Picrachinentins A-F, 14-Membered Cyclopeptide Alkaloid-Type Burpitides with Uncommon N-Terminal Modifications from Picrasma chinensis and Their Neuroprotective Activity.

Picrachinentins A-F (1-6, respectively), six novel cyclopeptide alkaloid-type burpitides (CPABs), were isolated and fully elucidated from the EtOH extract of the stems and leaves of Picrasma chinensis. Structurally, compounds 1-6 have a 14-membered paracyclophane ring system that was closed through an ether bond between the ß-hydroxy amino acid and tyrosine and modified with a 4,5-methylenedioxybenzoyloxy (MDBz, 3 and 5) or hexanoyl (Hexa, 1, 2, 4, and 6) group at the N-terminus. Interestingly, this is the first report on the isolation and characterization of CPABs from plants of the Simaroubaceae family. In addition, all compounds showed a neuroprotective effect against H2O2-damaged SH-SY5Y cells. Compound 1 was further investigated for its neuroprotective activities using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease animal model, and it dramatically improved MPTP-impaired motor behavioral performance. Biochemical analysis revealed compound 1 restored the tyrosine hydroxylase expression in the striatum of the MPTP-damaged mouse brain, which demonstrates its protective effect on dopaminergic neurons.

Anti-apoptotic, anti-inflammatory, and anti-melanogenic effects of the ethanol extract of Picrasma quassioides (D. Don) Benn.

ETHNOPHARMACOLOGICAL RELEVANCE: Picrasma quassioides (D. Don) Benn is a vascular plant belonging to the genus Picrasma of Simaroubaceae family and grows in Korea, China, India, Taiwan, and Japan. Picrasma quassioides extract has been reported to have anti-inflammatory, anti-bacterial, and anti-cancer properties. Moreover, this plant has been also traditionally used to alleviate symptoms of eczema, atopic dermatitis, psoriasis, scabies, and boils in skin. AIM OF THE STUDY: The Pq-EE has been reported in Chinese pharmacopoeia for its pharmacological effects on skin. However, the detailed mechanism on alleviating skin conditions is not understood. Hence, we investigated the skin improvement potential of Pq-EE against skin damage. MATERIALS AND METHODS: We used the human keratinocyte cell line (HaCaT) and mouse melanoma cell line (B16F10) to study the effects of Pq-EE on the epidermis. Additionally, in vitro antioxidant assays were performed using a solution that included either metal ions or free radicals. RESULTS: In colorimetric antioxidant assays, Pq-EE inhibited free radicals in a dose-dependent manner. The Pq-EE did not affect cell viability and promoted cell survival under UVB exposure conditions in the MTT assay. The Pq-EE downregulated the mRNA levels of apoptotic factors. Moreover, MMP1 and inflammatory cytokine iNOS mRNA levels decreased with Pq-EE treatment. With regard to protein levels, caspases and cleaved caspases were more powerfully inhibited by Pq-EE than UVB-irritated conditions. p53 and Bax also decreased with Pq-EE treatment. The melanin contents and secretion were decreased at nontoxic concentrations of Pq-EE. The pigmentation pathway genes also were inhibited by treatment with Pq-EE. CONCLUSIONS: In summary, we suggest the cell protective potential of Pq-EE against UVB and ROS, indicating its use in UV-protective cosmeceutical materials.

New sesquiterpenoids with neuroprotective effects in vitro and in vivo from the Picrasma chinensis.

Three undescribed sesquiterpenes, designed as pichinenoid A-C (1-3), along with nine known ones (4-12) were isolated from the stems and leaves of Picrasma chinensis. The new isolates including their absolute configurations were elucidated based on extensive spectroscopic methods, single crystal X-ray diffraction, and electronic circular dichroism (ECD) experiments, as well as comparison with literature data. Structurally, compounds 1 and 2 are descending sesquiterpenes, while pichinenoid C (3) is a rare sesquiterpene bearing a 2-methylenebut-3-enoic acid moiety at the C-6 side chain. All the isolated compounds were tested for their neuroprotective effects against the H2O2-induced damage on human neuroblastoma SH-SY5Y cells, and most of them showed moderate neuroprotective activity. Especially, compounds 1, 3-5, and 7 showed a potent neuroprotective effect at 25 or 50 µM. Moreover, the neuroprotective effects of compounds 1 and 4 were tested on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model. Results of western blot and immunofluorescence indicated that compound 4 significantly counteract the toxicity of MPTP, and reversed the expression of tyrosine hydroxylase (TH) in substantia nigra (SN) and striatum (ST) of the mouse brain. Interestingly, western blot data suggested compound 4 also enhanced B-cell lymphoma-2 (Bcl-2) and heme oxygenase 1 (HO-1) expressions in the brain tissues from MPTP damaged mouse.

Aromatic glycosides and lignans glycosides with their acetylcholinesterase inhibitory activities from the leaves of Picrasma quassioides.

In this study, eight new natural products were isolated from the leaves of Picrasma quassioides. Spectroscopic techniques were used for the elucidation of their planar structures. Their absolute configurations were elucidated on the basis of electron circular dichroism (ECD) techniques combined with the P/M helicity rule for the 2,3-dihydrobenzofuran chromophore, and saccharide hydrolysis. Cholinesterase inhibitors are often used as Alzheimer's disease inhibitors.Thus, acetylcholinesterase and butyrylcholinesterase inhibitory activity of these eight compounds were tested, and results showed that only compound 6 showed weakly acetylcholinesterase inhibitory activity. In particular, molecular docking was used to illustrate the bindings between compound 6 and the active sites of AChE.

Enhanced Anti-Rheumatoid Arthritis Activity of Total Alkaloids from Picrasma Quassioides in Collagen-Induced Arthritis Rats by a Targeted Drug Delivery System.

New drug delivery systems have rarely been used in the formulation of traditional Chinese medicine, especially those that are crude active Chinese medicinal ingredients. In the present study, hyaluronic acid decorated lipid-polymer hybrid nanoparticles were used to prepare a targeted drug delivery system (TDDS) for total alkaloid extract from Picrasma quassioides (TAPQ) to improve its targeting property and anti-inflammatory activity. Picrasma quassioides, a common-used traditional Chinese medicine (TCM), containing a series of hydrophobic total alkaloids including ß-carboline and canthin-6-one alkaloids show great anti-inflammatory activity. However, its high toxicity (IC50= 8.088±0.903 µg/ml), poor water solubility (need to dissolve with 0.8% Tween-80) and poor targeting property severely limits its clinical application. Herein, hyaluronic acid (HA) decorated lipid-polymer hybrid nanoparticles loaded with TAPQ (TAPQ-NPs) were designed to overcome above mentioned deficiencies. TAPQ-NPs have good water solubility, strong anti-inflammatory activity and great joint targeting property. The in vitro anti-inflammatory activity assay showed that the efficacy of TAPQ-NPs was significantly higher than TAPQ(P<0.001). Animal experiments showed that the nanoparticles had good joint targeting property and had strong inhibitory activity against collagen-induced arthritis (CIA). These results indicate that the application of this novel targeted drug delivery system in the formulation of traditional Chinese medicine is feasible.

Chemical constituents from the twigs and leaves of Picrasma quassioides.

Two new compounds, including a norsesquiterpenoid, annuionone H (1), and a quassinoid, picraqualide G (2), along with eleven known compounds (3-13), were isolated from the twigs and leaves of Picrasma quassioides. Comprehensive spectroscopic analyses and NMR calculation with DP4+ analysis were used to identify their structures. Moreover, of all these compounds, compound 4 showed a week inhibition rate in the anti-inflammatory screening results against mouse macrophage J774A.1 cell.

Chemical Constituents of the Branches and Leaves of Picrasma chinensis P.Y. Chen and Tyrosinase Inhibiting Activity.

One new alkaloid, picrasine A, two new quassinoids, picralactones A-B, together with eleven known compounds were isolated from Picrasma chinensis P.Y. Chen. The structures of these compounds were determined using 1D and 2D NMR, HR-ESI-MS, and IR spectroscopic data, and by comparison with published data. Some compounds were tested for tyrosinase inhibiting activity, however, none of them exhibited strong inhibitory effects.

ß-Carboline alkaloids from Picrasma quassioides and their 3D-QSAR study on anti-inflammation in LPS-induced RAW 264.7 cells.

Two new ß-carboline alkaloids (1-2), 1-pyrrolidone propionyl-ß-carboline (1) and 1-(3-hydroxy-2-oxopiperidine-1-ethyl)-4,8-dimethoxyl-ß-carboline (2), named kumujantine W and J respectively, together with ten known compounds (3-12) were isolated from the stems of Picrasma quassioides (D. Don) Benn. Their structures were elucidated from spectral data including 1D and 2D NMR, UV, IR, HR-ESI-MS spectroscopic analysis and ECD calculations as well as by comparison to the reference databases or literature. The anti-inflammatory effects of these alkaloids (1-12) and six other ß-carboline alkaloids (13-18) in LPS-induced RAW 264.7 cells were evaluated by measuring nitric oxide (NO) concentrations. Among them, compounds 1, 3, 6, 15, and 17 could inhibit the secretion of NO, displaying significant anti-inflammatory activity without affecting cell viability in vitro, and 3D-QSAR analysis further revealed the influence of groups on the activity in ß-carboline alkaloids.

Quassinoids from Picrasma chinensis with Insecticidal Activity against Adults and Larvae of Diaphorina citri Kuwayama and Neuroprotective Effect.

Eleven new tetracyclic quassinoids, picrachinensin A-K (1-11), along with six known congeners, were isolated from the stems and leaves of Picrasma chinensis. Their structures were elucidated by integrated multiple spectroscopic techniques, single-crystal X-ray diffraction analysis, and electronic circular dichroism. Notably, compounds 3 and 4 are a pair of undescribed epimers, and 8 and 9 are unusual quassinoids with a hydroxymethyl group at C-13. Biologically, compound 7 exhibited insecticidal activity on both adults and larvae of Diaphorina citri Kuwayama even more effectively than the positive control (abamectin), with an LD50 of 55.69 mg/L for adults and a corrected mortality rate of 30.42 ± 2.78% for larvae (100 mg/L). According to preliminary structure-activity relationship investigations, the hydroxymethyl at the C-13 position of quassinoids was beneficial for their insecticidal activity. In addition, compounds 1, 4, and 12 exhibited excellent neuroprotective effect against H2O2-induced oxidative injury on SH-SY5Y cells, with more potent activity than the positive control (Trolox), and all the compounds exhibited no cytotoxicity to SH-SY5Y and BV-2 cells at the indicated concentrations.

Quassinoids with Inhibitory Activities against Plant Fungal Pathogens from Picrasma javanica.

A bioactivity-guided study on the leaves of Picrasma javanica led to the isolation of 19 quassinoids, including 13 new compounds. The structures of the new compounds were elucidated by a combination of spectroscopic data analysis, X-ray crystallography studies, and electronic circular dichroism (ECD) data interpretation. Compounds 1-7 are rare examples of quassinoids with a keto carbonyl group at C-12. The biological activities of 11 of the more abundant isolates were evaluated against five phytopathogenic fungi in vitro, and several of them including 6 and 15 showed moderate inhibitory effects that were comparative to those of the positive control, carbendazim. In addition, the preliminary structure-activity relationships (SARs) of these quassinoids were also investigated.

Dehydrocrenatidine extracted from Picrasma quassioides induces the apoptosis of nasopharyngeal carcinoma cells through the JNK and ERK signaling pathways.

Nasopharyngeal carcinoma (NPC) is an indicator disease in Asia due to its unique geographical and ethnic distribution. Dehydrocrenatidine (DC) is a ß­carboline alkaloid abundantly present in Picrasma quassioides (D. Don) Benn, a deciduous shrub or small tree native to temperate regions of southern Asia, and ß­carboline alkaloids play anti­inflammatory and antiproliferative roles in various cancers. However, the mechanism and function of DC in human NPC cells remain only partially explored. The present study aimed to examine the cytotoxicity and biochemical role of DC in human NPC cells. The MTT method, cell cycle analysis, DAPI determination, Annexin V/PI double staining, and mitochondrial membrane potential examination were performed to evaluate the effects of DC treatment on human NPC cell lines. In addition, western blotting analysis was used to explore the effect of DC on apoptosis and signaling pathways in related proteins. The analysis results confirmed that DC significantly reduced the viability of NPC cell lines in a dose­ and time­dependent manner and induced apoptosis through internal and external apoptotic pathways (including cell cycle arrest, altered mitochondrial membrane potential, and activated death receptors). Western blot analysis illustrated that DC's effect on related proteins in the mitogen­activated protein kinase pathway can induce apoptosis by enhancing ERK phosphorylation and inhibiting Janus kinase (JNK) phosphorylation. Notably, DC induced apoptosis by affecting the phosphorylation of JNK and ERK, and DC and inhibitors (SP600125 and U0126) in combination restored the overexpression of p­JNK and p­ERK. To date, this is the first study to confirm the apoptosis pathway induced by DC phosphorylation of p­JNK and p­REK in human NPC. On the basis of evidence obtained from this study, DC targeting the inhibition of NPC cell lines may be a promising future strategy for NPC treatment.

N-methoxy-ß-carboline alkaloids with inhibitory activities against Aß42 aggregation and acetylcholinesterase from the stems of Picrasma quassioides.

Nine new N-methoxy-ß-carboline alkaloids (NMCAs) (1a/1b-3a/3b and 4-6) and two known NMCAs (7 and 8) were isolated from the stems of Picrasma quassioides. Their structures were elucidated by spectroscopic data analyses, quantum chemical calculations, and single-crystal X-ray crystallographic data. An analysis of the 13C NMR chemical shifts of the N-methoxy groups in these NMCAs and 41 gathered known compounds reveals the phenomenon that the chemical shifts of all these N-methoxy groups are greater than δC 62, which can be used to recognize the N-methoxy group rapidly. In addition, the acetylcholinesterase (AChE) and Aß42 aggregation inhibitory activities of 1-8 were evaluated. Compounds 1, 2, 7, and 8 displayed AChE inhibitory activity with IC50 values of 14.9, 13.2, 17.6, and 43.9 µM, respectively. Compound 2 showed inhibition activity against Aß42 aggregation with an IC50 value of 10.1 µM.

Anti-tumor Properties of Picrasma quassioides Extracts in H-RasG12V Liver Cancer Are Mediated Through ROS-dependent Mitochondrial Dysfunction.

BACKGROUND: Picrasma quassioides (PQ) is a traditional Asian herbal medicine with anti-tumor properties that can inhibit the viability of HepG2 liver cancer cells. H-Ras is often mutated in liver cancer, however, the effect of PQ treatment on H-Ras mutated liver cancer is unclear. This study aimed to investigate the role of PQ on ROS accumulation and mitochondrial dysfunction in H-ras mutated HepG2 (HepG2G12V) cells. MATERIALS AND METHODS: PQ ethanol extract-induced HepG2G12V apoptosis was analyzed by the MTT assay, fluorescence microscopy, flow cytometry and western blotting. RESULTS: PQ treatment affected cell migration and colony formation in HepG2G12V cells. Cleaved-caspase-3, cleaved-caspase-9 and BCL2 associated agonist of cell death (BAD) expression levels were increased, while the levels of B-cell lymphoma-extra large (Bcl-xL) were decreased with PQ treatment. PQ treatment led to a reduction of H-Ras expression levels in liver cancer cells, thus reducing their abnormal proliferation. Furthermore, it led to increased expression levels of Peroxiredoxin VI, which regulates the redox signal in cells. CONCLUSION: Taken together these results provide a new functional significance for the role of PQ in treating HepG2G12V liver cancer.

Three new quassinoids isolated from the wood of Picrasma javanica and their anti-Vpr activities.

Three new quassinoids, javanicinols A and B (1 and 2) and 4-keto-(16S)-methoxyjavanicin B (3), together with three known quassinoids (4-6) were isolated from the chloroform-soluble fraction of the methanol extract of the Picrasma javanica wood. The structures of 1-3 were determined by spectroscopic analyses, including 1D and 2D NMR, HRESIMS, and CD. The anti-HIV-1 viral protein R (Vpr) assay revealed that 1 and 2 exhibited potent anti-Vpr activities at 1.25 µM. Furthermore, the assay also revealed the potent anti-Vpr activities of (16R)-methoxyjavanicin B (7) and (16S)-methoxyjavanicin B (8), which were previously isolated from the Picrasma javanica wood.

Design, synthesis and in vitro biological evaluation of novel 4-methoxy-5-hydroxycanthin-6-one derivatives as potential anti-tumor agents.

Canthin-6-one analogue, 4-methoxy-5-hydroxycanthin-6-one (CAN1) was isolated from Picrasma quassioides (D.Don) Benn., and a series of derivatives containing the CAN1 framework were designed, synthesized, and evaluated for anti-proliferative activity against two human cancer cell lines, HepG2 and HCT116. Among these compounds, the most representative compound d exhibited better anti-proliferative activities in vitro compared with the positive control Fluorouracil (5-FU), with IC50 values of 5.05 µM (HepG2) and 6.65 µM (HCT116), respectively. Compound d triggered more significant HepG2 cell apoptosis than 5-FU did in a dose-dependent manner. Furthermore, western blot assay indicated that d could enhance the expression of p65 while promoting pro-apoptotic proteins and suppressing the anti-apoptotic proteins in a dose-dependent manner. All these results demonstrated that d might be a potential agent for cancer therapy deserving further exploring.

(±)-Quassidine K, a pair of cytotoxic bis-ß-carboline alkaloid enantiomers from Picrasma quassioides.

(±)-Quassidine K (1), a pair of new bis-ß-carboline alkaloid enantiomers, were isolated from Picrasma quassioides. Their structures were determined on the basis of detailed spectroscopic data analysis. The absolute configurations of (+)-S-quassidine K (1a) and (-)-R-quassidine K (1b) were determined by comparing with the reported experimental ECD spectra after chiral separation. The cytotoxicity assay showed activity against HeLa cells with IC50 values of 15.8 and 20.1 µM, respectively.

Quassinoids with Insecticidal Activity against Diaphorina citri Kuwayama and Neuroprotective Activities from Picrasma quassioides.

Six new quassinoids, named kumulactone F (1), kumulactone G (2), kumulactone H (4), kumulactone I (5), kumulactone J (6), and kumulactone K (7), a pair of undescribed epimers α- and ß-nigakihemiacetal G (3), 15 known quassinoids (8-22), and a mixture of the known compounds α- and ß-neoquassin (23) were separated from the dried stems of the medical plants Picrasma quassioides. The chemical structures of all of the new compounds were established by spectroscopic data analyses (HR-ESI-MS, 1D and 2D NMR spectroscopy, and electronic circular dichroism (ECD)). Biologically, compounds 9 and 21 showed toxicity toward the Asian citrus psyllid Diaphorina citri Kuwayama with potent activity even equal to that of the positive control (Abamectin), compound 11 exhibited an excellent neuroprotective effect against SH-SY5Y cells which were pretreated by H2O2 with potent activity equal to that of the positive control (Trolox), and none of them showed cytotoxic activity toward the HeLa or A549 cell lines (IC50 > 100 µM).

A pair of new tirucallane triterpenoid epimers from the stems of Picrasma quassioides.

A pair of new tirucallane triterpenoid epimers, picraquassins M and N (1> and 2), were isolated from the stems of Picrasma quassioides (D. Don) Benn. Their structures were determined based on comprehensive spectroscopic and X-ray crystallographic analyses. In addition, their AChE inhibitory activity, cytotoxicity against five human tumour cell lines (SW480, MCF-7, HepG2, Hela, and PANC-1), and antimicrobial activity against two bacteria (Staphylococcus. aureus 209P and Escherichia coli ATCC0111) and two fungi (Candida albicans FIM709 and Aspergillus niger R330) were evaluated.

A new cinnamamide derivative and two new ß-carboline alkaloids from the stems of Picrasma quassioides.

Picrasamide A (1), a new cinnamamide derivative, together with two new ß-carboline alkaloids (2 and 3) and five known ß-carboline alkaloids (4-8) were isolated from the stems of Picrasma quassioides (D. Don) Benn. Their structures were elucidated by detailed analyses of UV, IR, HRESIMS, and NMR data. Compound 1 was the first case of cinnamamide derivative from genus Picrasma. The AChE inhibitory activity and the antimicrobial activity of 1-8 were assessed. In addition, preliminary structure-activity relationships of these ß-carboline alkaloids on the AChE inhibitory activity and antimicrobial activity were proposed.

Effects of Picrasma quassioides and its active constituents on Alzheimer's disease in vitro and in vivo.

Alzheimer disease (AD), a prevalent neurodegenerative disorder, is one of the leading causes of dementia. However, there is no effective drug for this disease to date. Picrasma quassioides (D.Don) Benn, a Chinese traditional medicine, was used mainly for the treatment of inflammation, fever, microbial infection and dysentery. In this paper, we reported that the EtOAc extract of Picrasma quassioides stems showed potential neuroprotective activities in l-glutamate-stimulated PC12 and Aß25-35-stimulated SH-SY5Y cell models, as well as improved memory and cognitive abilities in AD mice induced by amyloid-ß peptide. Moreover, it was revealed that the anti-AD mechanism was related to suppressing neuroinflammatory and reducing Aß1-42 deposition using ELISA assay kits. To clarify the active components of the EtOAc extract of Picrasma quassioides stems, a systematic phytochemistry study led to isolate and identify six ß-carboline alkaloids (1-6), seven canthin-6-one alkaloids (7-13), and five quassinoids (14-18). Among them, four ß-carbolines (1-3, and 6) and six canthin-6-ones (7-11, and 13) exhibited potential neuroprotective activities in vitro. Based on these date, the structure-activity relationships of alkaloids were discussed. Furthermore, molecular docking experiments showed that compounds 2 and 3 have high affinity for both of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYPKIA) and butyrylcholinesterase (BuChE).