铁稳态代谢分子机制及铁磁纳米颗粒研究进展
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摘要
铁是人体必需微量元素,参与血红蛋白及多种酶的合成,在氧气运输、免疫调节、核酸合成及基因表达调控等多种生理过程中发挥重要作用.铁稳态代谢的维持对于机体正常生长发育至关重要,铁稳态代谢失衡会引发多种疾病.机体铁稳态代谢的调控由多个环节协调控制;在分子水平上,铁调素Hepcidin作为铁稳态代谢的关键调控因子,通过降解小肠上皮细胞和巨噬细胞上的铁外排蛋白Ferroportin,调控机体铁稳态.由此可见,机体内铁稳态代谢的维持是由多因素、多层次的复杂调控网络协调完成.铁不仅是必需的营养物质,还是新型生物材料的重要组分.铁磁纳米颗粒是一类以铁蛋白或Fe_3O_4等作为基础的生物大分子纳米粒子,因其较强的磁导向性和较好的生物兼容性,已被广泛应用于生物医学领域.本文围绕我们团队近年在铁稳态代谢领域的系列原创发现,就铁调素调控铁代谢稳态的分子网络及铁磁纳米颗粒研究国际前沿进展进行系统综述.
The essential trace element iron is a major structural component required for the synthesis and function of hemoglobin and various enzymes, and is therefore involved in many key physiological processes, including oxygen transport, nucleic acid synthesis, gene expression, and immune regulation. Iron homeostasis is therefore essential to maintaining health. For example, iron deficiency leads to anemia, whereas iron overload can lead to the formation of free radicals, which cause lipid peroxidation, DNA damage, and changes in other bioactive molecules. Thus, iron overload has been implicated in a wide range of diseases, including hemochromatosis, diabetes, cardiovascular disease, neurodegeneration, and cancer. Systemically, iron homeostasis is tightly regulated by several processes, including iron absorption in the intestine, iron circulation in the blood, iron utilization in various tissues, iron storage in the liver, and iron recycling in splenic red pulp macrophages. In recent years, new genetic animal models and cutting-edge technologies have led to considerable progress regarding the molecular mechanisms that underlie iron metabolism. Ferroptosis, a recently identified iron-dependent form of cell death, has been implicated in several disease conditions, including acute kidney failure following ischemia/reperfusion, Huntington's disease, cancer, and neurodegeneration. Although no definitive biomarkers have been identified, lipid peroxidation, PTGS2 expression, and NADPH levels have been suggested as possible biomarkers of ferroptosis. Nevertheless, the regulatory mechanisms underlying ferroptosis are fairly complex and poorly understood. Recently, our understanding of the pathways that regulate hepcidin, the master regulator of iron homeostasis, has increased considerably. Hepcidin regulates systemic iron levels by facilitating degradation of the sole iron exporter, Ferroportin, thereby controlling the absorption, utilization, and storage of iron. Hepcidin also cooperatively regulates iron homeostasis in response to various stimuli; specifically, iron overload and inflammation upregulate hepcidin expression, whereas erythropoiesis and hypoxic stress downregulate hepcidin expression. In addition, several epigenetic processes regulate hepcidin expression, thereby regulating iron metabolism. New studies are continually revealing novel molecular mechanisms related to the complex networks that regulate hepcidin, providing exciting new possibilities for treating iron-related diseases. Iron-containing biological materials have also been studied for their clinical potential. For example, ferromagnetic nanoparticles, which are ferritin-or Fe3 O4-containing biomacromolecules, have been applied in a wide variety of biomedical fields due to their superior magnetic properties and biocompatibility, making them ideal drug carriers. Importantly, nanoparticles readily penetrate the blood-brain barrier and enter the central nervous system, improving the bioavailability and therapeutic efficacy of drugs. Alternatively, an external magnetic field can be used to direct ferromagnetic nanoparticles to specific lesions. For example, a drug-containing transferrin nanoparticle complex could be used to targets specific tumor cells due to their increased expression of the transferrin receptor compared to healthy tissue. Superparamagnetic iron oxide nanoparticles may also be a promising tool for destroying cancer cells using a rapidly alternating external magnetic field. Thanks to their wide range of properties and features, ferromagnetic nanoparticles offer a wealth of promising biomedical applications. Here, we review the molecular mechanisms that regulate iron homeostasis, focusing on groundbreaking discoveries in hepcidin regulation and recent progress regarding biomedical applications for ferromagnetic nanoparticles.
The essential trace element iron is a major structural component required for the synthesis and function of hemoglobin and various enzymes, and is therefore involved in many key physiological processes, including oxygen transport, nucleic acid synthesis, gene expression, and immune regulation. Iron homeostasis is therefore essential to maintaining health. For example, iron deficiency leads to anemia, whereas iron overload can lead to the formation of free radicals, which cause lipid peroxidation, DNA damage, and changes in other bioactive molecules. Thus, iron overload has been implicated in a wide range of diseases, including hemochromatosis, diabetes, cardiovascular disease, neurodegeneration, and cancer. Systemically, iron homeostasis is tightly regulated by several processes, including iron absorption in the intestine, iron circulation in the blood, iron utilization in various tissues, iron storage in the liver, and iron recycling in splenic red pulp macrophages. In recent years, new genetic animal models and cutting-edge technologies have led to considerable progress regarding the molecular mechanisms that underlie iron metabolism. Ferroptosis, a recently identified iron-dependent form of cell death, has been implicated in several disease conditions, including acute kidney failure following ischemia/reperfusion, Huntington's disease, cancer, and neurodegeneration. Although no definitive biomarkers have been identified, lipid peroxidation, PTGS2 expression, and NADPH levels have been suggested as possible biomarkers of ferroptosis. Nevertheless, the regulatory mechanisms underlying ferroptosis are fairly complex and poorly understood. Recently, our understanding of the pathways that regulate hepcidin, the master regulator of iron homeostasis, has increased considerably. Hepcidin regulates systemic iron levels by facilitating degradation of the sole iron exporter, Ferroportin, thereby controlling the absorption, utilization, and storage of iron. Hepcidin also cooperatively regulates iron homeostasis in response to various stimuli; specifically, iron overload and inflammation upregulate hepcidin expression, whereas erythropoiesis and hypoxic stress downregulate hepcidin expression. In addition, several epigenetic processes regulate hepcidin expression, thereby regulating iron metabolism. New studies are continually revealing novel molecular mechanisms related to the complex networks that regulate hepcidin, providing exciting new possibilities for treating iron-related diseases. Iron-containing biological materials have also been studied for their clinical potential. For example, ferromagnetic nanoparticles, which are ferritin-or Fe3 O4-containing biomacromolecules, have been applied in a wide variety of biomedical fields due to their superior magnetic properties and biocompatibility, making them ideal drug carriers. Importantly, nanoparticles readily penetrate the blood-brain barrier and enter the central nervous system, improving the bioavailability and therapeutic efficacy of drugs. Alternatively, an external magnetic field can be used to direct ferromagnetic nanoparticles to specific lesions. For example, a drug-containing transferrin nanoparticle complex could be used to targets specific tumor cells due to their increased expression of the transferrin receptor compared to healthy tissue. Superparamagnetic iron oxide nanoparticles may also be a promising tool for destroying cancer cells using a rapidly alternating external magnetic field. Thanks to their wide range of properties and features, ferromagnetic nanoparticles offer a wealth of promising biomedical applications. Here, we review the molecular mechanisms that regulate iron homeostasis, focusing on groundbreaking discoveries in hepcidin regulation and recent progress regarding biomedical applications for ferromagnetic nanoparticles.
引文
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