Mechanisms of NF-κB p65 and strategies for therapeutic manipulation

Abstract

The transcription factor NF-κB is a critical regulator of immune and inflammatory responses. In mammals, the NF-κB/Rel family comprises five members: p50, p52, p65 (Rel-A), c-Rel, and Rel-B proteins, which form homo- or heterodimers and remain as an inactive complex with the inhibitory molecules called IκB proteins in resting cells. Two distinct NF-κB signaling pathways have been described: 1) the canonical pathway primarily activated by pathogens and inflammatory mediators, and 2) the noncanonical pathway mostly activated by developmental cues. The most abundant form of NF-κB activated by pathologic stimuli via the canonical pathway is the p65:p50 heterodimer. Disproportionate increase in activated p65 and subsequent transactivation of effector molecules is integral to the pathogenesis of many chronic diseases such as the rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and even neurodegenerative pathologies. Hence, the NF-κB p65 signaling pathway has been a pivotal point for intense drug discovery and development. This review begins with an overview of p65-mediated signaling followed by discussion of strategies that directly target NF-κB p65 in the context of chronic inflammation.

The Role of Dietary Antioxidants in the Pathogenesis of Neurodegenerative Diseases and Their Impact on Cerebral Oxidoreductive Balance

“…The primary consequences of oxidative stress include fragmentation of lipids or structural changes thereof, protein denaturation, disorders related to the DNA replication mechanisms, and deformation of cellular organelles, and consequently, entire cells ( Figure 1). ROS-induced oxidative stress leads not only to inflammation but also triggers the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) protein-dependent transcription of genes for various proinflammatory factors [28]. The activity of ROS leads to various types of intracellular damage, including enzyme activation, DNA damage, structural changes in protein and carbohydrate molecules.…”

Anti-Neuroinflammatory Effect of Alantolactone through the Suppression of the NF-κB and MAPK Signaling Pathways

“…In sum, Ala demonstrates anti-neuroinflammatory properties that contribute to the amelioration of CNS damage, and it could be a promising candidate for future applications in CNS injury treatment.be found that two signaling pathways stand out as being strongly associated with the production of proinflammatory factors: Nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) [10] and mitogen-activated protein kinase (MAPK) [11].Because it is responsible for the transcription of several proinflammatory cytokines, chemokines, and adhesion molecules, the NF-κB signaling pathway plays a crucial role in many diseases that involve dysregulation of the inflammatory response [12,13]. The NF-κB signaling pathway consists of a series of intracellular secondary reactions [14,15]. First, extracellular stimuli give rise to the phosphorylation and proteasomal degradation of the nuclear factor of the kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) [16,17].…”

“…Because it is responsible for the transcription of several proinflammatory cytokines, chemokines, and adhesion molecules, the NF-κB signaling pathway plays a crucial role in many diseases that involve dysregulation of the inflammatory response [12,13]. The NF-κB signaling pathway consists of a series of intracellular secondary reactions [14,15]. First, extracellular stimuli give rise to the phosphorylation and proteasomal degradation of the nuclear factor of the kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) [16,17].…”

Mechanistic Roles of Matrilin-2 and Klotho in Modulating the Inflammatory Activity of Human Aortic Valve Cells

“…NF-κB is retained in an inactive form in the cytoplasm in most cell types [51]. When it is activated, NF-κB translocates to the nucleus and plays a critical role in activating the inflammatory signaling network [52]. Our previous study found that NF-κB activation contributes to the inflammatory responses in human AVICs [44].…”