Metabolic characteristics of evodiamine were associated with its hepatotoxicity via PPAR/PI3K/AKT/NF-кB/tight junction pathway-mediated apoptosis in zebrafish.

Evodiae Fructus (EF), an herbal medicine, possesses remarkable anti-inflammatory and analgesic properties. It exhibits insecticidal activity as a potent insecticide candidate. However, the toxic characteristics of EF and the underlying mechanisms have not been comprehensively elucidated comprehensively. Thus, we comprehensively explored the toxic components of EF and established the relationship between the therapeutic and toxic effects of EF, encouraging its therapeutic use. We found that evodiamine (EVO), one of the main ingredients of EF, can truly reflect its analgesic properties. In phenotype observation trials, low doses of EVO (< 35 ng/mL) exhibited distinct analgesic activity without any adverse effects in zebrafish. However, EVO dose-dependently led to gross morphological abnormalities in the liver, followed by pericardial edema, and increased myocardial concentrations. Furthermore, the toxic effects of EVO decreased after processing in liver microsomes but increased after administering CYP450 inhibitors in zebrafish, highlighting the prominent effect of CYP450s in EVO-mediated hepatotoxicity. EVO significantly changed the expression of genes enriched in multiple pathways and biological processes, including lipid metabolism, inflammatory response, tight junction damage, and cell apoptosis. Importantly, the PPAR/PI3K/AKT/NF-кB/tight junction-mediated apoptosis pathway was confirmed as a critical functional signaling pathway inducing EVO-mediated hepatotoxicity. This study provided a typical example of the overall systematic evaluation of traditional Chinese medicine (TCM) and its active ingredients with significant therapeutic effects and simultaneous toxicities, especially metabolic toxicities.

Structural-Activity Relationship of Rare Ginsenosides from Red Ginseng in the Treatment of Alzheimer's Disease.

Rare ginsenosides are the major components of red ginseng. However, there has been little research into the relationship between the structure of ginsenosides and their anti-inflammatory activity. In this work, BV-2 cells induced by lipopolysaccharide (LPS) or nigericin, the anti-inflammatory activity of eight rare ginsenosides, and the target proteins expression of AD were compared. In addition, the Morris water maze test, HE staining, thioflavins staining, and urine metabonomics were used to evaluate the effect of Rh4 on AD mice. Our results showed that their configuration influences the anti-inflammatory activity of ginsenosides. Ginsenosides Rk1, Rg5, Rk3, and Rh4 have significant anti-inflammatory activity compared to ginsenosides S-Rh1, R-Rh1, S-Rg3, and R-Rg3. Ginsenosides S-Rh1 and S-Rg3 have more pronounced anti-inflammatory activity than ginsenosides R-Rh1 and R-Rg3, respectively. Furthermore, the two pairs of stereoisomeric ginsenosides can significantly reduce the level of NLRP3, caspase-1, and ASC in BV-2 cells. Interestingly, Rh4 can improve the learning ability of AD mice, improve cognitive impairment, reduce hippocampal neuronal apoptosis and Aß deposition, and regulate AD-related pathways such as the tricarboxylic acid cycle and the sphingolipid metabolism. Our findings conclude that rare ginsenosides with a double bond have more anti-inflammatory activity than those without, and 20(S)-ginsenosides have more excellent anti-inflammatory activity than 20(R)-ginsenosides.

Levels, tissue distribution and isomer stereoselectivity of Dechlorane Plus in humans: A critical review.

Exposure of human tissues to Dechlorane Plus (DP) has raised public concern because of the multiple health threats it may pose to humans. Therefore, it is important to summarize the main findings of previous studies on DP in human tissues and to provide potential guidance for future studies. In this paper, DP levels in different populations and human tissues worldwide since 2009 were systematically reviewed. DP levels in human tissues of workers in e-waste dismantling sites in Guangdong Province, China (median 190 ng·g-1 lw in serum) and DP manufacturing plants in Jiangsu Province, China (mean 857 ng·g-1 lw in whole-blood) are the highest reported worldwide. DP levels in tissues of the general population in recent studies are close to those of residents near e-waste dismantling sites, which should be of concern. DP levels in different human tissues were found to be positively correlated with a pattern of blood > breast milk > adipose tissue. The distribution of DP in different human tissues is mainly lipid-driven and may also be influenced by the interaction of DP with proteins such as human serum albumin. Most of the past studies determined the isomer stereoselectivity of DP in human tissues only by comparing the composition of DP in commercial DP products and human tissues, which lacks evidence of mechanism. Recently, a significantly different affinity of DP isomers for proteins was found, which seems to confirm the isomer selectivity of DP in human tissues. We simulated the binding of DP to human serum albumin and DP to thyroid hormone receptor ß by molecular docking and found differences in the binding behavior of syn-DP and anti-DP to the selected proteins. Molecular docking seems to be a feasible approach for future studies to predict and reveal the mechanisms of DP behavior and health effects in human tissues.

Saponins of ginseng products: a review of their transformation in processing.

The primary processed product of Panax ginseng C.A. Meyer (P. ginseng) is red ginseng. As technology advances, new products of red ginseng have arisen. Red ginseng products, e.g., traditional red ginseng, sun ginseng, black ginseng, fermented red ginseng, and puffed red ginseng, are commonly used in herbal medicine. Ginsenosides are the major secondary metabolites of P. ginseng. The constituents of P. ginseng are significantly changed during processing, and several pharmacological activities of red ginseng products are dramatically increased compared to white ginseng. In this paper, we aimed to review the ginsenosides and pharmacological activities of various red ginseng products, the transformation law of ginsenosides in processing, and some clinical trials of red ginseng products. This article will help to highlight the diverse pharmacological properties of red ginseng products and aid in the future development of red ginseng industrialization.

Rapid Simultaneous Determination of 43 Pesticide Residues in Schizonepeta tenuifolia by Gas Chromatography Mass Spectrometry.

A simple, fast, and reliable method was established for simultaneous determination of 43 pesticides in Schizonepeta tenuifolia. The samples were prepared using solid-phase extraction (SPE) method. Pesticides were extracted from Schizonepeta tenuifolia using acetonitrile, cleaned with Pesticarb/NH2, and eluted by mixed solvents of acetonitrile and toluene (3 : 1, v/v). Selected pesticides were identified using DB-35MS capillary column and detected by gas chromatography mass spectrometry. Samples were quantified by external standard method. Recoveries for the majority of pesticides at spike levels of 0.2, 0.5, and 1 mg kg-1 ranged between 70 and 120% (except for Chlorothalonil, Thiamethoxam, and Dicofol), and the relative standard deviations (RSDs n = 6) were 1.32%-13.91%. Limits of detection (LODs) were 0.0011-0.0135 mg kg-1, whereas limits of quantification (LOQs) were 0.0038-0.0451 mg kg-1. The satisfactory accuracy and precision, in combination with a good separation and few interferences, have demonstrated the strong potential of this technique for its application in Schizonepeta tenuifolia analysis.

Integrated Phytochemical Analysis Based on UPLC-Q-TOF-MS/MS, Network Pharmacology, and Experiment Verification to Explore the Potential Mechanism of Platycodon grandiflorum for Chronic Bronchitis.

BACKGROUND AND AIM: Platycodon grandiflorum (PG) has been widely used for treating chronic bronchitis (CB). However, the material basis and underlying mechanism of action of PG against CB have not yet been elucidated. METHODS: To analyze the ingredients in PG, ultraperformance liquid chromatography-quadrupole-time-of-flight tandem mass (UPLC-Q-TOF-MS/MS) technology was performed. Subsequently, using data mining and network pharmacology methodology, combined with Discovery Studio 2016 (DS), Cytoscape v3.7.1, and other software, active ingredients, drug-disease targets, and key pathways of PG in the treatment of CB were evaluated. Finally, the reliability of the core targets was evaluated using molecular docking technology and in vitro studies. RESULTS: A total of 36 compounds were identified in PG. According to the basic properties of the compounds, 10 major active ingredients, including platycodin D, were obtained. Based on the data mining approach, the Traditional Chinese Medicine Systems Pharmacology Database, and the Analysis Platform (TCMSP), GeneCards, and other databases were used to obtain targets related to the active ingredients of PG and CB. Network analysis was performed on 144 overlapping gene symbols, and twenty core targets, including interleukin-6 (IL-6) and tumor necrosis factor (TNF), which indicated that the potential signaling pathway that was most relevant to the treatment of CB was the IL-17 signaling pathway. CONCLUSION: In this study, ingredient analysis, network pharmacology analysis, and experiment verification were combined, and revealed that PG can be used to treat CB by reducing inflammation. Our findings provide novel insight into the mechanism of action of Chinese medicine. Furthermore, our data are of value for the research and development of novel drugs and the application thereof.

Uncovering the mechanism of the effects of Paeoniae Radix Alba on iron-deficiency anaemia through a network pharmacology-based strategy.

BACKGROUND: Paeoniae Radix Alba, the root of the plant Paeonia lactiflora Pall, is a common blood-enriching drug in traditional Chinese medicine. Its effectiveness in the clinical treatment of anaemia is remarkable, but its potential pharmacologic mechanism has not been clarified. METHODS: In this study, the potential pharmacologic mechanism of Paeoniae Radix Alba in the treatment of iron-deficiency anaemia was preliminarily elucidated through systematic and comprehensive network pharmacology. RESULTS: Specifically, we obtained 15 candidate active ingredients from among 146 chemical components in Paeoniae Radix Alba. The ingredients were predicted to target 77 genes associated with iron-deficiency anaemia. In-depth analyses of these targets revealed that they were mostly associated with energy metabolism, cell proliferation, and stress responses, suggesting that Paeoniae Radix Alba helps alleviate iron-deficiency anaemia by affecting these processes. In addition, we conducted a core target analysis and a cluster analysis of protein-protein interaction (PPI) networks. The results showed that four pathways, the p53 signalling pathway, the IL-17 signalling pathway, the TNF signalling pathway and the AGE-RAGE signalling pathway in diabetic complications, may be major pathways associated with the ameliorative effects of Paeoniae Radix Alba on iron-deficiency anaemia. Moreover, molecular docking verified the credibility of the network for molecular target prediction. CONCLUSIONS: Overall, this study predicted the functional ingredients in Paeoniae Radix Alba and their targets and uncovered the mechanism of action of this drug, providing new insights for advanced research on Paeoniae Radix Alba and other traditional Chinese medicines.

Chemical Characteristics of Platycodon grandiflorum and its Mechanism in Lung Cancer Treatment.

Objective: The technology, network pharmacology and molecular docking technology of the ultra performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) were used to explore the potential molecular mechanism of Platycodon grandiflorum (PG) in the treatment of lung cancer (LC). Methods: UPLC-Q-TOF-MS/MS technology was used to analyze the ingredients of PG and the potential LC targets were obtained from the Traditional Chinese Medicine Systems Pharmacology database, and the Analysis Platform (TCMSP), GeneCards and other databases. The interaction network of the drug-disease targets was constructed with the additional use of STRING 11.0. The pathway enrichment analysis was carried out using Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) in Metascape, and then the "Drug-Ingredients-Targets-Pathways-Disease" (D-I-T-P-D) network was constructed using Cytoscape v3.7.1. Finally, the Discovery Studio 2016 (DS) software was used to evaluate the molecular docking. Results: Forty-seven compounds in PG, including triterpenoid saponins, steroidal saponins and flavonoids, were identified and nine main bioactive components including platycodin D were screened. According to the method of data mining, 545 potential drug targets and 2,664 disease-related targets were collected. The results of topological analysis revealed 20 core targets including caspase 3 (CASP3) and prostaglandin-endoperoxide synthase 2 (PTGS2) suggesting that the potential signaling pathway potentially involved in the treatment of LC included MAPK signaling pathway and P13K-AKT signaling pathway. The results of molecular docking proved that the bound of the ingredients with potential key targets was excellent. Conclusion: The results in this study provided a novel insight in the exploration of the mechanism of action of PG against LC.

[Effects of different dose berberine on hemodynamic parameters and [Ca2+]i of cardiac myocytes of diastolic heart failure rat model].

OBJECTIVE: To study the effects of different doses of berberine on hemodynamic parameters and calcium ion concentration ([Ca2+]i) of diastole heart failure rat models. METHOD: The mouse models of diastole heart failure were made by the imcomplete ligation of abdominal aorta. Forty Wistar heart failure rats were divided randomly into four groups, with 10 for each group (n = 10). Heart failure rats were treated according to different doses drugs as follows: Model (natrii chloride 2 mL), berberine (63 mg x kg(-1) x d(-1)), berberine (42 mg x kg(-1) x d(-1)), berberine (21 mg x kg(-1) x d(-1)) ig, for each of the four groups respectively, 4 weeks after coarctation of ascending aorta operation; and 10 age matched sham operation group was taken as control (natrii chloridi, 2 mL). After administration four weeks, cardiac function was determined by catheter. Isolate single cardiomyocytes of rat which were loaded with Ca(2+)-sensitive fluorescent indicator Fluo-3/AM. [Ca2+]i represented by fluorescent intensity [FI] was measured by laser scanning cofocal microscope [LSCM]. RESULT: The rats of operation group have no significant changes with those of the control on left ventricular systolic pressure (LVSP) and maximal rising rate of ventricular pressure (+dp/dt(max)), left ventricular end diastolic pressure (LVEDP) was much higher in operation group (P < 0.01), but maximal falling rate of ventricular pressure (-dp/dt(max)) was depressed (P < 0.01), left ventricular relax time constant quantity (T) was markedly extended (P < 0.01). [Ca2+]i level in carkiac muscle cell was elevated markedly (P < 0.05). Compared with operation group, high dose of Ber can decrease LEVDP, improve (-dp/dt(max)) (P < 0.01), decurtate left ventricular relax time constant quantity (P < 0.01) and decrease [Ca2+]i level better than those of middle and low dose group (P < 0.01). CONCLUSION: Berberine is an effective new potent drug for conspicuous symptom relief of heart failure with positive dose dependency and step down [Ca2+]i of myocardial cell.

[Application of matrix solid-phase dispersion for the determination of phoxim in crucian carp samples by high performance liquid chromatography].

An analytical method was developed for the determination of phoxim residue in the muscle of crucian carp, which involved matrix solid-phase dispersion (MSPD) followed by high performance liquid chromatography (HPLC) with diode array detector. Under optimal conditions, 0.5 g tissue sample was dispersed with 1.5 g Florisil and 0.5 g anhydrous sodium sulphate, transferred to a cartridge. The cartridge was eluted with 25 mL acetone-hexane (40:60, v/v). The phoxim was separated on an ODS column (250 mm x 4.6 mm, 5 microm) with methanol-water (50:50, v/v) as the mobile phase at the flow rate of 0.6 mL/min, then detected by a diode array detector at 270 nm. The injection volume was 20 microL. The linear range of the method was 0.01 - 10 mg/L and the detection limit was 3.3 microg/kg. The average recoveries spiked at the levels of 0.05, 0.1, 1 mg/kg ranged from 88% to 112% with the relative standard deviations (RSDs) of 1.1% -6.3%. The method is quick, simple and can meet the requirement of the analysis of pesticide residues.

Chemiluminescence determination of surfactant Triton X-100 in environmental water with luminol-hydrogen peroxide system.

BACKGROUND: The rapid, simple determination of surfactants in environmental samples is essential because of the extensive use and its potential as contaminants. We describe a simple, rapid chemiluminescence method for the direct determination of the non-ionic surfactant Triton X-100 (polyethylene glycol tert-octylphenyl ether) in environmental water samples. The optimized experimental conditions were selected, and the mechanism of the Luminol-H2O2-Triton X-100 chemiluminesence system was also studied. RESULTS: The novel chemiluminescence method for the determination of non-ionic surfactant Triton X-100 was based on the phenomenon that Triton X-100 greatly enhanced the CL signal of the luminol-H2O2 system. The alkaline medium of luminol and the pH value obviously affected the results. Luminol concentration and hydrogen peroxide concentration also affected the results. The optimal conditions were: Na2CO3 being the medium, pH value 12.5, luminol concentration 1.0 x 10(-4) mol L(-1), H2O2 concentration 0.4 mol L(-1). The possible mechanism was studied and proposed. CONCLUSION: Under the optimal conditions, the standard curve was drawn up and quotas were evaluated. The linear range was 2 x 10(-4) g mL(-1)-4 x 10(-2) g mL(-1) (w/v), and the detection limit was 3.97 x 10-5 g mL(-1) Triton X-100 (w/v). The relative standard deviation was less than 4.73% for 2 x 10(-2) g mL(-1) (w/v) Triton X-100 (n = 7). This method has been applied to the determination of Triton X-100 in environmental water samples. The desirable recovery ratio was between 96%-102% and the relative standard deviation was 2.5%-3.3%. The luminescence mechanism was also discussed in detail based on the fluorescence spectrum and the kinetic curve, and demonstrated that Triton X-100-luminol-H2O2 was a rapid reaction.