Benzoate glycosides from Gentiana scabra Bge. and their lipid-lowering activity.

Seven undescribed benzoate glycosides (1-7) and five known ones (8-12) were isolated from the rhizomes of Gentiana scabra Bge. Their structures were characterized by comprehensive NMR and MS spectroscopic data analysis. The lipid-lowering effects of these compounds were evaluated by measuring the triglyceride (TG) contents and intracellular lipid droplets (LDs) in oleic acid (OA)-treated HepG2 cells. The results showed that compounds 1, 5, 7, and 11 significantly reduced the TG content at 20 µM, and the Bodipy staining displayed that OA enhanced the levels of LDs in the cell, while these compounds reversed the lipid accumulation caused by OA. These findings provide a basis for further development and utilization of G. scabra as a natural source of potential lipid-lowering agents.

Discovery of natural AMPK activator from the fruits of Xanthium sibiricum Patr.: Xanthiumine A, protoberberine alkaloid with unique C28 skeleton.

Two protoberberine alkaloids with a unique C28 skeleton, named xanthiumines A (1) and B (2), respectively, were isolated from the fruits of Xanthium sibiricum Patr. Their structures including absolute configurations were unequivocally established by the comprehensive NMR and MS spectroscopic data analysis together with gauge-independent atomic orbital (GIAO) NMR calculations, and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 are the first examples of natural protoberberine alkaloid with a phenolic acid group at C-13a. Their plausible biosynthetic pathway was proposed on the basis of the coexisting alkaloid monomer as the precursor. Furthermore, the effects and related molecular mechanism of compound 1 on hepatic lipid accumulation were also investigated in oleic acid (OA)-treated HepG2 cells.

New depside and rosmarinic acid derivatives from Perilla frutescens and their anti-inflammatory activity.

Two new depside derivatives 1 and 2 as well as a new pair of rosmarinic acid enantiomers 3a/b were isolated from the leaves of Perilla frutescens (L.) britt. The chemical structures of these compounds were identified based on detailed spectroscopic and physicochemical analyses (HR-ESI-MS, NMR) and comparison of literature data. Compounds 3a/b were obtained by chiral separation, and their absolute configurations were determined by comparison of experimental and calculated ECD spectra. Compounds 3a/b exhibited potential inhibitory activity on nitric oxide (NO) production induced by lipopolysaccharide in RAW264.7 cells with IC50 values of 15.92 ± 3.32 µM and 48.72 ± 4.12 µM.

Research Progress on the Antioxidant Activity of Natural Diarylheptanoids: Mechanisms and Structure-activity Relationships.

Antioxidant research has recently become a popular topic. Medicinal plants are important sources of novel active compounds. Diarylheptanoids, a typical family of secondary plant metabolites, are of great interest owing to their extensive spectrum of biological activities. They possess a unique 1,7-diphenylmethane structural skeleton. Thus, this review summarizes the natural linear or macrocyclic diarylheptanoids with antioxidant activity in the last two decades. In addition, the relationships between the structural characteristics of natural diarylheptanoids and their antioxidant capacity were also discussed. All the available data highlight the potential of natural diarylheptanoids as novel antioxidants.

New verticillane-diterpenoid as potent NF-κB inhibitor isolated from the gum resin of Boswellia sacra.

Two new verticillane-diterpenoids (1 and 2) were isolated from the gum resin Boswellia sacra. Their structures were elucidated by physiochemical and spectroscopic analysis, as well as ECD calculation. In addition, the in vitro anti-inflammatory activities of the isolated compounds were evaluated by determining the inhibitory effects on lipopolysaccharide (LPS)-induced NO production in RAW 264.7 mouse monocyte-macrophages. The results showed that compound 1 exhibited significant inhibitory effect on NO generation with an IC50 value of 23.3 ± 1.7 µM suggesting that it might be a candidate for an anti-inflammatory agent. Furthermore, 1 potently inhibited the release of inflammatory cytokines IL-6 and TNF-α induced by LPS in a dose-dependent manner. Using Western blot and Immunofluorescence methods, compound 1 was found to inhibit inflammation mainly by restraining the activation of NF-κB pathway. And in the MAPK signaling pathway, it was found to have inhibitory effects on the phosphorylation of JNK and ERK proteins and have no effect on the phosphorylation of p38 protein.

Anti-proliferative tirucallane triterpenoids from gum resin of Boswellia sacra.

Eight new tirucallane triterpenoids (1-2, 5-10) along with two known compounds (3-4) were isolated from the gum resin of Boswellia sacra. Their structures were elucidated by extensive physicochemical and spectroscopic analysis, as well as computational calculations, and single crystal X-ray diffraction. Spirosacraoic acid A (1) and B (2), possess an unusual 6/5/6/5 rearranged spirocyclic carbon skeleton. All the isolates were evaluated for their anti-proliferative activity against two tumor cell lines (HepG2 and HCT-116 cells). Compound 10 displayed remarkable inhibitory activity against HepG2 cells in a dose-dependent manner with the IC50 value of 28.01 µM. High content analysis (HCA) showed that 10 induces apoptosis in HepG2 cells. The western blotting results revealed that 10 could up-regulate the ratio of the expression of Bax/BCL-2, and promote the caspase 3 activation and PARP cleavage. Mechanically, molecular modeling studies demonstrated that 10 could dock into EGFR active site. Meanwhile 10 significantly decreased the protein expression of p-EGFR. Furthermore, inhibition of EGFR by addition of EGFR siRNA enhanced the growth inhibitory effects of 10 on HepG2 cells, indicating that the anti-tumor effect of 10 on HepG2 cells was mediated by inhibition of EGFR.

Two new ent-kaurane glucosides from the fruits of Xanthium strumarium subsp. sibiricum.

The chemical investigation of the fruits of Xanthium strumarium (Asteraceae) led to the isolation of two new ent-kauranoid glucosides named 2-O-(6-O-isocaleryl-ß-D-glucopyranosyl) atractyligenin (1) and 2-O-(2-O-isovaleryl-ß-D-glucopyranosyl) atractyligenin (2), together with one known compound. Their structures were established by comprehensive spectroscopic analysis coupled with single-crystal X-ray diffraction and electronic circular dichroism data. All compounds and their aglycone were evaluated for their anti-proliferative activities in vitro against three human cancer cell lines.

Highly Potent Inhibition of Tyrosinase by Mulberrosides and the Inhibitory Mechanism in Vitro.

Many stilbene glycosides can alleviate skin hyperpigmentation due to their inhibitory effect on tyrosinase. Mulberrosides in Morus alba L. are stilbene glycosides. In the present study, the inhibition of tyrosinase by five mulberrosides (S1-5), isolated from Morus alba L. was investigated and compared, and the inhibitory mechanism was explored. These five mulberrosides exhibited obvious inhibitory effects on tyrosinase only in a concentration-dependent manner, without time-dependence, indicating that they are reversible inhibitors of tyrosinase. S2, S1 and S5 inhibited tyrosinase activity with IC50 values of 28.93, 75.94 and 151.72 µM, respectively, and were more active than kojic acid (IC50 =169.13 µM). Kinetic studies revealed that S1, S2 and S4 were competitive inhibitors, while S3 and S5 were mixed inhibitors. Analysis of the fluorescent spectra showed that mulberrosides S1, S2 and S4 quenched the intrinsic fluorescence intensity of tyrosinase. A molecular docking study indicated that the interaction of tyrosinase with mulberrosides was reflected by compound scores as follows: S2>S5>S1>S3/S4>kojic acid, and hydroxy groups in the side chain of mulberrosides may play a crucial role in the binding of the enzyme. Our results suggest that mulberrosides in Morus alba L. could be further developed as whitening agents for enhanced performance against hyperpigmentation.

An integrated approach based on phytochemistry, network pharmacology and metabolomics reveals the mechanism of action of Xanthium strumarium L. for allergic rhinitis.

Xanthium strumarium L. (XS) is a traditional Chinese medicine (TCM) that has been widely used in Chinese medicine prescription for allergic rhinitis (AR). However, the action mechanisms of XS on the therapeutic effects on AR remain elusive. Herein, an integrated approach of phytochemistry, network pharmacology and metabolomics was first applied to uncover the action mechanisms of XS for AR. The therapeutic effect of XS extract on AR was evaluated in rat models of ovalbumin (OVA)-induced AR. The cytokine levels in rat serum and histopathological changes of nasal mucosa were assessed after oral treatment with XS. Chemical compositions of XS were elucidated by phytochemical methods, and active ingredients were identified via ADME-TOX screening in silico. Network pharmacology was performed to establish and analyze the compound-target-disease network so as to find the possible mechanism of XS in treating AR. In addition, metabolomics analysis was applied to investigate the changes in the endogenous metabolite levels that result from XS treatments. As result, the XS extract significantly increased the serum concentrations of IL-2 and reduced the levels of serum IL-4, while XS could ameliorate inflammation in the nasal sub-mucosal area, indicating that XS has significant therapeutic effects on AR model rats. Furthermore, a total of 119 compounds were isolated from XS, and 59 of these compounds were identified as active ingredients through ADME-TOX screening in silico. An in-depth analysis of the network pharmacology implied that the active ingredients of XS could regulate the inflammatory response via "multi-component, multi-target" patterns. In combination with the results of metabolomics, we found that the active ingredients of XS have a beneficial effect on AR through regulating the metabolism of arachidonic acid, which was reflected by medicating the Fc epsilon RI signaling pathway, and the neuroactive ligand-receptor interaction pathway, as well as the key proteins in arachidonic acid metabolism, such as PTGS2, PTGS1, PTGES and ALOX5. Additionally, molecular docking showed that multiple compounds have better binding with PTGS2 and ALOX5, which might be two crucial targets. Overall, these results suggest that the treatment of XS for AR is realized by regulating the metabolism of arachidonic acid via a combination form. This study provides the basis for clinical applications of XS.

miR-378a-3p sensitizes ovarian cancer cells to cisplatin through targeting MAPK1/GRB2.

Ovarian cancer has gradually become one of the commonest gynecological tumor in the world. Although various therapies have been developed by researchers, the chemoresistance of ovarian cancer is still a huge challenge. MircroRNAs (miRNAs) have been widely studied due to their anti-oncogenic functions. MiR-378a-3p has been reported to sensitize breast cancer cells to chemotherapy. Here, we hypothesized that miR-378a-3p is a potential chemosensitizer in ovarian cancer. Firstly, miR-378a-3p was uncovered to down-regulated in ovarian cancer tissues and cell lines through using qRT-PCR analysis and northern blot analysis. According to the result of Kaplan Meier analysis, low expression of miR-378a-3p is closely associated with unfavorable prognosis of ovarian cancer patients. Subsequently, gain-of function assays indicated that miR-378a-3p suppressed cell proliferation and promoted cell apoptosis. Moreover, miR-378a-3p was found to enhance cisplatin sensitivity of ovarian cancer cells. Mechanism investigations suggested that MAPK1 and GRB2 are two targets of miR-378a-3p. Finally, rescue assays revealed that MAPK1 and GRB2 can reverse the effects of miR-378a-3p on chemosensitivity of ovarian cancer cells. In conclusion, miR-378a-3p enhanced the sensitivity of ovarian cancer cells to cisplatin through targeting MAPK1 and GRB2.

Withapubesides A-D: natural inducible nitric oxide synthase (iNOS) inhibitors from Physalis pubescens.

Four new steroid glycosides, withapubesides A-D (1-4), were isolated from the stems of Physalis pubescens L. Their structures were elucidated primarily by NMR experiments. The absolute configurations of 1 and 2 were deduced by single-crystal X-ray diffraction and ECD data analysis, respectively. Compound 3 has shown significant inhibitory activity against LPS-induced nitric oxide production in RAW 264.7 macrophages with an IC50 value of 12.8 µM and moderate cytostatic activity against human carcinoma cells (786-O, C4-2B, 22Rvl, A375 and A375S2) with IC50 values in the range of 3.05-9.47 µM. Molecular docking simulation demonstrated that 3 is bound in the inducible nitric oxide synthase (iNOS) active site heme pocket very well, which suggests that 3 might be a candidate for the development of iNOS inhibitors.

A New Triterpenoid from the Aerial Parts of Agrimonia pilosa.

(1S,3R,17R,18R,19R,20R,22R)-1,3,19,22-tetrahydroxy-28-norurs-12-en-2-one (1), along with 5 known triterpenoids (2-6), were isolated from the aerial parts of Agrimonia pilosa Ledeb. Their structures were established based on extensive spectroscopic and MS analysis. The absolute configuration of compound 1 was deduced by circular dichroism (CD). Compound 1 was the first example of a 28-norursene backbone isolated from the genus Agrimonia. Compounds 2-6 were tested for anti-inflammatory activities against RAW 264.7 macrophages. A plausible biosynthetic pathway for compound 1 in A. pilosa was also proposed.