Effect of Exogenous Application of Tryptophan and Methyl Jasmonate on Some Metabolites and Antioxidant Activities of Feverfew

Tanacetum parthenium (L.) Schultz-Bip (feverfew) is among the important medicinal and aromatic plants due to its tryptophan (TRP), serotonin (SER), melatonin (MEL), and parthenolide (PRT) content. In recent studies, have reported TRP, MEL, and (PRT) are effective in the treatment of COVID-19, thus increasing the popularity of feverfew, which is rich in these valuable molecules. This study investigated the possible effects of exogenous foliar applications of methyl jasmonate (MeJA 0.5 mM) and TRP (20 mM) on plant TRP, SER, MEL, and PRT levels. During the pre-flowering period, endogenous TRP was measured as 128.9 mu g/mL and endogenous PRT as 1.53% mg/g in the leaves of the control group. During the flowering period, the MEL level was measured as 1.38 mu g/mL in the leaves of the TRP application group. In addition, in the pre-flowering period, MeJA-induced increases of 94.51% were determined in DPPH antioxidant activity and the total flavonoid content was 38.76 mg QE/g, whereas the highest total phenolic content of 51.63 mg GAE/g was found in flower samples of the control group. However, neither the developmental periods nor the treatments significantly affected the total phenolic content in the leaves.

The therapeutic effect and mechanism of parthenolide in skeletal disease, cancers, and cytokine storm.

Parthenolide (PTL or PAR) was first isolated from Magnolia grandiflora and identified as a small molecule cancer inhibitor. PTL has the chemical structure of C15H20O3 with characteristics of sesquiterpene lactones and exhibits the biological property of inhibiting DNA biosynthesis of cancer cells. In this review, we summarise the recent research progress of medicinal PTL, including the therapeutic effects on skeletal diseases, cancers, and inflammation-induced cytokine storm. Mechanistic investigations reveal that PTL predominantly inhibits NF-κB activation and other signalling pathways, such as reactive oxygen species. As an inhibitor of NF-κB, PTL appears to inhibit several cytokines, including RANKL, TNF-α, IL-1ß, together with LPS induced activation of NF-κB and NF-κB -mediated specific gene expression such as IL-1ß, TNF-α, COX-2, iNOS, IL-8, MCP-1, RANTES, ICAM-1, VCAM-1. It is also proposed that PTL could inhibit cytokine storms or hypercytokinemia triggered by COVID-19 via blocking the activation of NF-κB signalling. Understanding the pharmacologic properties of PTL will assist us in developing its therapeutic application for medical conditions, including arthritis, osteolysis, periodontal disease, cancers, and COVID-19-related disease.

Parthenolide reveals an allosteric mode to inhibit the deISGylation activity of SARS-CoV­2 papain-like protease.

The coronavirus papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for viral polypeptide cleavage and the deISGylation of interferon-stimulated gene 15 (ISG15), which enable it to participate in virus replication and host innate immune pathways. Therefore, PLpro is considered an attractive antiviral drug target. Here, we show that parthenolide, a germacrane sesquiterpene lactone, has SARS-CoV-2 PLpro inhibitory activity. Parthenolide covalently binds to Cys-191 or Cys-194 of the PLpro protein, but not the Cys-111 at the PLpro catalytic site. Mutation of Cys-191 or Cys-194 reduces the activity of PLpro. Molecular docking studies show that parthenolide may also form hydrogen bonds with Lys-192, Thr-193, and Gln-231. Furthermore, parthenolide inhibits the deISGylation but not the deubiquitinating activity of PLpro in vitro. These results reveal that parthenolide inhibits PLpro activity by allosteric regulation.

Modelling the DFT structural and reactivity study of feverfew and evaluation of its potential antiviral activity against COVID-19 using molecular docking and MD simulations.

Abstract: The unavailability of a proper drug against SARS-CoV-2 infections and the emergence of various variants created a global crisis. In the present work, we have studied the antiviral behavior of feverfew plant in treating COVID-19. We have reported a systematic in silico study with the antiviral effects of various phytoconstituents Borneol (C10H18O), Camphene (C10H16), Camphor (C10H16O), Alpha-thujene (C10H16), Eugenol (C10H14O), Carvacrol (C10H14O) and Parthenolide (C15H20O3) of feverfew on the viral protein of SARS-CoV-2. Parthenolide shows the best binding affinity with both main protease (Mpro) and papain-like protease (PLpro). The molecular electrostatic potential and Mulliken atomic charges of the Parthenolide molecule shows the high chemical reactivity of the molecule. The docking of Parthenolide with PLpro give score of -8.0 kcal/mol that validates the good binding of Parthenolide molecule with PLpro. This complex was further considered for molecular dynamics simulations. The binding energy of the complex seems to range in between -3.85 to -11.07 kcal/mol that is high enough to validate the stability of the complex. Free energy decomposition analysis have been also performed to understand the contribution of residues that reside into the binding site. Good binding affinity and reactivity response suggested that Parthenolide can be used as a promising drug against the COVID-19. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-022-02067-6.

TRYPTOPHAN DERIVATIVES, PHENOLIC COMPOUNDS AND ANTIOXIDANT POTENTIAL OF SOME WILD TANACETUM TAXA FROM TURKEY

The important molecule tryptophan and its derivatives serotonin and melatonin have vital functions in human and plant biosystem. Recent reports claimed these molecules and parthenolide may also have a role in COVID-19 treatments. Herewith the study, contents of chlorogenic acid, cynarin, quinic acid, parthenolide, and tryptophan derivatives in leaf and flowers of seven species of Tanacetum from Turkey were examined using HPLC. The methanolic extracts of the species were also screened for their total phenolic content and DPPH scavenging activity. Regarding to HPLC data, the highest amount of chlorogenic acid and cynarin were detected in T. cilicicum, quinic acid in T. densum subsp. amani and parthenolide in T. argenteum subsp. argenteum leaves. Also, the highest amount of tryptophan and serotonin were estimated in T. argenteum subsp. argenteum. Melatonin content was highest in T. densum subsp. amani. All Tanacetum species exhibited potent antioxidant activities. T. densum subsp. amani (Afsin) flowers had higher DPPH activity than control group BHT and T. cilicicum leaves and flowers had the highest total phenolic content. Herewith, phenolic profiles of T. argenteum subsp. argenteum, T. armenum and T. densum subsp. amani and tryptophan derivates of the species were reported for the first time.

Parthenolide: Suggested drug for COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the 2019 novel coronavirus (2019-nCoV) that causes acute respiratory distress syndrome (ARDS) which is the main reason for patients mortality. One of the effective treatments to reduce the effects of this virus is parthenolide (PN). Parthenolide is a sesquiterpene lactone found in medicinal plants. It can inhibit several pro-inflammatory signaling pathways, in particular the ATPase activity of NLRP3. Based on its ability to suppress inflammatory signal transduction and elevated level of serum IL-1β (a surrogate marker for NLRP3 activation) in COVID-19 patients, we suggest that PN could be potentiallyeffective for the treatment of COVID-19.

Chemical reactivities and molecular docking studies of parthenolide with the main protease of HEP-G2 and SARS-CoV-2.

We have used bioinformatics to identify drugs for the treatment of COVID-19, using drugs already being tested for the treatment as benchmarks like Remdesivir and Chloroquine. Our findings provide further support for drugs that are already being explored as therapeutic agents for the treatment of COVID-19 and identify promising new targets that merit further investigation. In addition, the epoxidation of Parthenolide 1 using peracids, has been scrutinized within the MEDT at the B3LYP/6-311(d,p) computational level. DFT results showed a high chemoselectivity on the double bond C3[bond, double bond]C4, in full agreement with the experimental outcomes. ELF analysis demonstrated that epoxidation reaction took place through a one-step mechanism, in which the formation of the two new C-O single bonds is somewhat asynchronous.

Cytokine storm in COVID-19 and parthenolide: Preclinical evidence.

A group of patients with pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were reported from China in December 2019. Although several antiviral drugs are widely tested, none of them has been approved as specific antiviral therapy for coronavirus disease 2019 (COVID-19). Accumulating evidence established a hyperinflammatory states or cytokine storm in COVID-19. Among these cytokines, IL-6 plays a key role in cytokine storm and can predict the adverse clinical outcomes and fatality in these patients. Based on the evidence of the significant role of IL-6 in cytokine storm, diabetes mellitus, and cardiovascular diseases as principal comorbidities, it seems that anti-cytokine therapy may be useful in patients with severe COVID-19 to reduce mortality. Recent studies demonstrated that herbal-derived natural products had immunosuppressive and anti-inflammatory properties and exhibited exceptional act on mediators of inflammation. Parthenolide is the principal sesquiterpene lactones and the main biologically active constituent Tanacetum parthenium (commonly known as feverfew) which has could significantly reduce IL-1, IL-2, IL-6, IL-8, and TNF-α production pathways established in several human cell line models in vitro and in vivo studies. Therefore, parthenolide may be one of the herbal candidates for clinical evaluation.