Cynaropicrin

Cynaropicrin inhibits the entry of pan-genomic Hepatitis C virus into cells and inhibits cell-cell transmission.[8]

Cynaropicrin also shows anti-hyperlipidemic activity. The oxygen functional groups and the methylene of the GBL ring were found the help in anti-hyperlipidemic activity. Inhibition of gastric emptying also plays a minor role in this property.[9]

Cynaropicrin inhibits the activation of major adhesion molecules CD29 and CD98 involved in inflammation, but not CD43. This indicates that it might be a specific immunopharmacological effect. These adhesion molecules are essential factors in regulating the inflammatory process. It is linked to the inhibition of extracellular signal-related kinase (ERK).[10]

Research shows that it had a pro-apoptotic activity on cancer cell lines U937, Eol-1 and Jurkat T cells. Its cytotoxic activity was inhibited by N-acetyl-L-cysteine and L-cysteine, reactive oxygen species and rottlerin (protein kinase Cδ inhibitor), indicating that PKCδ and ROS are important for its pro-apoptotic activity of cynaropicrin by proteolytic cleavage of PKCδ.[11]

Transcription factor ‘Signal inducer and activator of transcription 3’ (STAT3) is continuously activated in cancer cells. It plays a critical role in the inhibition of apoptosis and induces chemoresistance. The α-β-unsaturated carbonyl moiety in cynaropicrin leads to a drop of intracellular GSH concentration via the Michael reaction. This inhibits the phosphorylation of STAT3 and increases the S-glutathionylation of STAT3 and therefore deactivating it. This leads to an increase in the expression of apoptotic genes.[12]

Cynaropicrin is an inhibitor of TNF-α, a cytokine used in inflammation of tissue. It inhibits the production of TNF-α from lipopolysaccharide-stimulated murine macrophage RAW264.7 cells. It also inhibits the release of nitric oxide from lipopolysaccharide- and interferon-γ-stimulated RAW264.7 cells. Lastly. it also suppressed lymphocyte proliferation from splenocytes. All these compounds, TNF-α, nitric oxide and lymphocytes, are all essential for inflammation.[2]

Cynaropicrin is a potent activator of the ArH-Nrf2-Nqo1 pathway in human keratinocytes. It also inhibits the generation of ROS, and pro-inflammatory cytokines TNF-α and IL-6 in keratinocytes irradiated with UVB. These processes are important in photoaging which is a causative agent for skin cancer.[2]

Cynaropicrin binds to the thiol group of the Cys115 in the bacterial enzyme MurA through Michael addition reaction. The unsaturated ester side chain of cynaropicrin appears to mimic the substrate phosphoenolpyruvate (PEP). The irreversible inhibition of this enzyme stops the cytoplasmic biosynthesis of peptidoglycan precursor molecules.[2]

Cynaropicrin shows a reduction in parasitemia in murine models and has potent antitrypanosomal activity. It lowers intracellular GSH and trypanothione levels and inhibits trypanosomal ornithine decarboxylase with its α,β-unsaturated methylene moiety which acts as Michael acceptor. This leads to apoptosis of parasites. The 2-hydroxymethyl-2-propenoyl moiety was found to play an important role in the toxicity. Removal of this group led to a loss of toxicity towards T. brucei rhodesiense and a tenfold loss of activity against T brucei.[2]

Cynaropicrin has been shown to be an inhibitor against HCV in the early stages of its lifecycle. Eight of the eighteen[13] genotypes of the HCV virus (1a, 1b, 2b, 3a, 4a, 5a, 6a, and 7a) were inhibited using only small doses, revealing its potential against the disease.[2]

It was shown that leaf-extract of artichoke, with cynaropicrin as one of its functional compounds, put a restraint on the elevation of serum triglyceride elevation. This raises the possibility of the use against obesity related diseases and up to now incurable diseases.[2]

Cynaropicrin has a cytotoxic effect in various human cancer cell lines. It has been shown to inhibit cell proliferation in certain cancer cell lines (AGS and Hepa 1c1c7 cells), which is possible by, among other things, suppression of anti-apoptotic genes.[14] It also induces apoptosis in leukocyte cancer cells and affects the invasion, migration and metastasis of those cells. This is an example of diseases mediated by DC29 and DC98, of which the compound holds potential as a drug for treatment.[2]

Cynaropicrin has anti-inflammatory abilities through the proliferation of lymphocytes and the inhibition of the production of mediators. An example of which is the inhibition of cytokine-induced and TNF-α neutrophil chemoattractant-1 and nitric oxide release.[2]

Cynaropicrin can be used as an anti-photoaging agent, as it prevents UVB-induced photoaging. Additionally, an experiment with artichoke leaf extract resulted in a decrease in wrinkles and noticeable pores, as well as an increase in facial pigmentation. This is due to the lessened decline of dermal proteoglycan, a compound important for holding water.[2]

In bacterial cells the enzyme MurA is of vital importance, as it is responsible for the cytoplasmic biosynthesis of peptidoglycan precursor molecules. Cynaropicrin inhibits this enzyme, and thus it has potent antibacterial activity.[2]

It has been shown that cynaropicrin has anti-parasitic activities for various organisms (trypanosoma) both in vitro and in vivo. The compound is the first natural product that has in vivo potential against the T. brucei.[2]

Cynaropicrin is a compound with promising potential as an antifeedant, as it has been shown to have deterring activity against multiple species of Lepidoptera (Arctiidae and Saturniidae). It also works relatively well against Trogoderma granarium larvae, Tribolium confusum larvae and Sitophilus granarius beetles.[2] The compound works the best in combination with other sesquiterpene lactones and not in its pure form.[15]

The effect of cynaropicrin on all affected genotypes has been shown to be generally strong, with EC50 values in low micromolar ranges: 0.4 - 1.4 μM, with an average of 0.8 μM.[8]

Cynaropicrin has shown variable efficacy on different cancer cell lines. The IC50 lies between 0.068 and 8.7 μg/ml, with outliers of 30.22 and 116.96 μg/ml for the growth inhibition of AGS and Hepa1c1c7 cells respectively.[2]

The cytotoxic effect on some of the human tumor cell lines has been given contradictory ED50 values. SK-OV-3, SK-MEL-2 ,A549, HCT-15 and XF498 (CNS) cell lines have been tested and resulted in a range between 0.29 and 1.37 μg/ml. Another study has given values between 1.41 and 8.48 μg/ml for the SK-MEL-2, SK-OV-3, A549 and HCT cell lines. Additionally, the same study has given a range of ED50 values for the compound doxorubicin, which is 0.0038-0.089 μm/ml. This leaves cynaropicrin as the less effective compound.[2]

In keratinocytes, cynaropicrin has an EC50 of 0.89 μM and an CC50 of 47.6 μM on Nqo1 induction. This makes it a potent antioxidant there and thus a potent anti-photoaging compound.[2]

For the antiparasitic activity of cynaropicrin various species were tested, especially the trypanosoma. The IC50 values vary, but lie between 0.2 and 4.4 μM. In a mouse model the compound caused a reduction of parasitemia of 92% in comparison to the control.[2]