Free Radicals Abroad | March 2018

Yan-Zhong Chang, Ph.D.
Laboratory of Molecular Iron Metabolism
Colleges of Life Science, Hebei Normal University, China

The Hebei Normal University is one of the world-class universities in China. The Laboratory of Molecular Iron Metabolism in the Colleges of Life Science is one of the key labs that train graduate students for advanced research and teaching in the majors of neuroscience and physiology. It has 8 principal investigators working in the fields of physiology and neuroscience. Their major research topics include Mechanisms of Iron Metabolism; Iron Misregulation and CNS Diseases; Iron Metabolism, Sports and Diabetes Treatment; Nanomedicine and Safety Evaluation; and Apoptosis and Oxidant Stress Signaling Pathway.

Dr. Yan-Zhong Chang is Professor and Director of Laboratory of Molecular Iron Metabolism in the Department of Physiology at Hebei Normal University. He earned his Ph.D. degree from Hong Kong Polytechnic University. From 2008 to 2009, he was a Visiting Professor studying the regulation of brain iron metabolism in Dr. Tracey Rouault’s lab at the NICHD. In 2003, he founded the Lab of Molecular Iron Metabolism at Hebei Normal University. His major research direction focuses on the mechanisms of iron metabolism and related diseases. His research has attracted many highly competitive research funds from the National Natural Scientific Foundation of China (NSFC) and yielded high impact research publications and patents. He had published more than 90 papers in international journals, such as Cell Stem Cell, ACS nano, Biomaterial, Antioxidants & Redox Signaling, Cellular and Molecular Life Sciences, Cell Death and Disease, Neurobiology of Aging, Nanomedicine, Journal of Cellular Physiology, Molecular Pharmacology, etc.

Brain iron uptake and homeostasis are tightly regulated because iron deficiency slows down the development of the neural system and causes language and motion disorders, and iron overload is also closely related to neurodegenerative disease. However, the mechanisms of iron regulation in the brain remain unknown. One of Dr. Chang’s important projects is studying the mechanism of brain iron uptake.  His studies have found an important molecule “hepcidin” that is tightly involved in regulating brain iron uptake from the blood-brain barrier, and also plays an important role in the regulation of brain iron homeostasis. Dr. Chang’s team had revealed that the brain could express hepcidin, and especially abundantly in astrocytes. They also studied the expressions of DMT1, FPN1, CP, Heph, and TfR in the brain, and their regulations by aging, iron level, and other stress factors.

Dysregulation of brain iron homeostasis can lead to severe pathological changes in the neural system. Brain iron levels are significantly increased in Parkinson’s disease (PD) and iron deposition is observed in the substantia nigra (SN) of PD patients. Dr. Chang’s work suggests that iron overload in the brain exacerbates dopaminergic neuronal death in PD and may lead to the onset of PD. In their study, ceruloplasmin knockout mice and mice receiving an intracerebroventricular injection of ferric ammonium citrate (FAC) were established as mouse models with high levels of brain iron. These mice were administered with MPTP by intraperitoneal injection. They found that the injection of FAC or the absence of the CP gene may exacerbate both the observed apoptosis of TH-positive neurons and the behavioral symptoms of the MPTP-treated mice. The intracerebroventricular injection of deferoxamine (DFO) significantly alleviated the neuronal damage caused by MPTP in CP knockout mice.  His studies found an important molecule “hepcidin” that is tightly involved in brain iron metabolism. Dr. Chang’s team had revealed that astrocyte hepcidin is a key factor in LPS-induced neuronal apoptosis. This research provided new insights for prevention and treatment of brain iron imbalance-related diseases.

Excess free iron can result in the production of damaging free reactive oxygen species (ROS) during electron transport, therefore iron flux in mitochondria must be precisely regulated. Dysregulation of mitochondrial iron metabolism can severely affect the intracellular iron homeostasis, resulting in mitochondrial iron metabolism diseases, such as Friedreich ataxia. However, little is known about the regulatory mechanisms of iron trafficking and communication between cytosol and mitochondria. Dr. Chang’s work studied the functions of mitochondrial iron-storage protein, mitochondrial ferritin (FtMt), which modulates cellular iron metabolism, influences ROS level dramatically, and plays protective roles against iron-mediated free radical damage. In vivo, FtMt protected the murine myocardium from acute exhaustive exercise injury, and the mitochondrial ferritin deletion exacerbates β-Amyloid-induced and MPTP-induced neurotoxicity in mice. FtMt was also found to play a protective role in erastin-induced ferroptosis. These studies on the role of FtMt in mitochondria iron homeostasis provided new insights into the treatment of diseases associated with abnormal iron homeostasis.

Dr. Chang’s another work investigated the treatment supplement for iron-deficiency diseases. They found that encapsulation of iron in liposomes significantly improved the efficiency of iron supplementation in strenuously exercised rats. To investigate the effect of iron liposome supplementation. A rat model of exercise-associated anemia was established by subjecting the animals to high-intensity running exercises for 4 weeks. Rats with confirmed anemia were strenuously exercised for another 2 weeks while receiving iron supplements by intragastric administration of FAC liposomes or heme iron liposomes. The serum iron and liver iron contents significantly increased and reached much higher levels in anemic rats treated with iron liposomes, compared with those of control groups. The increase in SOD and decrease in MDA levels were also observed after supplementing with iron liposomes. These results demonstrate that iron liposomes can efficiently relieve the iron deficiency in strenuously exercised rats and may potentially be used as a supplement for the treatment of exercise-associated iron deficiency anemia with minimal side effects.

Besides, Dr. Chang also studied the cellular responses and endoplasmatic reticulum (ER) stress induced by ZnO nanoparitcles (NPs) in human umbilical vein endothelial cells (HUVECs). It was found that the dissolved zinc ion was the most significant factor for cytotoxicity in HUVECs. More importantly, ZnO NPs at noncytotoxic concentration can induce significant cellular ER stress response with higher expression of ER marker proteins including BiP, Chop, GADD34, p-PERK, p-eIF2R, and cleaved Caspase-12. Higher dosage of ZnO NPs quickly rendered ER stress response before inducing apoptosis. This study indicated that the ER stress response might be used as an earlier and sensitive endpoint for nanotoxicological study. In a subsequent study, they used endoplasmic reticulum (ER) stress as a sensitive and early biomarker to evaluate the toxic potential of AgNPs in three different human cell lines in vitro and in vivo in mice. Preliminary evaluation of AgNP toxicity by monitoring the ER stress signaling pathway provided new insights towards the understanding of the biological impacts of AgNPs. The adverse effects of exposure to AgNPs may be avoided by rationale use within a safe dose range.