Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Nexus Implicated in Bowel Disease Pathophysiology

Abstract

The endoplasmic reticulum (ER) is a complex protein folding and trafficking organelle. Alteration and discrepancy in the endoplasmic reticulum environment can affect the protein folding process and hence, can result in the production of misfolded proteins. The accumulation of misfolded proteins causes cellular damage and elicits endoplasmic reticulum stress. Under such stress conditions, cells exhibit reduced functional synthesis, and will undergo apoptosis if the stress is prolonged. To resolve the ER stress, cells trigger an intrinsic mechanism called an unfolded protein response (UPR). UPR is an adaptive signaling process that triggers multiple pathways through the endoplasmic reticulum transmembrane transducers, to reduce and remove misfolded proteins and improve the protein folding mechanism, in order to improve and maintain endoplasmic reticulum homeostasis. An increasing number of studies support the view that oxidative stress has a strong connection with ER stress. During the protein folding process, reactive oxygen species are produced as by-products, leading to impaired reduction-oxidation (redox) balance conferring oxidative stress. As the protein folding process is dependent on redox homeostasis, the oxidative stress can disrupt the protein folding mechanism and enhance the production of misfolded proteins, causing further ER stress. It is proposed that endoplasmic reticulum stress and oxidative stress together play significant roles in the pathophysiology of bowel diseases.

Oxidative stress/PERK/apoptotic pathways interaction contribute to tramadol neurotoxicity in rat cerebral and cerebellar cortex and thyme enhances the antioxidant defense system: histological, immunohistochemical and ultrastructural study

“…Meanwhile, changes in protein folding pathways produces an ROS imbalance, indirectly disturbing both ER and redox homeostasis and this response can be reversed by antioxidants like thyme vulgaris. 13,14 Thyme is a natural herb belongs to lamiacea family. It has antioxidant properties and free radical scavenger activity.…”

Antioxidants Maintain Cellular Redox Homeostasis by Elimination of Reactive Oxygen Species

“…However, chronic and excessive ROS production activates host inflammatory pathways and results in oxidative stress [133]. During IBD development, oxidative stress contributes to chronic inflammation and dysbiosis, control of oxidative stress may help to maintain the intestinal homeostasis [134, 135]. ROS can induce inflammation by triggering JNK, protein kinase C, growth factor tyrosine kinase receptor, and extracellular signal-regulated kinase signaling pathways.…”

Negative feedback loop of autophagy and endoplasmic reticulum stress in rapamycin protection against renal ischemia‐reperfusion injury during initial reperfusion phase

“…ER stress is a condition that disrupts normal protein folding via some pathologic and physiologic processes, such as I/R, calcium dyshomeostasis, inflammation, and reactive oxygen species accumulation; this disruption results in misfolded and unfolded protein accumulation in the ER lumen (22). With stimulation by ER stress, the unfolded protein response is sequentially activated through 3 signaling pathways, the PRKR-like ER kinase (PERK), inositol-requiring enzyme 1a (IRE1a), and activating transcription factor 6 (ATF6) pathways (23). Many studies have suggested that ER stress is involved in various renal diseases, including acute kidney injury, glomerulonephritis, renal I/R, and chronic kidney disease.…”