GPER mediates decreased chemosensitivity via regulation of ABCG2 expression and localization in tamoxifen-resistant breast cancer cells.

Rescue chemotherapy is usually the preferred treatment for patients with advanced estrogen receptor-positive (ER+) breast cancer with endocrinotherapy resistance. However, these patients often simultaneously show a poor response to cytotoxic drugs, and thus the detailed mechanism of this resistance needs to be further investigated. Our previous research indicated that the G-protein-coupled estrogen receptor (GPER) is a novel mediator of the development of multidrug resistance, including resistance to both endocrinotherapy and chemotherapy, and ATP binding cassette subfamily G member 2 (ABCG2) has been identified as an engine that confers cancer cells with chemoresistance by expelling xenobiotics and chemotherapeutics. Here, we are the first to show that the expression levels of GPER and ABCG2 are markedly increased in tamoxifen-resistant ER + metastases compared to the corresponding primary tumors. A plasma membrane expression pattern of GPER and ABCG2 was observed in patients with metastases. Furthermore, both ER modulator tamoxifen, GPER-specific agonist G1 and pure ER antagonist ICI 182,780 significantly enhanced ABCG2 expression in tamoxifen-resistant breast cancer cells (MCF-7R) but not in tamoxifen-sensitive cells (MCF-7). The activated downstream GPER/EGFR/ERK and GPER/EGFR/AKT signaling pathways were responsible for regulating the expression and cell membrane localization of ABCG2, respectively, in MCF-7R cells. Interestingly, the above phenomenon could be alleviated by inhibitors of both the indicated signaling pathways and by knockdown of GPER in MCF-7R cells. More importantly, the tamoxifen-induced GPER/ABCG2 signaling axis was shown to play a pivotal role in the development of chemotherapy (doxorubicin) resistance both in vitro and in vivo. The clinical data further revealed that tamoxifen-resistant patients with high GPER/ABCG2 signaling activation had poor progression-free survival (PFS) when given rescue anthracycline chemotherapy. Therefore, our data provide novel insights into GPER-mediated chemoresistance and provide a rationale for the GPER/ABCG2 signaling axis being a promising target for reversing chemoresistance in patients with advanced ER + tamoxifen-resistant breast cancer.

Phytochemistry and Comprehensive Chemical Profiling Study of Flavonoids and Phenolic Acids in the Aerial Parts of Allium Mongolicum Regel and Their Intestinal Motility Evaluation.

To clarify whether flavonoids and phenols in Allium mongolicum Regel have the effect of improving gastrointestinal function and analyze its quality, this study was designed to isolate and identify them from the aerial parts of A. mongolicum by using various chromatographic and spectrophotometric methods, a bioassay on motility of mouse isolated intestine tissue, as well as qualitative analysis using liquid chromatography/mass spectrometry (LC-MS) analysis. As a result, 31 flavonoids and phenolic acids were obtained and identified, including six new flavonoid glycosides, mongoflavonosides A1 (1), A2 (2), A3 (3), A4 (4), B1 (5), B2 (6), and four new phenolic acid glycosides, mongophenosides A1 (7), A2 (8), A3 (9), B (10). Among them, eleven flavonoids and three phenolic acids showed significant increase in the height of mouse small intestinal muscle. It was a first systematic bioactive constituents' study for A. mongolicum on gastrointestinal tract. Furthermore, according to the retention time (tR) and the exact mass-to-charge ratio (m/z), thirty-one compounds were unambiguously identified by comparing to the standard references by using LC-MS. Then, on the basis of generalized rules of MS/MS fragmentation pattern, chromatographic behaviors, as well as biosynthetic laws of the 31 isolates, five flavonoid glycosides and one phenolic acid glycoside were tentatively speculated. On the basis of the study, a fast analysis method for flavonoids and phenolic acids in A. mongolicum was established.

NMR and MS data for novel bioactive constituents from Pugionium cornutum L. Gaertn.

The data presented in this article are associated with the research article entitled "Bioactive Constituents Study of Pugionium cornutum L. Gaertn on Intestinal Motility" [1]. The aim of this data was to provide the 1D, 2D NMR and MS spectrum of novel bioactive compounds from P. cornutum.

Effects of Allium mongolicum Regel and Its Flavonoids on Constipation.

Constipation is a common bowel disease in adults with the symptoms of dry stool or difficulty passing stool. Compared with medication therapy, patients show more compliance with the diet therapy, and thus the diet therapy normally exhibits better therapeutic effect. Allium mongolicum Regel s a perennial herb of Liliaceae native to Mongolia, Kazakhstan, and China, which is traditionally used for constipation. In this paper, we partly clarify the effectiveness of A. mongolicum on constipation from two aspects, including maintaining colon water content and increasing intestinal transit. In loperamide-induced constipation mice model, nine days oral administration of A. mongolicum 50% ethanolic extract increased luminal side water content and regulated intestinal movement rhythm to normalize stools. The activity at least partly related to down-regulation of colon aquaporins 3 (AQP3) expression, and up-regulation and activation of G protein alpha (Gα) and phosphoinositide 3-kinases (PI3K). Further, activities on intestine movements were tested using compounds isolated from A. mongolicum. Three kinds of major flavonoids significantly increased cellular calcium flux in HCT116 cells and promoted mice intestine smooth muscle contraction. The activity may be related to M choline receptor, µ opioid receptor, 5-HT3 receptor, and inositol 1,4,5-trisphosphate (IP3) receptor.

Bioactive constituents study of Pugionium cornutum L. Gaertn on intestinal motility.

Thirty-one compounds were obtained and identified from the dried roots of Mongolian medicinal and edible plant, Pugionium cornutum L. Gaertn. Eight of them were new ones, and named as pugcornols A (1), B (2), C (3), and D (4), pugcornosides A (5), B (6), C (7), and D (8), respectively. Among them, 1-4 were rare naturally occurring thiohydantoin derivatives. Meanwhile, all the isolates were determined for their activities on isolated mice jejunum contraction, and ten of them increased height of the spontaneous contractions. Moreover, we partly clarified the mechanism of 5-(methylsulfinyl)-pentanenitrile (9), a characteristic compound in P. cornutum by using different kinds of inhibitor.

Citrus aurantium L. and Its Flavonoids Regulate TNBS-Induced Inflammatory Bowel Disease through Anti-Inflammation and Suppressing Isolated Jejunum Contraction.

Inflammatory bowel disease (IBD) is a serious digestive system disease, for which the clinical therapeutic choices remain limited. Dried fruits of Citrus aurantium L. (CAL) are a traditional medicine used for regulation of the digestive system. The aim of this study was to identify the regulatory effects of CAL on IBD and to clarify the mechanism of the active compounds. In trinitrobenzene sulfonic acid-induced IBD rats, 125 to 500 mg/kg of oral CAL significantly alleviated weight loss and diarrhea, decreased colitis inflammatory cell infiltration, and inhibited pro-inflammatory cytokine production. The mechanisms of characteristic flavonoids in CAL were evaluated involving inflammation and intestine contraction aspects. Naringenin, nobiletin, and hesperetin showed anti-inflammatory effects on lipopolysaccharide-induced RAW cells. The mechanism may be related to the inhibition of the tumor necrosis factor-α (TNF-α)-induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway to suppress cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions. Naringenin and nobiletin showed inhibitory effects on isolated jejunum contraction. The mechanism of naringenin is partly related to COX, NOS, inositol triphosphate (IP3), and finally, to decreased jejunum motility. This study demonstrated that CAL, and its flavonoids' regulatory effects on IBD through anti-inflammation and inhibition of intestine muscle contraction, can provide basic information on developing new drugs or supplements against IBD based on CAL.

Bioactive Constituents from the Whole Plants of Gentianella acuta (Michx.) Hulten.

As a Mongolian native medicine and Ewenki folk medicinal plant, Gentianella acuta has been widely used for the treatment of diarrhea, hepatitis, arrhythmia, and coronary heart disease. In the course of investigating efficacy compounds to treat diarrhea using a mouse isolated intestine tissue model, we found 70% EtOH extract of G. acuta whole plants had an inhibitory effect on intestine contraction tension. Here, nineteen constituents, including five new compounds, named as gentiiridosides A (1), B (2), gentilignanoside A (3), (1R)-2,2,3-trimethyl-4-hydroxymethylcyclopent-3-ene-1-methyl-O-ß-d-glucopyranoside (4), and (3Z)-3-hexene-1,5-diol 1-O-α-l-arabinopyranosyl(1→6)-ß-d-glucopyranoside (5) were obtained from it. The structures of them were elucidated by chemical and spectroscopic methods. Furthermore, the inhibitory effects on motility of mouse isolated intestine tissue of the above mentioned compounds and other thirteen iridoid- and secoiridoid-type monoterpenes (7-10, 13-16, 18, 19, 21, 22, and 25) previously obtained in the plant were analyzed. As results, new compound 5, some secoiridoid-type monoterpenes 7, 10, 12-14, 16, and 17, as well as 7-O-9'-type lignans 31 and 32 displayed significant inhibitory effect on contraction tension at 40 µM.