A systematic review on antimicrobial activities of green synthesised Selaginella silver nanoparticles.

BACKGROUND: Metallic nanoparticles from different natural sources exhibit superior therapeutic options as compared to the conventional methods. Selaginella species have attracted special attention of researchers worldwide due to the presence of bioactive molecules such as flavonoids, biflavonoids, triterpenes, steroids, saponins, tannins and other secondary metabolites that exhibit antimicrobial, antiplasmodial, anticancer and anti-inflammatory activities. Environment friendly green synthesised silver nanoparticles from Selaginella species provide viable, safe and efficient treatment against different fungal pathogens. OBJECTIVE: This systematic review aims to summarise the literature pertaining to superior antifungal ability of green synthesised silver nanoparticles using plant extracts of Selaginella spp. in comparison to both aqueous and ethanolic raw plant extracts by electronically collecting articles from databases. METHODS: The recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis were taken into consideration while preparing this review. The titles and abstracts of the collected data were stored in Endnote20 based on the inclusion and exclusion criteria. The search strategy included literature from established sources like PubMed, Google Scholar and Retrieval System Online using subject descriptors. RESULTS: The search yielded 60 articles with unique hits. After removal of duplications, 46 articles were identified, 40 were assessed and only seven articles were chosen and included in this review based on our eligibility criteria. CONCLUSION: The physicochemical and preliminary phytochemical investigations of Selaginella suggest higher drug potency of nanoparticles synthesised from plant extract against different diseases as compared to aqueous and ethanolic plant extracts. The study holds great promise as the synthesis of nanoparticles involves low energy consumption, minimal technology and least toxic effects.

Three New Benzophenone Derivatives from Selaginella tamariscina.

Six compounds including three new benzophenones, selagibenzophenones D-F (1-3), two known selaginellins (4-5) and one known flavonoid (6), were isolated from Selaginella tamariscina. The structures of new compounds were established by 1D-, 2D-NMR and HR-ESI-MS spectral analyses. Compound 1 represents the second example of diarylbenzophenone from natural sources. Compound 2 possesses an unusual biphenyl-bisbenzophenone structure. Their cytotoxicity against human hepatocellular carcinoma HepG2 and SMCC-7721 cells and inhibitory activities on lipopolysaccharide-induced nitric oxide (NO) production in RAW264.7 cells were evaluated. Compound 2 showed moderate inhibitory activity against HepG2 and SMCC-7721 cells, and compounds 4 and 5 showed moderate inhibitory activity to HepG2 cells. Compounds 2 and 5 also exhibited inhibitory activities on lipopolysaccharide-induced nitric oxide (NO) production.

Advances in the Anti-Tumor Activity of Biflavonoids in Selaginella.

Despite the many strategies employed to slow the spread of cancer, the development of new anti-tumor drugs and the minimization of side effects have been major research hotspots in the anti-tumor field. Natural drugs are a huge treasure trove of drug development, and they have been widely used in the clinic as anti-tumor drugs. Selaginella species in the family Selaginellaceae are widely distributed worldwide, and they have been well-documented in clinical practice for the prevention and treatment of cancer. Biflavonoids are the main active ingredients in Selaginella, and they have good biological and anti-tumor activities, which warrant extensive research. The promise of biflavonoids from Selaginella (SFB) in the field of cancer therapy is being realized thanks to new research that offers insights into the multi-targeting therapeutic mechanisms and key signaling pathways. The pharmacological effects of SFB against various cancers in vitro and in vivo are reviewed in this review. In addition, the types and characteristics of biflavonoid structures are described in detail; we also provide a brief summary of the efforts to develop drug delivery systems or combinations to enhance the bioavailability of SFB monomers. In conclusion, SFB species have great potential to be developed as adjuvant or even primary therapeutic agents for cancer, with promising applications.

Brasesquilignan A-E, Five New Furofurans Lignans from Selaginella braunii Baker.

Five new furofurans lignans, Brasesquilignan A-E (1-5), were isolated from the aqueous ethanol extract of Selaginella braunii Baker. Their structures were elucidated by extensive analysis of NMR and HRESIMS data. Their absolute configurations were determined by CD spectra, enzymatic hydrolysis, and GCMS analysis. Furthermore, all compounds were evaluated for anti-proliferative activities against various human cancer cellsin vitro. Compounds 2 and 3 exhibited weak inhibitorypotency against five human cancer cells.

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.

Lactate Dehydrogenase-Inhibitors Isolated from Ethyl Acetate Extract of Selaginella doederleinii by Using a Rapid Screening Method with Enzyme-Immobilized Magnetic Nanoparticles.

BACKGROUND: Lactate dehydrogenase (LDH) is one of the important enzyme systems for glycolysis and gluconeogenesis. It can catalyze the reduction and oxidation reaction between propionic acid and L-lactic acid, which is usually overexpressed in cancer cells. Therefore, inhibiting the activity of LDH is a promising way for the treatment of cancer. In this study, an effective method based on ligand fishing and ultra performance liquid chromatography-mass spectrum (UPLC-MS) was established to screen and identify active ingredients from Selaginella doederleinii with potential inhibitory activity for LDH. METHODS: Firstly, LDH was immobilized on the magnetic nanoparticles (MNPs), three immobilization parameters including LDH concentration, immobilization time and pH were optimized by single factor and response surface methodology for maximum (max) immobilization yield. Then, a mixed model of galloflavin and chlorogenic acid (inhibitors and non-inhibitors of LDH) was used to verify the specificity of immobilized LDH ligand fishing, and the conditions of ligand fishing were further optimized. Finally, combined with UPLC-MS, immobilized LDH was used to simultaneously screen and identify potential LDH inhibitors from the ethyl acetate extract of Selaginella doederleinii. RESULTS: The prepared fishing material was comprehensively characterized by scanning electron microscopy (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD) and fourier transform infrared spectrometer (FT-IR). The optimal immobilization conditions were obtained as LDH concentration of 0.7 mg/mL, pH value of 4.5, and immobilization time of 3.5 h. Under these conditions, the max immobilization yield was (3.79 ± 0.08) × 103 U/g. The specificity analysis showed that immobilized LDH could recognize and capture ligands, and the optimal ligand fishing conditions included that the incubation time was 30 min, the elution time was 20 min, and the concentration of methanol as eluent was 80%. Finally, two LDH inhibitors, amentoflavone and robustaflavone, were screened by immobilized LDH from the ethyl acetate extract of Selaginella doederleinii. CONCLUSIONS: The study provided a meaningful evidence for discovering the bioactive constituents in ethyl acetate extract of Selaginella doederleinii related to cancer treatment, and this ligand fishing method was feasible for screening enzyme inhibitors from similar complex mixtures.

Siamenflavones A-C, three undescribed biflavonoids from Selaginella siamensis Hieron. and biflavonoids from spike mosses as EGFR inhibitor.

Three undescribed biflavonoids (BFVs), siamenflavones A-C along with twelve BFVs were isolated from Selaginella siamensis Hieron. and Selaginella bryopteris (L.) Baker (Selaginellaceae). The chemical structures of undescribed compounds were established through comprehensive spectroscopic techniques, chemical correlations, and X-ray crystallography. The ten isolated BFVs, siamenflavones A-C, delicaflavone, chrysocauflavone, robustaflavone, robustaflavone-4-methylether, amentoflavone, tetrahydro-amentoflavone, and sciadopitysin were evaluated for the antiproliferative effects against four human cancer cell lines A549, H1975, HepG2 and T47D. Delicaflavone and robustaflavone 4'-methylether exerted strong effects on the four human cancer cell lines. Siamenflavone B, delicaflavone and robustaflavone 4'-methylether showed potent inhibitory activities against wild-type EGFR. The inhibition of the compounds was further supported by molecular docking and predictive intermolecular interactions. Molecular dynamics simulation studies of siamenflavone B and robustaflavone-4'-methylether complexed to EGFR-TK further supported inhibition of the compounds to the ATP binding site. Finally, analysis of pharmacokinetic and electronic properties using density-functional theory and known drug index calculations suggest that the compounds are pharmaceutically compatible for drug administration.

A new cyclic peptide from Selaginella tamariscina.

A new cyclic peptide selapeptin B (1), together with one known nor-lignan glycoside moellenoside C (2), was isolated from Selaginella tamariscina. The structures of 1 and 2 were elucidated on the basis of chemical and spectral analysis, including 1D, 2D NMR analyses and HRESIMS. Two compounds were evaluated for cytotoxic activities against B16F10, MDA-MB-231, and MDA-MB-468 cell lines by MTT assay. Compound 1 showed the potent activity against B16F10 melanoma cell lines.

Synthesis, biological evaluation, pharmacokinetic studies and molecular docking of 4'''-acetyl-delicaflavone as antitumor agents.

Structural modification of natural products is the effective option to improve their pharmacological effects and drug properties. DLF is a lead compound of antitumor drug, which is a broad-spectrum, low toxic and high-efficient component isolated from Selaginella doederleinii Hieron by our research group. Here, we report the structural modification method of this component, and find that the acetylated product of C4'''- OH (C4'''-acetyl-delicaflavone, 4'''ADLF) has better inhibitory effect on the selected cancer cell lines, including, lung, liver, colon and cervical cancer cell lines. Since the increased water solubility of 4'''ADLF may lead to higher absorption rate and activity, we evaluate the pharmacodynamics in vitro and in vivo, and the pharmacokinetic of 4'''ADLF. It shows that 4'''ADLF inhibit the proliferation and induce cycle arrest in tumor cells, and had better anticancer activity and bioavailability than DLF.

Two new flavonol glycosides from Selaginella tamariscina.

Two new flavonol glycosides 3,5,7-trimethoxyflavone-4'-O-[5'''-O-p-coumaroyl-ß-D-apiofuranoyl-(1'''→2'')-ß-D-glucopyranoside] (1) and 3,5,7-trimethoxyflavone -4'-O-ß-D-glucopyranoside (2) were isolated from Selaginella tamariscina. The structures of 1 and 2 were elucidated on the basis of chemical and spectral analysis, including 1D, 2D NMR analyses and HRESIMS spectrometry. Two compounds were evaluated for cytotoxic activities against A-375, MCF-7, MDA-MB-231 and MDA-MB-468 cell lines by MTT assay. Unfortunately, two compounds displayed no cytotoxic activities.

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.

Disclosing targets and pharmacological mechanisms of total bioflavonoids extracted from Selaginella doederleinii against non-small cell lung cancer by combination of network pharmacology and proteomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Previously, the total bioflavonoids extract from Selaginella doederleinii (SDTBE) presented favorable in vitro and in vivo activities against non-small cell lung cancer (NSCLC), hinting at its medicinal potential. However, up to nowadays, targets and integrative action mechanisms of SDTBE are still not very clear, which presents an obstacle to the development of herbal medicine. AIM OF THE STUDY: The present study aimed to disclose the potential targets and integrative action mechanism of SDTBE against NSCLC. MATERIALS AND METHODS: A system pharmacology-based strategy including target fishing, network pharmacology analysis and molecular docking were applied to predict the potential targets and pathways for the seven main active ingredients in SDTBE. A proteomics study was subsequently performed for validating the affected pathways and possible targets. Western blot assay, mouse xenograft tumor model and immunofluorescence assays were used to further confirm the key targets and integrative action mechanisms of SDTBE against NSCLC. RESULTS: By system pharmacology, it was inferred that SDTBE could mainly act on mitogen-activated protein kinase (MAPK) and PI3K-AKT signaling pathways by targeting epidermal growth factor receptor (EGFR), protein kinase B (AKT) and mitogen-activated or extracellular signal-regulated protein kinase (MEK), which was validated by proteomics results, and further confirmed in vitro and in vivo by Western blot and immunofluorescence assays. CONCLUSION: SDTBE targeting multi-targets including EGFR, AKT and MEK could exert its anti-NSCLC effect mainly via MAPK and PI3K-AKT signaling pathways.

A new triarylindanone and a new isobenzofuranone derivative from Selaginella tamariscina.

A new triarylindanone, namely selagindanone A (1), and a new isobenzofuranone (2), 3,4-bis(4-hydroxyphenyl)isobenzofuran-1(3H)-one, were isolated from Selaginella tamariscina. Their structures were elucidated by comprehensive spectroscopic and mass spectrometric analyses, including 1 D-, 2 D-NMR and HR-ESI-MS. Compound 1 possesses a unique structural feature of triaryl-substituted in the skeleton of 1-indanone. In addition, compound 2 showed weak cytotoxicity against human hepatocellular carcinoma SMMC-7721 and HepG2 cell lines.

Two new nor-lignans, siamensinols A and B, from Selaginella siamensis Hieron. and their biological activities.

Two new nor-lignans siamensinols A-B (1-2) and seven known compounds agatharesinol (3), syringaresinol-glucoside (4), noreugenin (5), 8-methyleugenitol (6), melachromone (7), uncinoside A (8) and daucosterol (9) were isolated from Selaginella siamensis Hieron. The structures of the new compounds were elucidated on the basis of comprehensive spectroscopic methods, including 1 D, 2 D-NMR, HR-ESI-MS and CD spectrometry. Compounds 1-2 showed moderate inhibitory effect on MOLT-3 cells while 8-methyleugenitol (6) exhibited moderate inhibitory effect on three tumor cells (HepG2, A549 and HuCCA-1). Compounds 2-3 showed the potent cancer chemoprevention in DPPH, XXO, IXO and AIA assays.

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.

The traditional and modern uses of Selaginella tamariscina (P.Beauv.) Spring, in medicine and cosmetic: Applications and bioactive ingredients.

ETHNOPHARMACOLOGICAL RELEVANCE: Extracts of the plant Selaginella tamariscina (P.Beauv.) Spring (spike moss) are used for a long time in Asia, for the treatment of multiple diseases and conditions. Aqueous and alcoholic leave extracts are used by local communities. In China, the plant (Juan bai) is listed on the Pharmacopoeia. In South Korea, the use of this plant (Kwon Baek) is mentioned in the book Dongui-Bogam (Heo Jun 1613), at the origin of the Hyungsang medicine. S. tamariscina is traditionally used in Vietnam (mong lung rong), Thailand (dok hin), Philippines (pakong-tulog) and other Asian countries. AIM OF THE STUDY: To provide an analysis of the multiple traditional and current uses of S. tamariscina extracts (STE) in the field of medicine and cosmetic. The review is also intended at identifying the main natural products at the origin of the many pharmacological properties reported with these extracts (anti-inflammatory, antioxidant, antidiabetic, antibacterial, antiallergic, anticancer effects). METHODS: Extensive database retrieval, such as SciFinder and PubMed, was performed by using keywords like " Selaginella tamariscina", "spike moss", "Selaginellaceae ". Relevant textbooks, patents, reviews, and digital documents were consulted to collate all available scientific literature and to provide a complete science-based survey of the topic. RESULTS: Different solvents and methods are used to prepare STE. The process can largely modify the natural product content and properties of the extracts. STE display a range of pharmacological effects, useful to treat metabolic disorders, several inflammatory diseases and various cancers. A specific carbonized extract (S. tamariscina carbonisatus) has shown hemostatic effects, whereas standard STE can promote blood circulation. Many patented STE-containing cosmetic preparations are reviewed here. Several biflavonoids (chiefly amentoflavone) and phenolic compounds (selaginellin derivatives) are primarily responsible for the observed pharmacological properties. Potent inhibitors of protein tyrosine phosphatase 1 B (PTP1B), phosphodiesterase-4 (PDE4), and repressor of pro-inflammatory cytokines expression have been identified from STE. CONCLUSION: The traditional use of STE supports the research performed with this plant. There are robust experimental data, based on in vitro and in vivo models, documenting the use of STE to treat type 2 diabetes, several inflammatory diseases, and some cancers (in combination with standard chemotherapy). Selaginella tamariscina (P.Beauv.) is a prime reservoir for amentoflavone, and many other bioactive natural products. The interest of the plant in medicine and cosmetic is amply justified.

Selaginellin Derivatives from Selaginella tamariscina and Their Upregulating Effects on Low-Density Lipoprotein Receptor Expression.

Two new dimeric selaginellins, diselaginellins C and D (1 and 2), a new unusual derivative, selapiginellin A (4), a new selaginpulvilin U (5), and a known derivative, diselaginellin A (3), were isolated from Selaginella tamariscina (P. Beauv.) Spring. Among these compounds, selapiginellin A (4) is the first naturally occurring compound comprising an ether-linked dimer of a selaginellin and a selaginpulvilin. The absolute configurations of 1, 2, and 4 were elucidated by spectroscopic data analyses. Compound 5 was found to regulate mRNA expression of the low-density lipoprotein receptor (LDLR) gene and LDLR-related genes.

Phytochemistry, Bioactivities, Pharmacokinetics and Toxicity Prediction of Selaginella repanda with Its Anticancer Potential against Human Lung, Breast and Colorectal Carcinoma Cell Lines.

In this study, we investigated the bioactive potential (antibacterial and antioxidant), anticancer activity and detailed phytochemical analysis of Selaginellarepanda (S. repanda) ethanolic crude extract for the very first time using different in vitro approaches. Furthermore, computer-aided prediction of pharmacokinetic properties and safety profile of the identified phytoconstituents were also employed in order to provide some useful insights for drug discovery. S. repanda, which is a rich source of potent natural bioactive compounds, showed promising antibacterial activity against the tested pathogenic bacteria (S. aureus, P. aeruginosa, E. coli and S. flexneri). The crude extract displayed favorable antioxidant activity against both 2,2-diphenyl-1-picrylhydrazyl (DPPH) (IC50 = 231.6 µg/mL) and H2O2 (IC50 = 288.3 µg/mL) molecules. S. repanda also showed favorable and effective anticancer activity against all three malignant cancer cells in a dose/time dependent manner. Higher activity was found against lung (A549) (IC50 = 341.1 µg/mL), followed by colon (HCT-116) (IC50 = 378.8 µg/mL) and breast (MCF-7) (IC50 = 428.3 µg/mL) cancer cells. High resolution-liquid chromatography-mass spectrometry (HR-LC-MS) data of S. repanda crude extract revealed the presence of diverse bioactive/chemical components, including fatty acids, alcohol, sugar, flavonoids, alkaloids, terpenoids, coumarins and phenolics, which can be the basis and major cause for its bioactive potential. Therefore, achieved results from this study confirmed the efficacy of S. repanda and a prospective source of naturally active biomolecules with antibacterial, antioxidant and anticancer potential. These phytocompounds alone with their favorable pharmacokinetics profile suggests good lead and efficiency of S. repanda with no toxicity risks. Finally, further in vivo experimental investigations can be promoted as probable candidates for various therapeutic functions, drug discovery and development.

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.