Tandem reduction and trifluoroethylation of quinolines and quinoxalines with trifluoroacetic acid and trimethylamine borane.

A metal-free tandem reduction and N-trifluoroethylation of quinolines and quinoxalines has been developed. It provided a convenient route to access trifluoroethylated tetrahydroquinolines and tetrahydroquinoxalines. This one-pot method avoids the purification process of the intermediate. Mechanistically, the in situ-generated boryl acetal species reacted with tetrahydroquinolines to generate iminiums followed by reduction to give the target compounds.

Switchable Reductive N-Trifluoroethylation and N-Trifluoroacetylation of Indoles with Trifluoroacetic Acid and Trimethylamine Borane.

The metal-free reductive N-trifluoroethylation and N-trifluoroacetylation of indoles have been developed. Bench stable and inexpensive trimethylamine borane and trifluoroacetic acid (TFA) were utilized as the reductive and fluorinating reagents, respectively. These transformations were switchable on the basis of altering the loading of trimethylamine borane and TFA. Preliminary experiments indicated indoline was the common intermediate in these two transformations.

Metabolomic profiling for drug-induced liver injury with autoantibodies.

BACKGROUNDS: Drug induced liver injury (DILI) is sometimes similar to autoimmune hepatitis (AIH) in serology and histology. Clinicians empirically screened DILI with significant autoimmune characteristics to implement clinical intervention. We tried to characterize DILI with autoantibodies by metabolomics. METHODS: Untargeted metabolomics coupled with pattern recognition approaches were performed on sera samples including AIH (n = 59), DILI with autoantibodies (DILIAb+, n = 68), and DILI without autoantibodies (DILIAb-, n = 75). The differential metabolites and fingerprint metabolites between AIH and DILIAb- were screened by orthogonal partial least squares-discriminant analysis and hierarchical clustering respectively. RESULTS: Of the 388 annotated differential metabolites between AIH and DILIAb-, 74 fingerprint metabolites were screened. The eigenmetabolite compressed from the fingerprint possessed high discrimination efficacy (AUC:0.891; 95 %CI, 0.838-0.944). In the fingerprint-based PCA model, AIH and DILIAb- were separated into three regions: the "pure region" of AIH (Region 1), the "pure region" of DILIAb- (Region 3), the mixture region of AIH and DILIAb- (Region 2). After incorporated into the PCA model, DILIAb+ samples were distributed into the three regions, indicating that DILIAb+ samples had different etiological tendencies. Moreover, the fingerprint-based radar model verified the results of PCA model characterizing DILIAb+. Notably, the antibody titers of DILIAb+ in the three regions did not differ significantly, while the response rates for glucocorticoids were obviously different. The metabolic difference among DILIAb+ in different regions mainly lies in energy metabolism. CONCLUSIONS: In terms of metabolic signature, DILIAb+ may not be a community of same pathogenesis, including AIH-inclined parts. Which deserves further study.

Metabolomic Analysis Uncovers Lipid and Amino Acid Metabolism Disturbance During the Development of Ascites in Alcoholic Liver Disease.

Ascites is one of the most common complications of cirrhosis, and there is a dearth of knowledge about ascites-related pathologic metabolism. In this study, 122 alcoholic liver disease (ALD) patients, including 49 cases without ascites, 18 cases with mild-ascites, and 55 cases with large-ascites (1) were established according to the International Ascites Club (2), and untargeted metabolomics coupled with pattern recognition approaches were performed to profile and extract metabolite signatures. A total of 553 metabolites were uniquely discovered in patients with ascites, of which 136 metabolites had been annotated in the human metabolome database. Principal component analysis (PCA) analysis was used to further identify 21 ascites-related fingerprints. The eigenmetabolite calculated by reducing the dimensions of the 21 metabolites could be used to effectively identify those ALD patients with or without ascites. The eigenmetabolite showed a decreasing trend during ascites production and accumulation and was negatively related to the disease progress. These metabolic fingerprints mainly belong to the metabolites in lipid metabolism and the amino acid pathway. The results imply that lipid and amino acid metabolism disturbance may play a critical role in the development of ascites in ALD patients and could be a potent prognosis marker.

Metabolomic Profiling for Histologically Fibrotic Stage in Chronic Drug-Induced Liver Injury.

Background and aims: Chronic drug-induced liver injury (DILI) is a rare but under-researched adverse drug reaction-related disease, which is highly likely to progress into liver fibrosis and even cirrhosis. In this study, metabolomics was used to screen out characteristic metabolites related to the histological progression of fibrosis in chronic DILI and analyze the metabolic changes during the development of fibrosis to explain the underlying mechanism. Methods: Chronic DILI patients who underwent liver biopsy were divided into different fibrosis grades. Serum was analyzed by untargeted metabolomics to find serological characteristic metabolite fingerprints. The screened fingerprints were validated by the validation group patients, and the identification ability of fingerprints was compared using FibroScan. Results: A total of 31 metabolites associated with fibrosis and 11 metabolites associated with advanced fibrosis were identified. The validation group confirmed the accuracy of the two metabolite fingerprints [area under the curve (AUC) value 0.753 and 0.944]. In addition, the fingerprints showed the ability to distinguish the grades of fibrosis by comparing using FibroScan. The metabolite fingerprint pathway showed that bile acid synthesis is disturbed while lipid metabolism is extremely active, resulting in an overload of lipid metabolites in the occurrence and development of chronic DILI-associated fibrosis. Conclusions: Our metabolomic analysis reveals the unique metabolomic fingerprints associated with chronic DILI fibrosis, which have potential clinical diagnostic and prognostic significances. The metabolomic fingerprints suggest the disturbance of the lipid metabolites as the most important factor in the development of DILI fibrosis.

Screening for Susceptibility-Related Biomarkers of Diclofenac-Induced Liver Injury in Rats Using Metabolomics.

Early identification of individuals susceptible to idiosyncratic drug-induced liver injury (IDILI) is a challenging unmet demand. Diclofenac, one of the most widely available over-the-counter drugs for pain management worldwide, may induce liver dysfunction, acute liver failure, and death. Herein, we report that diclofenac-related hepatobiliary adverse reactions occurred more frequently in cases with immune activation. Furthermore, experiments with rats demonstrated divergent hepatotoxicity responses in individuals exposed to diclofenac, and modest inflammation potentiated diclofenac-induced liver injury. Susceptible rats had unique plasma metabolomic characteristics, and as such, the metabolomic approach could be used to distinguish susceptible individuals. The 23 identified susceptibility-related metabolites were enriched by several metabolic pathways related to acute-phase reactions of immunocytes and inflammatory responses, including sphingolipid, tyrosine, phenylalanine, tryptophan, and lipid metabolism pathways. This finding implies a mechanistic role of metabolic and immune disturbances affects susceptibility to diclofenac-IDILI. Further nine metabolite biomarkers with potent diagnostic capabilities were identified using receiver operating characteristic curves. These findings elucidated the potential utility of metabolomic biomarkers to identify individuals susceptible to drug hepatotoxicity and the underlying mechanism of metabolic and immune disturbances occurring in IDILI.

Fuzhuan brick tea supplemented with areca nuts: Effects on serum and gut microbiota in mice.

Areca nut and Fuzhuan brick tea, a type of natural plant products, have obvious effects of fat reduction and weight loss; however, there is no report on their synergistic effect. This study investigated the effects of Fuzhuan brick tea supplemented with different concentrations of areca nut (5% (LAF), 10% (MAF), and 20% (HAF)) on serum and gut microbiota in Kunming (KM) mice. The results showed that Fuzhuan brick tea supplemented with areca nuts (AFTs) could reduce weight, prevent the accumulation of fat, inhibit the increase in the levels of serum triglyceride, total cholesterol, low-density lipoprotein cholesterol, blood glucose, free fatty acid, insulin, and total bile acid, alleviate the decrease in high-density lipoprotein cholesterol level, and regulate the composition of gut microbiota by high-fat diet intervention. The HAF group with 20% areca nut content showed the best effect. These results could provide a novel approach to prevent obesity and hyperlipidemia. PRACTICAL APPLICATIONS: Consumption of areca nut and tea is widespread in Asia and other regions. As a controversial raw material, the damage due to areca nut to oral mucosa health has often aroused public concern and heated discussion; however, its medicinal value has been confirmed in terms of its pharmacological effects in various aspects. Fuzhuan brick tea, a type of traditional postfermented dark tea, has been confirmed to exert effects of antiobesity. Therefore, the areca nut and Fuzhuan brick tea, as a type of natural plant products, have obvious effects of fat reduction and weight loss; however, their synergistic effect has not been reported. To our knowledge, this study is the first to explore the effects of the Fuzhuan brick tea supplemented with areca nuts (AFTs) on serum and gut microbiota in mice. On the premise of exerting their beneficial effects (especially in terms of easing food stagnation and eliminating indigestion) and reducing their toxic and side effects, the effects of AFTs on health were further clarified, which could provide a novel direction for the development and utilization of areca nut. Moreover, our research would increase public understanding of areca nut and provide guidance to the Fuzhuan brick tea processing industry.

Evaluation by electronic tongue and headspace-GC-IMS analyses of the flavor compounds in dry-cured pork with different salt content.

Traditional dry-cured pork, a meat product with a unique flavor and good chewability, occupies an important place in the Chinese market. However, the salt content of dry-cured pork is on the high side and long-term consumption of high-salt meat products is not good for human health. This study determined the role of salt in volatile organic substances and non-volatile taste components of dry-cured pork. Dry-cured pork samples with different salt content (0%, 1%, 3%, 5%, and 7%) were analyzed by electronic tongue for moisture content, pH, salt (NaCl) value, taste activity value, free amino acids, and taste components and by headspace-gas chromatography-ion mobility spectrometry for volatile organic components. The results showed that the moisture content of the tested samples decreased while the salt content increased. The highest amounts of free amino acids were found in dry-cured pork with 3% salt content (P < 0.05). The highest peak area of volatile organic compounds and the maximal taste indexes were found in dry-cured pork with 3% and 5% salt content.

Spatio-temporal dynamics of arbuscular mycorrhizal fungi and soil organic carbon in coastal saline soil of China.

A comprehensive understanding of the relationship between arbuscular mycorrhizal (AM) fungi and coastal saline soil organic carbon (SOC) is crucial for analysis of the function of coastal wetlands in soil carbon sequestration. In a field experiment, the temporal and spatial dynamics of AM fungi, glomalin-related soil protein (GRSP) - which is described as a N-linked glycoprotein and the putative gene product of AM fungi, SOC, and soil aggregates were investigated in halophyte Kosteletzkya virginica rhizosphere soil of coastal saline areas of North Jiangsu, China. Soil samples were collected from a depth of up to 30 cm in two plantation regions from August 2012 to May 2013. Results showed K. virginica formed a strong symbiotic relationship to AM fungi. AM colonization and spore density were the highest in the 10-20 cm soil layer of Jinhai farm in August 2012, because of the presence of numerous fibrous roots in this soil layer. The total GRSP and SOC were the highest in the 0-10 cm soil layer in May 2013 and November 2012, respectively. Correlation coefficient analysis revealed that AM colonization and spore density were positively correlated with total GRSP. Meanwhile, total GRSP was significantly positively correlated with large macroaggregates (>3 mm), SOC, total P, Olsen P, and soil microbial biomass carbon (SMBC), but negatively correlated with microaggregates (<0.25 mm), soil EC, total N, and pH. SOC was positively correlated with spore density, large macroaggregates, small macroaggregates (2-0.25 mm), alkaline N, and SMBC and negatively correlated with microaggregates, EC, pH, and total K. Although it may be a statistical artifact, we found an interesting phenomenon that there was no significant correlation between soil aggregates and AM colonization or spore density. Hence, total GRSP is a vital source of saline soil C pool and an important biological indicator for evaluating coastal saline SOC pool and soil fertility, while AM colonization or spore density may not be.

Schisandra chinensis water extract protects ethanol-induced neurotoxicity in Caenorhabditis elegans.

The protective effect of Schisandra chinensis water extract (SWE) on ethanol-induced neurotoxicity in Caenorhabditis elegans and the underlying mechanism were investigated. Young worms were exposed to ethanol or a mixture of ethanol and SWE for 24 hr. Locomotion ability, tissue ethanol concentration, free radical content, antioxidant enzyme activity, lifespan, and expression of key dopaminergic nervous system-related genes were evaluated. Ethanol affected the motion ability of worms and shortened their lifespan. Ethanol intake increased the tissue ethanol concentration, resulting in redox imbalance, and dopamine release and accumulation. SWE alleviated motility loss of C. elegans and extended their lifespan. It reduced the tissue ethanol concentration and free radical content, likely because it alleviated oxidative stress. Finally, SWE inhibited continuous dopamine excitement. These results suggest that SWE plays a protective role in dopaminergic neurons. It can be used to treat ethanol-induced neurotoxicity, and to investigate its potential mechanism. PRACTICAL APPLICATIONS: Schisandra chinensis is a traditional functional food that has protective effects on the liver and brain. Although S. chinensis is found in some anti-alcohol products, the effects of S. chinensis on neurological and behavioral disorders caused by alcohol are rarely reported. The manuscript explored the protective effect of SWE on ethanol-induced nerve injury in Caenorhabditis elegans, and we preliminarily discussed the underlying mechanism. The results suggested that SWE can alleviate ethanol-induced neurotoxicity. Meanwhile, the results provide a theoretical basis for better use of S. chinensis to develop products to antagonize the side effects of alcohol. In addition, the method of using C. elegans model to evaluate the protective effect of S. chinensis on ethanol-induced nerve injury can provide practical reference for the screening and utilization of other plant functional components.

NaCl impact on Kosteletzkya pentacarpos seedlings simultaneously exposed to cadmium and zinc toxicities.

Data regarding NaCl impact on halophyte plant species exposed to a polymetallic contamination remain scarce. Seedlings of the salt marsh species Kosteletzkya pentacarpos were simultaneously exposed to cadmium (10 µM) and zinc (100 µM) in the absence or presence of 50 mM NaCl. Heavy metal exposure reduced plant growth and increased Cd and Zn concentrations in all organs. Cd and Zn accumulation reduced net photosynthesis in relation to stomatal closure, decreased in chlorophyll concentration and alteration in chlorophyll fluorescence-related parameters. Salinity reduced Cd and Zn bioaccumulation and translocation, with a higher impact on Cd than Zn. It mitigated the deleterious impact of heavy metals on photosynthetic parameters. NaCl reduced the heavy metal-induced oxidative stress assessed by malondialdehyde, carbonyl, and H2O2 concentration. Subcellular distribution revealed that Cd mainly accumulated in the cell walls, but NaCl increased it in the cytosol fraction in the leaf and in the metal-rich granule fraction in the roots. It had no impact on Zn subcellular distribution. The additional NaCl contributed to a higher sequestration of Cd on phytochelatins and stimulated glutathione synthesis. The positive impact of NaCl on K. pentacarpos response to polymetallic pollution made this species a promising candidate for revegetation of heavy metal-contaminated salt areas.