Ptehoosines A and B: Two new sesamin-type sesquilignans with antiangiogenic activity from Pterocephalus hookeri (C.B. Clarke) Höeck.

Two undescribed sesamin-type sesquilignans ptehoosines A (1) and B (2), together with 4 known lignans (3-6), were isolated from Pterocephalus hookeri (C.B. Clarke) Höeck which was widely used as traditional Tibetan medicine for treatment of rheumatoid arthritis. Their structures were determined by HR-ESI-MS, NMR analysis and CD experiment. The in vitro antiangiogenic effect of all isolated compounds against human umbilical vein endothelial cells (HUVECs) were evaluated by CCK-8 assay. Among them, compound 1 exhibited significant proliferative inhibition on HUVECs with IC50 value of 32.82 ± 0.99 µM. Further in vitro study indicated 1 could arrest cell cycle at G0/G1 phase and reduce the migration of HUVECs. In vivo experiment exhibited 1 could inhibit tail vessels plexus in zebrafish. The above finding suggested that 1 was a promising lead compound against RA by inhibiting of angiogenesis.

Piperazine ring formation by a single-module NRPS and cleavage by an α-KG-dependent nonheme iron dioxygenase in brasiliamide biosynthesis.

Brasiliamides are a class of piperazine-containing alkaloids produced by Penicillium brasilianum with a range of pharmaceutical activities. The mechanism of brasiliamide biosynthesis, including piperazine ring formation and multiple tailoring modifications, still remains unclear. In this study, the biosynthetic gene cluster of brasiliamides, brs, was identified from the marine-derived fungal strain Penicillium brasilianum WZXY-M122-9. Deletion of a histone deacetylase-encoding gene using a CRISPR/Cas9 gene editing system led to the production of a new compound, namely brasiliamide I (1). The brs-encoded single-module nonribosomal peptide synthetase (NRPS) BrsA is involved in the formation of the piperazine skeleton of brasiliamides. Full-length BrsA protein (113.6 kDa) was purified, and reconstitution of enzymatic activity in vitro confirmed that BrsA stereoselectively accepts L-phenylalanine as the substrate. Multiple deletion of tailoring genes and analysis of purified proteins in vitro enabled us to propose a brasiliamide biosynthetic pathway. In the tailoring steps, an α-ketoglutarate (KG)-dependent nonheme iron dioxygenase, BrsJ, was identified to catalyze piperazine ring cleavage during biosynthesis of brasiliamide A (2). KEY POINTS: The gene cluster encoding brasiliamide biosynthesis, brs, is identified. Deletion of a histone deacetylase-encoding gene produces brasiliamide I. BrsA catalyzes brasiliamide piperazine skeleton formation. BrsJ catalyzes piperazine ring cleavage to produce brasiliamide A. Graphical abstract.

Inhibitory Effect of Sesamolin on Melanogenesis in B16F10 Cells Determined by In Vitro and Molecular Docking Analyses.

BACKGROUND: Melanin protects the skin against the harmful effects of ultraviolet irradiation. However, melanin overproduction can result in several aesthetic problems, including melasma, freckles, age spots and chloasma. Therefore, development of anti-melanogenic agents is important for the prevention of serious hyperpigmentation diseases. Sesamolin is a lignan compound isolated from sesame seeds with several beneficial properties, including potential for melanin inhibition. OBJECTIVE: The aim of this study was to evaluate the anti-melanogenic effect of sesamolin in cell culture in vitro and the underlying mechanism of inhibition using molecular docking simulation. METHODS: Melanogenesis was induced by 3-isobutyl-1-methylxanthine in B16F10 melanoma cells, and the inhibitory effects of sesamolin were evaluated using zymography, a tyrosinase inhibitory activity assay, western blotting, and real-time reverse transcription-polymerase chain reaction analysis. Docking simulations between sesamolin and tyrosinase were performed using Autodock vina. RESULTS: Sesamolin significantly inhibited the expression of melanogenesis-related factors tyrosinase, and tyrosinase-related proteins 1 and 2 at the mRNA and protein levels. Treatment of melanoma cells with 50 µM sesamolin demonstrated the strongest inhibition against intercellular tyrosinase and melanin synthesis without exerting cytotoxic effects. Sesamolin significantly reduced mushroom tyrosinase activity in a dose-dependent manner via a competitive inhibition mechanism. Tyrosinase docking simulations supported that sesamolin (-6.5 kcal/mol) bound to the active site of tyrosinase more strongly than the positive control (arbutin, -5.7 kcal/mol). CONCLUSION: Sesamolin could be developed as a melanogenesis inhibiting agent owing to its dual function in blocking the generation of melanogenesis-related enzymes and inhibiting the enzymatic response of tyrosinase.

Antiplasmodial activity and cytotoxicity, isolation of active alkaloids, and dereplication of Xylopia sericea leaves ethanol extract by UPLC-DAD-ESI-MS/MS.

OBJECTIVES: To assess the antiplasmodial activity of the ethanol extract of Xylopia sericea leaves, Annonaceae, often associated with antimalarial use and to perform a bioguided isolation of active compounds. METHODS: Dereplication of ethanol extract by the UPLC-DAD-ESI-MS/MS technique allowed the identification of the major constituents, isolation and identification of alkaloids. The antiplasmodial and cytotoxic activity of the extract, fractions and isolated compounds was evaluated against the chloroquine-resistant W2 strain Plasmodium falciparum and HepG2 cells, respectively. KEY FINDINGS: Ethanol extract showed high reduction of parasitemia as well as moderate cytotoxicity (86.5 ± 3.0% growth inhibition at 50 µg/ml and CC50 72.1 ± 5.1 µg/ml, respectively). A total of eight flavonoids were identified, and two aporphine alkaloids, anonaine and O-methylmoschatoline, were isolated. Anonaine disclosed significant antiplasmodial effect and moderate cytotoxicity (IC50 23.2 ± 2.7 µg/ml, CC50 38.3 ± 2.3 µg/ml, SI 1.6) while O-methylmoschatoline was not active against P. falciparum and showed a low cytotoxicity (33.5 ± 1.9% growth inhibition at 50 µg/ml, CC50 274.4 ± 0.5 µg/ml). CONCLUSIONS: Characterization of Xylopia sericea leaves ethanol extract by UPLC-DAD-ESI-MS/MS as well as its antiplasmodial activity and the occurrence of anonaine and O-methylmoschatoline in this Xylopia species are reported by the first time.

(-)-Asarinin from the Roots of Asarum sieboldii Induces Apoptotic Cell Death via Caspase Activation in Human Ovarian Cancer Cells.

Two tetrahydrofurofurano lignans (1 and 2), four phenylpropanoids (3⁻6), and two alkamides (7 and 8) were isolated from the EtOAc-soluble fraction of the roots of Asarum sieboldii. The chemical structures of the isolates were identified by analysis of spectroscopic data measurements, and by a comparison of their data with published values. The isolates (1, 2, 4⁻8) were evaluated for their cytotoxicity against human ovarian cancer cells (A2780 and SKOV3) and immortalized ovarian surface epithelial cells (IOSE80PC) using a MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) assay. Of the isolates, (-)-asarinin (1) exhibited the most potent cytotoxicity to both A2780 and SKOV3 cells. A propidium iodide/annexin V-fluorescein isothiocyanate (V-FITC) double staining assay showed that (-)-asarinin (1) induces apoptotic cell death in ovarian cancer cells. In addition, (-)-asarinin (1) increased the activation of caspase-3, caspase-8, and caspase-9 in ovarian cancer cells. Pretreatment with caspase inhibitors attenuated the cell death induced by (-)-asarinin (1). In conclusion, our findings show that (-)-asarinin (1) from the roots of A. sieboldii may induce caspase-dependent apoptotic cell death in human cancer cells.

Sesamin from Cuscuta palaestina natural plant extracts: Directions for new prospective applications.

The aim of this study is to disclose the potential bioactive components of Cuscuta palaestina, a native parasitic natural plant of flora palaestina and to open direction towards new prospective application. GC-MS analysis identified 18 components in the methanolic extract of C. palaestina for the first time. The most appealing among them are Sesamin and two other phytosterols (Campesterol and Stigmasterol), all of which are documented in the scientific literature for their anticancer activity. Quantitation of Sesamin extracted from C. palaestina by HPLC-PDA with the use of three organic solvents showed that the Sesamin content in the methanolic extract was the highest. Following the disclosure of Sesamin presence in C. palaestina, we raised the question of whether it is produced naturally in C. palaestina or acquired from the host plant. The quantitation of Sesamin in C. palaestina was performed while being with five different host plants, and was compared with the amount of Sesamin in C. palaestina grown alone. The findings reveal that Sesamin is an endogenous secondary metabolite in C. palaestina. Thus, further studies are required to prove if C. palaestina can be used as an alternative source of anticancer phytochemicals, mainly Sesamin, and if proteins in the Sesamin production pathway could be valid biological targets for the development of novel and selective pesticides for control/ eradication of C. palaestina and maybe some other Cuscuta species. As well, the findings from this study raise a big question of whether inferring Sesamin production in C. palaestina could reduce its attack ability to host plants.

ent-Sauchinone as Potential Anticancer Agent Inhibiting Migration and Invasion of Human Liver Cancer Cells via Suppressing the STAT3 Signaling Pathway.

ent-Sauchinone, a lignan isolated from Saururus chinensis (Lour.) Baill., was reported that it could modulate the expression of signal transducer and activator of transcription 3 (STAT3). Since STAT3 plays a key role in invasion, migration, and metastasis of cancer, we investigated whether ent-sauchinone could exert promising inhibitory effects on the invasion and migration of the metastatic human liver cancer cell line SMMC-7721 in the present study. ent-Sauchinone was extracted from dried herbs of Saururus chinensis (Lour.) Baill. Human liver cancer cell lines SMMC-7721 and HCCLM3 were used to test the effect of ent-sauchinone on cell viability. The IC50 values and time-dependent effect of ent-sauchinone were determined by MTT assay. Cell migration and invasion of SMMC-7721 were evaluated by the wound healing test and transwell assay respectively, the known anti-metastasis agent curcumin was used as a positive control. Western blotting assay was used to investigate relevant molecular mechanisms of cell invasion and migration. Though ent-sauchinone didn't show high cytotoxicity, the wound healing assay and transwell migration assay revealed a profound impairment in the metastatic potential of SMMC-7721 cells due to down-regulation of N-cadherin, MMP-2, and MMP-9 proteins induced by inhibiting the phosphorylation of STAT3. These findings suggest that ent-sauchinone could be used as a promising agent to treat cancer metastasis.

Molecular docking studies of bioactive compounds from Annona muricata Linn as potential inhibitors for Bcl-2, Bcl-w and Mcl-1 antiapoptotic proteins.

Annona muricata Linn or usually identified as soursop is a potential anticancer plant that has been widely reported to contain valuable chemopreventive agents known as annonaceous acetogenins. The antiproliferative and anticancer activities of this tropical and subtropical plant have been demonstrated in cell culture and animal studies. A. muricata L. exerts inhibition against numerous types of cancer cells, involving multiple mechanism of actions such as apoptosis, a programmed cell death that are mainly regulated by Bcl-2 family of proteins. Nonetheless, the binding mode and the molecular interactions of the plant's bioactive constituents have not yet been unveiled for most of these mechanisms. In the current study, we aim to elucidate the binding interaction of ten bioactive phytochemicals of A. muricata L. to three Bcl-2 family of antiapoptotic proteins viz. Bcl-2, Bcl-w and Mcl-1 using an in silico molecular docking analysis software, Autodock 4.2. The stability of the complex with highest affinity was evaluated using MD simulation. We compared the docking analysis of these substances with pre-clinical Bcl-2 inhibitor namely obatoclax. The study identified the potential chemopreventive agent among the bioactive compounds. We also characterized the important interacting residues of protein targets which involve in the binding interaction. Results displayed that anonaine, a benzylisoquinoline alkaloid, showed a high affinity towards the Bcl-2, thus indicating that this compound is a potent inhibitor of the Bcl-2 antiapoptotic family of proteins.

Antiproliferative activity of the Antrodia camphorata secondary metabolite 4,7-dimethoxy-5-methylbenzo[d][1,3]dioxole and analogues.

Both the traditional Chinese medicinal fungus, Antrodia camphorata, and its secondary metabolite, 4,7-dimethoxy-5-methylbenzo[d][1,3]dioxole, have been reported to possess promising anticancer activity. In this work the natural product and analogues bearing more polar substituents were synthesised and assessed for antiproliferative activity in the NCI-60 screen. Although each compound inhibited the growth of some cell lines at 10µM, none had sufficient activity to warrant further investigation.

Effects of asarinin on dopamine biosynthesis and 6-hydroxydopamine-induced cytotoxicity in PC12 cells.

This study investigated the effects of asarinin on dopamine biosynthesis and 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in rat adrenal pheochromocytoma (PC12) cells. Treatment with asarinin (25-50 µM) increased intracellular dopamine levels and enhanced L-DOPA-induced increases in dopamine levels. Asarinin (25 µM) induced cyclic AMP-dependent protein kinase A (PKA) signaling, leading to increased cyclic AMP-response element binding protein (CREB) and tyrosine hydroxylase (TH) phosphorylation, which in turn stimulated dopamine production. Asarinin (25 µM) also activated transient phosphorylation of extracellular signal-regulated kinase (ERK1/2) and Bad phosphorylation at Ser 112, both of which have been shown to promote cell survival. In contrast, asarinin (25 µM) inhibited sustained ERK1/2, Bax, c-Jun N-terminal kinase (JNK1/2) and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation and caspase-3 activity, which were induced by 6-OHDA (100 µM). These results suggest that asarinin induces dopamine biosynthesis via activation of the PKA-CREB-TH system and protects against 6-OHDA-induced cytotoxicity by inhibiting the sustained activation of the ERK-p38MAPK-JNK1/2-caspase-3 system in PC12 cells.

(-)-Neocaryachine, an Antiproliferative Pavine Alkaloid from Cryptocarya laevigata, Induces DNA Double-Strand Breaks.

Twelve benzylisoquinoline alkaloids, including pavine and phenanthroindolizidine types, were isolated from a MeOH/CH2Cl2 extract of Cryptocarya laevigata (stem bark) through bioactivity-guided fractionation for antitumor effects. Selected compounds were evaluated for antiproliferative activity against five human tumor cell lines, including a multidrug-resistant subline. Since more common 2,3,8,9-tetrasubstituted pavine alkaloids, such as crychine (3), exhibit very mild or no cytotoxicity, this compound type has not been well investigated for antitumor activity. Thus, this report is the first discovery of a 7-hydroxylated pavine alkaloid, (-)-neocaryachine (1), to demonstrate strong antiproliferative activity, with IC50 values of 0.06 to 0.41 µM against five tested tumor cell lines, including an MDR subline. Further mechanism of action studies revealed that 1 impacts the cellular S-phase by inducing DNA double-strand breaks.

Magnetic solid-phase extraction based on graphene oxide for the determination of lignans in sesame oil.

Graphene oxide was fabricated by a simple method and applied to magnetic solid-phase extraction. In a pretreatment procedure before the sesamol, sesamin and sesamolin in sesame oil were detected by high performance liquid chromatography. Several parameters affecting the extraction efficiency were investigated, including the type and volume of desorption solvent, desorption time and the amount of sorbent. Under the optimized conditions, the detection limits of sesamol, sesamin, and sesamolin were 0.05µg/g, 0.02µg/g, and 0.02µg/g, respectively. The limits of quantification were all 0.2µg/g. The average recoveries of sesamol, sesamin, and sesamolin were 84.55%, 85.47%, 86.83%, respectively and their relative standard deviations were 1.23%, 1.33%, and 0.84%, respectively.

Acanthopanax senticosus: Photochemistry and Anticancer Potential.

Acanthopanax senticosus (previously classified as Eleutherococcus senticosus), commonly known as Ciwujia or Siberian Ginseng, is a traditional Chinese medicine (TCM), widely used for its high medicinal value, such as antifatigue, anti-inflammation, antistress, anti-ulcer and cardiovascular functions, in China, Korea, Japan and Russia. In the past decades, researchers worldwide have conducted systematic investigations on this herb, from chemistry to pharmacology, and a large number of chemical components have been characterized for their significant pharmacological effects. However, reports about the anticancer effects of this plant had been rare until recently, when considerable pharmacological experiments both in vitro and in vivo were conducted to study the anticancer effects of this herb. A. senticosus has been found to have inhibitory effects on malignant tumors, such as those in the lung and liver, suggesting that A. senticosus has potential to be developed as an effective anticancer drug. This paper reviews recent findings on the pharmacological properties of A. senticosus, with a focus on its anticancer effects.

Determination and purification of sesamin and sesamolin in sesame seed oil unsaponified matter using reversed-phase liquid chromatography coupled with photodiode array and tandem mass spectrometry and high-speed countercurrent chromatography.

In Asian countries, sesame seed oil unsaponified matter is used as a natural food additive due to its associated antioxidant effects. We determined and purified the primary lignans sesamin and sesamolin in sesame seed oil unsaponified matter using reversed-phase liquid chromatography coupled with photodiode array and tandem mass spectrometry and high-speed countercurrent chromatography. Calibration curves showed good correlation coefficients (r2 > 0.999, range 0.08 and/or 0.15 to 5 µg/mL) with a limit of detection (at 290 nm) of 0.02 µg/mL for sesamin and 0.04 µg/mL for sesamolin. Sesame seed oil unsaponified matter contained 2.82% sesamin and 2.54% sesamolin, respectively. Direct qualitative analysis of sesamin and sesamolin was achieved using quadrupole mass spectrometry with positive-mode electrospray ionization. Pure (>99%) sesamin and sesamolin standards were obtained using high-speed countercurrent chromatographic purification (hexane/ethyl acetate/methanol/water; 7:3:7:3). An effective method for determining and purifying sesamin and sesamolin from sesame seed oil unsaponified matter was developed by combining these separation techniques for standardized food additives.

Simultaneous Determination of Seven Kinds of Fungicides in Citrus Fruits by Gas Chromatograghy/Mass Spectrometry.

A simple and accurate procedure was developed for the determination of seven fungicides, azoxystrobin (AZO), diphenyl (DP), fludioxonil (FLUDI), imazalil (IMZ), o-phenylphenol (OPP), pyrimethanil (PYRI) and thiabendazole (TBZ), in citrus fruits. The citrus fruit sample was extracted with acetonitrile and cleaned up with a graphite carbon/aminopropyl silanized silica gel solid-phase extraction cartridge using acetonitrile-toluene (3 : 1, v/v) as the eluent. Triphenylene was used as an internal standard (I.S.) at the concentration of 0.5 µg/mL. The sample solution was subjected to GC-MS utilizing the matrix-matched standard solution method. The recoveries of AZO, FLUDI, IMZ, OPP, PYRI and TBZ spiked in domestic citrus fruits (Satsuma mandarin) at the level of 0.01-10.0 µg/g were 72.8-104% and the limits of quantification were 0.01 µg/g. The recoveries of DP spiked in domestic citrus fruits at the level of 0.01-70.0 µg/g were 70.8-80.4% and the limit of quantification was 0.01 µg/g. The proposed method was applied to the determination of fungicides in citrus fruits purchased in various markets.

Preparative separation of sesamin and sesamolin from defatted sesame meal via centrifugal partition chromatography with consecutive sample injection.

A preparative separation method using consecutive sample injection centrifugal partition chromatography (CPC) was developed to obtain sesamin and sesamolin from defatted sesame meal extracts. A two-phase solvent system consisting of n-hexane-ethyl acetate-methanol-water (8:2:8:2, v/v) was applied in reversed-phase mode (descending mode). Preliminary experiments with an SCPC-100 (column volume: 100mL) were performed to select the appropriate two-phase solvent system and sample injection times; these parameters were then used with an SCPC-1000 (column volume: 1000mL) in a 10-fold scale-up preparative run. A sample containing 3g of crude extract was consecutively injected four times onto the SCPC-1000, which yielded 328mg of sesamin and 168mg of sesamolin. These compounds were analyzed by high-performance liquid chromatography and determined to have purities of 95.6% and 93.9%, respectively. Sesamin and sesamolin (30µM) increased antioxidant response element (ARE) luciferase activity 2.6-fold and 1.9-fold, respectively.

Schisandrol B protects against acetaminophen-induced acute hepatotoxicity in mice via activation of the NRF2/ARE signaling pathway.

AIM: The nuclear factor erythroid 2-related factor 2 (NRF2) acts through the antioxidant response element (ARE) to regulate the expression of many detoxifying and antioxidant genes responsible for cytoprotective processes. We previously reported that Schisandrol B (SolB) isolated from Schisandra sphenanthera produced a protective effect against acetaminophen (APAP)-induced liver injury. In this study we investigated whether the NRF2/ARE signaling pathway was involved in this hepato-protective effect. METHODS: Male C57BL/6 mice were treated with SolB (200 mg · kg(-1) · d(-1), ig) for 3 d before injection of APAP (400 mg/kg, ip). Serum and liver tissue samples were collected 6 h later. The mRNA and protein expression were measured using qRT-PCR and Western blot assay, respectively. The activation of NRF2 was examined in HepG2 cells using luciferase reporter gene assay. RESULTS: SolB pretreatment significantly alleviated the hepatic injury (large patchy necrosis and hyperemia of the hepatic sinus), the increase of serum AST, ALT levels and hepatic MDA contents, and the decrease of liver and mitochondrial glutathione levels in APAP-treated mice. Furthermore, SolB pretreatment significantly increased nuclear accumulation of NRF2 and increased hepatic expression of NRF2 downstream proteins, including GCLC, GSR, NQO1, GSTs, MRP2, MRP3 and MRP4 in APAP-treated mice. Moreover, treatment with SolB (2.5-20 µmol/L) dose-dependently increased the activity of NRF2 reporter gene in HepG2 cells. CONCLUSION: SolB exhibits a remarkable protective effect against APAP-induced hepatotoxicity, partially via activation of the NRF2/ARE pathway and regulation of NRF2 target genes, which induce detoxification and increase antioxidant capacity.

Anti-inflammatory effects of Saururus chinensis aerial parts in murine macrophages via induction of heme oxygenase-1.

Saururus chinensis (Lour.) Baill. is a perennial plant distributed throughout Northeast Asia and its roots have been widely used as a traditional medicine for hepatitis, asthma, pneumonia, and gonorrhea. This study was designed to investigate the anti-inflammatory activity of an extract of S. chinensis of the aerial parts (rather than the root), and the signaling pathway responsible for this effect in lipopolysaccharide-stimulated murine macrophages. The subfraction 4 (SCF4) from the n-hexane layer of the ethanol extract of the aerial parts of S. chinensis exhibited the highest nitrite-inhibitory activity. SCF4 significantly inhibited the production of nitrite and the expression of pro-inflammatory mediators via heme oxygenase-1 upregulation. SCF4 caused significant phosphorylation of p38 MAPK and Akt, which subsequently induced the nuclear translocation of p-p65 nuclear factor-κB and Nrf2. SCF4 also suppressed the phosphorylation of signal transducers and activators of transcription 1 (p-STAT1). The heme oxygenase-1 inhibitor zinc protoporphyrin attenuated the inhibitory effect of SCF4 on lipopolysaccharide-stimulated nitrite production and expression of inflammatory mediators, tumor necrosis factor alpha, and p-STAT1. We identified sauchinone as the active compound in S. chinensis extract and SCF4. Sauchinone was shown to significantly inhibit nitrite production and inflammatory mediators expression via heme oxygenase-1 upregulation. These results suggest that S. chinensis extract, SCF4, and its active compound, sauchinone, could be used as an anti-inflammatory agent.

New Bergamotane Sesquiterpenoids from the Plant Endophytic Fungus Paraconiothyrium brasiliense.

Brasilamides K-N (1-4), four new bergamotane sesquiterpenoids; with 4-oxatricyclo (3.3.1.0 (2,7))nonane (1)and 9-oxatricyclo(4.3.0.0 (4,7))nonane (2-4) skeletons; were isolated from the scale-up fermentation cultures of the plant endophytic fungus Paraconiothynium brasiliense Verkley. The previously identified sesquiterpenoids brasilamides A and C (5 and 6) were also reisolated in the current work. The structures of 1-4 were elucidated primarily by interpretation of NMR spectroscopic data. The absolute configurations of 1-3 were deduced by analogy to the co-isolated metabolites 5 and 6; whereas that of C-12 in 4 was assigned using the modified Mosher method. The cytotoxicity of all compounds against a panel of eight human tumor cell lines were assayed.

Schisantherin A protects against 6-OHDA-induced dopaminergic neuron damage in zebrafish and cytotoxicity in SH-SY5Y cells through the ROS/NO and AKT/GSK3ß pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Schisandra chinensis (Turcz.) Baill, has been traditionally used in management of liver diseases and ageing associated neurodegeneration. The bioactive compound from this medicinal plant would be valuable for its potential use in prevention and treatment of Parkinson׳s disease. AIM OF THE STUDY: The overall objective of the present study was to understand the neuroprotective effect of schisantherin A, a dibenzocyclooctadiene lignan from the fruit of S. chinensis (Turcz.) Baill, and to elucidate its underlying mechanism of action. MATERIAL AND METHODS: This study investigated the protective effect of schisantherin A against selective dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA)-induced neural damage in human neuroblastoma SH-SY5Y cells and zebrafish models. Oxidative stress and related signaling pathways underlying the neuroprotective effect were determined by multiple biochemical assays and Western blot. RESULTS: Pretreatment with schisantherin A offered neuroprotection against 6-OHDA-induced SH-SY5Y cytotoxicity. Moreover, schisantherin A could prevent 6-OHDA-stimulated dopaminergic neuron loss in zebrafish. Our mechanistic study showed that schisantherin A can regulate intracellular ROS accumulation, and inhibit NO overproduction by down-regulating the over-expression of iNOS in 6-OHDA treated SH-SY5Y cells. Schisantherin A also protects against 6-OHDA-mediated activation of MAPKs, PI3K/Akt and GSK3ß. CONCLUSION: These findings demonstrate that schisantherin A may have potential therapeutic value for neurodegenerative diseases associated with abnormal oxidative stress such as Parkinson׳s disease.