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.

Picrasidine J, a Dimeric ß-Carboline-Type Alkaloid from Picrasma quassioides, Inhibits Metastasis of Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) are associated with recurrence, distant metastasis, and poor overall survival. This highlights the need for identifying potential therapeutics with minimal side-effects. The present study was designed to investigate the anticancer effects of picrasidine J, a dimeric ß-carboline-type alkaloid isolated from the southern Asian plant Picrasma quassioides. The results showed that picrasidine J significantly inhibits HNSCC cell motility, migration, and invasion. Specifically, picrasidine J inhibited the EMT process by upregulating E-cadherin and ZO-1 and downregulating beta-catenin and Snail. Moreover, picrasidine J reduced the expression of the serine protease KLK-10. At the signaling level, the compound reduced the phosphorylation of ERK. All these factors collectively facilitated the inhibition of HNSCC metastasis with picrasidine J. Taken together, the study identifies picrasidine J as a potential anticancer compound of plant origin that might be used clinically to prevent the distant metastasis and progression of HNSCC.

Cytotoxicity of isolated compounds from Picrasma crenata (Vell.) Engl. in animal tumor cell (HTC).

The study aim was to evaluate the cytotoxic activity, using the MTT test [3-(4,5-Dimethilthiazol-2-yl)-2,5-diphenil tetrazolium bromide], from the crude extract of Picrasma crenata (Pau Tenente) and its isolated compounds, quassin and parain, in culture of rat liver tumor cells (HTC). The test was carried out exposing the cells for 24, 48 and 72 hours to concentrations of 5, 10, 50, 100, 200, 300, 400, 500 and 1000 µg of crude extract of Pau Tenente/mL of culture medium and 1, 5, 10, 15, 20, 40, 60, 80 and 100 µg of quassin or parain compounds/mL of culture medium. The absorbances averages results obtained showed that the crude extract did not present cytotoxicity for the HTC cells in all the concentrations and evaluated times. For quassin, the concentrations of 80 and 100 µg/mL were cytotoxic, after 72 hours of treatment. For parain, the concentrations of 1, 5, 20, 40, 60, 80 and 100 µg/mL, in 72 hours, were cytotoxic, revealing a new activity for this compound. Thus, the results demonstrate a first indication of the cytotoxic activity of compounds quassin and parain, adding an important social and economic value to them, and may have application in future research and in pharmaceutical industry.

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.

Research on Anti-inflammatory Targets and Mechanisms of alkaloids in Picrasma quassioides Benn Through Network Pharmacology

Abstract This study aimed to investigate the molecular mechanism of Picrasma quassioides Benn against inflammation by means of network pharmacology. The paper will provide a reference for multi-target and multi-channel treatment of inflammation with traditional Chinese medicine. Through screening and analysis, 11 active ingredients and 109 anti-inflammation prediction targets were obtained and constructed a compound-target network. The targets such as VEGFA, TLR4 and STAT3 may play a crucial role. Network enrichment analysis showed that the 109 potential targets constitute a number of pathways or inflammatory reactions closely related to inflammation, including NF-κB signaling pathway and MAPK signaling pathway. The docking results indicated that the binding energy of Picrasidine Y and the inflammatory factors VEGFA is the highest. This study predicted the role of multiple active compounds in the alkaloids of Picrasma in the inflammatory response, and provided a theoretical basis for the anti-inflammatory mechanism of Picrasma

In vivo and in vitro antifungal activities of five alkaloid compounds isolated from Picrasma quassioides (D. Don) Benn against plant pathogenic fungi.

Highly active and novel antifungal compounds are continuously researched from natural products for pesticide development. Picrasma quassioides (D. Don) Benn, a species of Simaroubaceae, is used in traditional Chinese medicine to treat colds and upper respiratory infections. In this study, the active ingredients of P. quassioides and their antifungal activities against plant pathogenic fungi are investigated to explore the practical application of the plant in the agricultural field. The results showed that the extracts of P. quassioides exhibited highly significant preventive and curative effects on apple valsa canker (AVC) with a reduction of lesion diameter were 80.28% and 83.63%, respectively, and can improve the resistance of apple trees to a pathogen. Five antifungal compounds, namely, canthin-6-one (T1), nigakinone (T2), 4,5-dimethoxycanthin-6-one (T3), 1-methoxycarbonyl-ß-carboline (T4), and 1-methoxycarbonyl-3-methoxyl-ß-carboline (T5), are isolated from P. quassioides using the bioassay-guided method. This is the first report of 1-methoxycarbonyl-3-methoxyl-ß-carboline as a natural product. Canthin-6-one shows strong in vitro inhibitory activity against 11 species of plant pathogenic fungi, and their EC50 values range from 1.49 to 8.80 mg/L. The control efficacy of canthin-6-one at 2000 mg/L are 87.88% and 94.37% against AVC and 80.10% and 84.73% against apple anthracnose (C. gloeosporioides), respectively. Additionally, V. mali is observed after treatment with cannin-6-one, although microscopic. This is the first study on the control of the secondary metabolites of P. quassioides against plant fungal diseases. The results show that P. quassioides is a potential resource for the development of botanical fungicides.

Methylnigakinone content determination and geographical origin discrimination for P. quassioides via fluorescence fingerprint and principal component analyses.

Picrasma quassioides is used as a bittersweet stomach medicine. Because it is a natural product obtained from various geographical regions, the production area is important when P. quassioides is used as a crude drug. Herein, we developed a method to determine the content of methylnigakinone, one of the major active ingredients in P. quassioides, and a protocol for discriminating the geographical origin of this natural product using a fluorescence fingerprint analysis and principal component analysis (PCA). Because methylnigakinone is fluorescent (excitation wavelength: 352 nm, emission wavelength: 458 nm), the content of this molecule can be determined in the concentration range of 0.1-1 µg/mL. The quantification results of methylnigakinone obtained using the developed method were similar to those obtained from an HPLC analysis. Furthermore, the PCA of the fluorescence fingerprint of P. quassioides produced a score plot with the three different geographical origins (Kyushu island (Japan), Shikoku island (Japan), and China) plotted in the regions. Thus, it was possible to discriminate the geographical origin of the P. quassioides samples. The developed method is simple, quick, and has a minimal environmental impact. Therefore, the developed method will be useful for confirming the origin of P. quassioides.

Canthin-6-one (CO) from Picrasma quassioides (D.Don) Benn. ameliorates lipopolysaccharide (LPS)-induced astrocyte activation and associated brain endothelial disruption.

BACKGROUND: Canthin-6-one (CO) is an active ingredient found in Picrasma quassioides (D.Don) Benn. (PQ) that displays various biological activities including anti-inflammatory properties. Several studies reported PQ displayed neuroprotective activities, but its effects on astrocytes have not yet been investigated. Astrocytes are crucial regulators of neuroinflammatory responses under pathological conditions in the central nervous system (CNS). Proinflammatory astrocytes can induce the blood-brain barrier (BBB) breakdown, which plays a key role in the progression of neurodegenerative disorder (ND). PURPOSE: This study aims to investigate the anti-neuroinflammatory effects of CO in LPS-induced astrocyte activation and its underlying mechanisms in protecting the blood-brain barrier (BBB) in vitro. METHODS: Mouse astrocytes (C8-D1A) were activated with lipopolysaccharide (LPS) with or without CO pretreatment. Effects of CO on astrocyte cell viability, secretions of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and nitric oxide (NO) were determined. Intracellular transcriptions and translations of proinflammatory mediators, molecular signaling, [Ca2+] and the levels of reactive oxygen species (ROS) were evaluated by RT-PCR, western blotting, and flow cytometry, respectively. Astrocyte-conditioned medium (ACM) was further prepared for incubating endothelial monolayer (bEnd.3) grown on transwell. Endothelial disruptions were evaluated by transendothelial electrical resistance (TEER), FITC-dextran permeability and monocyte adhesion assays. Endothelial tight junctions (TJs) and molecular signaling pathways were evaluated by immunofluorescence staining and western blotting. RESULTS: CO attenuated LPS-induced expression of astrocytic proinflammatory mediators (TNF-α, IL-1ß, IL-6, NO) and inhibited deleterious molecular activities including inducible nitric oxide synthase (iNOS), p-NFκB and p-STAT3 in astrocytes. Incubation of ACM collected from CO-treated astrocytes significantly ameliorated endothelial disruptions, reduced expressions of endothelial cytokine receptors (IL-6R, gp130 (IL-6RB), TNFR and IL-1R), suppressed proinflammatory pathways, MAPKs (p-AKT, p-MEK, p-ERK, p-p38, p-JNK) and p-STAT3, restored endothelial stabilizing pathways (p-Rac 1) and upregulated beneficial endothelial nitric oxide synthase (eNOS). CONCLUSION: Our study demonstrates for the first time CO exhibited potent protective effects against astrocyte-mediated proinflammatory responses and associated endothelial barrier disruptions.

Alkaloids from Picrasma quassioides: An overview of their NMR data, biosynthetic pathways and pharmacological effects.

Picrasma quassioides, a member of the Simaroubaceae family, is the subject of research in numerous pharmacological and chemical studies. This plant mainly contains alkaloids, quassinoids and terpenoids. These molecules exhibit various pharmacological benefits, such as anti-inflammatory, anticancer, and anti-viral effects, on the cardiovascular system. Alkaloids make up the majority of these molecules. This review describes 127 alkaloid substances from P. quassioides. These alkaloids can be divided into the following classes: ß-carbolines, canthinones and alkaloid dimers. A compilation of their nuclear magnetic resonance spectroscopy data and possible biosynthetic pathways of these compounds and the pharmacological effects of P. quassioides are also included.

Genus Picrasma: A comprehensive review on its ethnopharmacology, phytochemistry and bioactivities.

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Picrasma belongs to the Simaroubaceae family and contains six species which are mainly distributed in tropical and subtropical regions of Asia and America. The barks, roots, stems, branches, or leaves of several Picrasma species have been applied as folk medicines to treat fever, sore throat, dysentery, eczema, nausea, loss of appetite, diabetes mellitus, cancer, and hypertension. AIM OF THE STUDY: A systematic summary on the botanic characterization, ethnopharmacological uses, phytochemistry, bioactivities and toxicity of species belonging to Picrasma was presented to facilitate the exploitation of the therapeutic potential of these plants. MATERIALS AND METHODS: The literatures about Picrasma were retrieved from a series of scientific search engines including Web of Science, SciFinder, PubMed, CNKI, Google Scholar, Elsevier, Wiley, ACS publications, and SpringerLink between 1970 and 2020. Plant names were validated by "The Plant List" (www.theplantlist.org). RESULTS: As ethnopharmacological uses, Picrasma species are valuable folk medicines to treat fever, inflammation, dysentery, eczema, cancer, diabetics, skin infection, and so on. Up to now, a total of 361 compounds including 126 alkaloids, 132 quassinoids, 67 triterpenoids, and 36 miscellaneous compounds were reported from Picrasma species. Quassinoids and alkaloids are the principal constituents in the genus. The extracts and phytochemical constituents of Picrasma species demonstrate a wide range of bioactivities including cytotoxic, anti-inflammatory, antimicrobial, and other activities. CONCLUSIONS: Picrasma species are widely used as traditional medicines, have diverse chemical constituents with obvious biological activities. Nevertheless, further studies are required on the Picrasma species to assert the ethnopharmacological uses, clarify their bioactive constituents, determine pharmacological actions, and toxicity. Therefore, the present review may provide a critical clue for future studies and further exploitations on Picrasma species.

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.

Structure elucidation and absolute configuration determination of C26, C27 and C30 tirucallane triterpenoids from the leaves of Picrasma quassioides (D. Don) Benn.

Seven undescribed tirucallane-type triterpenoids, kumunorquassins A‒E and kumuquassins K and L, along with nine known analogues, have been isolated from the leaves of Picrasma quassioides (D. Don) Benn. Their structures and absolute configurations were elucidated based on comprehensive spectroscopic analyses, single-crystal X-ray diffraction analysis and electronic circular dichroism (ECD). The absolute configuration of cornusalterin J was unequivocally determined by X-ray diffraction based on its p-bromobenzoate derivative. A brief approach was presented in our study, which could rapidly and conveniently determine the relative and absolute configurations of OCH3-23 of kumuquassin L and cornusalterins J, H and G depending on the chemical shift differences (Δδ) of C-24 and C-25 and the chemical shifts of C-23, H-23 and H-24. In addition, the cytotoxicities of these compounds against two human tumour cell lines (HepG2 and Hep3B) were evaluated.

Picraquanines A－C, three new phenolic derivatives from the stems of Picrasma quassioides.

Three new phenolic derivatives, picraquanines A-C (1-3), along with 6 known ones 4-9 were obtained from the stems of Picrasma quassioides (D. Don) Benn. The new structures were determined by extensive spectroscopic data analysis, including IR, HRESIMS, 1H-NMR, 13C-NMR, HSQC, HMBC, 1H-1H COSY experiments. The absolute configuration of 1 was determined by comparison of its experimental and calculated ECD spectra. Furthermore, all the compounds were tested for their nitric oxide (NO) inhibitory effects against LPS-stimulated RAW 264.7 cells, however, none of them exhibited inhibitory effects (IC50 >100 µM).[Figure: see text].

The identification of alkaloids from the stems of Picrasma quassioides via computer-assisted structure elucidation and quantum chemical calculations.

Four new alkaloids (1-4) and one known alkaloid were isolated from the stems of Picrasma quassioides. The structures of these isolated compounds were elucidated by spectroscopic analyses, a combination of computer-assisted structure elucidation software (ACD/Structure Elucidator) and gauge-including atomic orbital (GIAO) calculation of 1 D NMR data. All compounds were evaluated for their cytotoxic activities against hepatocellular carcinoma HepG2 and Hep3B cells. However, they did not show obvious inhibitory activities.[Figure: see text].

Phytochemistry, Traditional Use and Pharmacological Activity of Picrasma quassioides: A Critical Reviews.

Picrasma quassioides is a member of the Simaroubaceae family commonly grown in the regions of Asia, the Himalayas, and India and has been used as a traditional herbal medicine to treat various illnesses such as fever, gastric discomfort, and pediculosis. This study aims to critically review the presence of phytochemicals in P. quassioides and correlate their pharmacological activities with the significance of its use as traditional medicine. Data were collected by reviewing numerous scientific articles from several journal databases on the pharmacological activities of P. quassioides using certain keywords. As a result, approximately 94 phytochemicals extracted from P. quassioides were found to be associated with quassinoids, ß-carbolines and canthinones. These molecules exhibited various pharmacological benefits such as anti-inflammatory, antioxidant, anti-cancer, anti-microbial, and anti-parasitic activities which help to treat different diseases. However, P. quassioides were also found to have several toxicity effects in high doses, although the evidence regarding these effects is limited in proving its safe use and efficacy as herbal medicine. Accordingly, while it can be concluded that P. quassioides may have many potential pharmacological benefits with more phytochemistry discoveries, further research is required to determine its real value in terms of quality, safety, and efficacy of use.