Herbs And Phytochemicals: French Study Shows That Shikonin, An Inhibitor of Inflammasomes Can Also Inhibit Epstein-Barr Virus Reactivation!

Herbs And Phytochemicals: Shikonin is a remarkable natural compound or phytochemical derived from the dried roots of Lithospermum erythrorhizon Siebold & Zucc, commonly known as zicao. With a long history of use in traditional Chinese medicine, shikonin has gained recognition for its effectiveness against various diseases with minimal side effects. While it is primarily sourced from L. erythrorhizon, several related plant species in the Boraginaceae family also contain shikonin derivatives, including Echium lycoris, Arnebia euchroma, Onosma armeniacum, and others.


 
Shikonin, a derivative of 1,4-naphthoquinone, is biosynthesized from two precursors: geranyl diphosphate (GPP) through the mevalonate pathway and p-hydroxybenzoic acid (PHB) through the phenylpropanoid pathway. This natural compound has garnered attention for its pharmacological potential, including antimicrobial, anticancer, antioxidant, wound healing, anti-inflammatory, and antithrombotic properties.
 
Epstein-Barr virus (EBV), a highly prevalent human herpesvirus, is responsible for lifelong infections in over 95% of the adult population. Typically, EBV establishes asymptomatic, persistent infections, but it is also associated with various malignancies, affecting B lymphocytes and epithelial cells predominantly. The virus transitions between latent and lytic phases, both of which play roles in the initiation of tumorigenesis. Currently, there are limited antiviral treatments targeting the lytic phase, most of which focus on viral replication. Recent research has unveiled the involvement of components of the NLRP3 inflammasome in EBV reactivation, triggered by various stimuli.
 
The Herbs And Phytochemicals study by French researchers form Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine-France delves into the intriguing connection between shikonin, a potent inflammasome inhibitor with minimal toxicity, and its ability to effectively suppress EBV reactivation. The study also explored the broader implications of this discovery in the context of viral infections and the potential therapeutic applications of shikonin.
 
Shikonin: An Overview
Shikonin, with its molecular formula C16H16O5, is scientifically known as 5,8-dihydroxy-2-[(1R)-1-hydroxy-4-methyl-3-pentenyl]-1,4-naphthoquinone. First identified by Brockmann and Liebigs in 1936, shikonin has an enantiomeric pair called alkannin (S-enantiomer), creating a chiral pair known as A/S. These chiral pairs, A and S, are derived from the roots of various plant species within the Boraginaceae family, including Lithospermum, Alkanna, Onosma, Echium, Cynoglossum, and Anchusa. Intriguingly, both A and S exhibit similar pharmacological properties despite their enantiomeric differences, highlighting their broad therapeutic potential which includes pharmacological properties such as antimicrobial, anticancer, antioxidant, wound healing, anti-inflammatory, and antithrombotic.
 
Epstein-Barr Virus and Its Role in Disease
Epstein-Barr virus, classified as HHV-4 within the human gamma-herpesvirus family, infects over 95% of adults worldwide and primarily targets human B lymphocytes and epithelial cells. Although primary EBV i nfection in childhood often goes unnoticed, it can manifest as infectious mononucleosis in adults. Subsequently, the virus establishes a persistent, latent infection within B cells, punctuated by reactivation phases. While most EBV infections remain asymptomatic, the virus is implicated in various cancers, including Post-Transplant Lymphoproliferative Diseases (PTLD), Burkitt lymphoma (BL), Hodgkin's disease, and certain T-cell lymphomas. Additionally, EBV has links to epithelial tumors such as undifferentiated nasopharyngeal cancer and some forms of gastric cancer. Importantly, EBV-related malignancies are closely tied to both latency and reactivation phases.
 
Reactivation of EBV can be induced ex vivo when latent B cells are exposed to chemical or biological triggers. This reactivation process involves the expression of immediate-early (IE) lytic genes, especially BZLF1 and BRLF1, leading to the production of early and late genes, eventually resulting in viral replication. In latently infected B cells, the BZFL1 gene promoter is kept silenced, primarily due to the actions of proteins like STAT3, KRAB domain-zinc finger proteins, and histone H3K9me3 methyltransferase SETDB1.
 
The Role of Inflammasomes in Immunity and Inflammation
Inflammasomes are multiprotein complexes found in the cytoplasm that play pivotal roles in immune responses, inflammation, and the pathogenesis of various diseases, including infectious diseases, inflammatory disorders, and cancer. These complexes activate inflammatory responses, culminating in the proteolytic maturation and secretion of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18). Furthermore, inflammasome activation can trigger pyroptosis, a form of programmed cell death distinct from apoptosis.
 
The activation of inflammasomes involves two key signals: priming (signal 1) and protein complex assembly (signal 2). Signal 1 is associated with the activation of Toll-like receptors (TLRs) or related signaling pathways, which leads to NFκB-dependent transactivation of the NLRP3, pro-IL18, and pro-IL1β promoters, resulting in mRNA expression and protein synthesis. Signal 2 is triggered by the presence of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), promoting inflammasome activation, caspase-1 activation, and the subsequent secretion of IL-1β and IL-18.
 
In the context of herpesvirus infections, several sensors can initiate inflammasome formation, such as IFI16, cGas (for viral DNAs), or RIG-I (for viral RNAs). In the case of EBV, it induces inflammasome activation through the recognition of viral DNAs (IFI16), EBER (RIG-I), or AIM2 in human monocytes.
 
NLRP3 Inflammasome Activation in EBV Reactivation
Recent research has highlighted the pivotal role of NLRP3 inflammasome activation in the EBV productive cycle. During EBV reactivation in B lymphocytes, NLRP3 assembly and pro-caspase-1 activation occur. It is believed that caspase-1 subsequently degrades KAP1 (key heterochromatin regulator 1), a component of a silencing complex responsible for repressing various lytic phase genes, including BZLF-1.
 
Additionally, recent findings have shown that HMGB1 (High Mobility Group Box 1) cooperates with the NLRP3 inflammasome to sustain the expression of Zta, a crucial protein in EBV reactivation.
 
Shikonin's Inhibition of Epstein-Barr Virus Reactivation
Shikonin, with its well-documented anti-inflammatory properties, has been found to suppress NFκB and inhibit the formation of NLRP3 and AIM2 inflammasomes. These actions prevent caspase-1 activation, a critical step in the inflammatory response. Shikonin and its derivatives have been the subject of extensive research in various therapeutic areas, including cancer, inflammatory diseases, viral infections, and bacterial infections.
 
In this study, well-established models of EBV reactivation were employed to investigate shikonin's antiviral activity. The results unequivocally demonstrated shikonin's ability to efficiently suppress EBV reactivation in Burkitt lymphoma-derived cell lines subjected to different stimuli. This inhibition was further explored in the context of its impact on NLRP3 inflammasome activation.
 
Conclusion
The study presented here sheds light on the promising potential of shikonin, a natural compound derived from Lithospermum erythrorhizon Siebold & Zucc roots, in inhibiting the reactivation of Epstein-Barr virus (EBV). EBV is a pervasive human herpesvirus associated with various malignancies, making it a significant public health concern. Shikonin's ability to inhibit NLRP3 inflammasome activation, a key component of EBV reactivation, highlights its potential as a therapeutic agent against EBV-related diseases.
 
While more research is needed to fully understand the mechanisms underlying shikonin's inhibitory effects on EBV reactivation, this study underscores its potential as a valuable tool in the fight against EBV-associated cancers and other viral infections. Additionally, the broader pharmacological properties of shikonin, including its antimicrobial, anticancer, antioxidant, and anti-inflammatory attributes, open up exciting possibilities for future therapeutic applications in diverse medical fields. As science continues to unveil the multifaceted benefits of natural compounds like shikonin, it offers hope for innovative approaches to tackling some of the most challenging health issues of our time.
 
The study findings were published in the peer reviewed journal: Antiviral Research.
https://www.sciencedirect.com/science/article/abs/pii/S0166354223001778
 
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