Tomentosin

Chemical composition, biological activities, and molecular mechanism of Inula viscosa (L.) bioactive compounds: a review.[Pubmed:38180555]

Naunyn Schmiedebergs Arch Pharmacol. 2024 Jan 5.

Inula viscosa is an herbaceous plant mainly found in Mediterranean regions, predominantly, used in developing countries as a folk remedy for treating numerous diseases using different traditional methods of preparation that includes infusion, decoction, and external application. Researchers have been interested in studying the antioxidant, anti-inflammatory, antifungal, antibacterial, antidiabetic, and antitumor effects of I. viscosa extracts, due to its high countenance of bioactive molecules. The chemical studies of ethanol, methanol, chloroform, aqueous, petroleum ether, dichloromethane, and ethyl acetate extracts from different parts of I. viscosa, growing around the world, and analyzed by different analytical techniques allowed to isolate and identify a great number of secondary metabolites from terpenes, flavonoids, phenylpropanoids, and polyketides, and complementary in vitro and in vivo studies indicated the pharmacological activities of an isolated compound, a mixture, or the crude extract. I. viscosa extracts had a great in vivo potential reducing mice paw, ear, and the severity of pulmonary edema, and the occurrence of skin carcinoma growing; in vitro recent study results showed, in addition, the high antioxidant, alpha-glucosidase, and alpha-amylase inhibitory activity, and neuroprotectivity effects; a correlation with the in vivo studies confirming the anti-inflammatory and antitumor proprieties, elucidating some molecular mechanisms: showing that Tomentosin reduced pro-inflammatory cytokine secretion (IFNgamma, IL-1, IL-2, TNF-alpha, and IL-6) via the suppression of transcription factor NF-kappaB and MAP kinase (p38/JNK) activation, and that the two phenolic compounds banaxanthone E and paxanthone inhibited the antiapoptotic protein BCL-2, activating the apoptotic process leading to the antiproliferative effect.

Phytochemical Extracts of Dittrichia viscosa (L.) Greuter from Agroecological Systems: Seed Antigerminative Properties and Effectiveness in Counteracting Alternaria Leaf Spot Disease on Baby-Leaf Spinach.[Pubmed:37372075]

Biology (Basel). 2023 May 30;12(6):790.

Dittrichia viscosa (L.) Greuter subsp. viscosa (Asteraceae) is a perennial species naturally distributed in arid and marginal areas whose agroecological cultivation could be a useful innovation to produce quality biomass to extract phenolic-rich phytochemical blends. Here, biomass-yield trends were profiled at different growth stages under direct cropping, and inflorescences, leaves, and stems were submitted to water extraction and hydrodistillation. Then, four extracts were investigated for their biological activities in invitro and in planta assays. Extracts inhibited cress (Lepidium sativum)- and radish (Raphanus sativus)-seed germination and root elongation. All samples showed dose-dependent antifungal activity in the plate experiments, inhibiting up to 65% of the growth of the fungal pathogen Alternaria alternata, a leaf-spot disease agent of baby spinach (Spinacea oleracea). However, only the extracts from dried green parts and fresh inflorescences at the highest concentration significantly reduced (54%) the extent of Alternaria necrosis on baby spinach. UHPLC-HRMS/MS analysis revealed that the main specialized metabolites of the extracts are caffeoyl quinic acids, methoxylated flavonoids, sesquiterpene compounds such as Tomentosin, and dicarboxylic acids, which may explain the observed bioactivity. Plant extracts obtained through sustainable methodology can be effective in biological agricultural applications.

Tomentosin suppressed M1 polarization via increasing MERTK activation mediated by regulation of GAS6.[Pubmed:37011736]

J Ethnopharmacol. 2023 Oct 5;314:116429.

ETHNOPHARMACOLOGICAL RELEVANCE: Xanthium sibiricum Patrin ex Widder (X. sibiricum) are widely used traditional herbal medicines for arthritis treatment in China. Rheumatoid arthritis (RA) is characterized by progressive destructions of joints, which is accompanied by chronic, progressive inflammatory disorder. According to our previous research, Tomentosin was isolated from X. sibiricum and revealed anti-inflammatory activity. However, the potential therapeutic effect of Tomentosin on RA and the anti-inflammatory mechanism of Tomentosin remain to be clarified. The present study lays theoretical support for X. sibiricum in RA treatment, also provides reference for further development of X. sibiricum in clinic. AIM OF THE STUDY: To investigate the effect of Tomentosin in collagen-induced arthritis (CIA) mice and reveal its underlying mechanism. MATERIALS AND METHODS: In vivo, Tomentosin (10, 20 and 40 mg/kg) was given to CIA mice for seven consecutive days, to evaluate its therapeutic effect and anti-inflammatory activity. In vitro, THP-1-derived macrophages were used to verify the effect of Tomentosin on inflammation. Then, molecular docking and experiments in vitro was conducted to predict and explore the mechanism of Tomentosin inhibiting inflammation. RESULTS: Tomentosin attenuated the severity of arthritis in CIA mice, which was evidenced by the swelling of the hind paws, arthritis scores, and pathological changes. Particularly, Tomentosin effectively reduced the ratio of M1 macrophage and TNF-alpha levels in vitro and vivo. Then, molecular docking and experiments in vitro was carried out, indicating that Tomentosin inhibited M1 polarization and TNF-alpha levels accompanied by the increase of MERTK and up-regulated GAS6 levels. Moreover, it has been proved that GAS6 was necessary for MERTK activation and Tomentosin could up-regulate GAS6 levels effectively in transwell system. Further mechanistic studies revealed that Tomentosin suppressed M1 polarization via increasing MERTK activation mediated by regulation of GAS6 in transwell system. CONCLUSION: Tomentosin relieved the severity of CIA mice by inhibiting M1 polarization. Furthermore, Tomentosin suppressed M1 polarization via increasing MERTK activation mediated by regulation of GAS6.

Antineoplastic Properties by Proapoptotic Mechanisms Induction of Inula viscosa and Its Sesquiterpene Lactones Tomentosin and Inuviscolide.[Pubmed:36359261]

Biomedicines. 2022 Oct 28;10(11):2739.

Cancer is a complex disease including approximately 200 different entities that can potentially affect all body tissues. Among the conventional treatments, radiotherapy and chemotherapy are most often applied to different types of cancers. Despite substantial advances in the development of innovative antineoplastic drugs, cancer remains one of the most significant causes of death, worldwide. The principal pitfall of successful cancer treatment is the intrinsic or acquired resistance to therapeutic agents. The development of more effective or synergistic therapeutic approaches to improve patient outcomes and minimize toxicity has become an urgent issue. Inula viscosa is widely distributed throughout Europe, Africa, and Asia. Used as a medicinal plant in different countries, I. viscosa has been characterized for its complex chemical composition in order to identify the bioactive compounds responsible for its biological activities, including anticancer effects. Sesquiterpene lactones (SLs) are natural, biologically active products that have attracted considerable attention due to their biological activities. SLs are alkylating agents that form covalent adducts with free cysteine residues within enzymes and key proteins favoring cancer cell cytotoxicity. They are effective inducers of apoptosis in several cancer cell types through different molecular mechanisms. This review focuses on recent advances in the cytotoxic effects of I. viscosa and SLs in the treatment of neoplastic diseases, with a special emphasis on their proapoptotic molecular mechanisms.

Tomentosin induces apoptosis in pancreatic cancer cells through increasing reactive oxygen species and decreasing mitochondrial membrane potential.[Pubmed:35988885]

Toxicol In Vitro. 2022 Oct;84:105458.

The aim of this study was to determine possible anticancer effect of Tomentosin, a natural sesquiterpene lactone, on pancreatic cancer cells. The cytotoxic effect of Tomentosin was determined by XTT analysis. Colony formation and apoptosis analyzes were performed, Reactive oxygen species (ROS) level and change in mitochondrial membrane potential (MMP) were evaluated in control and Tomentosin-treated cells. The effect of Tomentosin on expression levels of apoptosis-related genes was determined by qRT-PCR and Caspase-3 and Caspase-9 proteins were analyzed by western blot. And, the effect of Tomentosin on migration and invasion of cells were evaluated. The IC(50) dose of Tomentosin was found to be 31.11 muM in PANC-1 cells and 33.93 muM in MIA PaCa-2 cells for 48 h. And, treatment of Tomentosin at IC(50) dose suppressed the colony forming capacity of cells. While Tomentosin increased apoptosis rate and ROS production, an decrease was observed in MMP. Tomentosin affected expression level of apoptosis-related genes and increased Caspase-3 and Caspase-9 protein levels. After Tomentosin treatment, cell migration and invasion were suppressed. As a result, this study reveals that Tomentosin has anticancer effects on pancreatic cancer cells, and therefore it predicts that Tomentosin can be evaluated as an effective agent against pancreatic cancer.

Antioxidant Activities and Mechanisms of Tomentosin in Human Keratinocytes.[Pubmed:35624854]

Antioxidants (Basel). 2022 May 18;11(5):990.

Tomentosin, one of natural sesquiterpene lactones sourced from Inula viscosa L., exerts therapeutic effects in various cell types. Here, we investigated the antioxidant activities and the underlying action mechanisms of Tomentosin in HaCaT cells (a human keratinocyte cell line). Specifically, we examined the involvement of Tomentosin in aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways. Treatment with Tomentosin for up to 60 min triggered the production of reactive oxygen species (ROS), whereas treatment for 4 h or longer decreased ROS production. Tomentosin treatment also induced the nuclear translocation of Nrf2 and upregulated the expression of Nrf2 and its target genes. These data indicate that Tomentosin induces ROS production at an early stage which activates the Nrf2 pathway by disrupting the Nrf2-Keap1 complex. However, at a later stage, ROS levels were reduced by Tomentosin-induced upregulation of antioxidant genes. In addition, Tomentosin induced the phosphorylation of mitogen-activated protein kinases (MAPKs) including p38 MAPK and c-Jun N-terminal kinase (JNK). SB203580 (a p38 MAPK inhibitor) and SP600125 (a JNK inhibitor) attenuated the Tomentosin-induced phosphorylation of Nrf2, suggesting that JNK and p38 MAPK signaling pathways can contribute to the Tomentosin-induced Nrf2 activation through phosphorylation of Nrf2. Furthermore, N-acetyl-(L)-cysteine (NAC) treatment blocked both Tomentosin-induced production of ROS and the nuclear translocation of Nrf2. These data suggest that Tomentosin-induced Nrf2 signaling is mediated both by Tomentosin-induced ROS production and the activation of p38 MAPK and JNK. Moreover, Tomentosin inhibited the AhR signaling pathway, as evidenced by the suppression of xenobiotic-response element (XRE) reporter activity and the translocation of AhR into nucleus induced by urban pollutants, especially benzo[a]pyrene. These findings suggest that Tomentosin can ameliorate skin damage induced by environmental pollutants.

Design, Synthesis, and Biological Evaluation of Novel Tomentosin Derivatives in NMDA-Induced Excitotoxicity.[Pubmed:35455419]

Pharmaceuticals (Basel). 2022 Mar 30;15(4):421.

N-methyl-D-aspartate (NMDA) receptor stimulation may lead to excitotoxicity, which triggers neuronal death in brain disorders. In addition to current clinical therapeutic approaches, treatment strategies by phytochemicals or their derivatives are under investigation for neurodegenerative diseases. In the present study, novel amino and 1,2,3-triazole derivatives of Tomentosin were prepared and tested for their protective and anti-apoptotic effects in NMDA-induced excitotoxicity. Amino-Tomentosin derivatives were generated through a diastereoselective conjugate addition of several secondary amines to the alpha-methylene-gamma-butyrolactone function, while the 1,2,3-triazolo-Tomentosin was prepared by a regioselective Michael-type addition carried out in the presence of trimethylsilyl azide (TMSN(3)) and the alpha-methylene-gamma-lactone function. The intermediate key thus obtained underwent 1,3-dipolar Huisgen cycloaddition using a wide range of terminal alkynes. The possible effects of the derivatives on cell viability and free-radical production following NMDA treatment were measured by Water-Soluble Tetrazolium Salts (WST-1) and Dichlorofluorescein Diacetate (DCF-DA) assays, respectively. The alterations in apoptosis-related proteins were examined by Western blot technique. Our study provides evidence that synthesized triazolo- and amino-Tomentosin derivatives show neuroprotective effects by increasing cellular viability, decreasing ROS production, and increasing the Bcl-2/Bax ratio in NMDA-induced excitotoxicity. The findings highlight particularly 2e, 2g, and 6d as potential regulators and neuroprotective agents in NMDA overactivation.

Sesquiterpene lactones from Xanthium sibiricum Patrin alleviate asthma by modulating the Th1/Th2 balance in a murine model.[Pubmed:35263672]

Phytomedicine. 2022 May;99:154032.

BACKGROUND: Asthma is a complex airway disease involving a variety of cells and cytokines. Xanthium sibiricum Patrin ex Widder (X. sibiricum) is a traditional Chinese medicine for various immune diseases, especially allergic rhinitis and asthma. Sesquiterpene lactones are the main bioactive and most abundant constituent, and are characteristic component of the plant. We explore whether sesquiterpene lactones from X. sibiricum (SL-XS) is the main active constitute for its anti-asthma activity. PURPOSE: In the present study, SL-XS was isolated, the major compounds were isolated and identified in extract of SL-XS, and the anti-asthma activity of SL-XS was validated in vivo. METHODS: SL-XS was isolated by a standard phytochemical method. The structures of major sesquiterpene lactones were identified by NMR and LC-MS spectra. The contents of major SL-XS were analyzed by HPLC. The anti-asthma effect of SL-XS was evaluated in a house dust mite (HDM)-induced mouse model. RESULTS: The sesquiterpene lactones were isolated from X. sibiricum, and five major constituents i.e., 8‑epi-xanthatin-1beta, 5beta-epoxide (1), Tomentosin (2), 8‑epi-xanthatin (3), 2‑epi-xanthumin (4) and sibiriolide B (5) were identified from SL-XS. Oral administration of SL-XS dose-dependently ameliorated airway inflammation and remodeling in HDM-challenged asthma mouse model. Furthermore, SL-XS treatment inhibited the upregulation of proinflammatory and Th2 cytokines, while reversed the downregulation of Th1 related cytokines. In addition, SL-XS regulated the balance between T-bet and GATA-3. Moreover, SL-XS inhibited the upregulation of JAK1, p-JAK1, JAK2, p-JAK2, JAK3, p-JAK3 and p-STAT6 in HDM-challenged mice. CONCLUSION: The sesquiterpene lactones including five major constituents may be the main anti-asthma active constituent of X. sibiricum. SL-XS exerted its anti-asthma effect by modulating the Th1/Th2 balance via the JAK/STAT signaling pathway.

A new specific method for isolation of tomentosin with a high yield from Inula viscosa (L.) and determination of its bioactivities.[Pubmed:35243708]

Phytochem Anal. 2022 Jun;33(4):612-618.

INTRODUCTION: Tomentosin, the characteristic component of Inula viscosa (L.) is an important sesquiterpene lactone with anticarcinogenic effects. Methods of obtaining pure Tomentosin are not sufficient for anticancer drug research. OBJECTIVES: This study aims to develop a specific method to isolate Tomentosin from I. viscosa with high yield. It also aims to investigate the inhibitory effects of Tomentosin on human carbonic anhydrase I (hCAI), human carbonic anhydrase II (hCAII), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), alpha-glucosidase, and alpha-amylase enzymes. MATERIAL AND METHODS: Tomentosin was purified by a specific column chromatography method. The content of Tomentosin in dichloromethane, dichloromethane by Soxhlet method, ethanol and ethanol by Soxhlet method extracts of I. viscosa was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Half maximal inhibitory concentration (IC(50) ) and inhibition constant (K(i) ) values were calculated to determine in vitro enzyme inhibition effects. RESULTS: Tomentosin was isolated in high yield (0.64%). The IC(50) and K(i) values for Tomentosin were calculated as 5.00 +/- 0.19 (r = 0.9688) and 4.62 +/- 0.10 muM for hCAI, 5.40 +/- 0.26 (r = 0.9677) and 5.22 +/- 0.31 muM for hCAII, 6.75 +/- 0.208 (r = 0.9891) and 3.75 +/- 0.27 muM for AChE, 6.67 +/- 0.307 (r = 0.9820) and 0.51 +/- 0.11 muM for BChE, 26.61 +/- 0.236 (r = 0.9815) and 2.61 +/- 0.71 muM for alpha-glucosidase and 26.89 +/- 1.54 muM (r = 0.9670) for alpha-amylase, respectively. CONCLUSION: Tomentosin was isolated in high yield from the paste-like extract of I. viscosa compared to the positive controls, it was determined that Tomentosin was weakly effective against hCAI, hCAII, AChE and BChE, but thoroughly effective against alpha-glucosidase and alpha-amylase. These results suggested that Tomentosin has alpha-glucosidase and alpha-amylase inhibitor potential.

Dittrichia graveolens (L.) Greuter, a Rapidly Spreading Invasive Plant: Chemistry and Bioactivity.[Pubmed:35164160]

Molecules. 2022 Jan 28;27(3):895.

Dittrichia graveolens L. Greuter belonging to the Asteraceae family, is an aromatic herbaceous plant native to the Mediterranean region. This plant species has been extensively studied for its biological activities, including antioxidant, antitumor, antimicrobial, antifungal, anti-inflammatory, anticholinesterase, and antityrosinase, and for its peculiar metabolic profile. In particular, bioactivities are related to terpenes and flavonoids metabolites, such as borneol (40), Tomentosin (189), inuviscolide (204). However, D. graveolens is also well known for causing health problems both in animals and humans. Moreover, the species is currently undergoing a dramatic northward expansion of its native range related to climate change, now including North Europe, California, and Australia. This review represents an updated overview of the 52 literature papers published in Scopus and PubMed dealing with expansion, chemistry (262 different compounds), pharmacological effects, and toxicology of D. graveolens up to October 2021. The review is intended to boost further studies to determine the molecular pathways involved in the observed activities, bioavailability, and clinical studies to explore new potential applications.

Tomentosin a Sesquiterpene Lactone Induces Antiproliferative and Proapoptotic Effects in Human Burkitt Lymphoma by Deregulation of Anti- and Pro-Apoptotic Genes.[Pubmed:34833004]

Life (Basel). 2021 Oct 23;11(11):1128.

(1) Tomentosin is the most representative sesquiterpene lactone extracted by I. viscosa. Recently, it has gained particular attention in therapeutic oncologic fields due to its anti-tumor properties. (2) In this study, the potential anticancer features of Tomentosin were evaluated on human Burkitt's lymphoma (BL) cell line, treated with increasing Tomentosin concentration for cytotoxicity screening. (3) Our data showed that both cell cycle arrest and cell apoptosis induction are responsible of the antiproliferative effects of Tomentosin and may end in the inhibition of BL cell viability. Moreover, a microarray gene expression profile was performed to assess differentially expressed genes contributing to Tomentosin activity. Seventy-five genes deregulated by Tomentosin have been identified. Downregulated genes are enriched in immune-system pathways, and PI3K/AKT and JAK/STAT pathways which favor proliferation and growth processes. Importantly, different deregulated genes identified in Tomentosin-treated BL cells are prevalent in molecular pathways known to lead to cellular death, specifically by apoptosis. Tomentosin-treatment in BL cells induces the downregulation of antiapoptotic genes such as BCL2A1 and CDKN1A and upregulation of the proapoptotic PMAIP1 gene. (4) Overall, our results suggest that Tomentosin could be taken into consideration as a potential natural product with limited toxicity and relevant anti-tumoral activity in the therapeutic options available to BL patients.

Clarifying the molecular mechanism of tomentosin‑induced antiproliferative and proapoptotic effects in human multiple myeloma via gene expression profile and genetic interaction network analysis.[Pubmed:34643251]

Int J Mol Med. 2021 Dec;48(6):213.

Multiple myeloma (MM) is an aggressive B cell malignancy. Substantial progress has been made in the therapeutic context for patients with MM, however it still represents an incurable disease due to drug resistance and recurrence. Development of more effective or synergistic therapeutic approaches undoubtedly represents an unmet clinical need. Tomentosin is a bioactive natural sesquiterpene lactone extracted by various plants with therapeutic properties, including anti‑neoplastic effects. In the present study, the potential antitumor activity of Tomentosin was evaluated on the human RPMI‑8226 cell line, treated with increasing Tomentosin concentration for cytotoxicity screening. The data suggested that both cell cycle arrest and cell apoptosis could explain the antiproliferative effects of Tomentosin and may result in the inhibition of RPMI‑8226 cell viability. To assess differentially expressed genes contributing to Tomentosin activity and identify its mechanism of action, a microarray gene expression profile was performed, identifying 126 genes deregulated by Tomentosin. To address the systems biology and identify how Tomentosin deregulates gene expression in MM from a systems perspective, all deregulated genes were submitted to enrichment and molecular network analysis. The Protein‑Protein Interaction (PPI) network analysis showed that Tomentosin in human MM induced the downregulation of genes involved in several pathways known to lead immune‑system processes, such as cytokine‑cytokine receptor interaction, chemokine or NF‑kappaB signaling pathway, as well as genes involved in pathways playing a central role in cellular neoplastic processes, such as growth, proliferation, migration, invasion and apoptosis. Tomentosin also induced endoplasmic reticulum stress via upregulation of cyclic AMP‑dependent transcription factor ATF‑4 and DNA damage‑inducible transcript 3 protein genes, suggesting that in the presence of Tomentosin the protective unfolded protein response signaling may induce cell apoptosis. The functional connections analysis executed using the Connectivity Map tool, suggested that the effects of Tomentosin on RPMI‑8226 cells might be similar to those exerted by heat shock proteins inhibitors. Taken together, these data suggested that Tomentosin may be a potential drug candidate for the treatment of MM.

Antitumor Effect of Inula viscosa Extracts on DMBA-Induced Skin Carcinoma Are Mediated by Proteasome Inhibition.[Pubmed:33855081]

Biomed Res Int. 2021 Mar 27;2021:6687589.

The aim of this work is to evaluate the antitumor effect mediated by the proteasome inhibitors of Inula viscosa extracts on skin carcinogenesis. Female Swiss albino mice were divided into five groups depending on the combination of skin cancer-inducing 7,12-dimethylbenz(a)anthracene (DMBA) and extract of Inula viscosa treatments. Histology of the affected skin and measurement of proteasome activity were performed to demonstrate the effect of Inula viscosa on mice. The identification of the molecules responsible for this inhibitory activity was carried out through the docking studies. The results showed that Inula viscosa extracts inhibit the development of papilloma in mice. Therefore, the best chemopreventive action of Inula viscosa was observed on mice in which extract treatment was performed before and after the induction of skin carcinogenesis. It was revealed that the ingestion of extracts Inula viscosa delays the formation of skin papillomas in animals and simultaneously decreases the size and number of papillomas, which is also reflected on the skin histology of the mice treated. Structure-activity relationship information obtained from component of Inula viscosa particularly Tomentosin, inuviscolide, and isocosticacid demonstrated that distinct bonding modes in beta (1), beta (2), and beta (5) subunits determine its selectivity and potent inhibition for beta (5) subunit.

Tomentosin Reduces Behavior Deficits and Neuroinflammatory Response in MPTP-Induced Parkinson's Disease in Mice.[Pubmed:33639075]

J Environ Pathol Toxicol Oncol. 2021;40(1):75-84.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Tomentosin is an active compound isolated from the I. viscosa plant that has extensive therapeutic value. In this exploration, the neuroprotective actions of Tomentosin were investigated against MPTP-stimulated neuroinflammation in mice. PD was stimulated in C57/BL6 mice by injecting 20-mg/kg MPTP at 2-h intervals 4 times a day for 15 days simultaneously with Tomentosin treatment. The rota-rod test, grasping test, and pole climbing test were executed to investigate the motor functioning of the test animals. Proinflammatory cytokines, reactive oxygen species, and myeloperoxidase were assayed using commercial ELISA kits. Superoxide dismutase enzyme levels were measured by the standard method. Expression of TLR-4/NF-kappaB was analyzed by Western blot. Brain tissues of investigational animals were analyzed microscopically. Tomentosin treatment of the MPTP-intoxicated PD mice promoted appreciable regains in body weight and noticeably prevented MPTP-stimulated impairments in motor function. In the PD mice, proinflammatory cytokine, ROS, and MPO levels were lowered by Tomentosin, inhibited the TLR-4/NF-kappaB signaling pathway and prevented inflammation-mediated neuronal cell damage, and reduced glial cell damage and normalized ganglion layers. These findings confirmed the neuroprotective properties of Tomentosin against MPTP-induced PD in mice.

Are sesquiterpene lactones the elusive KARRIKIN-INSENSITIVE2 ligand?[Pubmed:33521891]

Planta. 2021 Feb 1;253(2):54.

The sunflower sesquiterpene lactones 8-epixanthatin and Tomentosin can bind to the hydrophobic pocket of sunflower KAI2 with an affinity much higher than for the exogenous ligand KAR. Sesquiterpene lactones (STLs) are secondary plant metabolites with a wide range of biological, such as anti-microbial, activities. Intriguingly, the STLs have also been implicated in plant development: in several Asteraceae, STL levels correlate with the photo-inhibition of hypocotyl elongation. Although this effect was suggested to be due to auxin transport inhibition, there is no structural-functional evidence for this claim. Intriguingly, the light-induced inhibition of hypocotyl elongation in Arabidopsis has been ascribed to HYPOSENSITIVE TO LIGHT/KARRIKIN-INSENSITIVE2 (HTL/KAI2) signaling. KAI2 was discovered because of its affinity to the smoke-derived karrikin (KAR), though it is generally assumed that KAI2 has another, endogenous but so far elusive, ligand rather than the exogenous KARs. Here, we postulate that the effect of STLs on hypocotyl elongation is mediated through KAI2 signaling. To support this hypothesis, we have generated homology models of the sunflower KAI2s (HaKAI2s) and used them for molecular docking studies with STLs. Our results show that particularly two sunflower STLs, 8-epixanthatin and Tomentosin, can bind to the hydrophobic pockets of HaKAI2s with high affinity. Our results are in line with a recent study, showing that these two STLs accumulate in the light-exposed hypocotyls of sunflower. This finding sheds light on the effect of STLs in hypocotyl elongation that has been reported for many decades but without conclusive insight in the elusive mechanism underlying this effect.