Rui-Feng Fan

Nuclear receptor coactive 4 (NCOA4) is a specific receptor for ferritinophagy, transporting ferritin to lysosomal degradation, releasing free iron, and excessive iron levels may lead to cellular redox imbalance, contributing to cell death, predominantly ferroptosis. NCOA4 is regulated by a variety of transcriptional, post-transcriptional, translational, and post-translational modifications. Targeted modulation of NCOA4-mediated ferritinophagy has been successfully used as a therapeutic strategy in several disease models. Recent evidences have elucidated that ferritinophagy and ferroptosis played a major role in heavy metals toxicity. In this review, we explored the regulatory mechanism of NCOA4 as the sole receptor for ferritinophagy from multiple perspectives based on previous studies. The significant role of ferritinophagy-mediated ferroptosis in heavy metals toxicity was discussed in detail, emphasizing the great potential of NCOA4 as a target for heavy metals toxicity.

Iron, an essential trace element, is involved in various physiological processes; however, consumption of excessive iron possesses detrimental effects. In practical feed production, the iron content added to feeds often far exceeds the actual demand, resulting in an excess of iron in the body. The liver as a central regulator of iron homeostasis is susceptible to damage caused by disorders in iron metabolism. A model of hepatic iron overload in laying hens was developed in this study by incorporating iron into their diet, and the specific mechanisms underlying iron overload-induced hepatic injury were investigated. Firstly, this study revealed that a high-iron diet resulted in hepatic iron overload, accompanied by impaired liver function. Next, assessment of oxidative stress markers indicated a decrease in activities of T-SOD and CAT, coupled with an increase in MDA content, pointing to the iron-overloaded liver oxidative stress. Thirdly, the impact of iron overload on hepatic glycolipid and bile acid metabolism-related gene expressions were explored, including PPAR-α, GLUT2, and CYP7A1, highlighting disruptions in hepatic metabolism. Subsequently, analyses of inflammation-related genes such as iNOS and IL-1β at both protein and mRNA levels demonstrated the presence of inflammation in the liver under conditions of dietary iron overload. Overall, this study provided comprehensive evidence that dietary iron overload contributed to disorders in glycolipid and bile acid metabolism, accompanied by inflammatory responses in laying hens. Further detailing the specific pathways involved and the implications of these findings could offer valuable insights for future research and practical applications in poultry nutrition.

Mercury is a highly toxic heavy metal with definite cardiotoxic properties and can affect the health of humans and animals through diet. Selenium (Se) is a heart-healthy trace element and dietary Se has the potential to attenuate heavy metal-induced myocardial damage in humans and animals. This study was designed to explore antagonistic effect of Se on the cardiotoxicity of mercuric chloride (HgCl₂) in chickens. Hyline brown hens received a normal diet, a diet containing 250 mg/L HgCl₂, or a diet containing 250 mg/L HgCl₂ and 10 mg/kg Na₂SeO₃ for 7 weeks, respectively. Histopathological observations demonstrated that Se attenuated HgCl₂-induced myocardial injury, which was further confirmed by the results of serum creatine kinase and lactate dehydrogenase levels assay and myocardial tissues oxidative stress indexes assessment. The results showed that Se prevented HgCl₂-induced cytoplasmic calcium ion (Ca²⁺) overload and endoplasmic reticulum (ER) Ca²⁺ depletion mediated by Ca²⁺-regulatory dysfunction of ER. Importantly, ER Ca²⁺ depletion led to unfolded protein response and endoplasmic reticulum stress (ERS), resulting in apoptosis of cardiomyocytes via PERK/ATF4/CHOP pathway. In addition, heat shock protein expression was activated by HgCl₂ through these stress responses, which was reversed by Se. Moreover, Se supplementation partially eliminated the effects of HgCl₂ on the expression of several ER-settled selenoproteins, including selenoprotein K (SELENOK), SELENOM, SELENON, and SELENOS. In conclusion, these results suggested that Se alleviated ER Ca²⁺ depletion and oxidative stress-induced ERS-dependent apoptosis in chicken myocardium after HgCl₂ exposure.

Mercury (Hg) is a highly toxic heavy metal with definite cardiotoxic properties. Selenium (Se) is a heart-healthy trace element and has been demonstrated to attenuate heavy metal induced organ toxicity. This study was designed to explore the antagonistic effect of Se on the cardiotoxicity of mercuric chloride (HgCl₂) in chicken. Histopathological observations demonstrated that Se attenuated HgCl₂-induced myocardial injury, which was further confirmed by the results of serum CK and LDH levels assay and myocardial tissues oxidative stress indexes assessment. The results showed that Se prevented HgCl₂-induced cytoplasmic Ca²⁺ overload and endoplasmic reticulum (ER) Ca²⁺ depletion mediated by Ca²⁺-regulatory dysfunction of the ER. Importantly, ER Ca²⁺ depletion led to unfolded protein response (UPR) and endoplasmic reticulum stress (ERS), resulting in apoptosis of cardiomyocytes via the PERK/ATF4/CHOP pathway. Subsequently, the heat shock proteins expression activated by HgCl₂ through these stress responses, which was reversed by Se. Moreover, Se supplementation partially eliminated the effects of HgCl₂ on the expression of several ER-settled selenoproteins, including selenoprotein K (SELENOK), SELENOM, SELENON and SELENOS. In conclusion, these results suggested that Se alleviated ER Ca²⁺ depletion and oxidative stress induced ERS dependent apoptosis via PERK/ATF4/CHOP pathway in chicken myocardium after HgCl₂ exposure.