Lycopene as a Therapeutic Agent against Aflatoxin B1-Related Toxicity: Mechanistic Insights and Future Directions.

Aflatoxin (AFT) contamination poses a significant global public health and safety concern, prompting widespread apprehension. Of the various AFTs, aflatoxin B1 (AFB1) stands out for its pronounced toxicity and its association with a spectrum of chronic ailments, including cardiovascular disease, neurodegenerative disorders, and cancer. Lycopene, a lipid-soluble natural carotenoid, has emerged as a potential mitigator of the deleterious effects induced by AFB1 exposure, spanning cardiac injury, hepatotoxicity, nephrotoxicity, intestinal damage, and reproductive impairment. This protective mechanism operates by reducing oxidative stress, inflammation, and lipid peroxidation, and activating the mitochondrial apoptotic pathway, facilitating the activation of mitochondrial biogenesis, the endogenous antioxidant system, and the nuclear factor erythroid 2-related factor 2 (Nrf2)/kelch-like ECH-associated protein 1 (KEAP1) and peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) pathways, as well as regulating the activities of cytochrome P450 (CYP450) enzymes. This review provides an overview of the protective effects of lycopene against AFB1 exposure-induced toxicity and the underlying molecular mechanisms. Furthermore, it explores the safety profile and potential clinical applications of lycopene. The present review underscores lycopene's potential as a promising detoxification agent against AFB1 exposure, with the intent to stimulate further research and practical utilization in this domain.

Non-cytotoxic nanomolar concentration of arctigenin protects neuronal cells from chemotherapy-induced ferroptosis by regulating SLC7A11-cystine-cysteine axis.

Neurotoxicity is a common side effect of certain types of therapeutic drugs, posing a major hurdle for their clinical application. Accumulating evidence suggests that ferroptosis is involved in the neurotoxicity induced by these drugs. Therefore, targeting ferroptosis is considered to be a reasonable approach to prevent such side effect. Arctigenin (ATG) is a major bioactive ingredient of Arctium lappa L., a popular medicinal plant in Asia, and has been reported to have multiple bioactivities including neuroprotection. However, the mechanisms underlying the neuroprotection of ATG has not been well elucidated. The purpose of this study was to investigate whether the neuroprotection of ATG was associated with its ability to protect neuronal cells from ferroptosis. Using neuronal cell ferroptosis model induced by either classic ferroptosis induces or therapeutic drugs, we demonstrated for the first time that ATG in the nanomolar concentration range effectively prevented neuronal cell ferroptosis induced by classic ferroptosis inducer sulfasalazine (SAS) and erastin (Era), or therapeutic drug oxaliplatin (OXA) and 5-fluorouracil (5-FU). Mechanistically, we uncovered that the anti-ferroptotic effect of ATG was attributed to its ability to activate SLC7A11-cystine-cysteine axis. The findings of the present study implicate that ATG holds great potential to be developed as a novel agent for preventing SLC7A11 inhibition-mediated neurotoxicity.

The research progress on the impact of antibiotics on the male reproductive system.

Antibiotics are extensively utilized in the livestock and poultry industry and can accumulate in animals and the environment, leading to potential health risks for humans via food and water consumption. Research on antibiotic toxicity, particularly their impact as endocrine disruptors on the male reproductive system, is still in its nascent stages. This review highlights the toxic effect of antibiotics on the male reproductive system, detailing the common routes of exposure and the detrimental impact and mechanisms of various antibiotic classes. Additionally, it discusses the protective role of food-derived active substances against the reproductive toxicity induced by antibiotics. This review aims to raise awareness about the reproductive toxicity of antibiotics in males and to outline the challenges that must be addressed in future research.

Glycyrol Alleviates Acute Kidney Injury by Inhibiting Ferroptsis.

Acute kidney injury (AKI) is a common clinical problem with high morbidity and mortality. The discovery of ferroptosis has provided novel insights into the mechanisms underlying AKI and paves the way for developing ferroptosis-based approaches to treat AKI. Glycyrol (GC) is a representative coumarin compound isolated from licorice that demonstrates various pharmacological activities. However, its potential for a protective effect against kidney injury remains unknown. We hypothesized that GC might be able to protect against AKI via suppression of ferroptosis. This hypothesis was tested in a cell-culture model of RSL3-induced nephrocyte ferroptosis and a mouse model of folic acid-induced AKI. The results showed that GC exerted a significant protective effect against nephrocyte ferroptosis in vitro and was effective against folic acid-induced AKI in vivo, where it was mechanistically associated with suppressing HO-1-mediated heme degradation. Collectively, the findings of the present study support the hypothesis that GC holds considerable potential to be developed as a novel agent for treating ferroptosis-related AKI.

Inversion of heavy metal content in soil using hyperspectral characteristic bands-based machine learning method.

The global concern regarding the adverse effects of heavy metal pollution in soil has grown significantly. Accurate prediction of heavy metal content in soil is crucial for environmental protection. This study proposes an inversion analysis method for heavy metals (As, Cd, Cr, Cu, Ni, Pb) in soil based on hyperspectral and machine learning algorithms for 21 soil reference materials from multiple provinces in China. On this basis, an integrated learning model called Stacked RF (the base model is XGBoost, LightGBM, CatBoost, and the meta-model is RF) was established to perform soil heavy metal inversion. Specifically, three popular algorithms were initially employed to preprocess the spectral data, then Random Forest (RF) was used to select the best feature bands to reduce the impact of noise, finally Stacking and four basic machine learning algorithms were used to establish comparisons and analysis of inversion model. Compared with traditional machine learning methods, the stacking model showcases enhanced stability and superior accuracy. Research results indicate that machine learning algorithms, especially ensemble learning models, have better inversion effects on heavy metals in soil. Overall, the MF-RF-Stacking model performed best in the inversion of the six heavy metals. The research results will provide a new perspective on the ensemble learning model method for soil heavy metal content inversion using data of hyperspectral characteristic bands collected from soil reference materials.

Targeted Detoxification of Aflatoxin B1 in Edible Oil by an Enzyme-Metal Nanoreactor.

Mycotoxin contamination is an important issue for food safety and the environment. Removing mycotoxins from food without losing nutrients and flavor components remains a challenge. In this study, a novel strategy was proposed for the targeted removal of aflatoxin B1 (AFB1) from peanut oil using an amphipathic enzyme-metal hybrid nanoreactor (PL-GOx-Fe3O4@COF) constructed with covalent organic frameworks (COFs) which can selectively adsorb AFB1. Due to the confined space provided by COFs and the proximity effect between GOx and Fe3O4, the detoxification of AFB1 is limited in the nanoreactor without affecting the composition and properties of the oil. The detoxification efficiency of AFB1 in the chemoenzymatic cascade reaction catalyzed by PL-GOx-Fe3O4@COF is six times higher than that of the combination of free GOx and Fe3O4. The AFB1 transformation product has nontoxicity to kidney and liver cells. This study provides a powerful tool for the targeted removal of mycotoxins from edible oils.

18ß-glycyrrhetinic acid suppresses Lewis lung cancer growth through protecting immune cells from ferroptosis.

PURPOSE: 18ß-glycyrrhetinic acid (GA), the main metabolite of glycyrrhizic acid extracted from the root of licorice, has been reported to possess anti-cancer and immunomodulatory activity, but the mechanisms are not well understood. Recent studies have shown that ferroptosis of immune cells is involved in tumor-associated immune suppression. The purpose of this study was to investigate whether the enhanced immune response via inhibiting immune cell ferroptosis contributed to the anticancer effect of 18ß-GA. METHODS: Lewis Lung carcinoma mouse model and Murine CD8 + T cell culture model were used to examine the changes of immune response and ferroptosis of immune cells. RESULTS: We found that 18ß-GA was effective against lung cancer accompanied by enhanced activation of tumor-infiltrating CD8+ T cells in Lewis Lung carcinoma mouse model. Furthermore, we demonstrated that the boosted immune response by GA was attributed to its ability to inhibit arachidonic acid (AA)-mediated CD8+ T ferroptosis via suppressing CD36 expression. CONCLUSION: The findings of the present study unraveled a novel mechanism underlying the anti-cancer and immunomodulatory activity of 18ß-GA and support that 18ß-GA holds potential to be used as an immune enhancer for lung cancer prevention or treatment.

Role of ferroptosis in food-borne mycotoxin-induced toxicities.

Contamination by toxic substances is a major global food safety issue, which poses a serious threat to human health. Mycotoxins are major class of food contaminants, mainly including aflatoxins (AFs), zearalenone (ZON), deoxynivalenol (DON), ochratoxin A (OTA), fumonisins (FBs) and patulin (PAT). Ferroptosis is a newly identified iron-dependent form of programmed or regulated cell death, which has been found to be involved in diverse pathological conditions. Recently, a growing body of evidence has shown that ferroptosis is implicated in the toxicities induced by certain types of food-borne mycotoxins, which provides novel mechanistic insights into mycotoxin-induced toxicities and paves the way for developing ferroptosis-based strategy to combat against toxicities of mycotoxins. In this review article, we summarize the key findings on the involvement of ferroptosis in mycotoxin-induced toxicities and propose issues that need to be addressed in future studies for better utilization of ferroptosis-based approach to manage the toxic effects of mycotoxin contamination.

Delta-tocotrienol disrupts PD-L1 glycosylation and reverses PD-L1-mediated immune suppression.

PD-L1-mediated immune escape plays an important role in cancer development and progression. Targeting PD-L1 is consider to be an attractive approach for cancer treatment. PD-L1 is a heavily N-linked glycosylated protein, and the glycosylation of PD-L1 is essential for its ability to interact with its receptor PD-1 to mediate immune suppression. In the present study, we demonstrated for the first time that delta-tocotrienol (δ-T3) not any of the other forms of vitamin E was able to disrupt PD-L1 glycosylation mechanistically associated with the suppression of TCF4-STT3a/STT3b axis. The inhibition of PD-L1 glycosylation by δ-T3 resulted in the decrease of PD-L1 expression and its exosomal secretion, leading to the reduction of PD-L1 and PD-1 interaction, and reversing PD-L1-mediated immune suppression, which in turn contributed to the inhibitory effect on tumor growth. The findings of the present study provide a novel mechanistic interpretation for the superior anticancer activity of δ-T3 among 8 isomers of the vitamin E.

Combination of Selenite and Butyrate Enhances Efficacy Against Colon Cancer by Targeting ASCT2-Mediated Amino Acid Metabolism.

Drug combination is considered to be an effective approach to improve the efficacy of cancer therapy and chemoprevention. Selenite, a representative of inorganic form of selenium, and butyrate, a major short-chain fatty acid, are two well-documented colon cancer dietary chemopreventive agents with distinct molecular mechanisms. We hypothesized that combination of selenite and butyrate might produce improved outcome against colon cancer. This hypothesis was tested using both HCT116 human colon cancer cells and its xenograft mouse model in the present study. The in vitro study showed a synergistically inhibitory effect on HCT116 colon cancer cells but not on NCM460 normal human colon mucosal epithelial cells. Consistent with the in vitro study, results of the xenograft mouse model further demonstrated that combination of selenite and butyrate led to improved efficacy in comparison with each agent alone. Mechanistically, the induction of alanine-serine-cysteine transporter 2 (ASCT2) by selenite repressed its inhibitory effect on colon cancer cells, which was reversed by its co-treatment with butyrate. The findings of the present study denote the likely potential for developing selenite/butyrate combination remedy to combat against colon cancer.

Liver protecting effects and molecular mechanisms of icariin and its metabolites.

As a detoxification and metabolism organ, the liver plays a vital role in human health. However, an excessive consumption of drugs and toxins, exposure to pathogenic viruses, and unhealthy living habits can lead to liver damage, which may even develop into liver cirrhosis and liver cancer. Epimedium brevicornum Maxim. is a traditional Chinese medicine and dietary supplement in which the flavonoid icariin is a main functional component. Although the protective mechanisms of icariin and its metabolites against liver injury are not yet comprehensively understood, an increasing number of studies have confirmed their liver-protective and anticancer effects. Indeed, icaritin, one of the metabolites of icariin, is currently utilized as an active component of an anti-cancer drug. This paper presents a review of the molecular mechanisms through which icariin and its metabolites actively protect against the occurrence and development of liver injury, and, thus, provides a comprehensive reference for further research and their application in liver protection.

Managing ferroptosis-related diseases with indirect dietary modulators of ferroptosis.

Ferroptosis is an iron-dependent form of programmed cell death driven by excessive oxidation of polyunsaturated phospholipids on cellular membranes. Accumulating evidence suggests that ferroptosis has been implicated in the pathological process of various diseases, such as cardiovascular diseases, neurological diseases, liver diseases, kidney injury, lung injury, diabetes, and cancer. Targeting ferroptosis is therefore considered to be a reasonable strategy to fight against ferroptosis-associated diseases. Many dietary bioactive agents have been identified to be able to either suppress or promote ferroptosis, indicating that ferroptosis-based intervention by dietary approach may be an effective strategy for preventing and treating diseases associated with ferroptosis dysregulation. In this review, we summarize the present understanding of the functional role of ferroptosis in the pathogenesis of aforementioned diseases with an emphasis on the evidence of managing ferroptosis-related diseases with indirect dietary modulators of ferroptosis and propose issues that need to be addressed to promote practical application of dietary approach targeting ferroptosis.

Methylseleninic acid overcomes gefitinib resistance through asparagine-MET-TOPK signaling axis in non-small cell lung cancer cells.

Acquired resistance compromises the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-based therapy for non-small cell lung cancer (NSCLC), and activation of hepatocyte growth factor receptor (MET) is one of the pivotal strategies for cancer cells to acquire refractory phenotype. However, the mechanisms involved in regulating MET activity remain to be further elucidated. Using gefitinib-resistant HCC827GR cell line as a model, we unraveled that the dysregulated amino acid metabolisms reflected by elevated expression of cysteine-preferring transporter 2 (ASCT2), cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) and asparagine synthetase (ASNS) might contribute to survival advantage of HCC827GR cells, and rendered the cells more sensitive to asparagine (ASN) deprivation compared to parental HCC827 cells. We further identified that the increased ASNS expression is a contributing factor for the activation of MET in HCC827GR cells. More importantly, we found that methylseleninic acid (MSeA), a precursor of methylselenol, effectively suppressed tumor growth in HCC827GR xenograft model, which is associated with decrease of intracellular ASN content along with inactivation of MET- T-lymphokine-activated killer cell-originated protein kinase (TOPK) signaling axis. Finally, we demonstrated that combination of MSeA and gefitinib induced a synergistic growth inhibition in HCC827GR cells. The findings of our work reveal that ASN-MET-TOPK signaling axis as a novel mechanism contributed to gefitinib-resistance and combined utilization of gefitinib and MSeA holds potential to improve the efficacy for gefitinib-resistant NSCLC.

Xanthohumol inhibits non-small cell lung cancer via directly targeting T-lymphokine-activated killer cell-originated protein kinase.

Xanthohumol is a principal prenylated chalcone isolated from hops. Previous studies have shown that xanthohumol was effective against various types of cancer, but the mechanisms, especially the direct targets for xanthohumol to exert an anticancer effect, remain elusive. Overexpression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) promotes tumorigenesis, invasion and metastasis, implying the likely potential for targeting TOPK in cancer prevention and treatment. In the present study, we found that xanthohumol significantly inhibited the cell proliferation, migration and invasion of non-small cell lung cancer (NSCLC) in vitro and suppressed tumor growth in vivo, which is well correlated with inactivating TOPK, evidenced by reduced phosphorylation of TOPK and its downstream signaling histone H3 and Akt, and decreased its kinase activity. Moreover, molecular docking and biomolecular interaction analysis showed that xanthohumol was able to directly bind to the TOPK protein, suggesting that TOPK inactivation by xanthohumol is attributed to its ability to directly interact with TOPK. The findings of the present study identified TOPK as a direct target for xanthohumol to exert its anticancer activity, revealing novel insight into the mechanisms underlying the anticancer activity of xanthohumol.

Autophagy-Based Intervention Strategy in the Management of Hepatotoxicity.

Significance: Ample evidence has demonstrated an important role for autophagy as either a protective mechanism or a cause for hepatotoxicity, denoting the likely potentials for targeting autophagy in the prevention or treatment of hepatotoxicity. Recent Advances: The functional role of autophagy in the pathogenesis of hepatotoxicity has been gradually recognized. Mechanistically, the autophagy-mediated protective or promoting effect on hepatotoxicity is attributed to its functions in regulation of oxidative stress, endoplasmic reticulum (ER) stress, lipid metabolism, iron homeostasis, inflammatory response, and programmed cell death. Targeting autophagy as a novel strategy for fighting against hepatotoxicity has demonstrated encouraging efficacy in a number of models. Critical Issues: Clarifying the precise functional role of autophagy in different types of hepatotoxicity is essential for developing a type-specific autophagy-based intervention. Identification of molecular targets and novel agents for effectively and accurately manipulating autophagy is needed for better utilization of an autophagy-based approach to exert beneficial effects on hepatotoxicity. Future Directions: Well-designed clinical trials are needed to validate the efficacy of an autophagy-targeting intervention strategy for hepatotoxicity. Further studies should be also focused on developing novel autophagy-targeting agents that can accurately regulate autophagy based on the characteristics of each type of hepatotoxicity. Antioxid. Redox Signal. 38, 1082-1100.

Docosahexaenoic acid reverses PD-L1-mediated immune suppression by accelerating its ubiquitin-proteasome degradation.

PD-L1 interacts with its receptor PD-1 on T cells to negatively regulate T cell function, leading to cancer cell immune escape from the immune surveillance. Therefore, targeting PD-L1 is considered to be an attractive approach for cancer immunotherapy. In this study, we demonstrated for the first time that ω-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) reduced the expression of PD-L1 in cancer cells both in vitro and in vivo. Promotion of PD-L1 ubiquitin-proteasome degradation by DHA resulted in a decrease of PD-L1 expression, leading to reduction of PD-L1 and PD-1 interaction, and reversing PD-L1-mediated immune suppression, which in turn contributed to the inhibitory effect on tumor growth. Furtherly, DHA significantly reduced fatty acid synthase (FASN) expression in cancer cells, which inhibited the palmitoyltransferases DHHC5, promoting the CSN5-dependent PD-L1 degradation. Our present finding uncovered a novel mechanism involved in the anti-cancer activity of DHA, and implicated that DHA holds promising potential to be developed as a novel immune-enhancer for cancer treatment and prevention.

Effects of High-Pressure Homogenization Treatment on the Development of Antioxidant Zanthoxylum bungeanum Leaf Powder Films for Preservation of Fresh-Cut Apple.

This study determined that Zanthoxylum bungeanum leaves (ZBLs) are rich in functional components such as cellulose, protein, flavone, and polyphenols. Therefore, they were used as the main raw material, with sodium alginate as a thickener and glycerol as a plasticizer, to investigate the preparation of active films from ZBL powder through high-pressure homogenization (HPH). The physical, optical, mechanical, and antioxidant properties of the films were evaluated, and their application in preserving fresh-cut apples was examined. The results showed that the optimal concentration of ZBL powder was 1.5% under a 30 MPa HPH treatment. The resulting HPH-treated films exhibited a denser microstructure and improved water vapor barrier properties and mechanical strength. Compared to the films without HPH treatment, the tensile strength increased from 4.61 MPa to 12.13 MPa, the elongation at break increased from 21.25% to 42.86%, the water vapor permeability decreased from 9.9 × 10-9 g/m·s·Pa to 8.0 × 10-9 g/m·s·Pa, and the transparency increased from 25.36% to 38.5%. Compared to the control group, the fresh-cut apples packaged with the HPH-treated ZBL active films exhibited effective preservation of apple quality during a five-day period at 4 °C and 70% humidity, showing better preservation effects than the other groups. In conclusion, the use of HPH treatment in developing novel biopolymer active films from ZBL powders with enhanced properties holds potential for various applications.

18ß-glycyrrhetinic acid protects neuronal cells from ferroptosis through inhibiting labile iron accumulation and preventing coenzyme Q10 reduction.

Ferroptosis is a new form of iron-dependent cell death. A growing body of evidence suggests that abnormal ferroptosis is involved in developing neurodegenerative diseases. 18ß-glycyrrhetinic acid (GA) is a major bioactive component of licorice with multiple biological activities including neuroprotection. Give the role of ferroptosis in the neurodegenerative diseases, we hypothesized that the neuroprotective effect of GA might be associated with its ability to protect neuro-cells from ferroptosis. Results demonstrated that GA was able to prevent a well-known ferroptosis inducer ferroptosis inducer 56 (FIN56)-triggered ferroptosis in HT22 mouse neuronal cell. Further mechanistic investigation revealed that the protection of GA on ferroptosis is attributed its inhibiting effect on cellular labile iron accumulation and up-regulating coenzyme Q10 (CoQ10) levels. The findings of the present study uncovered a novel mechanism involved in the neuroprotective effect of GA, and imply that GA could be developed as a novel agent to manage ferroptosis-related diseases.

Ciprofloxacin and enrofloxacin can cause reproductive toxicity via endocrine signaling pathways.

Ciprofloxacin (CIP) and enrofloxacin (ENR) are veterinary antibiotics commonly utilized to treat and prevent animal diseases. Environmental and dietary antibiotic residues can directly and indirectly affect the reproductive development of animals and humans. This article investigated the reproductive toxicity of CIP in male zebrafish, showing that it could decrease the spermatogonial weight and damage the spermatogonial tissue. The sex hormone assays showed that CIP decreased fshb and lhb gene expression and plasma testosterone (T). In addition, transcriptome analysis indicated that the effect of CIP on zebrafish might be related to the endocrine signaling pathways. ENR, which was selected for further study, inhibited mouse Leydig (TM3) and Sertoli (TM4) cell proliferation and caused cell cycle arrest. The sperm concentration, serum luteotropic hormone (LH) and follicle-stimulating hormone (FSH), and T levels decreased in adolescent mice after ENR treatment for 30d in vivo. Hematoxylin and eosin (H&E) staining showed that ENR exposure potentially induced testicular injury, while the real-time quantitative PCR (qPCR) results indicated that ENR inhibited the mRNA expression of key genes in the Leydig cells (cyp11a1, 3ß-HSD, and 17ß-HSD), Sertoli cells (Inhbß and Gdnf) and spermatogenic cells (Plzf, Stra8 and Dmc1). In conclusion, these findings indicated that ENR exposure might influence the development of the testes of pubescent mice.

Combined toxicity of food-borne mycotoxins and heavy metals or pesticides.

Food can be contaminated by multiple classes of toxic substances, mainly including mycotoxins, heavy metals and pesticides, which leads to a possibility of simultaneous exposure to two or more food contaminants for humans. Thus, it is necessary to examine whether the combined exposure could result in enhanced toxicity. Initially, the studies on the combined toxicity of food contaminants mainly focus on the mixtures of same classes of food contaminants due to their co-occurrence feature in foodstuffs, such as mixtures of mycotoxins or mixtures of heavy metals. Given the possibility that consumers are likely exposed to mixtures of different classes of food contaminants, recently, studies on the combined toxicity of different classes of food contaminants have been receiving increasing attentions. In this review article, we summarize the findings of combined toxicity studies related to co-exposure to food-borne mycotoxins and other classes of food contaminants mainly heavy metals or pesticides, and propose issues that need to be addressed in future studies for more accurately performing risk assessment of co-exposure to mycotoxins and other classes of food contaminants.