User:PTRK22/sandbox

I lived in Wisconsin my whole life and enjoy watching sports such as baseball and basketball. I have a Welsh Corgi named Tucker and he is 12 years old. During the summer, I like to fish and golf. My career goal is to become a nurse.

Ferroptosis Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis.[1] Ferroptosis is initiated by the failure of the glutathione-dependent antioxidant defences, resulting in unchecked lipid peroxidation and eventual cell death.[2] Lipophilic antioxidants and iron chelators can prevent ferroptotic cell death. The accumulation of lipid peroxides that results in the process of ferroptosis makes it peroxidation-driven, meaning it is driven by the oxidative degradation of lipids. The process that results in this form of cell death occurs when free radical molecules take electrons from a lipid molecule to cause the degradation of the lipid molecule that is losing its electrons, being oxidized, by the free radical molecule. This processes makes ferroptosis a regulatory form of cell death. The reason the process of oxidative degradation of a lipid drives ferroptosis is because glutathione peroxidase 4 (GXP4), a lipid repair enzyme, undergoes a loss of activity (Yang & Stockwell 2016). This form of cell death is proven to be beneficial to the human body because it can be induced into the human body in the form of two different types of classes of small-molecules (Chen, Guo, Wang, Xie & Yu 2016). The role ferroptosis plays in the human body by inducing it revolves around the regulation of growth and proliferation of some types of tumor cells. The research so far for this particular role of ferroptosis is an indication that there is room for more research opportunities to identify the roles ferroptosis may acquire to help the human body. While it has benefits it can contribute to the human body, it can also have detrimental effects. The main negative effects it may have on the body are the disruption of metabolic pathways, or disruption to the homeostasis of the body. Since ferroptosis is a form of regulated cell death, some of the molecules involved in its regulation are also molecules involved in regulating biological metabolic pathways. It also plays a role in physiological and pathological cell death events such as kidney failure, iron overload, and cystine deprivation.[3][4][5] “Ferroptosis, an iron-dependent form of nonapoptotic cell death, was identified in cancer cells and mouse embryonic development (24–26). Ferroptosis is distinguishable from other forms of regulated cell death in that it does not require caspases (mediators of apoptosis and pyroptosis), ATP depletion or mitochondrial ROS generation (mediators of necroptosis), Bax/Bak (essential mediators of mitochondrial outer membrane permeabilization), or elevations in intracellular Ca2+ (26).”- Chen. Ferroptosis in Neurons Neural connections are constantly changing within the nervous system. Synaptic connections that are used more often are kept intact and promoted, while synaptic connections that are rarely used are subject to degradation. Elevated levels of synaptic connection loss and degradation of neurons are linked to neurodegenerative diseases. [1] More recently, ferroptosis has been linked to these neurodegenerative diseases. Neurons that are degraded through ferroptosis release lipid metabolites from inside the cell body. This is a key difference between ferroptosis and apoptosis. Apoptosis kills the cell in such a way that intracellular fluid is not released. (possibly expand on this with information from other section) The lipid metabolites are harmful to surrounding neurons, causing inflammation in the brain. Inflammation is a pathological feature of Alzheimer’s disease. 1             	In a study performed using mice it was found that absence of a certain enzyme, glutathione peroxidase 4 (Gpx4), enhanced activity of ferroptosis. Foods high in Vitamin E promotes Gpx4 activity, consequently inhibiting ferroptosis and preventing inflammation in brain regions. In the experimental group of mice that were manipulated to have decreased Gpx4 levels, mice were observed to have cognitive impairment and neurodegeneration of hippocampal neurons, again linking ferroptosis to neurodegenerative diseases. 1 (draw out graph and post on website) Similarly, presence of transcription factors, specifically ATF-4, can determine how readily a neuron can undergo cell death. The presence of ATF-4 promotes resistance in cells against ferroptosis. However, this resistance can cause other diseases, such as cancer, to progress and become malignant. While ATF-4 provides resistance ferroptosis, an abundance of ATF-4 causes neurodegeneration. Comparison to Apoptosis in the Nervous System Another form of cell death that occurs in the nervous system is apoptosis. Named after the Greek word meaning “to fall away from”, apoptosis results in cell breakage into small, apoptotic bodies taken up through phagocytosis2. This process occurs continuously within mammalian nervous system processes that begin at fetal development and continue through adult life. Apoptotic death is crucial for the correct population size of neuronal and glial cells. Deficiencies in apoptotic processes can result in many health complications, including neurodegeneration3. Within the study of neuronal apoptosis, most research has been conducted on the neurons of the superior cervical ganglion3. In order for these neurons to survive and innervate their target tissues, they must have nerve growth factor (NGF)3. In normal development, NGF binds to a tyrosine kinase receptor, TrkA, which activates phosphatidylinositol 3-kinase-Akt (PI3K-Akt) and extracellular signal-regulated kinase (Raf-MEK-ERK) signaling pathways which promote neuronal growth in the sympathetic nervous system3. During embryonic development, the absence of NGF activates apoptosis by decreasing the activity of the signaling pathways normally activated by NGF3. Without NGF, the neurons of the sympathetic nervous system begin to atrophy, glucose uptake rates fall and the rates of protein synthesis and gene expression slow3. Apoptotic death from NGF withdrawal also requires caspase activity3. Upon NGF withdrawal, caspase-3 activation occurs through an in-vitro pathway beginning with the release of Cytochrome c from the mitochondria3. In a surviving sympathetic neuron, the overexpression of anti-apoptotic B-cell CLL/lymphoma 2 (Bcl-2) proteins prevents NGF withdrawal-induced death. However, overexpression of a separate, pro-apoptotic Bcl-2 gene—Bax--stimulates the release of Cytochrome c2. Cytochrome c promotes the activation of caspase-9 through the formation of the apoptosome. Once caspase-9 is activated, it can cleave and activate caspase-3 resulting in cell death.3. This pathway has also been named the intrinsic pathway, as it is activated by intrinsic factors over external factors.

[1] Hambright, W. S., Fonseca, R. S., Chen, L., Na, R., & Ran, Q. (2017). Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biology, 12, 8–17. http://doi.org/10.1016/j.redox.2017.01.021 [2]Reed, J. C. (2000). Mechanisms of Apoptosis. The American Journal of Pathology, 157(5), 1415–1430. [3]Kristiansen, M., & Ham, J. (2014). Programmed cell death during neuronal development: The sympathetic neuron model. Cell Death & Differentiation, 21(7), 1025-1035. doi:10.1038/cdd.2014.47 General Mechanism of Ferroptosis Table 1: 4 Treatment System Observation Glutamate Rat postnatal hippocampal slice culture Death suppressed by Fer-1, CPX Cystine deprivation Rat postnatal pre-oligodendrocyte cultures Death suppressed by Fer-1 Huntington gene fragment overexpression Transfected postnatal corticostrial rat brain slcie Death suppressed by Fer-1 Iron overload Mouse kidney proximal tubules Death suppressed by Fer-1 Acetaminophen Mouse hepatocytes Death suppressed by Fer-1 Gpx4 deletion MEFs, mouse kidney cells, mouse T cells Rapid death, supressed by vitamin E, Fer-1 p53 upregulation MEFs (mouse embryonic fibroblasta) p53 upregulation leads to sensitization of ferroptosis Small molecules such as Erastin, Sulfasalazine, Sorafenib, Altretamine, RSL-3, ML 162 and ML 210 are known inhibitors of this tumor cell growth and induce ferroptosis. They do not trigger a response of change in apoptosis and therefore have no chromatin margination or cleave poly ADP-ribose polymerase (PARP). Instead, the phenotype of the mitochondria is changed using primarily Erastin or RSL3. Iron is also a necessity for these activators. They therefore can be inhibited by iron chelators. Ultimately, cell death induced by Erastin and RSL-3 in the phenotype is what makes up ferroptosis. Ferroptosis can also be induced by blocking the enzyme GPX4. Triggering ferroptosis is also caused by inhibiting GSH, which is necessary for the function of GPX4, and ultimately inducing a ferroptotic response in a cell.4

4 Cao, J. Y., & Dixon, S. J. (2016). Mechanisms of ferroptosis. Cellular and Molecular Life Sciences, 73, 2195–2209. http://doi.org/10.1007/s00018-016-2194-1 Role of Ferroptosis in Cancer Treatment Ferroptosis is a more controlled form of programmed cell death. With small molecules inducing ferroptosis, it inhibits tumor growth and increases drug resistance. It is still unknown the exact mechanism in which ferroptosis inhibits tumor growth, but based on early experiments, it could be used to treat tumor cells and ultimately cancer. Based on the figure shown, initiating ferroptosis can be done by eliminating GPX4 activity through Xc- (erastin mediated). The inhibition or degradation of GPX4 has been noticed to be the primary mechanism through which erastin or RSL3 can inhibit the activity and ultimately trigger ferroptosis and cell death. Having ferroptosis be an iron dependent mechanism, an accumulation of lipid ROS kills the cells that have begun to undergo ferroptosis, eliminating them completely.

Ferroptosis can be used to treat several different types of cancer, each seemingly different forms of the disease. This method of cell death has been tested either in mice, or is in the early stages of research and has not yet been fully tested. This includes cancer types such as: Breast Acute myeloid leukemia Pancreatic ductal adenocarcinoma Ovarian B cell lymphoma Renal cell carcinomas Lung Glioblastoma These forms of cancer have been hypothesized to be highly sensitive to ferroptosis, or react to Erastin or Xc- in a way that minimizes the tumor cells or responds to this treatment with a result of cell death. An upregulation of iron levels has also been seen to induce ferroptosis in certain types of cancer, such as breast cancer. 5

5 Lu, B., Chen, X. B., Ying, M. D., He, Q. J., Cao, J., & Yang, B. (2017). The Role of Ferroptosis in Cancer Development and Treatment Response. Frontiers in Pharmacology, 8, 992. http://doi.org/10.3389/fphar.2017.00992