Diseases are Associated with Cell Death
Regulation of cell death is vital in the development, pathogenesis and homeostasis, acute and chronic Diseases are associated with excessive cell death resulting tissue damage. Caspase dependent apoptosis is a programmed cell death which is implicated in normal and disease pathogenesis. Ferroptosis was shown to be distinct from other cell death modalities, based on morphological, biochemical, and genetic criteria.
Ferroptosis represents pathogenic programmed cell death characterized by iron mediated production of toxic lipid hydroperoxides. Its 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.
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How it works
Ferroptosis cell death involves accumulation of toxic lipid peroxides and enzymes involved in generation or detoxification of lipid peroxides modulate ferroptosis. Oxidative stress and activation of lipoxygenase (oxygenate polyunsaturated fatty acid (PUFA)-phospholipids) are key inducers of Ferroptosis. Glutathione and Glutathione peroxidase 4 plays critical role in detoxification of phospholipid hydroperoxides and protects 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 GPX4 for 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.
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 in the presence enzyme i.e. GCL (glutamate cysteine ligase) and glutathione synthetase (GSS). Erastin which is known as potent inducer of ferroptosis inhibits the cellular import of cystine, this reduces the formation of GSH.
Chronic oxidative stress is a major cause for ferroptosis which is implicated in various diseases condition i.e. Neurodegenerative diseases, Respiratory diseases, Diabetes & cardiac diseases. Medicinal plants are commonly used for the treatment of various diseases, as they are considered to have advantage over the conventionally used drugs that are expensive and known to have harmful side effects, therefore considerable attention has been focused among phytotherapy research in identifying dietary and medicinal phytochemicals with antioxidants and anti-inflammatory activity that can inhibit retard or reverse the multi stage pathophysiological events underlying the diseases pathology.