Mycotoxins are produced primarily as secondary fungal metabolites. Mycotoxins are toxic in nature and naturally produced by various species of fungi, which usually contaminate food and feed ingredients. The growth of these harmful fungi depends on several environmental factors, such as pH, humidity, and temperature; therefore, the mycotoxin distribution also varies among global geographical areas. Various rules and regulations regarding mycotoxins are imposed by the government bodies of each country, which are responsible for addressing global food and health security concerns. Despite this legislation, the incidence of mycotoxin contamination is continuously increasing. In this review, we discuss the geographical regulatory guidelines and recommendations that are implemented around the world to control mycotoxin contamination of food and feed products. Researchers and inventors from various parts of the world have reported several innovations for controlling mycotoxin-associated health consequences. Unfortunately, most of these techniques are restricted to laboratory scales and cannot reach users. Consequently, to date, no single device has been commercialized that can detect all mycotoxins that are naturally available in the environment. Therefore, in this study, we describe severe health hazards that are associated with mycotoxin exposure, their molecular signaling pathways and processes of toxicity, and their genotoxic and cytotoxic effects toward humans and animals. We also discuss recent developments in the construction of a sensitive and specific device that effectively implements mycotoxin identification and detection methods. In addition, our study comprehensively examines the recent advancements in the field for mitigating the health consequences and links them with the molecular and signaling pathways that are activated upon mycotoxin exposure. Graphical Abstract

Phorbol 12-myristate 13-acetate (PMA) is a potent tumor promoter and highly inflammatory in nature. Here, we investigated the toxic effects of PMA on different model system. PMA (10 μg) caused chromosomal aberrations on the Allium cepa root tip and induced mitotic dysfunction. Similarly, PMA caused embryonic and larval deformities and a plummeted survivability rate on zebrafish embryo in a dose-dependent manner. Persistently, PMA treatment on immortalized human keratinocyte human keratinocyte (HaCaT) cells caused massive inflammatory rush at 4 h and a drop in cell survivability at 24 h. Concomitantly, we replicated a cutaneous inflammation similar to human psoriasis induced by PMA. Herein, we used tangeretin (TAN), as an antagonist to counteract the inflammatory response. Results from an in vivo experiment indicated that TAN (10 and 30 mg/kg) significantly inhibited PMA stimulated epidermal hyperplasia and intra-epidermal neutrophilic abscesses. In addition, its treatment effectively neutralized PMA induced elevated reactive oxygen species (ROS) generation on in vitro and in vivo systems, promoting antioxidant response. The association of hypoxia-inducible factor 1-alpha (HIF-1α)-nuclear factor kappa-light-chain-enhancer of activated b cells (NF-κB) crosstalk triggered by PMA enhanced PKCα-ERK1/2-NF-κB pathway; its activation was also significantly counteracted after TAN treatment. Conclusively, we demonstrated TAN inhibited the nuclear translocation of HIF-1α and NF-κB p65. Collectively, TAN treatment ameliorated PMA incited malignant inflammatory response by remodeling the cutaneous microenvironment.

Polymethoxyflavanoids (PMFs) have exhibited a vast array of therapeutic biological properties. 5-O-Demethylnobiletin (5-DN) is one such PMF having anti-inflammatory activity, yet its role in hepatoprotection has not been studied before. Results from in vitro study revealed that 5-DN did not exert a high level of cytotoxicity on HepG2 cells at 40 μM, and it was able to rescue HepG2 cell death induced by carbon tetrachloride (CCl₄). Subsequently, we investigated acute liver injury on BALB/c mice induced by CCl₄ through the intraperitoneal injection of 1 mL/kg CCl₄ and co-administration of 5-DN at (1 and 2 mg/kg) by oral gavage for 15 days. The results illustrated that treatment with 5-DN attenuated CCl₄-induced elevated serum aminotransferase (AST)/alanine aminotransferase (ALT) ratio and significantly ameliorated severe hepatic damage such as inflammation and fibrosis evidenced through lesser aberrations in the liver histology of 5-DN dose groups. Additionally, 5-DN efficiently counteracted and equilibrated the production of ROS accelerated by CCl₄ and dramatically downregulated the expression of CYP2E1 vitally involved in converting CCl₄ to toxic free radicals and also enhanced the antioxidant enzymes. 5-DN treatment also inhibited cell proliferation and inflammatory pathway abnormally regulated by CCl₄ treatment. Furthermore, the apoptotic response induced by CCl₄ treatment was remarkably reduced by enhanced Bcl-2 expression and noticeable reduction in Bax, Bid, cleaved caspase 3, caspase 9, and apaf-1 expression. 5-DN treatment also induced the conversion of LC3 and promoted the autophagic flux. Conclusively, 5-DN exhibited hepatoprotective effects in vitro and in vivo and prevented liver fibrosis induced by CCl₄.