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.

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.

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.

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.

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.

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.

New isoindolinones from the fruiting bodies of Hericium erinaceum.

Hericium erinaceus is a well-known medicinal and edible mushroom, which is considered as a potential source to obtain antitumor candidates. In this work, five new isoindolinones, named erinaceolactams A-E (1-5), along with five known compounds (6-10), were isolated from 70% ethanol extract of the fruiting bodies of H. erinaceus. The structures of new compounds were validated by HRESIMS and 1D, 2D NMR. It's worth mentioning that there are two pairs of isomers included in the new compounds. Moreover, their cytotoxicity against metastatic human hepatocellular carcinoma cell lines SMMC-7221 and MHCC-97H were evaluated. The results showed that compounds 6 and 7 exhibited promising inhibitory potency against the growth of two cell lines.

Cyclooxygenase-2 inhibitors in lung cancer treatment: Bench to bed.

The most common and leading cause of cancer-related death in men is lung cancer. Despite the recent advances in chemotherapy, advanced lung cancer still remains incurable. For this, the understanding of molecular mechanisms involved in lung carcinogenesis is necessary to provide potentially effective therapeutic targets for the treatment of lung cancer, and thus the therapeutic limitations can be overcome. Cyclooxygenase-2 (COX-2) is an important inflammation factor that is reported to be up-regulated in different cancers. A number of COX-2 inhibitors have been developed, but most of them are restricted due to the different risk factors. Currently, the FDA has allowed celecoxib to remain on the market but advised physicians to apply this drug with alternative therapies or to use at a low dosage. Some other COX-2 inhibitors, such as, apricoxib and etoricoxib are under critical investigation currently. Celecoxib is being tested in clinical trials against lung cancer, as a single agent or in combination with other agents. Recent studies have suggested celecoxib as a feasible and clinically active regimen in the treatment of patients with lung cancer. However, more clinical trials are necessary for the better understanding of the role of selective COX-2 inhibitors in the prevention and treatment of lung cancer along with their assessment of toxicity. In this review, we have discussed the mechanism of actions of COX-2 in cancer progression and the therapeutic use of COX-2 inhibitors in the treatment of lung cancer with subsequent clinical studies and future management.

Unciflavones A-F, six novel flavonoids from Selaginella uncinata (Desv.) Spring.

Six new flavonoids, unciflavones A-F (1-6), have been isolated from medicinal plant Selaginella uncinata (Desv.) Spring. Their structures were established on the basis of extensive NMR analysis including 1D NMR ((1)H, (13)C and DEPT) and 2D NMR (COSY, HSQC, HMBC) experiments as well as HRESIMS analysis. All compounds possess exceptional structural features with an aryl substituent at the C-8 position, which are uncommonly encountered in natural resources and firstly reported in genus Selaginella.

Computational Prediction of DrugTarget Interactions Using Chemical, Biological, and Network Features.

Drugtarget interactions (DTIs) are central to current drug discovery processes. Efforts have been devoted to the development of methodology for predicting DTIs and drugtarget interaction networks. Most existing methods mainly focus on the application of information about drug or protein structure features. In the present work, we proposed a computational method for DTI prediction by combining the information from chemical, biological and network properties. The method was developed based on a learning algorithm-random forest (RF) combined with integrated features for predicting DTIs. Four classes of drugtarget interaction networks in humans involving enzymes, ion channels, G-protein-coupled receptors (GPCRs) and nuclear receptors, are independently used for establishing predictive models. The RF models gave prediction accuracy of 93.52 %, 94.84 %, 89.68 % and 84.72 % for four pharmaceutically useful datasets, respectively. The prediction ability of our approach is comparative to or even better than that of other DTI prediction methods. These comparative results demonstrated the relevance of the network topology as source of information for predicting DTIs. Further analysis confirmed that among our top ranked predictions of DTIs, several DTIs are supported by databases, while the others represent novel potential DTIs. We believe that our proposed approach can help to limit the search space of DTIs and provide a new way towards repositioning old drugs and identifying targets.

Inhibitory effect of selaginellin on high glucose-induced apoptosis in differentiated PC12 cells: role of NADPH oxidase and LOX-1.

Hyperglycemia clearly plays a key role in the development and progression of diabetic neuropathy. Hyperglycemia induces oxidative stress to generate reactive oxygen species in diabetic neurons resulting in neuronal damage and dysfunction. Apoptosis has been proposed as a possible mechanism for high glucose-induced neural dysfunction and neuronal cell injury. High glucose per se enhances lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) expression via activation of NADPH oxidase/reactive oxygen species pathway in endothelial cells. Selaginellin, a component extracted from Saussurea pulvinata (Hook. et Grev.) Maxim, was assessed for its ability to protect rat pheochromocytoma (PC12) cells against oxidative toxicity induced by high glucose. The differentiated PC12 cells were pretreated with various concentrations (10(-7), 3×10(-7) or 10(-6) M) of selaginellin for 1 h and then co-treated with selaginellin and D-glucose (75 mM) for 72 h. Selaginellin was shown to protect differentiated PC12 cells against high glucose toxicity, as determined by characteristic morphological features, cell viability, and apoptosis as evaluated by Hoechst 33,258 staining assay, annexin V-propidium iodide double staining assay and caspase-3 activity. In addition, the increase in NADPH oxidase activity, mRNA expression of NADPH oxidase subunits (NOX-1 and NOX-2) and LOX-1, and reactive oxygen species production induced by high glucose were significantly inhibited by selaginellin or by anti-LOX-1 antibody. The present study demonstrated that inhibitory effect of selaginellin on high glucose-induced cell injury and apoptosis in differentiated PC12 cells is related to inhibition of LOX-1/NADPH oxidase-reactive oxygen species/caspase-3 signaling pathway.

Protective effect of selaginellin on glutamate-induced cytotoxicity and apoptosis in differentiated PC12 cells.

L-glutamate plays a key role in neuronal cell death associated with many neurodegenerative conditions such as cerebral ischemia, hypoxia, Alzheimer's, Huntington's, and Parkinson's diseases. Selaginellin, a component extracted from Saussurea pulvinata (Hook.et Grev.) Maximo, was assessed for its ability to protect rat pheochromocytoma (PC12) cells against oxidative toxicity induced by glutamate. The differentiated PC12 cells were pretreated with various concentrations (10(-7), 3 x 10(-7), or 10(-6) M) of selaginellin for 1 h prior to exposure to L-glutamate. Selaginellin was shown to protect PC12 cells against glutamate toxicity, as determined by characteristic morphological features, lactate dehydrogenase release and cell viability, and apoptosis as evaluated by Hoechst 33342 staining assay and caspase-3 activity. In addition, the increase in levels of reactive oxygen species and decrease in klotho gene expression induced by glutamate were significantly reversed by selaginellin. Our study suggests that selaginellin has a neuroprotective effect against L-glutamate-induced neurotoxicity through mechanisms related to anti-oxidation and anti-apoptosis via scavenging reactive oxygen species and up-regulating the expression of klotho gene.

Asymmetric dimethylarginine induces TNF-alpha production via ROS/NF-kappaB dependent pathway in human monocytic cells and the inhibitory effect of reinioside C.

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, has been implicated in vascular inflammation through induction of reactive oxygen species (ROS) and proinflammatory genes in endothelial cells. However, relatively few attentions have been paid to the effect of ADMA on monocytes, one of the important cells throughout all stages of atherosclerosis. In the present study, we found that reinioside C, the main component extracted from Polygala fallax Hemsl., dose-dependently inhibited tumor necrosis factor-alpha (TNF-alpha) production induced by ADMA in monocytes, Furthermore, reinioside C attenuated ADMA-induced generation of reactive oxygen species and activation of nuclear factor-kappaB (NF-kappaB) activity in monocytes in a dose-dependent manner, this effect was inhibited by l-arginine (NOS substrate) and PDTC (inhibitor of NF-kappaB). These data suggest that reinioside C could attenuate the increase of TNF-alpha induced by exogenous ADMA through inhibition ROS/NF-kappaB pathway in monocytes.

Protective effects of rutaecarpine in cardiac anaphylactic injury is mediated by CGRP.

Previous investigations have indicated that rutaecarpine activates the vanilloid receptor to evoke calcitonin gene-related peptide (CGRP) release. CGRP has been shown to alleviate cardiac anaphylactic injury. In the present study, the effect of rutaecarpine on cardiac anaphylaxis was examined. Challenge of presensitized guinea-pig hearts with a specific antigen caused marked decreases in coronary flow (CF), left ventricular pressure (LVP) and its derivatives (+/- dp/dt(max)), an increase in heart rate, and prolongation of the P-R interval. Rutaecarpine (0.3 or 1 microM) markedly increased the content of calcitonin gene-related peptide (CGRP) in the coronary effluent and decreased the content of tumor necrosis factor-alpha (TNF-alpha) in myocardial tissues concomitantly with a significant improvement of cardiac function and alleviation of the extension of the P-R interval. Rutaecarpine at the concentration of 1 microM also inhibited the sinus tachycardia. The protective effects of rutaecarpine on cardiac anaphylaxis were abolished by CGRP (8-37), a selective CGRP receptor antagonist. These results suggest that the protective effects of rutaecarpine on cardiac anaphylactic injury are related to inhibition of TNF-alpha production by stimulation of CGRP release.

Demethylbellidifolin inhibits adhesion of monocytes to endothelial cells via reduction of tumor necrosis factor alpha and endogenous nitric oxide synthase inhibitor level.

The effect of demethylbellidifolin (DMB), a major compound of Swertia davidi Franch, on the adhesion of monocytes to endothelial cells induced by oxidized low-density lipoprotein (ox-LDL) was studied. Adhesion of monocytes to endothelial cells was induced by treatment with ox-LDL (100 microg/mL) for 48 h. Levels of tumor necrosis factor-alpha (TNF-alpha) and asymmetric dimethylarginine (ADMA, an endogenous inhibitor of NOS) in conditioned medium and the activity of dimethylarginine dimethylaminohydrolase (DDAH) in endothelial cells were measured. DMB (3 or 10 micromol/L) significantly inhibited the adhesion of monocytes to endothelial cells, attenuated an increase in levels of TNF-alpha and ADMA, and a decrease in the activity of DDAH by ox-LDL. The present results suggest that DMB inhibits the increased adhesion of monocytes to endothelial cells induced by ox-LDL, and that the effect of DMB is related to reduction of the ADMA concentration via reduction of TNF-alpha production in cultured endothelial cells treated with ox-LDL.