Recent advances in gut microbiota-associated natural products: structures, bioactivities, and mechanisms.

Covering: 2014 to June 2022The gut microbiota has attracted increasing attention from researchers due to its critical role in regulating human physiology and pathophysiology. Natural products (NPs) produced or transformed by gut microbes are key signalling mediators for a variety of physiological functions. On the other hand, NPs from ethnomedicines have also been found to generate health benefits through modulation of the gut microbiota. In this highlight, we review the most recent studies related to gut microbiota-derived NPs and bioactive NPs that regulate physiological and pathological processes via gut microbiota-associated mechanisms. We also outline the strategies for the discovery of gut microbiota-derived NPs and the methodologies of how to elucidate the crosstalk between bioactive NPs and the gut microbiota.

Lanostane Triterpenoids with PTP1B Inhibitory and Glucose-Uptake Stimulatory Activities from Mushroom Fomitopsis pinicola Collected in North America.

A chemical investigation on the fruiting bodies of Fomitopsis pinicola led to the isolation and identification of 28 lanostane triterpenoids including 11 new compounds (1-11) and 17 known analogues (12-28). Their structures were elucidated by extensive one-dimensional NMR, two-dimensional NMR, and MS spectra. All isolates were tested for their anti-inflammatory activity, protein tyrosine phosphatase 1B (PTP1B) inhibitory activity in vitro, and effect on glucose uptake in insulin-resistant HepG2 cells. Compounds 1, 4, 22, 23, and 27 inhibited the nitric oxide released from the LPS-induced RAW 264.7 cell assay with IC50 values in the range of 21.4-27.2 µM. Compounds 18, 22, 23, and 28 showed strong PTP1B inhibitory activity with IC50 values in the range of 20.5-29.9 µM, comparable to that of the positive control of oleanolic acid (15.0 µM). Compounds 18 and 22 were confirmed to be good competitive inhibitors of PTP1B by kinetic analysis. In addition, compounds 18, 22, and 28 were found to stimulate glucose uptake in the insulin-resistant HepG2 cells in the dose from 6.25 to 100 µM. These findings indicated the potential of F. pinicola in the development of functional food or medicine for the prevention and treatment of diabetes.

Identification and α-Glucosidase Inhibitory Activity of Meroterpenoids from Hericium erinaceus.

Hericium erinaceus is a very popular edible and medicinal mushroom used for the treatment of enervation and gastrointestinal diseases in Eastern Asia. Chemical investigation on the fruiting body of Hericium erinaceus led to the isolation of 4 new (1:  - 4: ) and 10 known meroterpenoids (5:  - 14: ). The structures of new compounds were determined via analysis of NMR and MS data in combination with chemical derivatization. The inhibitory activities of 1:  - 14: against α-glucosidase were evaluated using p-nitrophenyl-α-D-glucopyranoside, sucrose, or maltose as substrate. Compounds 6, 9, 11:  - 13: were demonstrated to show the α-glucosidase inhibitory activities. This work confirms the potential of H. erinaceus in the treatment of diabetes.

Lanostane Triterpenoids with Glucose-Uptake-Stimulatory Activity from Peels of the Cultivated Edible Mushroom Wolfiporia cocos.

A chemical study on the peels of the cultivated edible mushroom Wolfiporia cocos led to the isolation and identification of 47 lanostane triterpenoids including 16 new compounds (1-16). The structures of the new compounds were determined by analysis of the NMR, MS, and electronic circular dichroism (ECD) data. Compounds 1 and 2 represent new members of the family of 4,5-secolanostane triterpenes. Compound 3 is a new aromatic lanostane triterpene with an unusual methyl rearrangement from C-10 to C-6. The absolute configurations of 1 and 8 were assigned by ECD spectra calculation. All compounds were evaluated for cytotoxicity (K562, SW480, and HepG2) and glucose-uptake-stimulating effects. Compounds 23, 25, 29, and 31 showed weak inhibition on the K562 cells with IC50 in the range of 25.7 to 68.2 µM, respectively. Compounds 21, 28, and 30 increased the glucose uptake in 3T3-L1 cells by 25%, 14%, and 50% at 5 µM, respectively. In addition, compounds 14, 23, 29, 35, and 43 showed insulin-sensitizing activity by increasing the insulin-stimulated glucose uptake at 2.5 µM in 3T3-L1 adipocytes. A preliminary structure-activity relationship analysis indicates that the 6/6/6/5 ring skeleton and the double bond between C-8 and C-9 are beneficial for the glucose-uptake-stimulating and insulin-sensitizing activities. Furthermore, the alkaline-insoluble fraction mainly containing compounds 22, 24, 28, and 31 were confirmed to have hypoglycemic and hypolipidemic activity on high-fat-diet-induced obese mice. This work confirms the potential of the peels' extracts of W. cocos as a functional food or dietary supplements.

Eight new triterpenoids with inhibitory activity against HMG-CoA reductase from the medical mushroom Ganoderma leucocontextum collected in Tibetan plateau.

Eight new triterpenoids, ganoleucoins T-Z(1-3, 5-8), and AA (9), together with eleven known triterpenes were isolated and identified from the wild fruiting bodies of the medicinal mushroom Ganoderma leucocontextum. The structures of new compounds were determined on the basis of NMR and MS spectral analysis. The inhibitory effects of 1-9 on HMG-CoA reductase were tested in vitro. Compounds 1, 7 and 8 showed significant HMG-CoA reductase inhibition with IC50 values of 10.2, 9.72 and 8.68 µM, respectively. The other isolated compounds presented relatively weak inhibitory activity with IC50 values >100 µM. Preliminary structure-activity relationship analysis showed that the HMG moiety in 7 and 8 contributed greatly to their inhibitory activity against HMG-CoA reductase. This work further demonstrates the mushroom G. leucocontextum to be valuable herbal medicine that deserves deep investigation.

Diketopiperazines and 2H-pyran-2-ones with antioxidant activity from the rice fermented with Aspergillus luchuensis.

Aspergillus luchuensis is widely used as a starter of saccharification in the koji industry, but no secondary metabolites have been reported from this fungus. Herein, we report the isolation and identification of four new diketopiperazine derivatives (1-4), one new methyl 4-(3-acetyl-2, 6-dihydroxyphenyl)-2-methoxybutanoate (5), and six known compounds (6-11) from the rice koji of A. luchuensis. The structures of 1-5 were determined by extensive spectral analysis including 1D and 2D NMR, HRESIMS, and CD, and ECD calculation. In antioxidant assays, compound 10 displayed moderate DPPH scavenging activity with an EC50 value of 60.8µM; compounds 1-4, 10 and 11 showed reducing ability with EC50 values ranging from 8.73 to 176.39µM. Compounds 1-11 showed no cytotoxicity against cell lines A549, K562, ASPC, and H460 at 200µM. Our current reports support the safety of A. luchuensis in food chemistry and confirm this fungus to be a new source of natural antioxidants.

New sesquiterpenoids from the edible mushroom Pleurotus cystidiosus and their inhibitory activity against α-glucosidase and PTP1B.

Nine new sesquiterpenoids, clitocybulol derivatives, clitocybulols G-O (1-9) and three known sesquiterpenoids, clitocybulols C-E (10-12), were isolated from the solid culture of the edible fungus Pleurotus cystidiosus. The structures of compounds 1-12 were determined by spectroscopic methods. The absolute configurations of compounds 1-9 were assigned via the circular dichroism (CD) data analysis. Compounds 1, 6 and 10 showed moderate inhibitory activity against protein tyrosine phosphatase-1B (PTP1B) with IC50 values of 49.5, 38.1 and 36.0µM, respectively.

Sesquiterpenoids with PTP1B Inhibitory Activity and Cytotoxicity from the Edible Mushroom Pleurotus citrinopileatus.

One new perhydrobenzannulated 5,5-spiroketal sesquiterpene, pleurospiroketal F (1), as well as six new modified bisabolene sesquiterpenes pleurotins A-F (2-7) were isolated from solid-state fermentation of Pleurotus citrinopileatus. The structures of compounds 1-7 were determined by NMR and MS spectroscopic analysis. The absolute configuration of 1 was determined by X-ray diffraction analysis, while the absolute configurations of 3-7 were assigned using the in situ dimolybdenum circular dichroism method and circular dichroism data comparison. Protein tyrosine phosphatase 1B plays a crucial role as a negative regulator of the insulin-dependent signal cascades. Therefore, the protein tyrosine phosphatase 1B inhibitor can be used for treating type 2 diabetes mellitus and obesity. Compounds 2 and 6 showed moderate inhibitory effects on protein tyrosine phosphatase 1B with IC50 s of 32.1 µM and 30.5 µM, respectively. The kinetic study confirmed compound 2 to be a noncompetitive inhibitor. Compounds 1-7 did not show cytotoxic activity against cancer cell lines (IC50 > 50 µM).

Lanostane Triterpenes from the Tibetan Medicinal Mushroom Ganoderma leucocontextum and Their Inhibitory Effects on HMG-CoA Reductase and α-Glucosidase.

Sixteen new lanostane triterpenes, ganoleucoins A-P (1-16), together with 10 known tripterpenes (17-26), were isolated from the cultivated fruiting bodies of Ganoderma leucocontextum, a new member of the Ganoderma lucidum complex. The structures of the new compounds were elucidated by extensive spectroscopic analysis and chemical transformation. The inhibitory effects of 1-26 on HMG-CoA reductase and α-glucosidase were tested in vitro. Compounds 1, 3, 6, 10-14, 17, 18, 23, 25, and 26 showed much stronger inhibitory activity against HMG-CoA reductase than the positive control atorvastatin. Compounds 13, 14, and 16 presented potent inhibitory activity against α-glucosidase from yeast with IC50 values of 13.6, 2.5, and 5.9 µM, respectively. In addition, the cytotoxicity of 1-26 was evaluated against the K562 and PC-3 cell lines by the MTT assay. Compounds 1, 2, 6, 7, 10, 12, 16, 18, and 25 exhibited cytotoxicity against K562 cells with IC50 values in the range 10-20 µM. Paclitaxel was used as the positive control with an IC50 value of 0.9 µM. This is the first report of secondary metabolites from this medicinal mushroom.

New α-glucosidase inhibitors with p-terphenyl skeleton from the mushroom Hydnellum concrescens.

The purpose of this study is to elucidate the bioactive components responsible for the the α-glucosidase inhibitory activity detected in the EtOAc extract of the mushroom Hydnellum concrescens. Two new p-terphenyl derivatives, concrescenins A (1) and B (2), in along with six known compounds thelephantins L (3), I (4), J (5), K (6), dihydroauran-tiacin dibenzoate (7), and curtisian A (8) were isolated from the fruiting bodies of H. concrescens. Their chemical structures were elucidated by NMR experiments. Compounds 1-4 and 6-8 showed the inhibitory activity against α-glucosidase with the IC50 of 0.99, 3.11, 4.53, 18.77, 2.98, 5.16, and 8.34 µM, respectively. Kinetic analysis of α-glucosidase indicated that compounds 1 and 2 inhibited the activity of α-glucosidase in a noncompetitive fashion with a Ki value of 0.02 and 0.21 µM, respectively. In antioxidant evaluation, compounds 1 and 4 showed weak DPPH scavenging activity (EC50=82.50 and 161.75 µM) and weak reducing ability (EC50=193.57 and 152.94 µM). The current research supports the potential use of mushroom-derived p-terphenyl derivatives for the treatment of diabetes.

A new benzoquinone and a new benzofuran from the edible mushroom Neolentinus lepideus and their inhibitory activity in NO production inhibition assay.

The fruiting bodies or mycelia of mushrooms have been used as food and food-flavoring material for centuries due to their nutritional and medicinal value and the diversity of their bioactive components. The present research is the first to investigate the bioactive secondary metabolites from the solid culture of the edible mushroom Neolentinus lepideus. Two new secondary metabolites, 5-methoxyisobenzofuran-4,7(1H,3H)-dione (1) and 1,3-dihydroisobenzofuran-4,6-diol (2), as well as seven known compounds including one benzoquinone derivative (3) and six cinnamic acid derivatives (4-9) were obtained. Their structures were established by means of spectroscopic methods, including 1D and 2D NMR. The bioactivity on the nitric oxide production in lipopolysaccharide-induced macrophages was evaluated for all metabolites (1-9) isolated. Compound 1 showed strong NO inhibitory activity with the IC50 value of 6.2 µM. Compound 2 displayed moderate NO inhibitory activity with the IC50 value of 88.8 µM. In the DPPH scavenging assay, compound 2 displayed antioxidant activity with IC50 of 68.6 µM. The discovery of new NO production inhibitors from N. lepideus expands its usage as a functional food.

Isolation and identification of a new anti-inflammatory cyathane diterpenoid from the medicinal fungus Cyathus hookeri Berk.

A new cyathane diterpene, named as cyathin I (1), as well as two known cyathane diterpenes (12R)-11a,14a-epoxy-13a,14b,15-trihydroxycyath-3-ene (2) and erinacine I (3), were isolated from the liquid culture of Cyathus hookeri Berk. Their structures were elucidated on the basis of extensive spectroscopic analysis. Compounds 1-3 showed inhibition against nitric oxide production in macrophages with an IC50 value of 15.5, 52.3, and 16.8 µM, respectively.

Anti-inflammatory and cytotoxic cyathane diterpenoids from the medicinal fungus Cyathus africanus.

Five novel cyathane diterpenes, cyathins D-H (1-5), as well as three known diterpenes, neosarcodonin O (6), cyathatriol (7),and 11-O-acetylcyathatriol (8), were isolated from the solid culture of Cyathus africanus. The structures of the new compounds were elucidated by spectroscopic methods. The absolute configurations of compounds 2 and 8 were determined by single-crystal X-ray crystallographic analysis, whereas the absolute configuration of C-14 in 1 was determined via the circular dichroism data of the [Rh(2)(OCOCF(3))(4)] complex. Compounds 3, 5, 6, 8, and 9 showed potent inhibition against nitric oxide production in lipopolysaccaride-activated macrophages with an IC(50) value of 2.57, 1.45, 12.0, 10.73, and 9.45µM, respectively. Compounds 6 and 8 showed strong cytotoxicity against Hela and K562 cell lines with the IC(50) value less than 10µM.