Aflatoxins are food-borne secondary fungal metabolites that are hepatotoxic, hepatocarcinogenic, and mutagenic. Urinary and serum biomarkers are more efficient in reflecting dietary exposure to aflatoxin B₁ (AFB₁) than other methods such as food sampling and dietary questionnaires. Chronic infection of the hepatitis B virus (HBV) and dietary exposure to AFB₁ are the major risk factors in a multifactorial etiology of hepatocellular carcinogenesis, raising the possibility of a synergistic interaction between 2 agents. These effects are due to the formation of DNA and protein adducts and lipid peroxidation. Most patients with hepatocellular carcinoma and HBV infection had prevalent GC → TA transversion mutation at the third position of codon 249 of the p53 gene. The HBx protein of HBV also promotes cell cycle progression, increases the expression of telomerase reverse transcriptase, inactivates negative growth regulators, and binds to and inhibits the expression of p53 (antiapoptotic activity) and other tumor suppressor genes and senescence-related factors. Some reports also evidence the role of hepatitis C virus in the pathogenesis of HCC. Inhibitors of AFB₁ adducts are found to be potent chemoprotective agents against AFB₁-induced HCC. This review focuses on the interaction of aflatoxin, HBV, and hepatitis C virus in the development of HCC.

Scope: Extra virgin olive oil (EVOO) is rich in phenolic compounds, including hydroxytyrosol (HTy) and hydroxytyrosyl acetate (HTy-Ac), which have presented multiple beneficial properties. Their impact on inflammatory responses in human keratinocytes and modes of action have not been addressed yet. Methods and results: Primary human keratinocytes are pretreated with HTy-Ac or HTy for 30 min and stimulated with IL-1 or Toll-like receptor 3 ligand (TLR3-l). Thymic stromal lymphopoietin (TSLP), measured by ELISA, is attenuated by both polyphenols in a dose-dependent manner. The expression of several inflammation-related genes, including distinct TSLP isoforms and IL-8, are assessed by quantitative RT-PCR and likewise inhibited by HTy-Ac/HTy. Mechanistically, EVOO phenols counteracts I B degradation and translocation of NF-B to the nucleus, a transcription factor of essential significance to TSLP and IL-8 transcriptional activity; this is evidenced by immunoblotting. Accordingly, NF-B recruitment to critical binding sites in the TSLP and IL-8 promoter is impeded in the presence of HTy-Ac/HTy, as demonstrated by chromatin immunoprecipitation. Promoter reporter assays finally reveal that the neutralizing effect on NF-B induction has functional consequences, resulting in reduced NF-B-directed transcription.

Summary Background Thymic stromal lymphopoietin (TSLP) mediates proallergic T helper 2‐type responses by acting on leucocytes. Endogenous pathways regulating TSLP production are poorly defined. Objectives To uncover the mechanisms by which skin barrier disruption elicits TSLP production and to delineate the level at which individual mechanistic components may converge. Methods A combination of primary keratinocytes, skin explants and in vivo strategies was employed. Murine skin was tape stripped in the presence of neutralizing antibodies or antagonists. Cells and explants were stimulated with interleukin (IL)‐1 and protease‐activated receptor 2 agonist (PAR‐2‐Ag). TSLP levels were quantified by enzyme‐linked immunosorbent assay and real‐time quantitative polymerase chain reaction. Chromatin immunoprecipitation and promoter reporter assays were used to examine recruitment and functional activity of nuclear factor kappa B (NF‐κB) at the TSLP promoter. Results TSLP induction in mouse skin occurred in a PAR‐2‐ and IL‐1‐dependent manner. This scenario was duplicated by exogenous IL‐1 plus PAR‐2‐Ag vs. each stimulus alone. Joint activity of PAR‐2 and IL‐1 was also observed in human keratinocytes. The TSLP promoter was identified as the target of PAR‐2/IL‐1, whereby PAR‐2 activation augmented the recruitment of NF‐κB and transcriptional activation over IL‐1 alone. Combined treatment showed activity at concentrations of IL‐1 unable to elicit NF‐κB activity on their own. Conclusions Skin barrier disruption activates the IL‐1 and the PAR‐2 pathways, which act in concert to activate the TSLP promoter and possibly other inflammatory genes. Awareness of this combined activity may permit a more flexible clinical management by selective targeting of either pathway individually or collectively. What's already known about this topic? Thymic stromal lymphopoietin (TSLP) is rapidly induced upon skin perturbation and mediates proallergic T helper 2‐type responses by acting on leucocytes. Endogenous control of TSLP expression is poorly understood, but interleukin (IL)‐1 is one regulator in the cutaneous environment In addition to IL‐1, protease‐activated receptor 2 (PAR‐2) organizes central inflammatory pathways in the skin. What does this study add? IL‐1 and PAR‐2 pathways cooperate in driving TSLP production in mice and humans. Pathway integration occurs at the level of the TSLP promoter through enhanced recruitment and transcriptional activation of nuclear factor kappa B. When PAR‐2 is co‐stimulated, very low IL‐1 levels (inactive by themselves) can induce biologically meaningful responses in the skin environment. What is the translational message? Physical skin irritation results in robust TSLP production by simultaneous activation of PAR‐2 and IL‐1 pathways.

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Dipeptidyl peptidase-III is an important enkephalin degrading enzyme and its inhibitors are expected to be promising in pain management. Some of its inhibitors showed an antinociceptive potential. The present study investigated the evaluation of dietary proteins as potential precursors of dipeptidyl peptidase-III inhibitors by measuring occurrence frequency of dipeptidyl peptidase-III inhibitory peptides. In silico analysis of 69 proteins from 17 food commodities revealed 2659 dipeptidyl peptidase-III inhibitory peptides. β-subunit of hemoglobin and annexin A5 of chicken showed highest dipeptidyl peptidase-III inhibiting potential followed by 12S seed storage globulin 2 of oat, β-conglycinin of soyabean, α-lactalbumin of cow milk, cruciferin CRU4 of rapeseed, and zein-alpha of maize But overall occurrence frequency of dipeptidyl peptidase-III inhibitory peptides was observed highest in maize followed by pumpkin, soyabean, and rapeseed, whereas barley showed the lowest frequency among plant based foods. Chicken and maize had the highest dipeptidyl peptidase-III inhibitory potential in animal and plant derived foods respectively, thus may serve as a natural dietary source for pain modulation.

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