Cadmium aggravates liver injury by activating ferroptosis and neutrophil extracellular traps formation in Nile tilapia (Oreochromis niloticus).

Cadmium (Cd) is a pervasive environmental contaminant and a significant risk factor for liver injury. The present study was undertaken to evaluate the involvement of ferroptosis and neutrophil extracellular traps (NETs) in Cd-induced liver injury in Nile tilapia (Oreochromis niloticus), and to explore its underlying mechanism. Cd-induced liver injury was associated with increased total iron, malondialdehyde (MDA), and Acyl-CoA synthetase long-chain family member 4 (ACSL4), together with reduced levels of glutathione, glutathione peroxidase-4a (Gpx4a), and solute carrier family 7 member 11 (SLC7A11), which are all hallmarks of ferroptosis. Moreover, liver hyperemia, neutrophil infiltration, increased inflammatory factors and myeloperoxidase, as well as elevated serum DNA content in Cd-stimulated Nile tilapia suggested that a considerable number of neutrophils were recruited to the liver. Furtherly, in vitro experiments demonstrated that Cd induced the formation of NETs, and the possible mechanism was related to the generation of reactive oxygen species and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, along with the P38 and extracellular regulated protein kinase (ERK) signaling pathways. We concluded that ferroptosis and NETs are the critical mechanisms contributing to Cd-induced liver injury in Nile tilapia. These findings will contribute to Cd toxicological studies in aquatic animals.

ß-Carotene Protects Mice against Lipopolysaccharide and D-Galactosamine Induced Acute Liver Injury via Regulation of NF-κB, MAPK, and Nrf2 Signaling.

Acute liver injury (ALI), posing a serious threaten to our life, has emerged as a public health issue around the world. ß-carotene has plenty of pharmacologic effects, such as anti-inflammatory, antioxidant, and antitumor activities. In this study, we focused on studying the protective role and potential molecular mechanisms of ß-carotene against D-galactosamine (D-GalN) and lipopolysaccharide (LPS) induced ALI. Our results indicated that ß-carotene pretreatment effectively hindered abnormal changes induced by LPS/D-GalN in liver histopathology. Meanwhile, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were downgraded with ß-carotene pretreatment. ß-carotene pretreatment also decreased malondialdehyde content and myeloperoxidase activity, increased glutathione peroxidase and superoxide dismutase levels, and reduced the levels of tumor necrosis factor-a (TNF-α) and interleukin 6 (IL-6) in liver tissues. Further investigations found that ß-carotene mediated multiple signaling pathways in LPS/D-GalN-induced ALI, inhibiting NF-κB and MAPK signaling and upregulating the expression of Nrf2 and HO-1 proteins. All findings indicate that ß-carotene appears to protect mice against LPS/D-GalN induced ALI by reducing oxidative stress and inflammation, possibly via regulating NF-κB, MAPK, and Nrf2 signaling.

Exposure to ZnO nanoparticles induced blood-milk barrier dysfunction by disrupting tight junctions and cell injury.

Zinc oxide nanoparticles (ZnO-NPs) are one of the most widely used nanomaterials with excellent chemical and biological properties. However, their widespread application has led to increased risk to the natural environment and public health. A growing number of studies have shown that ZnO-NPs deposited in target organs interact with internal barriers to trigger injurious responses. The underlying mechanism of ZnO-NPs on the blood-milk barrier dysfunction remains to be understood. Our results revealed that excessive accumulation of ZnO-NPs induced histopathological injuries in the mammary gland, leading to the distribution of ZnO-NPs in the milk of lactating mice. A prominent diffusion of blood-milk barrier permeability marker, albumin-fluorescein isothiocyanate conjugate (FITC-albumin) was observed at cell-cell junction after ZnO-NPs exposure. Meanwhile, ZnO-NPs weakened the blood-milk barrier function by altering the expression of tight junction proteins. The excessive accumulation of ZnO-NPs also induced inflammatory response by activating the NF-κB and MAPK signaling pathways, leading to the dysfunctional blood-milk barrier. Furthermore, we found that ZnO-NPs led to increased iron accumulation and lipid oxidation, thus increasing oxidative injury and ferroptosis in mammary glands. These results indicated that ZnO-NPs weaken the integrity of the blood-milk barrier by directly affecting tight junctions and cellular injury in different ways.

Quercetin Alleviates Deoxynivalenol-Induced Intestinal Damage by Suppressing Inflammation and Ferroptosis in Mice.

Deoxynivalenol (DON), one of the most prevalent mycotoxins found in food and feed, can cause gastrointestinal inflammation and systemic immunosuppression, presenting a serious hazard to human and animal health. Quercetin (QUE) is a plant polyphenol with anti-inflammatory and antioxidant properties. In this research, we investigated the potential function of QUE as a treatment for DON-induced intestinal damage. Thirty male specific-pathogen-free BALB/c mice were randomly allocated to treatment with QUE (50 mg/kg) and/or DON (0, 0.5, 1, and 2 mg/kg). We found that QUE attenuated DON-induced intestinal damage in mice by improving jejunal structural injury and changing tight junction proteins (claudin-1, claudin-3, ZO-1, and occludin) levels. QUE also suppressed DON-triggered intestinal inflammation by inhibiting the TLR4/NF-κB signaling pathway. Meanwhile, QUE decreased the oxidative stress caused by DON by enhancing the concentrations of SOD and GSH, while diminishing the contents of MDA. In particular, QUE reduced DON-induced intestinal ferroptosis. DON-induced intestinal damage elevated TfR and 4HNE levels, along with transcription levels of ferroptosis-related genes (PTGS2, ACSL4, and HAMP1) while diminishing mRNA levels of FTH1, SLC7A11, GPX4, FPN1, and FSP1, all of which were reversed by QUE treatment. Our findings imply that QUE alleviates DON-induced intestinal injury in mice by inhibiting the TLR4/NF-κB signaling pathway and ferroptosis. In this study, we elucidate the toxicological mechanism of DON, provide a basic foundation or theory for future DON prevention and treatment, and explore strategies to prevent and alleviate DON's hazardous effects.

Saxitoxin induces the release of human neutrophil extracellular traps.

Saxitoxin (STX) is a potent shellfish toxin found in freshwater and marine ecosystems which threatens human health by contaminating drinking water and shellfish. The formation of neutrophil extracellular traps (NETs) is a defense mechanism employed by polymorphonuclear leukocytes (PMNs) to destroy invading pathogens, and also plays a critical role in the pathogenesis of various diseases. In this study, we aimed to investigate the role of STX on human NET formation. Typical NETs-associated characteristics were detected from STX-stimulated PMNs using immunofluorescence microscopy. Moreover, NET quantification based on PicoGreen® fluorescent dye revealed that STX triggered NET formation in a concentration-dependent manner, and NET formation peaked at 120 min (with a total time of 180 min) after induction by STX. Intracellular reactive oxygen species (iROS) detection showed that iROS were significantly elevated in STX-challenged PMNs. These findings present insight into the effects of STX on human NET formation and serve as a basis for further investigations of STX immunotoxicity.