The quality of Paeoniae Radix Alba and Paeoniae Radix Rubra is evaluated by root thickness, and paeoniflorin serves as a common quality indicator of them. However, the correlation between the content of bioactive compounds and the root size is still unclear. Therefore, this study characterized the distribution patterns and content of seven bioactive compounds including paeoniflorin in different tissues of Paeonia lactiflora roots, analyzed the correlation between the root size and the content of bioactive compounds based on the xylem-to-bark ratio, and further determined the index components for quality assessment. Nine samples of fresh P. lactiflora roots were collected from the genuine cultivation area. The distribution of bioactive compounds in different tissues on the cross-section of the root was firstly analyzed by desorption electrospray ionization-mass spectrometry imaging(DESI-MSI). Subsequently, the content of bioactive compounds was determined in the xylems and barks of the roots by UPLC. The compounds with the largest difference between the xylem and the bark were selected by orthogonal partial least squares discriminant analysis(OPLS-DA). The results indicated that paeoniflorin, benzoylpaeoniflorin, oxypaeoniflorin, gallic acid, and 1,2,3,4,6-pentagalloylglucose were significantly accumulated in the xylems, while albiflorin and catechin were mainly distributed in the barks. Paeoniflorin and albiflorin, with the largest differences in the xylem and the bark, had the highest content in the two tissues. The root diameter was positively correlated with paeoniflorin content and negatively correlated with albiflorin content. As isomers with different efficacies, paeoniflorin or albiflorin can be chosen as the quality marker corresponding to specific clinical application to launch quality classification evaluation of multi-functional Chinese medicines.
Bridged-Ring Compounds ; Catechin/analysis* ; Chromatography, High Pressure Liquid/methods* ; Gallic Acid/analysis* ; Monoterpenes/analysis* ; Paeonia/chemistry* ; Plant Roots/chemistry* ; Spectrometry, Mass, Electrospray Ionization

Paeoniflorin, a representative pinane monoterpene glycoside, is the main active component and quality index of Paeoniae Radix Alba and Paeoniae Radix Rubra.The possible biosynthesis of paeoniflorin is as follows: GPP is derived from mevalonate(MVA) and/or 2-C-methyl-D-erythritol 4-phosphate(MEP) pathway(s) followed by the catalysis with terpene synthase, cytochrome P450(CYP450), UDP-glucuronosyltransferase(UGT), and acyltransferase(AT), respectively.This study aims to explore the genes rela-ted to the biosynthesis of paeoniflorin.To be specific, the cDNA libraries for flowers, leaves, and roots of Paeonia lactiflora were established and sequenced.A total of 30 609 open reading frames(ORFs) were yielded.Through functional annotation and expression analysis of all CYP450 genes in the transcriptome, 11 CYP450 genes belonging to CYP71 A and CYP71 D subfamilies and showing expression trend consistent with monoterpene synthase PlPIN that may be involved in paeoniflorin biosynthesis were screened out.Subsequently, 7 UGT genes and 9 AT genes demonstrating the expression trend consistent with PlPIN which were possibly involved in paeoniflorin biosynthesis were further screened by functional annotation analysis, full-length sequence analysis, expression analysis, and phylogeny analysis.This study provided a systematic screening method with smaller number of candidate genes, thus reducing the workload of functional gene verification.The result laid a foundation for analyzing the biosynthesis pathway of paeoniflorin and the formation mechanism.
Bridged-Ring Compounds ; Gene Expression Profiling ; Glucosides/metabolism* ; Monoterpenes/metabolism* ; Paeonia/genetics*

This study aims to establish a rapid and sensitive UPLC-MS/MS method for simultaneously determining the content of strychnine and paeoniflorin in plasma and brain tissue of rats, and compare the pharmacokinetic behavior and brain tissue distribution of paeoniflorin combined with normal and toxic doses of strychnine in rats after percutaneous administration. Compared with those in the toxic-dose strychnine group, the AUC_(0-t), AUC_(0-∞), and C_(max) of strychnine decreased by 51.51%, 45.68%, and 46.03%, respectively(P<0.01), and the corresponding values of paeoniflorin increased by 91.41%, 102.31%, and 169.32%, respectively(P<0.01), in the compatibility group. Compared with the normal-dose strychnine group, the compatibility group showed insignificantly decreased C_(max), AUC_(0-t), and AUC_(0-∞) of strychnine, increased C_(max) and T_(max) of paeoniflorin(P<0.01), 66.88% increase in AUC_(0-t), and 70.55% increase in AUC_(0-∞) of paeoniflorin. In addition, the brain tissue concentration of strychnine decreased and that of paeoniflorin increased after compatibility. The combination of paeoniflorin with normal dose and toxic dose of strychnine can inhibit the percutaneous absorption of strychnine, and greatly promote the percutaneous penetration of paeoniflorin, whereas the interaction mechanism remains to be explored. The UPLC-MS/MS method established in this study is easy to operate and has good precision. It is suitable for in vivo study of pharmacokinetic behavior and brain tissue distribution of paeoniflorin and strychnine after percutaneous administration in rats, which provides reference for the safe and rational clinical use of strychnine and the combined use of drugs, and lays a solid foundation for the development of external preparations containing Strychni Semen.
Administration, Cutaneous ; Animals ; Brain ; Bridged-Ring Compounds/pharmacology* ; Chromatography, Liquid/methods* ; Glucosides ; Monoterpenes ; Rats ; Rats, Sprague-Dawley ; Strychnine ; Tandem Mass Spectrometry/methods* ; Tissue Distribution

Ornithine decarboxylase (ODC) is a key enzyme in the biosynthetic pathway of polyamines and catalyzes the decarboxylation of ornithine to produce putrescine. Inhibition of ODC activity is a potential approach for the prevention and treatment of many diseases including cancer, as the expression levels and the activities of ODC in many abnormal cells and tumor cells are generally higher than those of normal cells. The discovery and evaluation of ODC inhibitors rely on the monitoring of the reaction processes catalyzed by ODC. There are several commonly used methods for analyzing the activity of ODC, such as measuring the yield of putrescine by high performance liquid chromatography, or quantifying the yield of isotope labelled carbon dioxide. However, the cumbersome operation and cost of these assays, as well as the difficulty to achieve high-throughput and real-time detection, hampered their applications. In this work, we optimized a real-time label-free method for analyzing the activity of ODC based on the macromolecule cucurbit[6]uril (CB6) and a fluorescent dye, DSMI (trans-4-[4-(dimethylamino) styryl]-1-methylpyridinium iodide). Finally, the optimized method was used to determine the activities of different ODC inhibitors with different inhibition mechanisms.
Bridged-Ring Compounds ; Imidazoles ; Ornithine ; Ornithine Decarboxylase ; Ornithine Decarboxylase Inhibitors ; Putrescine

BACKGROUND: Taxanes are an essential class of antineoplastic agents used to treat various cancers and are a fundamental cause of hypersensitivity reactions. In addition, other adverse events, such as bone marrow toxicity and peripheral neuropathy, can lead to chemotherapy discontinuation. This study aimed to evaluate the safety of taxanes in the real world. METHODS: Taxane-associated adverse events were identified by the Medical Dictionary for Regulatory Activities Preferred Terms and analyzed and compared by mining the US Food and Drug Administration Adverse Event Reporting System pharmacovigilance database from January 2004 to December 2019. Reported adverse events, such as hypersensitivity reaction, bone marrow toxicity, and peripheral neuropathy, were analyzed with the following signal detection algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), multi-item gamma Poisson shrinker (MGPS), Bayesian confidence propagation neural network (BCPNN), and logistic regression methods. Adverse outcome events and death outcome rates were compared between different taxane groups using Pearson's χ2 test, whereas significance was determined at P < 0.05 with a 95% confidence interval (CI). RESULTS: A total of 966 reports of hypersensitivity reactions, 1109 reports of bone marrow toxicity, and 1374 reports of peripheral neuropathy were analyzed. Compared with paclitaxel and docetaxel, bone marrow toxicity following the use of nab-paclitaxel had the highest ROR of 6.45 (95% two-sided CI, 6.05-6.88), PRR of 5.66, (χ2 = 4342.98), information component of 2.50 (95% one-sided CI = 2.34), and empirical Bayes geometric mean of 5.64 (95% one-sided CI = 5.34). Peripheral neuropathy following the use of nab-paclitaxel showed a higher ROR of 12.78 (95% two-sided CI, 11.55-14.14), PRR of 12.16 (χ2 = 4060.88), information component of 3.59 (95% one-sided CI = 3.25), and empirical Bayes geometric mean of 12.07 (95% one-sided CI = 11.09). CONCLUSIONS The results showed that bone marrow toxicity and peripheral neuropathy were the major adverse events induced by taxanes. Nab-paclitaxel exhibited the highest potential for taxane-associated adverse events. Further research in the future is warranted to explain taxane-associated adverse effects in real-world circumstances.
Adverse Drug Reaction Reporting Systems ; Bayes Theorem ; Bridged-Ring Compounds ; Taxoids/adverse effects* ; United States ; United States Food and Drug Administration

BACKGROUND: Autophagy plays a crucial role in chemotherapy resistance of triple-negative breast cancer (TNBC). Hence, autophagy-related gene 5 (ATG5), an essential molecule involved in autophagy regulation, is presumably associated with recurrence of TNBC. This study was aimed to investigate the potential influence of single-nucleotide polymorphisms in ATG5 on the disease-free survival (DFS) of early-stage TNBC patients treated with anthracycline- and/or taxane-based chemotherapy. METHODS: We genotyped ATG5 SNP rs473543 in a cohort of 316 TNBC patients treated with anthracycline- and/or taxane-based chemotherapy using the sequenom's MassARRAY system. Kaplan-Meier survival analysis and Cox proportional hazard regression analysis were used to analyze the association between ATG5 rs473543 genotypes and the clinical outcome of TNBC patients. RESULTS: Three genotypes, AA, GA, and GG, were detected in the rs473543 of ATG5 gene. The distribution of ATG5 rs473543 genotypes was significantly different between patients with and without recurrence (P = 0.024). Kaplan-Meier survival analysis showed that patients carrying A allele of ATG5 rs473543 had an increased risk of recurrence and shorter DFS compared with those carrying the variant genotype GG in rs473543 (P = 0.034). In addition, after adjusting for clinical factors, multivariate Cox regression analyses revealed that the AA/GA genotype of rs473543 was an independent predictor for DFS (hazard risk [HR], 1.73; 95% confidence interval [CI], 1.04-2.87; P = 0.034). In addition, DFS was shorter in node-negative patients with the presence of A allele (AA/GA) than in those with the absence of A allele (P = 0.027). CONCLUSION ATG5 rs473543 genotypes may serve as a potential marker for predicting recurrence of early-stage TNBC patients who received anthracycline-and/or taxane-based regimens as adjuvant chemotherapy.
Adult ; Aged ; Anthracyclines ; administration & dosage ; adverse effects ; Autophagy-Related Protein 5 ; genetics ; Bridged-Ring Compounds ; administration & dosage ; adverse effects ; Chemotherapy, Adjuvant ; Disease-Free Survival ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Kaplan-Meier Estimate ; Middle Aged ; Neoplasm Recurrence, Local ; drug therapy ; genetics ; pathology ; Polymorphism, Single Nucleotide ; genetics ; Taxoids ; administration & dosage ; adverse effects ; Triple Negative Breast Neoplasms ; drug therapy ; genetics ; pathology

OBJECTIVE: To systematically review the efficacy and safety of taxane, cisplatin, and fluorouracil (Tax-PF) as induction chemotherapy for advanced head and neck cancer. METHOD: Literature about the efficacy and safety of Taxane-cisplatin-fluorouracil as induction chemotherapy for advanced head and neck cancer was retrieved from digital databases of PubMed, Embase, SpringerLink, MEDLINE and the Cochrane Library before February 2015. Data extraction and quality assessment of included studies were conducted by two reviewers independently. Stata 13.0 was then used to perform Meta-analysis. RESULT: A total 7 randomized controlled trials involving 2,702 were included. The 3-year OS rate [HR = 1.14, 95% CI (1.03, 1.25), P < 0.01], 3-year PFS rate [HR = 1.24, 95% CI (1.08, 1.43), P < 0.01], 5-year OS rate [HR = 1.30, 95% CI (1.09, 1. 55), P < 0. 01], 5-year PFS rate [HR = 1.39, 95% CI (1.14, 1.70), P < 0.01] and ORR to chemotherapy [OR = 1.66, 95% CI (1.35, 2.05), P < 0.01] of the patients in the Tax-PF group were statistically superior to those in the PF group. In terms of toxicities, the incidence of febrile neutropenia [OR = 2.36, 95% CI (1.62, 3.46), P < 0.01], alopecia [OR = 8.22, 95% CI (3.99, 16.92), P < 0.01], diarrhea [OR = 1.57, 95% CI (1.05, 2.36), P< 0.05] and leucopenia [OR = 2.79, 95% CI (1.86, 4.21), P < 0.01] was higher in the Tax-PF group than that in the PF group. CONCLUSION The Tax-PF induction chemotherapy improved PFS and OS, and the ORR was better as compared to PF-based therapy regimens at the cost of a higher incidence of adverse events.
Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Bridged-Ring Compounds ; therapeutic use ; Cisplatin ; therapeutic use ; Fluorouracil ; therapeutic use ; Head and Neck Neoplasms ; drug therapy ; Humans ; Induction Chemotherapy ; Randomized Controlled Trials as Topic ; Taxoids ; therapeutic use

Paeonia lactiflora root (baishao in Chinese) is a commonly used herb in traditional Chinese medicines (TCM). Two isomers, paeoniflorin (PF) and albiflorin (AF), are isolated from P. lactiflora. The present study aimed to investigate the protective effects of PF and AF on myelosuppression induced by chemotherapy in mice and to explore the underlying mechanisms. The mouse myelosuppression model was established by intraperitoneal (i.p.) injection of cyclophosphamide (CP, 200 mg·kg(-1)). The blood cell counts were performed. The thymus index and spleen index were also determined and bone morrow histological examination was performed. The levels of tumor necrosis factor-α (TNF-α) in serum and colony-stimulating factor (G-CSF) in plasma were measured by Enzyme-Linked Immunosorbent Assays (ELISA) and the serum levels of interleukin-3 (IL-3), granulocyte-macrophagecolony-stimulatingfactor (GM-CSF), and interleukin-6 (IL-6) were measured by radioimmunoassay (RIA). The levels of mRNA expression protein of IL-3, GM-CSF and G-CSF in spleen and bone marrow cells were determined respectively. PF and AF significantly increased the white blood cell (WBC) counts and reversed the atrophy of thymus. They also increased the serum levels of GM-CSF and IL-3 and the plasma level of G-CSF and reduced the level of TNF-α in serum. PF enhanced the mRNA level of IL-3 and AF enhanced the mRNA levels of GM-CSF and G-CSF in the spleen. PF and AF both increased the protein levels of GM-CSF and G-CSF in bone marrow cells. In conclusion, our results demonstrated that PF and AF promoted the recovery of bone marrow hemopoietic function in the mouse myelosuppression model.
Animals ; Antineoplastic Agents ; adverse effects ; Bridged-Ring Compounds ; administration & dosage ; Cyclophosphamide ; adverse effects ; Drugs, Chinese Herbal ; administration & dosage ; Glucosides ; administration & dosage ; Granulocyte Colony-Stimulating Factor ; genetics ; metabolism ; Granulocyte-Macrophage Colony-Stimulating Factor ; genetics ; metabolism ; Hematologic Diseases ; etiology ; genetics ; metabolism ; prevention & control ; Humans ; Interleukin-3 ; genetics ; metabolism ; Interleukin-6 ; metabolism ; Male ; Mice ; Monoterpenes ; administration & dosage ; Paeonia ; chemistry ; Tumor Necrosis Factor-alpha ; genetics ; metabolism

To compare the chemical change of Paeoniae Radix Alba (PRA) after vinegar-baking processing, as well as the effect of vinegar types exerted on the processing, 1H NMR-based metabolomic approach combined with multivariate statistical analysis was used to investigate the different metabolites between the raw and two vinegar-baked PRA. More than thirty metabolites were identified in the 1H NMR spectrum of PRA, and the multivariate statistical analysis showed that raw and two vinegar-baked PRA could be separated obviously. After vinegar-baking, the contents of isoleucine, lactate, alanine, arginine, albiflorin, and 5-hydroxymethyl furfural (5-HMF) elevated, while those of sucrose, paeoniflorin and its analogues (calculated by benzoate) decreased. The chemical compositions of two vinegar-baked PRA were also different. Shanxi vinegar- baked PRA showed higher levels of leucine, isoleucine, valine, and albiflorin, while rice vinegar-baked PRA contained more sucrose and paeoniflorin's analogues (calculated by benzoate). And the chemical changes in Shanxi vinegar-baked PRA were greater than those of rice vinegar-baked PRA. The results revealed the chemical differences between raw and vinegar-baked PRA, as well as the influence of vinegar type on processing, in a holistic manner, the results obtained suggested that the correlations between the chemical change and the drug action after processing, as well as the vinegar type used in processing, should be further studied.
Acetic Acid ; Benzoates ; Bridged-Ring Compounds ; Cooking ; Drugs, Chinese Herbal ; Furaldehyde ; analogs & derivatives ; Glucosides ; Metabolome ; Metabolomics ; Monoterpenes ; Paeonia ; chemistry ; Plant Roots ; chemistry

OBJECTIVETo assess the efficacy of vinorelbine (NVB)-based regimens in patients with metastatic triple negative breast cancer (mTNBC) pretreated with anthracyclines and taxanes.

METHODSClinical data of 48 patients diagnosed and treated for mTNBC between 2004 and 2012 at the Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) were retrospectively analyzed. All patients were pretreated with anthracyclines and at least one taxane in neo-adjuvant, adjuvant or chemotherapy for mTNBC and patients should be having at least one measurable metastatic lesion. Totally, 48 patients were included in this study, of which 21 cases received first-line chemotherapy and 27 cases received second-line chemotherapy. Based on the regimen they received, 22 patients were treated with NVB plus platinum (NP), and 26 patients with NVB plus capecitabine (NX).

RESULTSAfter 70 months follow-up, in the total group of patients, the objective response rate was 20.8%, clinical benefit rate was 43.8%, median progression free survival (PFS) was 4.4 months and median overall survival (OS) was 15.5 months. In addition, the ORR was significantly better in the NP arm versus NX arm (33.8% vs.7.7%, P=0.029) as well as PFS was statistically improved in the NP arm than NX arm (5.3 m vs. 3.0 m, P=0.023). Similar trend was observed in the OS, although the difference was not statistically significant (27.7 m vs. 14.8 m, P=0.077). In all, the most frequently reported adverse events were G1/2 gastrointestinal toxicity (68.8%) and neutropenia (62.5%) . No significant difference was observed between the NP arm and NX arm (P>0.05). The percentage of patients who delayed chemotherapy administration in the NP arm and NX arm was 9.1% (n=2), and 3.8% (n=1), respectively.

CONCLUSIONSNVB-based combination chemotherapy demonstrates moderate efficacy in mTNBC patients pretreated with anthracyclines and one taxane with manageable toxicity. NP regimen shows potential superiority over NX regimen, and should be further verified in randomized phase III clinical trial in larger cohort.

Anthracyclines ; therapeutic use ; Antibiotics, Antineoplastic ; adverse effects ; therapeutic use ; Antineoplastic Agents, Phytogenic ; adverse effects ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Bridged-Ring Compounds ; therapeutic use ; Capecitabine ; administration & dosage ; Cisplatin ; administration & dosage ; Disease-Free Survival ; Humans ; Neutropenia ; chemically induced ; Retrospective Studies ; Taxoids ; therapeutic use ; Triple Negative Breast Neoplasms ; drug therapy ; pathology ; Vinblastine ; adverse effects ; analogs & derivatives ; therapeutic use