Tight Regulation of Cell Death is Vital during Development

Category: Biology
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Tight regulation of cell death is vital during development, normal homeostasis as well as in pathogenesis of various diseases. Several acute and chronic Diseases are associated with excessive cell death resulting tissue damage and organ failure. Caspase dependent apoptosis is well studied programmed cell death which is implicated in normal and disease pathogenesis. Ferroptosis was shown to be distinct from other described cell death modalities, based on morphological, biochemical, and genetic criteria .

Ferroptosis is representing a pathogenic programmed cell death characterized by iron mediated production of toxic lipid hydroperoxides. Ferroptosis is not inhibited by caspase inhibitors and therefore represent a unique form cells death which is widely implicated in several acute and chronic diseases such as asthma, COPD, Ischemic heart diseases, brain trauma, neurological diseases and renal failure.

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Since Ferroptosis involves accumulation of toxic lipid peroxides, enzymes involved in generation and or detoxification of lipid peroxides modulate ferroptosis. Oxidative stress and activation of lipoxygenase (oxygenate polyunsaturated fatty acid (PUFA)-phospholipids) are key inducers of Ferroptosis. On the other hand Glutathione and Glutathione peroxidase 4 plays critical role in detoxification of phospholipid hydroperoxides and protect from ferroptosis. Pharmacological depletion of GSH or inhibition of GPX4 activity is shown to induce ferroptosis. In contrast, agents that increase GSH or GPX4 activity are shown to inhibit ferroptosis.

Glutathione is a tripeptide composed of glycine-cysteine-glutamate. As a cysteine is a limiting factor for tri-peptide which serves as co-substrate for GPX4for the repair of oxPL. Due to the dysfunction in the cysteine metabolism glutathione formation depletes which is responsible for GPX4 inactivation causes the accumulation oxPLs and ultimately lead to cell death in tissues such as, hepatocytes, kidney tubular cells, sperm cells, T-cells, Endothelial cells, Reticulocytes and Photoreceptor cells.

In addition to these commonly accepted functions mediated by activated p53, accumulating evidence indicates that other activities of p53 are also involved in tumour suppression, including ferroptosis. SLC7A11, a key component of the cysteine/glutamate antiporter, leading to inhibition of cysteine uptake and sensitization of cells to ferroptosis, expression of SLC7A11 is posttranscriptionally inhibited by the p53. The suppression of SLC7A11 by p53 subsequently leads to the reduction of glutathione production and ROS accumulation, which are important components of ferroptosis. Gao et al identified GLS2, a p53 regulated glutaminase, as essential for ferroptosis. All of these studies support the potential relevance of p53 to ferroptosis and the tumoursuppressing activity of p53 via the regulation of ferroptosis. In erastininduced ferroptotic death, p53 was activated as a posttranscriptional suppressor of SLC7A11 and induced ROS generation.

There is evidence that vitamin E, alpha-tocopherol hydroquinone, is a potent inhibitor of ferroptosis through its reduction of the non-heme iron in 15-lipoxygenase from its active Fe3+ state to its inactive Fe2+ state.

GPx4(glutathione peroxidase 4) is a phase II detoxification enzyme regulated by Nrf2 gene, GPx4 utilizes the major cellular antioxidant GSH(glutathione), which is synthesized by the tripeptide(cysteine, gluatamate, glycine) in presence of the enzyme GCL(glutamate cysteine ligase) and glutathione synthetase(GSS). The rate limiting step of glutathione synthesis is the ligation of cysteine(cys) and glutamate(glu) to glutamate-cysteine ligase. Erastin inhibits the cellular import of cystine by the glutamate cystine antiporter system xc- so, this reduces the formation of GSH, hence concentration of lipid peroxides in the cytoplasm increases thus leads to ferroptosis.

p45, NF-E2, Nrf1, Nrf2 and Nrf3 are CNC nuclear transcription factors, NF-E2 related factors are a conserved family of vertebrates. In normal unstressed cell ,Nrf2 is sequestered in the cytoplasm by the actin-bound cytosolic-repressor Keap-1(Kelch-like ECH-associated protein 1), a cysteine-rich protein which also acts as a sensor of ROS. Upon exposure to stressors, Nrf2 dissociates from its cytoplasmic inhibitor Keap1, translocate to the nucleus, binds with small Maf proteins(MafG) to form a trans-activation complex that binds to cis element called Antioxidant Response Element(ARE) or the Electrophilic Response Element( EpRE), in the promoter region of its target genes and activates transcription. Numerous studies have shown that upregulation of Nrf2 mitigate the diseases which are associated with the oxidative stress.

Figure 2. Ferroptosis and its molecular regulation by Nrf2. Glutathione peroxidase 4 (Gpx4) utilizes the major cellular antioxidant glutathione (GSH) as a substrate to reduce lipid hydroperoxides (LOOH).

Oxidative stress is a major cause for ferroptosis which is implicated in various acute and chronic diseases such as Neurodegenerative diseases( Alzheimer’s, Parkinson’s disease), Respiratory diseases(asthma, COPD, acute lung injury, pulmonary fibrosis), Diabetic co-morbidities(Retinopathy, Nephropathy) Ischemic heart diseases and renal failure. So, for that there is a urgent need for developing pharmacological inhibitors of ferroptosis for treatment of diseases by activating the most potential therapeutic transcriptional factor i.e Nrf2(Nuclear erythroid-2 related factor-2) which regulates the various cytoprotective defense that includes , GSH biosynthesizing enzymes, cellular antioxidants, phase II detoxifying enzymes NADPH biosynthesizing enzymes and scavenger receptor(CD36). So, this implies to extract the phytochemicals which inhibits the ferroptosis from medicinal plants prepared as aqueous and soxhlation extracts and screened by using in vivo studies.

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Tight Regulation of Cell Death Is Vital During Development. (2021, May 24). Retrieved from https://papersowl.com/examples/tight-regulation-of-cell-death-is-vital-during-development/