Tackling Chronic Inflammation with Withanolide Phytochemicals—A Withaferin A Perspective

Abstract

Chronic inflammatory diseases are considered to be one of the biggest threats to human health. Most prescribed pharmaceutical drugs aiming to treat these diseases are characterized by side-effects and negatively affect therapy adherence. Finding alternative treatment strategies to tackle chronic inflammation has therefore been gaining interest over the last few decades. In this context, Withaferin A (WA), a natural bioactive compound isolated from Withania somnifera, has been identified as a promising anti-cancer and anti-inflammatory compound. Although the majority of studies focus on the molecular mechanisms of WA in cancer models, recent evidence demonstrates that WA also holds promise as a new phytotherapeutic agent against chronic inflammatory diseases. By targeting crucial inflammatory pathways, including nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2 related factor 2 (Nrf2) signaling, WA suppresses the inflammatory disease state in several in vitro and preclinical in vivo models of diabetes, obesity, neurodegenerative disorders, cystic fibrosis and osteoarthritis. This review provides a concise overview of the molecular mechanisms by which WA orchestrates its anti-inflammatory effects to restore immune homeostasis.

Role of Withaferin A and Its Derivatives in the Management of Alzheimer’s Disease: Recent Trends and Future Perspectives

“…Additionally, reduced expression of STAT and JAK, and increased expression of IKBKG and IKBKB have been observed ( Figure 2 ) [ 162 ]. By targeting critical inflammatory pathways like NF-κB and nuclear factor erythroid 2 related factors 2 signaling, WA defeats inflammatory disease in numerous in vitro and preclinical in vivo models of neurodegenerative disorders like AD and PD, cystic fibrosis, and osteoarthritis ( Table 1 ) [ 20 ].…”

“…Among these mechanisms is in silico analysis, which has shown a solid probable intermolecular interaction between WA and IKKγ that interrupts the development of the IKK complex and inhibits IκB depletion [ 171 ]. Another suggested mechanism of WA-mediated inhibition of NF-κB is by straight interaction of WA with NF-κB itself [ 172 ] or its IκB inhibitor [ 20 , 172 ]. Thus, it was concluded that pure WA has important NF-κB inhibitor activity, which makes it a novel anti-inflammatory agent for the treatment of AD [ 163 ].…”

“…Withaferin A (WA), a steroidal glycowithanolide lactone obtained from the Ayurvedic medicinal plant Withania somnifera has the potential to be a therapeutic agent for AD. WA is a major biologically active withanolides with a wide range of activities, such as anti-inflammatory, antitumor, anti-angiogenic, and antioxidant activities, and it also inhibits mitochondrial apoptosis [ 20 , 21 ]. According to published research, WA seems to have inhibitory effects against the development of a pathological marker associated with AD.…”

Building a Case for Withaferin A as a Treatment for FTD/ALS Syndromes

“…The present study follows up on prior work from this group that has been investigating the role of NFκB signaling in the pathogenesis of amyotrophic lateral sclerosis [4][5][6]. One of the activities that has been credited to WFA is to inhibit NFκB signaling to reduce neuroinflammation (reviewed in [7]). In prior work, TDP43 with mutations associated with amyotrophic lateral sclerosis and frontotemporal dementia was shown to interact with NFκB and aberrantly activate neuroinflammatory pathways [5].…”

Withaferin A inhibits LFA-1-stimulated ZAP70 activity and T-cell motility

“…Withaferin A (WFA), an archetype withanolide, discovered from the root extract of Withania somnifera , is well known for immunomodulatory properties (8). Little is known about the effect of this compound on T-lymphocyte migration.…”