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.

A new abietane diterpenoid from Lycopodium complanatum.

A new abietane diterpenoid, 1ß, 11-epoxyabieta-12-hydroxy-8, 11, 13-triene-7-one (1), along with three known compounds (2-4), was isolated from Lycopodium complanatum. Their structures were confirmed by the analysis of 1D, 2D NMR and HRESIMS data, and comparison with previous spectral data. All compounds were tested for inhibitory activities against A549, HepG2 and MCF-7 tumor cell lines. [Figure: see text].

Two New C21 Steroidal Glycosides from Selaginella Braunii Baker.

Two new C21 steroidal glycosides, brapreguanes A and B (1-2) were isolated from 75 % aqueous ethanol extract of Selaginella braunii Baker. Their structures were established by spectroscopic analyses (1D/2D NMR spectra and HR-ESI-MS). The absolute configurations of sugar were elucidated by enzymatic hydrolysis and GCMS analysis. In addition, all compounds were evaluated for the anti-proliferative activities against various human cancer cells in vitro. Compounds exhibited no inhibition to various human cancer cells.

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.

Cytotoxic triterpenoid glycosides from leaves of Cyclocarya paliurus.

Three previously undescribed dammarane triterpenoid glycosides (1-3) along with five known analogues (4-8) were isolated from the leaves of Cyclocarya paliurus. Their structures and configurations were determined on the basis of comprehensive spectroscopic analyses, chemical hydrolysis and DFT GIAO 13C NMR calculation. All the isolates were evaluated cytotoxic activities against seven human cancer cell lines (MCF-7, PC-3, Du145, NCI-H1975, PC-9, SKVO3 and HepG2). Moreover, compound 4 showed a wide spectrum of cytotoxicity against human cancer cells with IC50 values ranging from 11.31 to 29.51 µM.

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.

Cyclocarioside O-Q, three novel seco-dammarane triterpenoid glycosides from the leaves of Cyclocarya paliurus.

Three previously undescribed seco-dammarane triterpenoid glycosides O-Q (1-3) along with two known compounds (4 and 5) were isolated and characterized from the leaves of Cyclocarya paliurus. Their structures were determined by comprehensive analysis of 1 D, 2 D NMR and HRESIMS data. Compounds 1-5 were evaluated for their inhibitory effects against human pancreatic tumor (ASPC-1), human gastric carcinoma (SNU5), liver hepatocellular carcinoma (HEPG-2) and human colon tumor (HCT116) cell lines. Among them cyclocarioside P (2) showed somewhat inhibitory activity towards those tumor cells.

Triterpenoids with antiproliferative activities from the twigs and leaves of Melaleuca linariifolia.

One new pentacyclic triterpenoid, urs-12,16-dien-3-one (1), together with twelve known pentacyclic triterpenoids (2‒13), were isolated from the twigs and leaves of Melaleuca linariifolia. Their structures were characterized by their 1D- and 2 D-NMR spectra analysis and mass spectra studies. Furthermore, all isolated compounds were tested the inhibitory effect on proliferation of six human cancer cell lines in vitro, including NCI-H441, NCI-H460, A549, SKOV3, hela, and caki-1 cells. Among them, compounds 3, 5, 7, 9, 12, and 13 exhibited moderate antiproliferative activities with IC50 values ranging from 3.85 to 33.31 µM.

Two New Abietane Diterpenoids from Selaginella moellendorffii Hieron.

Two new abietane diterpenoids, (3S,5R,10S)-3-hydroxy-12-O-demethyl-11-deoxy-19(4→3)-abeo-cryptojaponol, 12,19-dihydroxyabieta-8,11,13-trien-7-one, were isolated from Selaginella moellendorffii Hieron., together with one known abietane diterpenoid and four known tetracyclic triterpenoids. Their structures were characterized by their 1D- and 2D-NMR, ECD and mass spectral studies. All compounds were tested for their inhibitory effects on proliferation of three human cancer cells (human non-small-cell lung carcinoma cell lines A549 and human breast adenocarcinoma cell lines MDA-MB-231 and MCF-7) in vitro. Among them, three compounds displayed modest cytotoxic activities against the above three human cancer cell lines with IC50 values ranging from 16.28 to 40.67 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.

Metabolic profiling of the anti-tumor drug regorafenib in mice.

Regorafenib is a novel tyrosine kinase inhibitor, which has been approved by the United States Food and Drug Administration for the treatment of various tumors. The purpose of the present study was to describe the metabolic map of regorafenib, and investigate its effect on liver function. Mass spectrometry-based metabolomics approach integrated with multiple mass defect filter was used to determine the metabolites of regorafenib in vitro incubation mixtures (human liver microsomes and mouse liver microsomes), serum, urine and feces samples from mice treated with 80 mg/kg regorafenib. Eleven metabolites including four novel metabolites were identified in the present investigation. As halogen substituted drug, reductive defluorination and oxidative dechlorination metabolites of regorafenib were firstly report in present study. By screening using recombinant cytochrome P450 s (CYPs), CYP3A4 was found to be the principal isoforms involved in regorafenib metabolism. The predication with a molecular docking model confirmed that regorafenib had potential to interact with the active sites of CYP3A4, CYP3A5 and CYP2D6. Serum chemistry analysis revealed no evidence of hepatic damage from regorafenib exposure. This study provided a global view of regorafenib metabolism and its potential side-effects.

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.

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.

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.

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.