Current insights into transcriptional role(s) for the nutraceutical Withania somnifera in inflammation and aging – PubMed Black Hawk Supplements

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The health-beneficial effects of nutraceuticals in various diseases have received enhanced attention in recent years. Aging is a continuous process wherein physiological activity of an individual declines over time and is characterized by various indefinite hallmarks which contribute toward aging-related comorbidities in an individual which include many neurodegenerative diseases, cardiac problems, diabetes, bone-degeneration, and cancer. Cellular senescence is a homeostatic biological process…
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Current insights into transcriptional role(s) for the nutraceutical Withania somnifera in inflammation and aging - PubMed

Review

Current insights into transcriptional role(s) for the nutraceutical Withania somnifera in inflammation and aging

Praful Saha et al. Front Nutr. .

Abstract

The health-beneficial effects of nutraceuticals in various diseases have received enhanced attention in recent years. Aging is a continuous process wherein physiological activity of an individual declines over time and is characterized by various indefinite hallmarks which contribute toward aging-related comorbidities in an individual which include many neurodegenerative diseases, cardiac problems, diabetes, bone-degeneration, and cancer. Cellular senescence is a homeostatic biological process that has an important function in driving aging. Currently, a growing body of evidence substantiates the connection between epigenetic modifications and the aging process, along with aging-related diseases. These modifications are now being recognized as promising targets for emerging therapeutic interventions. Considering that almost all the biological processes are modulated by RNAs, numerous RNA-binding proteins have been found to be linked to aging and age-related complexities. Currently, studies have shed light on the ability of the nutraceutical Withania somnifera (Ashwagandha) to influence RNA expression, stability, and processing, offering insights into its mechanisms of action. By targeting RNA-related pathways, Withania somnifera may exhibit promising effects in ameliorating age-associated molecular changes, which include modifications in gene expression and signaling networks. This review summarizes the potential role of Withania somnifera as a nutraceutical in modulating RNA-level changes associated with aging, encompassing both in vitro and in vivo studies. Taken together, the putative role(s) of Withania in modulation of key RNAs will provide insights into understanding the aging process and facilitate the development of various preventive and therapeutic strategies employing nutraceuticals for healthy aging.

Keywords: Ashwagandha; RNA; Withania somnifera; aging; inflammation; noncoding RNA; nutraceuticals; transcription.

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Conflict of interest statement

PS, SA, DMa, SS, DMe, and SN were employed by PhytoVeda Pvt. Ltd. and Viridis Biopharma Pvt. Ltd., Mumbai, India. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1

Withania somnifera (9).

Figure 2
Figure 2

Chemical structures of major constituents of Withania somnifera (A) Withaferin A; (B) Withanlide; (C) Withanone. Structures of the constituents were drawn using Chemdraw Version 20.1.1.125.

Figure 3
Figure 3

Hallmarks of aging.

Figure 4
Figure 4

Biosynthesis of Withanolides from plant-derived sources.

Figure 5
Figure 5

Signaling pathways implicating Withania somnifera in modulation of RNAs in inflammation. (1) TNFα, a tumor suppressive cytokine, binds to TNFR1 releasing SODD and activating TRADD complex which further activates NIK and TAK/TAB1/2/3 complex resulting in NF-κB and MAPK signaling pathway activation that transcribes TNFα mRNA via NF-κB, CREB, C/EBPβ and AP-1 signaling. (2) TNFα is inhibited by Withania somnifera at transcriptional level which further inhibits inflammation. In addition, IL-6 binds to IL-6R activating JAK/STAT signaling pathway which transcribes IL-6 mRNA. Withania somnifera inhibits IL-6 at transcriptional level which, in turn, inhibits JAK/STAT signaling. Moreover, TGFβ1, anti-inflammatory cytokine binds to TGFβR1 initiating SMAD signaling leading to transcription of TGFβ1 mRNA. Withania somnifera induces the expression of TGFβ1 resulting in attenuation of inflammation.

Figure 6
Figure 6

Signaling pathways implicating Withania somnifera in modulation of RNAs in neurodegeneration. AGE (advanced glycation endproduct) is made and secreted by microgial cells when activated. This induces RAGE expression in neurons leading to cell death causing neurodegenerative diseases. Also, iNOS is activated by AGE which further enhances apoptosis and degeneration of neuronal cells. AGE, when increased in quantity, augments formation of amyloid-beta (Aβ), tau protein and amyloid precursor protein (APP). This, in turn, induces tau hyperphosphorylation as well as AGE-Aβ cross-linking. Further, Aβ binds to RAGEs to activate ERK1/2 pathway. This leads to phosphorylation of NF-κB and proteasomal degradation of IKBα. This, in turn, enables NF-κB translocation toward nucleus and their gene target is expressed simultaneously. Moreover, IL-1β binds to IL-1R and activates IRAK1/4/MyD88/TRAF6 complex leading to NF-κB signaling via TAK1/TAB. This results in expression of their target genes which contribute to neurodegeneration. Withania somnifera inhibits the expression of Aβ and IL-1β at transcriptional level which leads to further inhibition of the downstream pathways. Thus, it reduces the expression of pro-inflammatory genes. Furthermore, Withania somnifera induces the activity of brain-derived neurotropic factor (BDNF) which is inhibited in neurodegeneration. The binding of BDNF to tropomyosin-related kinase receptor type B (TrkB) leads to homodimerization and activation of adaptor protein such as Src homology domain 2 (SH2). Thereafter, SH2 activation leads to the activation of phosphoinositide 3-kinases (PI3K)-AKT, Ras-mitogen-activated kinase (Ras-MAPK) and phospholipase Cγ1-protein kinase C (PKC) signaling pathway.

Figure 7
Figure 7

Signaling pathways implicating Withania somnifera in modulation of RNAs in ER stress. In ER stress, GRP78 (glucose-regulated protein) attaches to the misfolded proteins present in the endoplasmic reticulum (ER) which releases transmembrane proteins from endoplasmic reticulum (ER) namely inositol-requiring enzyme (IRE1), PRKR-like ER kinase (PERK) and activating transcription factor 6 (ATF6). These three proteins, when activated, initiate UPR signaling cascades. XBP1 mRNA is transcribed into XBP1s after cleaving by IRE1. PERK dimerization leads to phosphorylation of eIF2a that causes inhibition of protein translation. Withaferin A induces the splicing of XBP1 which in turn activates CHOP expression which resulting in inhibition of mitochondrial mediated apoptosis.

Figure 8
Figure 8

Signaling pathways implicating Withania somnifera in modulation of RNAs in organ fibrosis. TNF-α binds to TNFR and releases SODD leading to activation of TRADD/RIP1/TRAF2/5 complex; the complex activates TAK1/TAB1/2/3 and NIK; TAK1/TAB1/2/3 activates CREB and C/EBPβ via p38 and MKK4/7-JNK signaling. NIK activates IKK/NFκB signaling; IL-1 ligand receptor complex activates IRAK1/4/MyD88/TRAF6 complex further activating IKK/NFκB signaling. Moreover, LPS binds to TLR4 activating NFκB via TRAF6 signaling. CREB, C/EBPβ and NFκB results in the transcription of IL-1β and TNF-α. WS inhibits the binding of TNF-α, IL-1β and LPS to TNFR, IL-1R and TLR4, respectively, and suppresses inflammation resulting in attenuation of fibrosis.

Figure 9
Figure 9

Signaling pathway implicating Withania somnifera in modulation of RNAs in muscle impairment. During oxidative stress, the mRNA level of Bax is increased while the mRNA level of Bcl is decreased in mitochondria. This leads to muscular apoptosis. Another pathway which is caspase dependent includes apoptosis due to stimulation of Caspase-3. Further, cytochrome c oozes out of the mitochondria in response to changes in Bax/Bcl-2 ratio. Introduction of WS inhibits Bax expression at transcriptional level which further inhibits apoptosis in muscle.

Figure 10
Figure 10

Signaling pathways implicating Withania somnifera in modulation of RNAs in other complications. Growth factor (GF) and receptor tyrosine kinase (RTK) binding leads to its phosphorylation which further initiates PI3K/AKT/SP1 signaling; RAS/RAF activates SP1 via MAP3K; both the events lead to transcription of VEGF resulting in angiogenesis. Withaferin A inhibits SP1 suppressing VEGF expression which results in the prevention of angiogenesis and oncogenic potential.

Figure 11
Figure 11

Genes modulated by Withania somnifera.

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Current insights into transcriptional role(s) for the nutraceutical Withania somnifera in inflammation and aging – PubMed