Xanthones from Gentianella acuta (Michx.) Hulten Ameliorate Colorectal Carcinoma via the PI3K/Akt/mTOR Signaling Pathway.

Colorectal carcinoma (CRC) is a kind of malignant tumor closely related to ulcerative colitis. Xanthone derivatives are one of the most promising therapeutic drugs which have been used in phase I/II clinical trials for cancer therapy. Our previous study indicated that the aerial parts of Gentianella acuta Michx. Hulten (GA) was rich in xanthones and showed a good therapeutic effect on ulcerative colitis in mice, suggesting that GA xanthones might have some therapeutic or ameliorative effects on CRC. However, no relevant study has been reported. This study aims to find the effective substances of GA inhibiting CRC and clarify their mechanism. Solvent extraction, column chromatographic separation, and LC-MS analysis were used to characterize the 70% EtOH extract of GA and track xanthones abundant fraction XF. MTT assay was carried out to clarify the activity of GA fractions; the result showed XF to be the main active fraction. LC-MS analysis was executed to characterize XF, 38 xanthones were identified. Network pharmacology prediction, in vitro activity screening, and molecular docking assay were combined to predict the potential mechanism; the PI3K/Akt/mTOR signaling pathway was found to be most important. Western blot assay on the main active xanthones 1,3,5-trihydroxyxanthone (16), 1,3,5,8-tetrahydroxyxanthone (17), 1,5,8-trihydroxy-3-methoxyxanthone (18), and 1,7-dihydroxy-3,8-dimethoxyxanthone (19) was used to verify the above prediction; these xanthones were found to inhibit the PI3K/Akt/mTOR signaling pathway, and 17 played a significant role among them through Western blot assay using PI3K/AKT/mTOR agonist IGF-1. In conclusion, this study demonstrated that GA xanthones were effective compounds of GA inhibiting CRC by regulating PI3K/Akt/mTOR signaling pathway transduction, at least. Importantly, 1,3,5,8-tetrahydroxyxanthone (17), the most abundant active xanthone in GA, might be a candidate drug for CRC.

NO Release Inhibitory Activity of Flavonoids from Aesculus Wilsonii Seeds through MAPK (P38), NF-κB, and STAT3 Cross-Talk Signaling Pathways.

The flavonoid constituents of Aesculus wilsonii, a source of the Chinese medicinal drug Suo Luo Zi, and their in vitro anti-inflammatory effects were investigated. Fifteen flavonoids, including aeswilflavonosides IA-IC (1:  - 3: ) and aeswilflavonosides IIA-IIE (4:  - 8: ), along with seven known derivatives were isolated from a seed extract. Their structures were elucidated by extensive spectroscopic methods, acid and alkaline hydrolysis, and calculated electronic circular dichroism spectra. Among them, compounds 3: and 7: possess a 5-[2-(carboxymethyl)-5-oxocyclopent-yl]pent-3-enylate or oleuropeoylate substituent, respectively, which are rarely reported in flavonoids. Compounds 2, 3, 7: , and 12:  - 15: were found to inhibit lipopolysaccharide-induced nitric oxide production in RAW 264.7 cell lines. In a mechanistic assay, the flavonoid glycosides 2, 3: , and 7: reduced the expressions of interleukin-6 and tumor necrosis factor-alpha induced by lipopolysaccharide. Further investigations suggest that 2: and 3: downregulated the protein expression of tumor necrosis factor-alpha and interleukin-6 by inhibiting the phosphorylation of p38. Compound 7: was found to reduce the production of inducible nitric oxide synthase, and the secretion of tumor necrosis factor-alpha and interleukin-6 through inhibiting nuclear factor kappa-light-chain-enhancer of activated B signaling pathway. Compounds 2, 3: , and 7: possessed moderate inhibitory activity on the expression of signal transducer and activator of transcription-3. Taken together, the data indicate that the flavonoid glycosides of A. wilsonii seeds exhibit nitric oxide release inhibitory activity through mitogen-activated protein kinase (p38), nuclear factor kappa-light-chain-enhancer of activated B, and signal transducer and activator of transcription-3 cross-talk signaling pathways.

Polyphenols from the Peels of Punica granatum L. and Their Bioactivity of Suppressing Lipopolysaccharide-Stimulated Inflammatory Cytokines and Mediators in RAW 264.7 Cells via Activating p38 MAPK and NF-κB Signaling Pathways.

Punica granatum L. (Punicaceae) is a popular fruit all over the world. Owning to its enriched polyphenols, P. granatum has been widely used in treating inflammation-related diseases, such as cardiovascular diseases and cancer. Twenty polyphenols, containing nine unreported ones, named punicagranins A-I (1-9), along with eleven known isolates (10-20), were obtained from the peels. Their detailed structures were elucidated based on UV, IR, NMR, MS, optical rotation, ECD analyses and chemical evidence. The potential anti-inflammatory activities of all polyphenols were examined on a lipopolysaccharide (LPS)-induced inflammatory macrophages model, which indicated that enhancing nitric oxide (NO) production in response to inflammation stimulated in RAW 264.7 cells was controlled by compounds 1, 3, 5-8, 10, 11, 14 and 16-20 in a concentration-dependent manner. The investigation of structure-activity relationships for tannins 6-8 and 12-20 suggested that HHDP, flavogallonyl and/or gallagyl were key groups for NO production inhibitory activity. Western blotting indicated that compounds 6-8 could down-regulate the phosphorylation levels of proteins p38 MAPK, IKKα/ß, IκBα and NF-κB p65 as well as inhibit the levels of inflammation-related cytokines and mediators, such as IL-6, TNF-α, iNOS and COX-2, at the concentration of 30 µM. In conclusion, polyphenols are proposed to be the potential anti-inflammatory active ingredients in P. granatum peels, and their molecular mechanism is likely related to the regulation of the p38 MAPK and NF-κB signaling pathways.

Structural characterization of phenolic constituents from the rhizome of Imperata cylindrica var. major and their anti-inflammatory activity.

As one of raw materials, the rhizome of Imperata cylindrica var. major (Nees) C.E. Hubb. is used in kinds of preparations curing inflammation related diseases, while its effective substances are not yet clear. In this paper, its chemical constituents and their anti-inflammatory activities were investigated. As results, ten compounds, named as imperphenoside A (1), imperphenols B (2) and C (3), imperphenosides D-F (4-6), and imperlignanosides A-D (7-10), along with previously reported thirty-seven known ones (11-47) were obtained from it. Their structures were ascertained basing on the extensive spectroscopic methods and electronic circular dichroism data analysis. Meanwhile, compounds 4, 11, 12, 24, 27, 31, 32, 37, 43, 45, and 47 exhibited nitric oxide inhibitory effects in concentration dependent at 3, 10, and 30 µM on lipopolysaccharides induced RAW 264.7 cells. Moreover, the western blot analysis indicated that compounds 4, 11, 43, and 47 could restrain the phosphorylation of nuclear factor kappa-B kinase to down-regulate the protein expression of inflammatory cytokines such as inducible nitric oxide synthase, interleukin-6 and tumor necrosis factor-α. In conclusion, they might play the anti-inflammatory effects through regulating NF-κB signaling pathway.

Effects of Benzophenones from Mango Leaves on Lipid Metabolism.

The mango tree (Mangifera indica L.) is a tropical, perennial, woody evergreen plant belonging to the Anacardiaceae. In traditional medicine, dried mango tree leaves were considered useful in treating diabetes and respiratory infections. In this paper, we review the phytochemical research on mango leaves and the mechanisms of benzophenones in lipid metabolism regulation. Thirty-six benzophenones have been isolated from mango leaves; among them, mangiferin is the major compound. Structure-activity relationships of benzophenones in lipid accumulation and the mechanisms of action of mangiferin in lipid metabolism are summarized. After oral administration, mangiferin is partly converted to its active metabolite, northyariol, which contributes to the activation of sirtuin-1 and liver kinase B1 and increases the intracellular AMP level and AMP/adenosine triphosphate ratio, followed by AMP-activated protein kinase phosphorylation, leading to increased phosphorylation of sterol regulatory element-binding protein-1c. Current evidence supports ethnopharmacological uses of mango leaves in diabetes and points toward potential future applications.

Relationship between Structural Characteristics and Plant Sources along with Pharmacology Research of Quassinoids.

Quassinoids, one kind of triterpenoids with multiple bioactivities such as anti-cancer, anti-malarial, anti-oxidative, anti-microbial, anti-diabetic, anti-viral, and anti-inflammatory effects, have drawn much attention in recent years. Between 2004 and 2018, the structural characteristics and plant sources of 190 quassinoids were reported. Herein, the structure-activity relationships (SARs) of quassinoids along with the anti-cancer mechanisms of four representative quassinoids, eurycomanone, bruceine D, dehydrobruceine B, and brusatol are discussed. This review might be useful for further research and development of quassinoids.

Anti-inflammatory steroids from the rhizomes of Dioscorea septemloba Thunb.

Seven new steroid glycosides, dioscorosides A1 (1), A2 (2), B1 (3), B2 (4), C1 (5), C2 (6), and D (7), together with 22 known ones (8-29) were isolated from the rhizomes of Dioscorea septemloba, their structures were elucidated by chemical and spectroscopic methods. All isolates were evaluated for in vitro anti-inflammatory potential using LPS-stimulated RAW 264.7 murine macrophages. Among them, spirostane glycosides 18 and 21-24 exhibited significant inhibition of nitrite production. Moreover, the structure-activity relationship was summarized.