Cellular stress induces non-canonical activation of the receptor tyrosine kinase EphA2 through the p38-MK2-RSK signaling pathway.

The receptor tyrosine kinase ephrin type-A receptor 2 (EphA2) is overexpressed in malignant tumors. We previously reported that non-canonical EphA2 phosphorylation at Ser-897 was catalyzed by p90 ribosomal S6 kinase (RSK) via the MEK-ERK pathway in ligand- and tyrosine kinase-independent manners. Non-canonical EphA2 activation plays a key role in tumor progression; however, its activation mechanism remains unclear. In the present study, we focused on cellular stress signaling as a novel inducer of non-canonical EphA2 activation. p38, instead of ERK in the case of epidermal growth factor signaling, activated RSK-EphA2 under cellular stress conditions, including anisomycin, cisplatin, and high osmotic stress. Notably, p38 activated the RSK-EphA2 axis via downstream MAPK-activated protein kinase 2 (MK2). Furthermore, MK2 directly phosphorylated both RSK1 Ser-380 and RSK2 Ser-386, critical residues for the activation of their N-terminal kinases, which is consistent with the result showing that the C-terminal kinase domain of RSK1 was dispensable for MK2-mediated EphA2 phosphorylation. Moreover, the p38-MK2-RSK-EphA2 axis promoted glioblastoma cell migration induced by temozolomide, a chemotherapeutic agent for the treatment of glioblastoma patients. Collectively, the present results reveal a novel molecular mechanism for non-canonical EphA2 activation under stress conditions in the tumor microenvironment.

Pentacyclic triterpenoids from spikes of Prunella vulgaris L. with thyroid tumour cell cytostatic bioactivities.

Five new triterpenoids, including four ursane types (1-4) and one oleanane type (5), together with 15 known ursane types pentacyclic triterpenoids (6-20) were isolated from the fruit spikes of Prunella vulgaris L., a traditional Chinese herbal medicine. Their structures were elucidated based on IR, HR-ESI-MS, and NMR spectroscopic data. The SW579 cell line was used to evaluate anti-thyroid cancer activities of (1-20). The results indicated that (7-9), (16), and (19) exhibited apparent inhibitory activity with IC50 values of 25.73-71.41 µM (cisplatin as positive control, IC50 14.49 ± 0.97 µM). Network pharmacology and molecular docking were also used for the prediction of the synergistic actions and the underlying mechanisms. Accordingly, four potential targets have been characterized.

Two new stilbenoid diglycosides from the stems of Dendrobium 'Sonia'.

Two undescribed stilbenoid diglycosides, dendrosonside A and dendrosonside B (1 and 2), were isolated from the stems of Dendrobium 'Sonia'. Their structures were elucidated based on 1 D/2D NMR and HRESIMS. The glycosyls contained in the two isolates were determined as D-glucose by acid hydrolysis and GC-MS analyses. In addition, 1 and 2 were further tested for the inhibition of nitric oxide production.

Seven new 2-(2-phenylethyl) chromone derivatives from agarwood of Aquilaria agallocha with inhibitory effects on nitric oxide production.

Seven new 2-(2-Phenethyl) chromone derivatives (1-7), including four 2-(2-Phenethyl) chromones (1-4), one 6, 7, 8 trihydroxy-2-(2-Phenethyl) chromone (5), one acetylated 5, 6, 7, 8-tetrahydroxy-2-(2-Phenethyl) chromone (6), and one chlorine-containing 5, 6, 7, 8-tetrahydro-2-(2-Phenethyl) chromone (7), along with eight known compounds (8-15), were isolated from agarwood originating from Aquilaria agallocha Roxb.. Their structures were determined mainly by high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) and nuclear magnetic resonance (NMR) analysis. The absolute configurations of 3-7 were resolved by electronic circular dichroism (ECD) calculations. Nearly all compounds were evaluated for their anti-inflammatory activities in RAW264.7 cells. Compounds 1 and 7-11 displayed significant anti-inflammatory activities with IC50 values ranging from 3.71 to 32.04 µM.

Eudesmane-type and agarospirane-type sesquiterpenes from agarwood of Aquilaria agallocha.

Eleven previously unreported sesquiterpenes, including nine eudesmane-type (agalleudesmanol A-I) and two agarospirane-type sesquiterpenes (agarospiranic aldehyde A-B), together with eight known sesquiterpenes, were isolated from the agarwood of Aquilaria agallocha Roxb. The structures were established based on extensive spectroscopic analyses, including infrared (IR), high-resolution electrospray ionisation mass spectrometry (HRESIMS), nuclear magnetic resonance (NMR), X-ray diffraction, quantum chemical calculations based on empirical electronic circular dichroism (ECD) data, and DP4+ probability analysis. The bioactivity of these undescribed compounds against lipopolysaccharide (LPS)-induced NO production in RAW 264.7 cells was evaluated. Compounds 1 and 2 exhibited significant anti-inflammatory activities, with IC50 values of 5.46-14.07 µM (aminoguanidine as positive control, IC50 20.33 ± 1.08 µM).

Ginsenoside Rg5 inhibits cancer cell migration by inhibiting the nuclear factor-κB and erythropoietin-producing hepatocellular receptor A2 signaling pathways.

The majority of cancer-associated deaths are caused by cancer metastasis, the first step of which is the acquisition of migratory ability by cancer cells. Therefore, the suppression of cancer cell migration represents a potential efficient strategy to inhibit cancer metastasis. Inflammation induces cancer cell migration through the activation of nuclear factor-κB (NF-κB), which is a transcription factor that serves a central role in inflammatory signaling. Recent studies have demonstrated that the phosphorylation of the receptor tyrosine kinase erythropoietin-producing hepatocellular receptor A2 (EphA2) at S897 promotes cancer cell migration. Therefore, a compound with the ability to abolish these two factors may suppress cancer metastasis. In the present study, ginseng saponin ginsenoside Rg5 was found to inhibit the phosphorylation of NF-κB and EphA2. Therefore, this study aimed to elucidate the molecular mechanisms of ginsenoside Rg5 and determine whether it inhibited cancer cell migration. The results demonstrated that ginsenoside Rg5 inhibited the activation of NF-κB by suppressing its upstream kinase transforming growth factor ß-activated kinase 1 in TNF-α treated HeLa or A549 cells compared with that in the untreated control group. Furthermore, ginsenoside Rg5 attenuated the expression of EphA2 by lysosomal degradation, which inhibited its phosphorylation. In addition, ginsenoside Rg5 suppressed inflammatory cytokine-induced cancer cell migration. In conclusion, the results of the present study provided a scientific basis for the development of ginsenoside Rg5 as a potential antimetastatic drug.

Structures and biological evaluation of phenylpropanoid derivatives from Dendrobium Sonia.

Two new phenylpropanoid derivatives (1-2), together with eight known compounds (3-10) were isolated from the stems of Dendrobium sonia. The structures of these compounds were elucidated on the basis of spectroscopic analyses, including HRESIMS, 1 D and 2 D NMR experiments. All of the isolated compounds were tested for their Nitric Oxide (NO) Inhibitory Activities. The results of bioactive screening showed that compounds 2, 8, 9 and 10 exerted inhibitory effects on NO production with IC50 values in the range of 26.3 to 31.6 µM. Compound 8 and 9 exhibited stronger anti-inflammatory activities with IC50 values 26.3 and 27.7 µM, comparable to that of the positive control.