From Hyperglycemia to Oxidative Stress to Apoptosis

-Dr. Jutishna Bora, Amity Institute of Biotechnology, Amity University Kolkata

All forms of diabetes are preliminarily characterized by hyperglycemia. Hyperglycemia is a condition during which there is an excess accumulation of glucose in the bloodstream of an individual for a prolonged time. Not only does it play a significant role by being the causal link between diabetes and diabetes-induced complications but has also been found to be one of the major contributors to the development of oxidative stress. Under hyperglycemic or diabetic condition processes such as auto-oxidation of glucose, glycation of proteins, and also the polyol metabolism increases to a great extent and such changes accelerate the production of some intracellular highly reactive species such as reactive oxygen species or ROS.

Although some of the reactive species does play an important role in intracellular signalling processes it is evident that with an impaired antioxidant defense mechanism in the body the rate of production of ROS exceeds their rate of utilization and its imbalances the redox homeostasis of the body and augments the level of oxidative stress and associated cellular damages. When the body fails to neutralize such reactive species it results in the accumulation of a large amount of ROS inside the cells. The overabundance of ROS is efficient in changing the structure and function of all types of molecules containing proteins, membrane lipids, and nucleic acids with significant repercussions to cell potentiality.

Particularly, the accumulation of superoxide (O₂^–) anion inside the mitochondria tends to disintegrate its outer cellular membrane and also increases its permeability thus making it more vulnerable to the attack by ROS. Because of such alterations in the cell membrane structure, the mitochondria release cytochrome C to the cytosol, such event then leads to activation of a class of proteins known as B-cell lymphoma-2 or Bcl-2 proteins, which also can regulate the permeabilization of the mitochondrial membrane and also act as modulators of apoptotic cell death. These proteins can be broadly categorized as pro-apoptotic (Bak, Bax, Bad, Bim) which directly permeabilize the mitochondrial membrane, BH3 proteins which directly or indirectly activate the pore-forming class members inside the cell, and the anti-apoptotic (Bcl-2, Bcl-x, Bcl-XL, Bcl-w) which restrains the pro-apoptotic proteins and maintains the cell membrane integrity.

Upon binding of cytochrome C to an apoptotic protease activating factor Apaf-1, it activates another family of protease enzyme also known as cysteine-dependent aspartate specific protease of caspase. Initially, an initiator caspase i.e caspase 9 is activated which further forms a complex with cytochrome C and activates a series of effector caspases such as 3, 6, and 7 respectively. Caspase 3 eventually activates a caspase-dependent DNase or CAD enzymes which induces DNA fragmentation and chromatin condensation and eventually brings about the process of programmed cell death or apoptosis.

References:

1. Jutishna B., Donkupar S and Surya B (2018). Methanolic flower extract of phlogacanthusthyrsiflorusNees. attenuates diabetic nephropathy in alloxan-induced diabetic mice. Asian Journal of Pharmaceutical and Clinical Research. 11(7): 113-116. DOI: https://doi.org/10.22159/ajpcr.2018.v11i7.25393

2. Jutishna B., Plabita S., Abani Kumar P., Donkupar S and Surya B (2018). Attenuation of diabetic hepatopathy in alloxan-induced diabetic mice by methanolic flower extract of Phlogacanthus thyrsiflorusNees. Journal of applied pharmaceutical science. 8(7): 114-120. DOI: 10.7324/JAPS.2018.8718

Also read: Molecules for Life- Thioredoxin System

For more articles, please visit bioxone.in