Cell Death and Chronic Diseases
Cell death is vital in the process of development, homeostasis and pathogenesis of acute and chronic Diseases resulting in tissue damage. apoptosis which is known to be Caspase dependent programmed cell death implicated in normal and disease pathogenesis. Ferroptosis is known to be distinct from other cell death modalities, based on their morphological, biochemical & genetic criteria.
Ferroptosis represents a type of cell death which is characterized by iron mediated production of toxic lipid hydroperoxides, its widely implicated in several acute and chronic diseases i.e. asthma, COPD, Ischemic heart diseases & neurological disorder
Ferroptotic cell death involves accumulation of toxic lipids & enzymes involved in the generation or detoxification of lipid peroxides modulate ferroptosis. Severe oxidative stress and activation of lipoxygenase (PUFA) are key inducers of Ferroptosis. Glutathione and Glutathione peroxidase 4 plays critical role in detoxification of phospholipids , 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 (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 major cause for ferroptosis which is implicated in various diseases condition. 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 attention has been focused among phytotherapy research in identifying dietary and medicinal phytochemicals with antioxidants and anti-inflammatory activity that can inhibit the multi stage pathophysiological events underlying the diseases pathology.