Aflatoxin B1 and Epstein-Barr virus-induced CCL22 expression stimulates B cell infection.

Epstein-Barr Virus (EBV) infects more than 90% of the adult population worldwide. EBV infection is associated with Burkitt lymphoma (BL) though alone is not sufficient to induce carcinogenesis implying the involvement of co-factors. BL is endemic in African regions faced with mycotoxins exposure. Exposure to mycotoxins and oncogenic viruses has been shown to increase cancer risks partly through the deregulation of the immune response. A recent transcriptome profiling of B cells exposed to aflatoxin B1 (AFB1) revealed an upregulation of the Chemokine ligand 22 (CCL22) expression although the underlying mechanisms were not investigated. Here, we tested whether mycotoxins and EBV exposure may together contribute to endemic BL (eBL) carcinogenesis via immunomodulatory mechanisms involving CCL22. Our results revealed that B cells exposure to AFB1 and EBV synergistically stimulated CCL22 secretion via the activation of Nuclear Factor-kappa B pathway. By expressing EBV latent genes in B cells, we revealed that elevated levels of CCL22 result not only from the expression of the latent membrane protein LMP1 as previously reported but also from the expression of other viral latent genes. Importantly, CCL22 overexpression resulting from AFB1-exposure in vitro increased EBV infection through the activation of phosphoinositide-3-kinase pathway. Moreover, inhibiting CCL22 in vitro and in humanized mice in vivo limited EBV infection and decreased viral genes expression, supporting the notion that CCL22 overexpression plays an important role in B cell infection. These findings unravel new mechanisms that may underpin eBL development and identify novel pathways that can be targeted in drug development.

High-pressure acidified steaming with varied citric acid dosing can successfully detoxify mycotoxins.

Mycotoxins are toxic fungal metabolites that exert various toxicities, including leading to death in lethal doses. This study developed a novel high-pressure acidified steaming (HPAS) for detoxification of mycotoxins in foods and feed. The raw materials, maize and peanut/groundnut, were used for the study. The samples were separated into raw and processed categories. Processed samples were treated using HPAS at different citric acid concentrations (CCC) adjusted to pH 4.0, 4.5, and 5.0. The enzyme-linked immunosorbent assay (ELISA) kit method for mycotoxins analysis was used to determine the levels of mycotoxins in the grains, with specific focus on total aflatoxins (AT), aflatoxins B1 (AFB1), aflatoxin G1 (AFG1), ochratoxin A (OTA), and citrinin. The mean values of the AT, AFB1, AFG1, OTA, and citrinin in the raw samples were 10.06 ± 0.02, 8.21 ± 0.01, 6.79 ± 0.00, 8.11 ± 0.02, and 7.39 ± 0.01 µg/kg for maize, respectively (p ≤ .05); and for groundnut (peanut), they were 8.11 ± 0.01, 4.88 ± 0.01, 7.04 ± 0.02, 6.75 ± 0.01, and 4.71 ± 0.00 µg/kg, respectively. At CCC adjusted to pH 5.0, the AT, AFB1, AFG1, OTA, and citrinin in the samples significantly reduced by 30%-51% and 17%-38% for maize and groundnut, respectively, and were reduced to 28%-100% when CCC was adjusted to pH 4.5 and 4.0 (p ≤ .05). The HPAS process either completely detoxified the mycotoxins or at least reduced them to levels below the maximum limits of 4.00-6.00, 2.00, 2.00, 5.00, and 100 µg/kg for AT, AFB1, AFG1, OTA, and citrinin, respectively, set by the European Union, WHO/FAO, and USDA. The study clearly demonstrates that mycotoxins can be completely detoxified using HPAS at CCC adjusted to pH 4.0 or below. This can be widely applied or integrated into many agricultural and production processes in the food, pharmaceutical, medical, chemical, and nutraceutical industries where pressurized steaming can be applied for the successful detoxification of mycotoxins.

Mycotoxins' Toxicological Mechanisms Involving Humans, Livestock and Their Associated Health Concerns: A Review.

Mycotoxins are well established toxic metabolic entities produced when fungi invade agricultural/farm produce, and this happens especially when the conditions are favourable. Exposure to mycotoxins can directly take place via the consumption of infected foods and feeds; humans can also be indirectly exposed from consuming animals fed with infected feeds. Among the hundreds of mycotoxins known to humans, around a handful have drawn the most concern because of their occurrence in food and severe effects on human health. The increasing public health importance of mycotoxins across human and livestock environments mandates the continued review of the relevant literature, especially with regard to understanding their toxicological mechanisms. In particular, our analysis of recently conducted reviews showed that the toxicological mechanisms of mycotoxins deserve additional attention to help provide enhanced understanding regarding this subject matter. For this reason, this current work reviewed the mycotoxins' toxicological mechanisms involving humans, livestock, and their associated health concerns. In particular, we have deepened our understanding about how the mycotoxins' toxicological mechanisms impact on the human cellular genome. Along with the significance of mycotoxin toxicities and their toxicological mechanisms, there are associated health concerns arising from exposures to these toxins, including DNA damage, kidney damage, DNA/RNA mutations, growth impairment in children, gene modifications, and immune impairment. More needs to be done to enhance the understanding regards the mechanisms underscoring the environmental implications of mycotoxins, which can be actualized via risk assessment studies into the conditions/factors facilitating mycotoxins' toxicities.

Epigenetic Alteration of the Cancer-Related Gene TGFBI in B Cells Infected with Epstein-Barr Virus and Exposed to Aflatoxin B1: Potential Role in Burkitt Lymphoma Development.

Burkitt lymphoma (BL) is a malignant B cell neoplasm that accounts for almost half of pediatric cancers in sub-Saharan African countries. Although the BL endemic prevalence is attributable to the combination of Epstein-Barr virus (EBV) infection with malaria and environmental carcinogens exposure, such as the food contaminant aflatoxin B1 (AFB1), the molecular determinants underlying the pathogenesis are not fully understood. Consistent with the role of epigenetic mechanisms at the interface between the genome and environment, AFB1 and EBV impact the methylome of respectively leukocytes and B cells specifically. Here, we conducted a thorough investigation of common epigenomic changes following EBV or AFB1 exposure in B cells. Genome-wide DNA methylation profiling identified an EBV-AFB1 common signature within the TGFBI locus, which encodes for a putative tumor suppressor often altered in cancer. Subsequent mechanistic analyses confirmed a DNA-methylation-dependent transcriptional silencing of TGFBI involving the recruitment of DNMT1 methyltransferase that is associated with an activation of the NF-κB pathway. Our results reveal a potential common mechanism of B cell transformation shared by the main risk factors of endemic BL (EBV and AFB1), suggesting a key determinant of disease that could allow the development of more efficient targeted therapeutic strategies.

African Nightshade (Solanum scabrum Mill.): Impact of Cultivation and Plant Processing on Its Health Promoting Potential as Determined in a Human Liver Cell Model.

Plant cultivation and processing may impact nutrient and phytochemical content of vegetables. The present study aimed at determining the influence of cultivation and processing on the health promoting capacity of African nightshade (Solanum scabrum Mill.) leaves, an indigenous vegetable, rich in nutrients and phytochemicals. Anti-genotoxicity against the human liver carcinogen aflatoxin B1 (AFB1) as determined by the comet assay and radical oxygen species (ROS) scavenging capacity of ethanolic and aqueous extracts were investigated in human derived liver (HepG2) cells. ROS scavenging activity was assessed using electron paramagnetic spin resonance and quantification of ARE/Nrf2 mediated gene expression. The cultivation was done under different environmental conditions. The processing included fermentation and cooking; postharvest ultraviolet irradiation (UV-C) treatment was also investigated. Overall, S. scabrum extracts showed strong health promoting potential, the highest potential was observed with the fermented extract, which showed a 60% reduction of AFB1 induced DNA damage and a 38% reduction in FeSO4 induced oxidative stress. The content of total polyphenols, carotenoids and chlorophylls was indeed affected by cultivation and processing. Based on the present in vitro findings consumption of S. scabrum leaves could be further encouraged, preferentially after cooking or fermentation of the plant.

The role of plant processing for the cancer preventive potential of Ethiopian kale (Brassica carinata).

Background: Ethiopian kale (Brassica carinata) is a horticulturally important crop used as leafy vegetable in large parts of East and Southern Africa. The leaves are reported to contain high concentrations of health-promoting secondary plant metabolites. However, scientific knowledge on their health benefits is scarce. Objective: This study aimed to determine the cancer preventive potential of B. carinata using a human liver in vitro model focusing on processing effects on the pattern of secondary plant metabolites and bioactivity. Design: B. carinata was cultivated under controlled conditions and differentially processed (raw, fermented, or cooked) after harvesting. Human liver cancer cells (HepG2) were treated with ethanolic extracts of raw or processed B. carinata leaves and analyzed for their anti-genotoxic, anti-oxidant, and cytostatic potential. Chemical analyses were carried out on glucosinolates including breakdown products, phenolic compounds, carotenoids, and chlorophyll content. Results: Pre-treatment with B. carinata extracts concentration dependently reduced aflatoxin-induced DNA damage in the Comet assay, reduced the production of reactive oxygen species as determined by electron paramagnetic resonance spectroscopy, and induced Nrf2-mediated gene expression. Increasing extract concentrations also promoted cytostasis. Processing had a significant effect on the content of secondary plant metabolites. However, different processing methodologies did not dramatically decrease bioactivity, but enhanced the protective effect in some of the endpoints studied. Conclusion: Our findings highlight the cancer preventive potential of B. carinata as indicated by the protection of human liver cells against aflatoxin in vitro. In general, consumption of B. carinata should be encouraged as part of chemopreventive measures to combat prevalence of aflatoxin-induced diseases.

Normal human immune cells are sensitive to telomerase inhibition by Brassica-derived 3,3-diindolylmethane,partly mediated via ERα/ß-AP1 signaling.

SCOPE: Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) from Brassica plants are regarded as promising anticancer phytochemicals. The enzyme telomerase is a very attractive target for cancer therapeutics; in normal cells such as lymphocytes, it plays a decisive role for cell maintenance. The effect of I3C and DIM on telomerase in normal human immune cells (PBMC) was studied compared to leukaemia cells (HL-60). Signalling of telomerase regulation via estrogen receptor (ER) was addressed. METHODS AND RESULTS: Short-term treatment with I3C and DIM inhibited telomerase activity in leukaemia cells (>30 µM I3C; >3 µM DIM). In CD3/CD28 activated PBMC, inhibition was stronger, though (>3 µM I3C; >1 µM DIM). DIM long-term treatment resulted in DNA damage induction and proliferation inhibition in PBMC as determined by the comet assay and CFSE staining, respectively. A relevance of ERα/ß-AP1 signaling for telomerase inhibition on enzyme activity, but not transcription level became evident indicating a nonclassical mode for ER regulation of telomerase by DIM. CONCLUSION: Although desired in cancer cells, this study identified a potential adverse impact of I3C and DIM on telomerase action in normal human immune cells, partly mediated by an ER-dependent mechanism. These new findings should be considered for potential chronic high-dose chemoprevention strategies using these compounds.