Diseases are Associated with Cell Death

Regulation of cell death is vital for development, pathogenesis, and homeostasis. Both acute and chronic diseases are associated with excessive cell death, which results in tissue damage. Caspase-dependent apoptosis is a type of programmed cell death implicated in both normal and disease pathogenesis. Ferroptosis is distinct from other cell death modalities based on morphological, biochemical, and genetic criteria.

Ferroptosis is a pathogenic programmed cell death characterized by the iron-mediated production of toxic lipid hydroperoxides. This unique form of cell death is widely implicated in several acute and chronic diseases, such as asthma, COPD, ischemic heart diseases, brain trauma, and neurological diseases.

The process of ferroptosis involves an accumulation of toxic lipid peroxides. The enzymes involved in the generation or detoxification of these lipid peroxides modulate ferroptosis. Oxidative stress and the activation of lipoxygenase, which oxygenate polyunsaturated fatty acid (PUFA)-phospholipids, are key inducers of ferroptosis. Glutathione and glutathione peroxidase 4 play critical roles in the detoxification of phospholipid hydroperoxides and protect against ferroptosis. Pharmacological depletion of GSH or inhibition of GPX4 activity has been shown to induce ferroptosis. In contrast, agents that increase GSH or GPX4 activity have been shown to inhibit ferroptosis.

Glutathione is a tripeptide composed of glycine-cysteine-glutamate. Dysfunctions in cysteine metabolism can cause a depletion of glutathione, which is responsible for GPX4 inactivation, leading to the accumulation of oxPLs and ultimately causing cell death.

GPx4 (glutathione peroxidase 4) is a phase II detoxification enzyme regulated by the Nrf2 gene. GPx4 utilizes the major cellular antioxidant GSH (glutathione), which is synthesized by the tripeptide in the presence of enzymes such as GCL (glutamate cysteine ligase) and glutathione synthetase (GSS). Erastin, a potent inducer of ferroptosis, inhibits the cellular import of cystine, thus reducing the formation of GSH.

Chronic oxidative stress is a major cause of ferroptosis, which is implicated in various disease conditions such as neurodegenerative diseases, respiratory diseases, diabetes, and cardiac diseases. Medicinal plants are commonly used for the treatment of various diseases. They are considered to have advantages over conventionally used drugs that are expensive and known to have harmful side effects. Therefore, considerable attention has been focused on phytotherapy research in identifying dietary and medicinal phytochemicals with antioxidant and anti-inflammatory activity that can inhibit, retard, or reverse the multistage pathophysiological events underlying disease pathology.

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