, and feed. Among them, T-2, HT-2, and diacetoxyscirpenol (DAS; the major type A trichothecene) are primarily produced from Fusarium species. These mycotoxins exert numerous toxicological effects in animals and humans, such as dermatotoxicity, haematotoxicity, hepatotoxicity, nephrotoxicity, neurotoxicity, and immunotoxicity. In the present study, human Jurkat T cells were used as a model to investigate apoptotic cell death induced by T-2, HT-2, and DAS. The results showed that T-2, HT-2, and DAS decreased cell viability and increased production of Reactive Oxygen Species in a time- and dose-dependency. Based on their IC 50 values, they could be ranked in decreasing order of cytotoxicity as T-2 > HT-2 > DAS. All tested mycotoxins caused DNA fragmentation, up-regulated cytochrome C, caspase 3, and caspase 9 mRNA levels, and down-regulated the relative expression of Bcl-2 and caspase 8. The effects of these trichothecenes on apoptosis were determined based on flow cytometry. At the IC 50 concentrations, the percentages of apoptotic cells were significantly higher than for the controls. Taken together, these data suggested that T-2, HT-2, and DAS could induce apoptosis through the mitochondrial apoptotic pathway. [Display omitted] • Trichothecene type A induce apoptotic cell death in human Jurkat T cells. • Cell viability, gene expression and protein expression were effected in human Jurkat cells exposed to T-2, HT-2 and DAS. • Trichothecene type A induce apoptosis through the mitochondrial apoptotic pathway. [ABSTRACT FROM AUTHOR]

Abstract Food and feed commodities are often contaminated by more than one mycotoxin. Among the several combinations that frequently occur, fusariotoxins are often mentioned. The multi-mycotoxins contamination is a serious threat for health. In the present study we investigated the toxic interactions between deoxynivalenol (DON), nivalenol (NIV), and fusarenon-X (FX) in Jurkat T cells by using the MTT assay. The tested mycotoxins alone or in combination had a dose dependent effect on proliferating lymphocytes. According to IC 50 , it could be classified in decreasing order of toxicity: FX > NIV > DON > DON + FX > NIV + FX > DON + NIV > DON + NIV + FX. The type of mycotoxin interactions was assessed by calculating the combination index (CI) and the dose reduction index (DRI). Our data indicate that an antagonistic effect was strongly observed in binary combination between DON and NIV at higher concentrations and ternary mixtures. Meanwhile, the DON and FX mixtures generated moderate antagonism, while NIV and FX provoked different interactions. The effects of tested mycotoxins on apoptosis were also determined using a FACScan flow cytometer. At IC 75 , the percentages of apoptotic cells in all treatment groups were significantly different when compared to control group but no significant differences among treatment groups was observed. Taken together, our data suggest that immunotoxicity among multi-mycotoxins contamination cannot be predicted based on individual effects but depends on the mixtures, ratio and/or concentrations in the product, as well as type of target cells. Highlights • The natural co-occurrence of mycotoxins in cereal grains and animal feeds are frequently noted around the world. • DON, NIV, and FX alone or in combination induce cytotoxicity and apoptosis on Jurkat human T cells. • The toxic interaction depends on the mixed of mycotoxin, their ratio and concentrations, as well as type of target cells. [ABSTRACT FROM AUTHOR]

Fusarenon X, a member of the type B trichothecene mycotoxin group, has been frequently observed, along with deoxynivalenol (DON) and nivalenol (NIV) as a contaminant in cereals. Our previous study demonstrated that a 14-day FX exposure caused apoptosis in the lymphoid tissues of mice, especially at 0.5 mg/kg bodyweight. However, the relationship between low concentrations of FX and apoptotic molecular machinery remains unclear. In the present study, we investigated the genetic regulatory mechanisms in the thymus and Peyer's patches of mice after 14 days oral administration of FX at 0.5 mg/kg bodyweight. FX caused the up-regulation of Bax, Bid, Trp53 , and Caspase-9 mRNA but the relative expression of Fas, TNF , and Caspase-8 remained unchanged. Furthermore, we also determined the toxicity of FX in Jurkat T-cells. FX exhibited a concentration- and time-dependent inhibition of cell viability. Thus, incubation time and FX concentration influence the percentage of apoptotic cells. These data suggested that treatment with low dosage of FX can induce apoptosis in lymphocytes through an effect on Bax, Bid, Trp53, and Caspase-9 and therefore the mitochondrial apoptotic pathway. [ABSTRACT FROM AUTHOR]

One hundred and twenty chicken samples from feces (n = 80), the carcass surface at slaughter at 2 meat chicken farms (n = 20), and retail chicken meat from 5 markets (n = 20) collected during 2018 and 2019 were examined for the prevalence of plasmid-mediated quinolone resistance (PMQR) in Escherichia coli. We detected qnrS -positive E. coli in a total of 74 samples from feces (n = 59), the carcass surface (n = 7), and retail meat (n = 8). These 74 qnrS -positive isolates were tested for antimicrobial susceptibility to determine the minimum inhibitory concentrations (MICs) of certain antimicrobials and genetically characterized. Ampicillin-resistance accounted for 71 of the 74 isolates (96%), followed by resistance to oxytetracycline (57/74; 77%), enrofloxacin (ERFX) (56/74; 76%), sulfisoxazole (SUL) (56/74; 76%), trimethoprim (TMP) (49/74; 66%), and dihydrostreptomycin (48/74; 65%). All farm-borne SUL- and TMP-resistant isolates except one were obtained from samples from farm A where a combination of sulfadiazine and TMP was administered to the chickens. Concentrations of ERFX at which 50 and 90% of isolates were inhibited were 2 μg/mL and 32 μg/mL, respectively. Diverse pulsed-field gel electrophoresis (PFGE) patterns of Xba I-digested genomic DNA were observed in the qnrS -positive isolates from fecal samples. Several isolates from feces and the carcass surface had identical Xba I-digested PFGE patterns. S1-nuclease PFGE and Southern blot analysis demonstrated that 7 of 11 dfrA13 -positive fecal isolates carried both the qnrS and dfrA13 genes on the same plasmid, and 2 of 3 dfrA1 -positive isolates similarly carried both qnrS and dfrA1 on the same plasmid, although the PFGE patterns of Xba I-digested genomic DNA of the isolates were different. These results suggest that the qnrS gene is prevalent in chicken farms via horizontal transfer of plasmids and may partly be co-selected under the use of TMP. [ABSTRACT FROM AUTHOR]

Lymphocytes are involved in the adaptive immune response and are highly sensitive to type B trichothecenes. In grains and their products, deoxynivalenol (DON) is the most widely distributed trichothecene. It usually co-occurs with other type B members, such as nivalenol (NIV) and fusarenon-X (FX), because they are all produced by the same Fusarium fungi. However, the combined effects of mycotoxins are complex and cannot be predicted based on individual toxicity. Thus, the adverse effects of combined toxins are of increasing concern. The aim of this study was to compare the toxicity to lymphoid tissues of mice of DON alone or mixed with NIV or FX. Forty, 3-week-old male ICR mice were given a single oral administration of a vehicle control, one toxin, binary, or ternary mixtures and then sacrificed at 12 h after exposure. Mice treated with FX alone showed marked nuclear condensation and fragmentation of lymphocytes in the cortical thymus and germinal center of Peyer's patches and spleen. Similarly, these animals clearly displayed TUNEL- and Caspase-3-positive cells in the regions. In contrast, minimal changes were noticed in the lymphoid tissues of mice receiving combined toxins when compared to this toxin alone. In addition, oral exposure to FX alone significantly up-regulated the relative expression of Bax , Caspase-3 , Caspase-9 , and Trp53. These data increase our understanding of the toxic actions of DON, NIV, and FX alone or in combination to lymphocytes and can be used to assess the possible risk associated with their co-occurrences in foodstuffs to human and animal health. • FX alone showed marked apoptotic cell death in the lymphoid tissues of mice after oral administration. • Mycotoxin mixtures are less toxicity to lymphocytes apoptosis than that of individual exposure. • In natural co-occurrence, the combined mycotoxins might be less impact on lymphoid mortality. [ABSTRACT FROM AUTHOR]

Abstract: Human enterovirus 71 (HEV71) has emerged as a major cause of epidemics of hand, foot and mouth disease associated with severe neurological sequelae in the Asia-Pacific region. In this study, a passive protection mouse model was used to evaluate the protective efficacy of formalin-inactivated HEV71 vaccines derived from a Chinese C4 genotype strain. Pregnant mice were immunised using a prime/boost strategy and ≥50U of vaccine protected five-day-old pups from lethal challenge with a mouse-adapted (B3 genotype) strain of HEV71. Immunised mice developed a neutralising antibody response to both the immunising C4 strain and to the mouse-adapted strain. Mice born to immunised dams showed significantly less myositis and reduced viral loads in tissues. [Copyright &y& Elsevier]