Analgesic Activity of Jin Ling Zi Powder and Its Single Herbs: A Serum Metabonomics Study.

OBJECTIVE: To compare the analgesic effect of Jin Ling Zi Powder (JLZ) and its two single herbs. METHODS: The hot plate method was used to induce pain. Totally 36 mice were randomly divided into 6 groups by a complete random design, including control, model, aspirin (ASP, 0.14 g/kg body weight), JLZ (14 g/kg body weight), Corydalis yanhusuo (YHS, 14 g/kg body weight), and Toosendan Fructus (TF, 14 g/kg body weight) groups, 6 mice in each group. The mice in the control and model groups were given the same volume of saline, daily for 2 consecutive weeks. At 30, 60, 90, and 120 min after the last administration, the pain threshold of mice in each group was measured, and the improvement rate of pain threshold was calculated. Serum endogenous metabolites were analyzed by gas chromatography-mass spectrometry (GC-MS). RESULTS: There was no statistical difference in pain threshold among groups before administration (P>0.05). After 2 weeks of administration, compared with the model group, the pain threshold in JLZ, YHS, TF and ASP groups were increased to varying degrees (P<0.05). JLZ had the best analgesic effect and was superior to YHS and TF groups. A total of 14 potential biomarkers were screened in serum data analysis and potential biomarkers levels were all reversed to different degrees after the treatment with JLZ and its single herbs. These potential biomarkers were mainly related to glyoxylate and dicarboxylate metabolism, glycine, serine and threonine metabolism, valine, leucine and isoleucine biosynthesis, aminoacyl-tRNA biosynthesis and inositol phosphate metabolism. CONCLUSIONS: The analgesic mechanism of JLZ and YHS was mainly due to the combination of glycine and its receptor, producing post-synaptic potential, reducing the excitability of neurons, and weakening the afferent effect of painful information.

[Anti-inflammation effect of Jinlingzi San in rat metabonomics based on 1H-NMR and LC-MS technology].

To further explore the regulatory effect of Jinlingzi San on in vivo inflammatory mechanism during inflammatory treatment, this study adopted 1H-NMR and LC-MS technology to analyze differences in in vivo metabolites of carrageen-induce rat foot swelling model. Besides, biomarkers related to inflammation models of Jinlingzi San in SD rats were discovered to speculate the regulatory mechanism of Jinlingzi San in resisting carrageen-induce inflammation. Through the analysis of detection spectrum, we found 18 biomarkers of metabolites(citrate, pyruvate, malic acid, succinate, glutamate, lysine, tartrate, 2-oxobutyric acid, glycine, guanosine, 9-cis-retinoic acid, triphosphate, inosine 5'-diphosphate, inosine diphosphate, tripolyphosphate, inorganic triphosphate, glycerophosphocholine, 21-deoxycortisol). Relevant pathway analysis results were TCA cycle, pyruvate metabolism, glycine, serine and threonine metabolism, and dicarboxylic acid metabolism. From the metabolic network, we can see that the anti-inflammatory effect of Jinlingzi San can regulate citric acid, succinic acid and glycine content to resist oxygen free radical and reduce body damage by ROS, so as to down-regulate inflammatory factors generated from body tissues and resist inflammation.

[Subacute toxicity metabonomics of Jinlingzi powder based on LC-MS].

To further understand the metabolic characteristics of Jinlingzi powder toxicity effect in rats and explore the effect of Jinlingzi powder on unknown biological pathways in the treatment process. In this experiment, the effect of three doses of Jinlingzi powder decoction on rat liver and kidney was investigated to explore the characteristics and rules of Jinlingzi powder on in vivo metabonomic changes in rats. First, urine and serum samples of the rats were used for LC-MS analysis. Under the XCMS online analysis, 44 differential substances were found in the identification of metabolites. Finally, Metpa was used for metabolic pathways enrichment and analysis, and five related metabolic pathways were obtained: steroid hormone biosynthesis, tryptophan metabolism, pentose and glucuronate interconversions, ascorbate and aldarate metabolism, as well as glutathione metabolism. Metabolic network diagram showed that the toxicity-related pathways were mainly associated with lysine metabolism in living organisms, glucuronic acid conversion, and hormone metabolism, especially the metabolism imbalance of lysine and glutathione would result in the disorder of energy metabolism or oxidative stress regulation, and thus inducing the damage in rats. Subacute toxicity test results for three doses groups (low, middle and high doses) showed that, Jinlingzi powder with doses of 19.7 g•kg⁻¹ and 39.4 g•kg⁻¹ caused obvious toxic effect, indicating Jinlingzi powder could produce toxic effect in vivo in a dose-dependent manner, and cause irreversible damage to the body.

[Nuclear magnetic resonance-based metabonomics for sedative and hypnotic effect of Banxia Houpo decoction].

Insomnia was a common disease, which might be correlated with γ-aminobutyric acid A (GABAA) receptor mechanism, cytokine regulatory mechanism, excitatory amino acid mechanism and hydroxytryptamine (5-HT) receptor mechanism, but the correlations between these independent mechanisms and pathological characterization were still unclear. To further explore the effect of Banxia Houpo decoction on known or unknown biological pathways during treatment of insomnia, the metabonomics method based on ¹H-NMR was developed for detecting the significant changes in metabolomics after the administration with Banxia Houpo decoction in pentobarbital sodium-induced rat sleeping experiment. Serum and urine samples were analyzed by ¹H-NMR. Principal component analysis (PCA) was carried out for endogenous small molecule metabolites in urine and serum. H-NMR spectroscopies and relevant metabolites were found and identified by Simca-p 17.0 (Umet-rics, Umea, Sweden) and Chenomx NMR Suite 7.1 (Chenomx, Inc., Edmonton, Alberta, Canada) software. The result suggests that Banxia Houpo decoction group and indiplon group had significant differences. The load diagram showed the biggest variation metabolites and intergroup significant differences among 10 metabolic substances. According to the experiment, Banxia Houpo decoction group and indiplon group can prolonge the sleeping time of pentobarbital sodium-induced sprague-dawley rats, with a synergistic effect. The significant changes of these biomarkers indicated that the Banxia Houpo decoction could aid sleep by adjusting the content of glutamine, creatine phosphate, 2-oxoglutarate, and reducing the activity of brain nerves.

Meta-analysis of seven randomized control trials to assess the efficacy and toxicity of combining EGFR-TKI with chemotherapy for patients with advanced NSCLC who failed first-line treatment.

BACKGROUND: Some recent clinical trials have been conducted to evaluate a combination of EGFR- TKI with chemotherapy for advanced NSCLC patients as second-line therapy, but the results on the efficacy of such trials are inconsistent. The aim of this meta-analysis was to evaluate the efficacy and safety of combination of EGFR-TKI and chemotherapy for patients with advanced NSCLC who failed first-line treatment. MATERIALS AND METHODS: We searched relative trials from PubMed, EMBASE, ASCO Abstracts, ESMO Abstracts, Cochrane Library and Clinical Trials.gov. Outcomes analyzed were overall response rate (ORR), progression- free survival (PFS), overall survival (OS) and major toxicity. RESULTS: Seven trails eventually were included in this meta-analysis, covering 1,168 patients. The results showed that the combined regimen arm had a significant higher ORR (RR 1.76 [1.16, 2.66], p=0.007) and longer PFS (HR 0.75 [0.66-0.85], p<0.00001), but failed to show effects on OS (HR 0.88 [0.68- 1.15], p=0.36). In terms of subgroup results, continuation of EGFR-TKI in addition to chemotherapy after first-line EGFR-TKI resistance confered no improvement in ORR (RR 0.95 [0.68, 1.33], p=0.75) and PFS (HR 0.89[0.69, 1.15], p=0.38), and OS was even shorter (HR1.52 [1.05- 2.21], p=0.03). However, combination therapy with EGFR-TKI and chemotherapy after failure of first-line chemotherapy significantly improved the ORR (RR 2.06 [1.42, 2.99], p=0.0002), PFS (HR 0.71 [0.61, 0.82], p<0.00001) and OS (HR 0.74 [0.62- 0.88], p=0.0008), clinical benefit being restricted to combining EGFR-TKI with pemetrexed, but not docetaxel. Grade 3-4 toxicity was found at significantly higher incidence in the combined regimen arm. CONCLUSIONS: Continuation of EGFR-TKI in addition to chemotherapy after first-line EGFR-TKI resistance should be avoided. Combination therapy of EGFR-TKI and pemetrexed for advanced NSCLC should be further investigated for prognostic and predictive factors to find the group with the highest benefit of the combination strategy.

(1)H NMR metabolic profiling analysis offers evaluation of Nilestriol treatment in ovariectomised rats.

Nilestriol (NIL) has been applied to treat menopausal dysfunctions, yet its mechanism has remained unknown. To understand the relationship between the changes in homeostatic metabolites and ovarian oestrogen deficiency syndromes after NIL treatment, proton Nuclear Magnetic Resonance ((1)H NMR)-based metabonomic technologies were used to analyse a rat model of oestrogen deficiency. An orthogonal partial least-squares regression (OPLS) differentiation model was used on 12-week metabolic analyses of ovariectomised (OVX) rats treated or mock treated with NIL. Furthermore, data analysis using Chenomx software quantified results to identify the most significantly altered metabolite concentrations, allowing for metabolic explanations of the effects of NIL therapies. In this study, PLS results revealed that there are considerably distinct differences between treatment groups. Additionally, a total of 45 metabolites shown to have a high variation between groups were selected for target quantification. Using a one-way LSD ANOVA analysis, 32 metabolite concentrations were significantly altered in the OVX group. A total of 21 metabolites were altered significantly in the NIL-treatment group but later returned to normal. According to the OPLS VIP calculation, the metabolites most affected by NIL treatment were mostly involved in insulin resistance. In addition, abnormal concentration changes in lactate in the NIL-treatment group and 3-indoxylsulfate in the OVX group were observed. To our knowledge, this study is the first to address the molecular mechanism of NIL from a metabonomic perspective, and, more specifically, to establish a catalogue of endo-molecular changes effected by NIL in the regulation of oestrogen deficiency disorder.

[A new triterpenoid fom Radix Pittospori].

To investigate chemical constituents from Radix Pittospori, chloroform extract of the roots was subjected to column chromatography with various chromatographic techniques. The structures were elucidated on the basis of physico-chemical property and spectral analysis. Two triterpenoids were identified as 22-acetyl-21-(2-acetoxy-2-methylbutanoyl)-R1-barrigenol(1) and 3alpha-hydroxyl-20-demethylisoaleuritolic-14(15)-ene-28, 30-dioic acid (2). Compound 1 is a new triterpene and compound 2 is isolated from this plant for the first time.

Studies on the Effect of Recombinant Human Tumor Necrosis Factor-alpha on Leukemic Cell Lines by (31)P-NMR.

31P nuclear magnetic resonance (NMR) spectroscopy has been used for monitoring cellular metabolism in human lymphoma cell line Molt-4 and human promyelocyte leukemia cell line HL-60. (31)P-NMR spectra of Molt-4 cells and HL-60 cells consist primarily of peaks of phosphomonoesters, inorganic phosphate (Pi), diphosphodiesters and ATP. A decrease in the ATP/Pi ration occurred after treatment of the Molt-4 cells with recombinant human tumor necrosis factor-alpha(rhTHF-alpha). The ATP decreased after treatment of the Hl-60 cells with rhTNF-alpha.