The ethnopharmacology, phytochemistry and pharmacology of the genus Hericium.

ETHNOPHARMACOLOGICAL RELEVANCE: Mushrooms in the genus Hericium are used as functional food and traditional medicines for a long history in East Asian countries such as China, India, Japan, and Korea. Some species of Hericium are called as monkey head mushroom (Houtougu) in China and Yamabushitake in Japan, which are traditionally considered as rare and precious health promoting food and medicinal materials for the treatment of dyspepsia, insomnia, chronic gastritis, and digestive tract tumors. THE AIM OF THE REVIEW: This review aims to summarize the ethnopharmacology and structural diversity of secondary metabolites from Hericium species, as well as the pharmacological activities of the crude extracts and pure compounds from Hericium species in recent years. MATERIALS AND METHODS: All the information was gathered by searching Scifinder, PubMed, Web of Science, ScienceDirect, Springer, Wiley, ACS, CNKI, Baidu Scholar, Google Scholar databases and other published materials (books and Ph.D. and M. Sc. Dissertations) using the keywords "Hericium", "Traditional uses", "Chemical composition", "Quality control" and "Pharmacological activity" (1971-May 2023). The species name was checked with https://www.mycobank.org/. RESULTS: The traditional uses of Hericium species were summarized, and 230 secondary metabolites from Hericium species were summarized and classified into six classes, mainly focusing on their chemical diversity, biosynthesis, biological activities. The modern pharmacological experiments in vivo or in vitro on their crude and fractionated extracts showed that the chemical components from Hericium species have a broad range of bioactivities, including neuroprotective, antimicrobial, anticancer, α-glucosidase inhibitory, antioxidant, and anti-inflammatory activities. CONCLUSIONS: The secondary metabolites discovered from Hericium species are highly structurally diverse, and they have the potential to be rich resources of bioactive fungal natural products. Moreover, the unveiled bioactivities of their crude extracts and pure compounds are closely related to critical human health concerns, and in-depth studies on the potential lead compounds, mechanism of pharmacological effects and pharmaceutical properties are clearly warranted.

Design, synthesis and evaluation of nitric oxide releasing derivatives of 2,4-diaminopyrimidine as novel FAK inhibitors for intervention of metastatic triple-negative breast cancer.

To search for novel medicines for intervention of triple-negative breast cancer (TNBC), a series of phenylsulfonyl furoxan-based 2,4-diaminopyrimidine derivatives (8a-t) were designed and synthesized based on blocking FAK-mediated signaling pathways through both kinase-dependent and -independent manners. The most active compound 8f not only significantly inhibited FAK kinase activity (IC50 = 27.44 nM), displayed potent inhibitory effects on the proliferation (IC50 = 0.126 µM), invasion and migration of MDA-MB-231 cells, superior to the most widely studied FAK inhibitor, TAE226, bearing 2,4-diaminopyrimidine, but also released high levels of NO, contributing to blockage of FAK mediated-signaling pathways by upregulating of p53 as well as suppressing the Y397 phosphorylation and its downstream effectors, including p-Akt, MMP-2, and MMP-9 via kinase-independent manner, leading to apoptosis induction and decrease of FAs and SFs in TNBC cells. Importantly, 8f inhibited the lung metastasis of TNBC in vivo. Together, 8f may serve as a promising candidate for the treatment of metastatic TNBC.

Discovery of novel chloropyramine-cinnamic acid hybrids as potential FAK inhibitors for intervention of metastatic triple-negative breast cancer.

To search for novel focal adhesion kinase (FAK) inhibitors for intervention of metastatic triple-negative breast cancer (TNBC), a series of hybrids 7a-s from chloropyramine and cinnamic acid analogs were designed, synthesized and biologically evaluated. The most active compound 7d could potently inhibit the proliferation, invasion and migration of TNBC cells in vitro. The docking analysis of 7d was performed to elucidate its possible binding modes to focal adhesion targeting (FAT) domain of FAK scaffold. Further mechanism studies indicated the ability of 7d in disrupting Y925 autophosphorylation of FAK, reducing formation of focal adhesions (FAs) and stress fibers (SFs) as well as inducing apoptosis of TNBC cells. Together, 7d is a novel FAK inhibitor to inhibit the essential nonkinase scaffolding function of FAK via binding FAT domain and may be worth studying further for intervention of TNBC.

Trichocladabiflavone A, a chalcone-flavonone type biflavonoid from Selaginella trichoclada Alsto.

A chalcone-flavonone type biflavonoid, trichocladabiflavone A (1), along with eight known biflavonoids (2-9) were isolated from the 70% EtOH extract of Selaginella trichoclada. Their structures were elucidated by extensive spectroscopic analyses. Compound 1 was the first chalcone-flavonone type biflavonoid reported in the genus Selaginella. Moreover, compound 1 exhibited moderate cytotoxicity against DU145, MCF-7 and PC3 human cancer cell lines.

Cytotoxic effects of the biflavonoids isolated from Selaginella trichoclada on MCF-7 cells and its potential mechanism.

A new biflavonoid, (2''S)-6''-methyl-2'',3''-dihydroochnaflavone (1), along with two known ochnaflavones (2, 3), four known amentoflavones (4-7) and two known robustaflavones (8, 9) were obtained from the 70% EtOH extract of Selaginella trichoclada. The chemical structures of isolated compounds were elucidated by extensive spectroscopic analyses. Overall, compounds 1-9 displayed moderate cytotoxic effects against human breast cancer MCF-7 cell lines. Among them, compounds 2 and 8 exhibited relatively strong cytotoxic effects against MCF-7 cells with an IC50 value of 7.7 and 6.9 µΜ, respectively. The results of RNA-sequencing and KEGG functional enrichment analysis showed that 8 could induce ferroptosis in MCF-7 cells by down-regulating the expression of ferroptosis-related genes including ACSL4, NOXO1, NOXA1, ACSL5, STEAP3, LPCAT3, ATG7 and TP53. Then 8 could inhibit the expression of ACSL4 proteins through molecule docking analysis, which showed a strong interaction of - 11.89 Kcal/mol binding energy. Those results indicate that 8 could be chemotherapy agents to fight drug resistance in breast cancer by down-regulating the expression level of ACSL4 proteins via ferroptosis, which needs to be further certified in vitro.

Biflavonoids from Selaginella doederleinii as Potential Antitumor Agents for Intervention of Non-Small Cell Lung Cancer.

Four new biflavonoids (1-4) were isolated from Selaginella doederleinii together with a known biflavonoid derivative (5). Their structures contained a rare linker of individual flavones to each other by direct C-3-O-C-4''' bonds, and were elucidated by extensive spectroscopic data, including HRESIMS, NMR and ECD data. All isolates significantly inhibited the proliferation of NSCLC cells (IC50 = 2.3-8.4 µM) with low toxicity to non-cancer MRC-5 cells, superior to the clinically used drug DDP. Furthermore, the most active compound 3 suppressed XIAP and survivin expression, promoted upregulation of caspase-3/cleaved-caspase-3, as well as induced cell apoptosis and cycle arrest in A549 cells. Together, our findings suggest that 3 may be worth studying further for intervention of NSCLC.

A novel Apigenin derivative suppresses renal cell carcinoma via directly inhibiting wild-type and mutant MET.

MET, the receptor of hepatocyte growth factor (HGF), is a driving factor in renal cell carcinoma (RCC) and also a proven drug target for cancer treatment. To improve the activity and to investigate the mechanisms of action of Apigenin (APG), novel derivatives of APG with improved properties were synthesized and their activities against Caki-1 human renal cancer cell line were evaluated. It was found that compound 15e exhibited excellent potency against the growth of multiple RCC cell lines including Caki-1, Caki-2 and ACHN and is superior to APG and Crizotinib. Subsequent investigations demonstrated that compound 15e can inhibit Caki-1 cell proliferation, migration and invasion. Mechanistically, 15e directly targeted the MET kinase domain, decreased its auto-phosphorylation at Y1234/Y1235 and inhibited its kinase activity and downstream signaling. Importantly, 15e had inhibitory activity against mutant MET V1238I and Y1248H which were resistant to approved MET inhibitors Cabozantinib, Crizotinib or Capmatinib. In vivo tumor graft study confirmed that 15e repressed RCC growth through inhibition of MET activation. These results indicate that compound 15e has the potential to be developed as a treatment for RCC, and especially against drug-resistant MET mutations.

Xylarinaps A-E, five pairs of naphthalenone derivatives with neuroprotective activities from Xylaria nigripes.

Five pairs of undescribed naphthalenone derivative enantiomers, xylarinaps A-E, including one pair of indole naphthalenones and four pairs of naphthalene-naphthalenone dimers, were isolated from the ethyl acetate extracts of the solid fermentation of Xylaria nigripes, which has been used as a traditional Chinese medicinal fungus for the treatment of insomnia, trauma, and depression. The structures of these enantiomers were elucidated based on comprehensive spectroscopic analysis, including NMR and HRESIMS. Their absolute configurations were assigned by the experimental and calculated ECD data. The neuroprotective effects of all the compounds against damage to PC12 cells by oxygen and glucose deprivation (OGD) were evaluated by an in vitro bioassay. The results revealed that xylarinaps A, B, D, and E significantly enhanced cell viability, decreased the levels of malondialdehyde (MDA), increased the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), as well as further markedly inhibiting apoptosis, which indicated that these results could be the mode of action of their neuroprotective effect.

Identification of a new natural biflavonoids against breast cancer cells induced ferroptosis via the mitochondrial pathway.

Breast cancer is one of the major malignant tumors in females, and currently, recurrence and metastasis are the main obstacles preventing effective breast cancer treatment. Biflavonoids of secondary metabolites from plants are excellent anticancer agents to fight sensitive and resistant breast cancer cell lines. In this study, six C-3'-C-6″ biflavonoids, including one new robustaflavone A (1, RF-A) and five known robustaflavone derivatives (2-6), were isolated from Selaginella trichoclada for the first time. We aimed to evaluate the inhibitory effects of compounds 1-6 against human breast cancer MCF-7 cells. Among the six compounds, RF-A showed the strongest activity, decreasing cell viability with an IC50 value of 11.89 µΜ. Furthermore, RF-A strikingly induced MCF-7 nonapoptotic cell death through ferroptosis by enhancing the expression of VDAC2 channels and reducing the expression of Nedd4 E3 ubiquitin ligase, leading to lipid peroxidation and ROS production. The results suggested that RF-A has potential as a novel breast cancer treatment through its regulation of the mitochondrial VDAC2 and Nedd4 pathways.

Two new biflavanoids from Selaginella trichoclada Alsto.

Two new robustaflavones, (±)-trichocladabiflavone A (1) and uncinatabiflavone E (2), along with seven known biflavanoids (3-9) were isolated from the 70% EtOH extract of Selaginella trichoclada. Their structures and absolute configurations were established by extensive spectroscopic and circular dichroism (CD) analyses. Compound 1 was resoluted into optically pure enantiomers (+)-1 and (-)-1 by chiral-phase HPLC. Moreover, compounds 1 and 2 exhibited moderate cytotoxicity against A549 and HepG2 human cancer cell lines.

New cytotoxic biflavones from Selaginella doederleinii.

Three new biflavones, apigenin-(3',8″)-chrysin (1), (2S)-2,3-Dihydroametoflavone 5,4'-dimethyl ether (2), and (2S)-5″,7″-Dihydroxy-2″-phenoxychromonyl-(4'″,3')-naringenin (3), together with seven known biflavones (4-10) were isolated from the 75% EtOH extract of Selaginella doederleinii. The structures of new compounds were established by application of spectroscopic methods, including 1D and 2D NMR, HRMS, and CD measurements. In addition, all new compounds were evaluated for their cytotoxic potential against three human cancer cell lines A549, MCF-7, and SMMC-7721 in vitro. Compound 2 exhibited potent cytotoxic activity with IC50 values ranging from 6.35 to 10.18 µM.

Eutyscoparols A-G, polyketide derivatives from endophytic fungus Eutypella scoparia SCBG-8.

The chemical investigation on Eutypella scoparia SCBG-8, an endophytic fungus isolated from the leaves of Leptospermum brachyandrum, has resulted in the isolation of six new phenolic compounds eutyscoparols A-F (1-6) and one new natural product eutyscoparol G (7). The structures and absolute configurations of compounds 1-7 were determined by extensive chemical and spectroscopic analyses such as single crystal X-ray diffractions. Moreover, all compounds were evaluated for their antibacterial and cytotoxic activities in vitro.

Two new anthraquinone derivatives and one new triarylbenzophenone analog from Selaginella tamariscina.

Two new anthraquinone derivatives, selaginones A (1) and B (2), and one new triarylbenzophenone analog, selagibenzophenone B (3), were isolated from Selaginella tamariscina (Beauv.) Spring. Their structures were established by 1D-, 2D-NMR and HR-ESI-MS data. Compounds 1 and 2 represent the uncommon examples of aryl substituted anthraquinone derivatives. Especially, compound 2 is a unique anthranone with exceptional structural feature, in which a p-hydroxyphenyl moiety is attached to the C-10 position. Compound 3 is the second naturally occurring triarylbenzophenone and showed moderate activity against SMCC-7721 and MHCC97-H cell lines with IC50 values of 39.8, 51.5 µM respectively.

Cytotoxic polyhydroxy serratene triterpenoids from Lycopodium complanatum.

Phytochemical investigation of the 70% aqueous EtOH extract of Lycopodium complanatum led to six new polyhydroxy serratene triterpenoids (serrat A-F, 1-6), along with a known analogue (7). Their structures and configurations were elucidated by data analysis of HRESIMS, 1D and 2D NMR, in combination with comparisons of reported experimental spectroscopic data. All the isolates were evaluated cytotoxic activities against HepG2 cells, MCF-7 cells and series human lung cancer cell lines A549, Calu-6, NCI-H441, NCI-H226 and NCI-H1975. The results indicated that certain compounds inhibited proliferation of human cancer cells. Moreover, all compounds possessed selective cytotoxic activities on MCF-7 cells. Further, possible biosynthesis pathways of these compounds were proposed.

Sinensiols B-G, six novel neolignans from Selaginella sinensis.

Six new neolignans, sinensiols B-G (1-6), together with three known analogues (7-9) were isolated from the whole plant of Selaginella sinensis. Their planar structures were established by comprehensive spectroscopic analyses including 1D, 2D NMR, IR and HRESIMS data. The absolute configurations of new compounds were elucidated by comparing their experimental CD spectra with known ones and using the reversed helicity rule for the 1Lb band ECD of dihydrobenzofuran neolignans. Sinensiols A-D (7, 1-3) belong to sesquilignan with a dimer of dihydrobenzo[b]furan moiety. The potential precursors of sinensiols A, B, D were also reported in this paper. In addition, all new compounds were screened for their cytotoxicity against A549 and HepG2 human cancer cell lines, and they didn't show inhibition on the growth of cancer cells.

Abietane diterpenoids from Lycopodium complanatum.

Five new abietane diterpenoids (complanatins A-E, 1-5) have been isolated from the club moss Lycopodium complanatum, along with two known abietane diterpenoids (xanthoperol and sugiol). Their structures were determined by comprehensive analysis of 1D, 2D NMR, CD and HRESIMS data. The cytotoxic effects of five compounds (1-4, 7) were evaluated in three human lung cancer cell lines (MSTO-211H, NCI-H2052 and NCI-H226). Compounds 3 and 4 exhibited cytotoxic activities against the three cell lines. In addition, a plausible biogenetic pathway of compounds 1-7 was proposed.

Two new compounds from the green peel of Juglans mandshurica.

A new cyclic diarylheptanoid (1) and a new flavone glucoside (2), along with seven known compounds, were isolated from the green peel of Juglans mandshurica. Their structures were elucidated based on extensive spectroscopic analyses. Moreover, the cytotoxicity against NCI-H460, A549, and K562 cancer cells of compounds 1-6 was evaluated. The results showed that compound 3 exhibited moderate inhibitory potency against the growth of three cell lines.

A new androstanoid metabolite from a soil fungus Curvularia borreriae strain HS-FG-237.

A new androstanoid metabolite, 4α-methyl-9α-methoxyandrosta-8,15-diene-3,17-dione (1), was isolated from a soil fungus Curvularia borreriae (Pleosporaceae) strain HS-FG-237. Its structure was determined by extensive spectroscopic and X-ray diffraction analyses. Compound 1 exhibited poor cytotoxicity toward HCT-116 cells by CCK-8 assay and weak anti-inflammatory activity in an ANA-1 murine macrophages model.

Selagintriflavonoids with BACE1 inhibitory activity from the fern Selaginella doederleinii.

Eight triflavonoids, selagintriflavonoids A-H, were isolated from whole herbs of Selaginella doederleinii. The structures of compounds selagintriflavonoids A-C consisted of three naringenin units, whereas those of selagintriflavonoids D-H consisted of apigenin and two naringenin moieties. The structures and absolute configurations of the compounds were determined based on NMR, HRESIMS, and experimental and calculated electronic circular dichroism (ECD) data. The ability of the compounds to inhibit ß-secretase (BACE1) was also evaluated. All compounds exhibited BACE1 inhibition with IC50 values ranging from 0.75 to 46.99 µM. Selagintriflavonoid A exhibited the strongest inhibition (0.75 µM) and is thus a promising compound for treating Alzheimer's disease.

Seladoeflavones A-F, six novel flavonoids from Selaginella doederleinii.

Six new flavonoids, seladoeflavones A-F (1-6), were isolated from the whole herbs of Selaginella doederleinii, together with one known flavonoid (7). Their structures including absolute configuration were characterized on the basis of extensive spectroscopic methods including NMR, HRMS, and electronic circular dichroism (ECD). All compounds consist of an aryl substituent at the C-3' position of naringenin or apigenin skeletons, and compounds 1 and 6 were identified as R configurations, which are uncommonly encountered in nature. A possible biosynthetic pathway was postulated. In addition, bioassay of the isolates revealed that 5-7 exhibited moderate cytotoxicity against three human cancer cell lines NCI-H460, A549, and K562 in vitro with IC50 values ranging from 8.17 to 18.66µM.