ABSTRACT
Gastric cancer (GC) remains the third leading cause of cancer-related mortality in the world, and ninety-five percent of GC are stomach adenocarcinomas (STAD). The active ingredients of Croci Stigma, such as Isorhamnetin, Crocin, Crocetin and Kaempferol, all have antitumor activity. However, their chemical and pharmacological profiles remain to be elusive. In this study, network pharmacology was used to characterize the action mechanism of Croci Stigma. All compounds were obtained from the traditional Chinese medicine systems pharmacology (TCMSP) database, and active ingredients were selected by their oral bioavailability and drug-likeness index. The targets of Croci Stigma active ingredients were obtained from the traditional Chinese medicine integrated database (TCMID), whereas the related genes of STAD were obtained from DisGeNET platform. Cytoscape was used to undertake visual analyses of the Drug Ingredients-Gene Symbols-Disease (I-G-D) network, and 2 core genes including MAPK14, ERBB3 were obtained, which are the predicted targets of isorhamnetin (IH) and quercetin, respectively. Data analysis from TCGA platform showed that MAPK14 and ERBB3 all upregulated in STAD patients, but only the effect of MAPK14 expression on STAD patients' survival was significant. Molecular docking showed that IH might affect the function of MAPK14 protein, and then the underlying action mechanisms of IH on STAD were experimentally validated using human gastric cancer cell line, HGC-27 cells. The results showed that IH can inhibit cell proliferation, migration, clonal formation, and arrest cell cycle, but promote the apoptosis of HGC-27 cells. qRT-PCR data demonstrated that IH downregulated the MAPK14 mRNA expression and EMT related genes. WB results showed that IH regulates MAPK/mTOR signaling pathway. These findings suggest that IH has the therapeutic potential for the treatment of STAD.
Subject(s)
Adenocarcinoma , Drugs, Chinese Herbal , Mitogen-Activated Protein Kinase 14 , Stomach Neoplasms , Humans , Quercetin/pharmacology , Molecular Docking Simulation , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Signal Transduction , TOR Serine-Threonine Kinases/genetics , Adenocarcinoma/drug therapy , Adenocarcinoma/geneticsABSTRACT
Phytoconstituents of the peels of Callistemon viminalis has been investigated for the first time. As a result, two pair of diastereomers of hybrids of ß-triketone and α-phellandrene, named viminalisones A-B (1-2) and viminalisones CD (3-4), and three known analogues were obtained. Their structures and absolute configurations were elucidated through a combination of the analysis of their MS data, NMR spectra, single-crystal X-ray diffraction, and their experimental and calculated electronic circular dichroism (ECD) spectra. All isolates were evaluated for their antimicrobial activities against Botrytis cinerea and Cutibacterium acnes. Meroterpenoid 7 exhibited antibacterial activity against Botrytis cinerea with a MIC value of 0.256 mg/mL.
Subject(s)
Monoterpenes , Myrtaceae , Molecular Structure , Microbial Sensitivity Tests , Myrtaceae/chemistryABSTRACT
Excessive utilization of chemical fertilizers (CF) is not a sustainable agricultural development strategy due to adverse effects on soil health. In contrast, a combination of organic and mineral fertilizers has a positive effect on both soil health and productivity. Chinese medicinal herbal residues (CMHR) is the plant material wastes remaining after drug extraction but has not been extensively used as fertilizer. We evaluated application of CMHR to maize fields over 3 consecutive growing seasons in the presence and absence of standard CF to assess improvements in soil fertility, maize yields and sustainable development. CMHR fertilization increased soil organic matter and total N and K when mixed with chemical fertilizer at 50 and 75% the standard application rate. Soil organic matter increased by 27.0-51.4% and available -N, -P and -K levels and grain yields as well as N and P use efficiency in the presence of CMHR mixes were similar to levels obtained with chemical fertilizer only. These increases in production were due to increased leaf areas, photosynthetic rates, grain number and 1000-grain weights. The addition of CMHR to fields posed a slightly risk of toxic-metal pollution. Overall, we found that (1) CMHR can be used as an effective organic fertilizer and replace up to 50% of the amount of chemical fertilizer normally applied to fields without hampering maize grain yields and (2) CMHR application to agricultural fields is an effective recycling strategy and nutrient management practice to improve soil fertility under CF usage reduction.
Subject(s)
Fertilizers , Soil , Agriculture , China , Fertilizers/analysis , Nitrogen/analysis , Zea maysABSTRACT
Two nonbiaryl axially chiral ß-carboline-quinazoline dimers, pegaharmols A (1) and B (2), were isolated from the roots of Peganum harmala. Their planar structures were elucidated by the spectroscopic methods of high-resolution mass spectrometry and 1D and 2D nuclear magnetic resonance (NMR). The stereochemistry was established by a comparison between the experimental data of NMR and electronic circular dichroism and the computed data by quantum mechanical calculations. It is discovered for the first time that the ß-carboline at the C-8 position is bonded to the vasicine at the C-9 position. 1 exhibited moderate cytotoxic activity against HL-60 and A549 cell lines.
Subject(s)
Alkaloids/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Carbolines/pharmacology , Peganum/chemistry , Plant Roots/chemistry , Quinazolines/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Carbolines/chemistry , Carbolines/isolation & purification , Drug Screening Assays, Antitumor , HL-60 Cells , Humans , Molecular Structure , Plant Extracts/chemistryABSTRACT
Studies that evaluate the human health risk of heavy metal(loid)s pollution have not been widely performed for organic waste-amended soils on the Loess Plateau of China. With this respect, we conducted a 3-year field trial to estimate the heavy metal(loid)s contamination of soil and maize, the resultant nutritional quality of maize grains and the health risk under treatments of conventional fertilizer (CF), traditional Chinese medicine residue (TCMR) and sheep manure (SM). We found that protein, amino acids and lysine in maize grains were increased by 12.3, 11.3 and 5.88 % under TCMR treatments relative to SM application, respectively. Meanwhile, this treatment reduced the levels of Cr, Pb, Cd, As and Hg in soil and maize grains. All fertilization regimens resulted in greater health risks for children, with HI values ranging from 1.06 to 1.52 and CR levels for Cr and As being ï¹¥1.0 × 10-4, especially higher in SM treatments. This presented the beneficial effect of TCMR than SM. The further investigated of toxic metal(loid)s level in SM and its application risks, based on meta-analysis and Monte Carlo simulation, indicated Cd, Hg and Pb were the most cautionary heavy metal(loid)s and contamination risk were greater on the southwest regions of China.
Subject(s)
Metals, Heavy , Soil Pollutants , Animals , China , Environmental Monitoring , Metals, Heavy/analysis , Nutritive Value , Risk Assessment , Sheep , Soil , Soil Pollutants/analysisABSTRACT
Aiming to obtain the more effective pathogen inhibitive ingredients and explore the influence of introducing different heterocyclic units to carvacrol and thymol esters, twenty ester derivatives with different heterocyclic units were synthesized. And the in vitro antifungal activity of title compounds against five plant pathogenic fungi was evaluated by mycelium growth rate method. The results showed that some carvacrol and thymol esters showed good to excellent antifungal activity, and compound 9d (4-bromo-5-isopropyl-2-methylphenyl picolinate) exhibited a broad antifungal spectrum. Preliminary study indicated that the introduction of furan, thiophene and pyridine unit could enhance the antifungal activity of carvacrol and thymol esters against Botrytis cinerea and a bromine atom on the para position of benzene moiety could enhance their antifungal activity.
Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Monoterpenes/chemistry , Thymol/chemistry , Botrytis/drug effects , Botrytis/pathogenicity , Carboxylic Acids/chemistry , Cymenes , Drug Evaluation, Preclinical/methods , Esters/chemistry , Fungicides, Industrial/chemical synthesis , Fungicides, Industrial/chemistry , Fungicides, Industrial/pharmacology , Microbial Sensitivity Tests , Monoterpenes/chemical synthesis , Monoterpenes/pharmacology , Mycelium/drug effects , Structure-Activity Relationship , Thymol/chemical synthesisABSTRACT
Baicalein and scutellarein are bioactive flavones found in the medicinal plant Scutellaria baicalensis Georgi, used in traditional Chinese medicine. Extensive previous work has demonstrated the broad biological activity of these flavonoids, such as antifibrotic, antiviral and anticancer properties. However, their supply from plant material is insufficient to meet demand. Here, to provide an alternative production source and increase production levels of these flavones, we engineered an artificial pathway in an Escherichia coli cell factory for the first time. By first reconstructing the plant flavonoid biosynthetic pathway genes from five different species: phenylalanine ammonia lyase from Rhodotorula toruloides (PAL), 4-coumarate-coenzyme A ligase from Petroselinum crispum (4CL), chalcone synthase from Petunia hybrida (CHS), chalcone isomerase from Medicago sativa (CHI) and an oxidoreductase flavone synthase I from P. crispum (FNSI), production of the intermediates chrysin and apigenin was achieved by feeding phenylalanine and tyrosine as precursors. By comparative analysis of various versions of P450s, a construction expressing 2B1 incorporated with a 22-aa N-terminal truncated flavone C-6 hydroxylase from S. baicalensis (F6H) and partner P450 reductase from Arabidopsis thaliana (AtCPR) was found most effective for production of both baicalein (8.5â¯mg/L) and scutellarein (47.1â¯mg/L) upon supplementation with 0.5â¯g/L phenylalanine and tyrosine in 48â¯h of fermentation. Finally, optimization of malonyl-CoA availability further increased the production of baicalein to 23.6â¯mg/L and scutellarein to 106.5â¯mg/L in a flask culture. This report presents a significant advancement of flavone synthetic production and provides foundation for production of other flavones in microbial hosts.
Subject(s)
Apigenin/biosynthesis , Escherichia coli/genetics , Escherichia coli/metabolism , Flavanones/biosynthesis , Metabolic Engineering/methods , Phenylalanine/metabolism , Plants/metabolism , Tyrosine/metabolism , Biosynthetic Pathways/genetics , Flavonoids/biosynthesis , Malonyl Coenzyme A/metabolism , Scutellaria baicalensisABSTRACT
Human telomeres can form DNA G-quadruplex (G4), an attractive target for anticancer drugs. Human telomeric G4s bear inherent structure polymorphism, challenging for understanding specific recognition by ligands or proteins. Protoberberines are medicinal natural-products known to stabilize telomeric G4s and inhibit telomerase. Here we report epiberberine (EPI) specifically recognizes the hybrid-2 telomeric G4 predominant in physiologically relevant K+ solution and converts other telomeric G4 forms to hybrid-2, the first such example reported. Our NMR structure in K+ solution shows EPI binding induces extensive rearrangement of the previously disordered 5'-flanking and loop segments to form an unprecedented four-layer binding pocket specific to the hybrid-2 telomeric G4; EPI recruits the (-1) adenine to form a "quasi-triad" intercalated between the external tetrad and a T:T:A triad, capped by a T:T base pair. Our study provides structural basis for small-molecule drug design targeting the human telomeric G4.
Subject(s)
Berberine/analogs & derivatives , G-Quadruplexes/drug effects , Telomere , Base Sequence , Berberine/metabolism , Berberine/pharmacology , Binding Sites , Circular Dichroism , Drugs, Chinese Herbal , Humans , Intercalating Agents/chemistry , Nucleic Acid Conformation , Potassium/chemistry , Proton Magnetic Resonance SpectroscopyABSTRACT
Five pairs of new 2-oxoindole alkaloids, (±)-peganumalines A-E (1-5), and a new indole alkaloid, peganumaline F (6), along with two known analogues, were isolated from the seeds of Peganum harmala. Their structures and absolute configurations were elucidated through spectroscopic analyses and quantum chemistry calculations. Notably, (±)-peganumalines A (1) represent a pair of rare 2-oxoindole dimeric alkaloid enantiomer with the hitherto unknown carbon skeleton. All isolates were tested for antiproliferative and antibacterial activities.
Subject(s)
Indole Alkaloids/chemistry , Peganum/chemistry , Seeds/chemistry , Cell Line, Tumor , Humans , Indole Alkaloids/isolation & purification , Microbial Sensitivity Tests , Molecular StructureABSTRACT
Inspired by the intriguing structures and bioactivities of dimeric alkaloids, 11 new thalifaberine-type aporphine-benzylisoquinoline alkaloids, thalicultratines A-K, a tetrahydroprotoberberine-aporphine alkaloid, thalicultratine L, and five known ones were isolated from the roots of Thalictrum cultratum. Their structures were defined on the basis of NMR and HRESIMS data. The antiproliferative activities of compounds 1-17 were evaluated against human leukemia HL-60 and prostate cancer PC-3 cells. Most alkaloids showed potent cytotoxicity against selected cancer cells. Preliminary SARs are discussed. The most active new compound (3), with an IC50 value of 1.06 µM against HL-60 cells, was selected for mechanism of action studies. The results revealed that compound 3 induced apoptosis and arrested the HL-60 cell cycle at the S phase with the loss of mitochondria membrane potential. The nuclear morphological Hoechst 33258 staining assay was also carried out, and the results confirmed apoptosis.
Subject(s)
Alkaloids/isolation & purification , Alkaloids/pharmacology , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/pharmacology , Aporphines/isolation & purification , Aporphines/pharmacology , Drugs, Chinese Herbal/isolation & purification , Drugs, Chinese Herbal/pharmacology , Plant Roots/chemistry , Thalictrum/chemistry , Alkaloids/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Aporphines/chemistry , Berberine Alkaloids , Drugs, Chinese Herbal/chemistry , HL-60 Cells , Humans , Inhibitory Concentration 50 , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Structure-Activity RelationshipABSTRACT
Investigation of the alkaloids from Peganum harmala seeds yielded two pairs of unique racemic pyrroloindole alkaloids, (±)-peganines A-B (1-2); two rare thiazole derivatives, peganumals A-B (3-4); six new ß-carboline alkaloids, pegaharmines F-K (5-10); and 12 known analogues. Their structures, including stereochemistry, were elucidated through spectroscopic analyses, quantum chemistry calculations, and single-crystal X-ray diffraction. Notably, the incorporation of pyrrole and indole moieties in peganines A-B, thiazole fragments in peganumals A-B, and a C-1 α,ß-unsaturated ester motif in pegaharmine F (5) are all rare, and their presence in the genus Peganum were demonstrated for the first time. All isolates were tested for antiproliferative activities against the HL-60, PC-3, and SGC-7901 cancer cell lines, and compounds 9, 11, 12, and 13 exhibited moderate cytotoxicity against HL-60 cancer cell lines with IC50 values in the range of 4.36-9.25 µM.
Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/isolation & purification , Indole Alkaloids/chemistry , Indole Alkaloids/isolation & purification , Peganum/chemistry , Seeds/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Carbolines/chemistry , Drug Screening Assays, Antitumor , Drugs, Chinese Herbal/pharmacology , HL-60 Cells , Humans , Indole Alkaloids/pharmacology , Inhibitory Concentration 50 , Molecular Structure , Nuclear Magnetic Resonance, BiomolecularABSTRACT
Three new butenolides containing 5-hydroxyfuran-2(5H)-one core, asperteretal A (1), asperteretal B (2), and asperteretal C (3), together with seven known butenolides (4-10), were obtained from an endophytic fungus Aspergillus terreus PR-P-2 isolated from the plant Camellia sinensis var. assamica. The structures of compounds 1-3 were elucidated on the basis of detailed spectroscopic analysis including UV, IR, HRESIMS, 1D and 2D NMR, and ECD spectra. Compounds 1, 3, 5 and 6-8 showed potent inhibitory effects on NO production in RAW 264.7 lipopolysaccharide-induced macrophages, and compounds 5 and 8 also exhibited moderate cytotoxicity against HL-60 cell line.
Subject(s)
4-Butyrolactone/analogs & derivatives , Aspergillus/chemistry , Camellia sinensis/microbiology , 4-Butyrolactone/chemistry , 4-Butyrolactone/isolation & purification , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Endophytes/chemistry , HL-60 Cells , Humans , Mice , Molecular Structure , Nitric Oxide/metabolism , RAW 264.7 CellsABSTRACT
In this study, we screened 17 medicinal plants for binding activity to G-quadruplex d(TTGGGTT)4 by (1)H NMR spectroscopy and found that the crude extract of Peganum harmala L. seeds showed the most potential binding activity. Subsequently, (1)H NMR- and bioassay-guided isolation of the extract of P. harmala L. was performed to obtain four pairs of partially racemized ß-carboline alkaloids, pegaharmines A-D (1-4). Their structures and absolute configurations were determined by extensive NMR analyses, X-ray crystallography, ECD calculations, and CD exciton chirality approaches. Interestingly, pegaharmine D (4), which showed the strongest G-quadruplex interaction, exhibited significant cytotoxic activity against three cancer cell lines. This work contributed a practical strategy for the discovery of novel G-quadruplex ligands from natural products and provided potential insights for using ß-carboline alkaloids as anticancer lead compounds specifically targeting G-quadruplexes.
Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Carbolines/chemistry , Oligodeoxyribonucleotides/chemistry , Peganum/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/pharmacology , Base Sequence , Biosynthetic Pathways , Carbolines/isolation & purification , Carbolines/pharmacology , Drug Screening Assays, Antitumor , G-Quadruplexes , HL-60 Cells , Humans , Inhibitory Concentration 50 , Molecular Structure , Peganum/metabolism , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Seeds/chemistryABSTRACT
This study examined a pair of neighbouring small watersheds with contrasting vegetations: artificial forestland and natural grassland. Since 1954, afforestation which mainly planted with black locust has been conducted in one of these watersheds and natural revegetation in the other. The differences in soil total N, nitrate, ammonium, foliar litterfall δ(15)N and dual stable isotopes of δ(15)N and δ(18)O in soil nitrate were investigated in the two ecosystems. Results showed that there was no significant difference in soil total N storage between the two ecosystems, but the black locust forestland presented higher soil nitrate than the grassland. Moreover, the foliar litterfall N content and δ(15)N of the forestland were significant higher than the grassland. These results indicate that 60 years of watershed black locust afforestation have increased soil N availability. The higher nitrate in the forestland was attributed to the biological N fixation of black locust and difference in ecosystem hydrology. The dual stable isotopes of δ(15)N and δ(18)O revealed that the two ecosystems had different sources of soil nitrate. The soil nitrate in the forestland was likely derived from soil N nitrification, while the soil nitrate in the grassland was probably derived from the legacy of NO3(-) fertiliser.
Subject(s)
Nitrogen/analysis , Robinia/classification , Robinia/growth & development , Soil/chemistry , China , Ecosystem , Forests , Grassland , Nitrification , Nitrogen Isotopes/analysis , Oxygen Isotopes/analysisABSTRACT
Two novel rare chloro-containing benzylisoquinoline alkaloids, thalfoliolosumines A (1) and B (2), along with eight known isoquinoline alkaloids (3-10) were isolated from the whole plant of Thalictrum foliolosum. The structures of these compounds were elucidated by spectral analyses, including 1D and 2D NMR (COSY, HSQC, HMBC and NOESY) experiments. The antiproliferative effects of all the isolated compounds were evaluated by MTT method against MCF-7, PC-3, and U937 cells, and trypan blue method against HL-60 cells. New compounds 1 and 2 exhibited moderate in vitro antiproliferative activity against MCF-7, PC-3, and HL-60 cells, and good inhibitory effects against U937 cells with IC50 values of 7.50 and 6.97 µM, respectively. Compounds 7 and 10 showed the strongest in vitro antiproliferative with IC50 values of 0.93 and 1.69 µM against HL-60 cell line. The antioxidant properties were also measured, bisbenzyltetrahydroisoquinoline alkaloids 3-6 showed the strongest antioxidant activities in ABTS assay.
Subject(s)
Alkaloids/pharmacology , Antioxidants/pharmacology , Benzylisoquinolines/pharmacology , Cell Proliferation/drug effects , Plant Extracts/pharmacology , Thalictrum , Alkaloids/chemistry , Alkaloids/isolation & purification , Antioxidants/chemistry , Antioxidants/isolation & purification , Benzylisoquinolines/chemistry , Benzylisoquinolines/isolation & purification , Cell Proliferation/physiology , HL-60 Cells , Humans , MCF-7 Cells , Plant Extracts/chemistry , Plant Extracts/isolation & purification , U937 CellsABSTRACT
Two prenylated biflavonoids, podoverines B-C, were isolated from the dried roots and rhizomes of Sinopodophyllum emodi using a Sephadex LH-20 column (SLHC) and high-speed counter-current chromatography (HSCCC). The 95% ethanol extract was partitioned with ethyl acetate in water. Target compounds from the ethyl acetate fraction were further enriched and purified by the combined application of SLHC and HSCCC. n-Hexane-ethyl acetate-methanol-water (3.5:5:3.5:5, v/v) was chosen as the two phase solvent system. The flow rate of mobile phase was optimized at 2.0 mL·min(-1). Finally, under optimized conditions, 13.8 mg of podoverine B and 16.2 mg of podoverine C were obtained from 200 mg of the enriched sample. The purities of podoverines B and C were 98.62% and 99.05%, respectively, as determined by HPLC. For the first time, podoverins B and C were found in the genus Sinopodophyllum. Their structures were determined by spectroscopic methods (HR-ESI-MS, ¹H-NMR, (13)C-NMR, HSQC, HMBC). Their absolute configurations were elucidated by comparison of their experimental and calculated ECD spectra. The cytotoxic activities were evaluated against MCF-7 and HepG2 cell lines. The separation procedures proved to be practical and economical, especially for trace prenylated biflavonoids from traditional Chinese medicine.
Subject(s)
Biflavonoids/isolation & purification , Plant Roots/chemistry , Podophyllum/chemistry , Rhizome/chemistry , Biflavonoids/chemistry , Biflavonoids/pharmacology , Cell Proliferation/drug effects , Cell Survival/drug effects , Countercurrent Distribution/methods , Dextrans/chemistry , Hep G2 Cells , Humans , MCF-7 Cells , Molecular StructureABSTRACT
Modulation of urinary excretion of green tea polyphenols (GTPs) and oxidative DNA damage biomarker, 8-hydroxydeoxyguanosine (8-OHdG), were assessed in urine samples collected from a randomized, double-blinded and placebo-controlled phase IIa chemoprevention trial with GTP in 124 individuals. These individuals were sero-positive for both HBsAg and aflatoxin-albumin adducts, and took GTP capsules daily at doses of 500 mg, 1000 mg or a placebo for 3 months. Twenty-four hour urine samples were collected before the intervention and at the first and third month of the study. Urinary excretion of 8-OHdG and GTP components was measured by HPLC-CoulArray electrochemical detection. The baseline levels of 8-OHdG and GTP components among the three groups showed homogeneity (P > 0.70), and a non-significant fluctuation was observed in the placebo group over the 3 months (P > 0.30). In GTP-treated groups, epigallocatechin (EGC) and epicatechin (EC) levels displayed significant and dose-dependent increases in both the 500 mg group and 1000 mg group (P < 0.05). The 8-OHdG levels did not differ between the three groups at the 1 month collection, with medians of 1.83, 2.08 and 1.86 ng/mg-creatinine for placebo, 500 and 1000 mg group, respectively (P = 0.999). At the end of the 3 months' intervention, 8-OHdG levels decreased significantly in both GTP-treated groups, with medians of 2.02, 1.03 and 1.15 ng/mg-creatinine for placebo, 500 mg and 1000 mg group, respectively (P = 0.007). These results suggest that urinary excretions of EGC and EC can serve as practical biomarkers for green tea consumption in human populations. The results also suggest that chemoprevention with GTP is effective in diminishing oxidative DNA damage.