A Dual Coverage Monitoring of the Bile Acids Profile in the Liver-Gut Axis throughout the Whole Inflammation-Cancer Transformation Progressive: Reveal Hepatocellular Carcinoma Pathogenesis.

Hepatocellular carcinoma (HCC) is the terminal phase of multiple chronic liver diseases, and evidence supports chronic uncontrollable inflammation being one of the potential mechanisms leading to HCC formation. The dysregulation of bile acid homeostasis in the enterohepatic circulation has become a hot research issue concerning revealing the pathogenesis of the inflammatory-cancerous transformation process. We reproduced the development of HCC through an N-nitrosodiethylamine (DEN)-induced rat model in 20 weeks. We achieved the monitoring of the bile acid profile in the plasma, liver, and intestine during the evolution of "hepatitis-cirrhosis-HCC" by using an ultra-performance liquid chromatography-tandem mass spectrometer for absolute quantification of bile acids. We observed differences in the level of primary and secondary bile acids both in plasma, liver, and intestine when compared to controls, particularly a sustained reduction of intestine taurine-conjugated bile acid level. Moreover, we identified chenodeoxycholic acid, lithocholic acid, ursodeoxycholic acid, and glycolithocholic acid in plasma as biomarkers for early diagnosis of HCC. We also identified bile acid-CoA:amino acid N-acyltransferase (BAAT) by gene set enrichment analysis, which dominates the final step in the synthesis of conjugated bile acids associated with the inflammatory-cancer transformation process. In conclusion, our study provided comprehensive bile acid metabolic fingerprinting in the liver-gut axis during the inflammation-cancer transformation process, laying the foundation for providing a new perspective for the diagnosis, prevention, and treatment of HCC.

The Biological Fate of Pharmaceutical Excipient ß-Cyclodextrin: Pharmacokinetics, Tissue Distribution, Excretion, and Metabolism of ß-Cyclodextrin in Rats.

ß-cyclodextrin has a unique annular hollow ultrastructure that allows encapsulation of various poorly water-soluble drugs in the resulting cavity, thereby increasing drug stability. As a bioactive molecule, the metabolism of ß-cyclodextrin is mainly completed by the flora in the colon, which can interact with API. In this study, understanding the in vivo fate of ß-cyclodextrin, a LC-MS/MS method was developed to facilitate simultaneous quantitative analysis of pharmaceutical excipient ß-cyclodextrin and API dextromethorphan hydrobromide. The established method had been effectively used to study the pharmacokinetics, tissue distribution, excretion, and metabolism of ß-cyclodextrin after oral administration in rats. Results showed that ß-cyclodextrin was almost wholly removed from rat plasma within 36 h, and high concentrations of ß-cyclodextrin distributed hastily to organs with increased blood flow velocities such as the spleen, liver, and kidney after administration. The excretion of intact ß-cyclodextrin to urine and feces was lower than the administration dose. It can be speculated that ß-cyclodextrin metabolized to maltodextrin, which was further metabolized, absorbed, and eventually discharged in the form of CO2 and H2O. Results proved that ß-cyclodextrin, with relative low accumulation in the body, had good safety. The results will assist further study of the design and safety evaluation of adjuvant ß-cyclodextrin and promote its clinical development.

Metabolic Study of Tetra-PEG-Based Hydrogel after Pelvic Implantation in Rats.

In vivo metabolism of polyethylene glycol (PEG) hydrogels has rarely been studied. In this study, we prepared a chemically crosslinked hydrogel formulation using 14C-labeled tetra-armed poly (ethylene glycol) succinimidyl succinate (Tetra-PEG-SS) and 3H-labeled crosslinking agent for implantation into the pelvis of Sprague-Dawley (SD) rats. This radioactive labeling technique was used to investigate the radioactivity excretion rates in of feces and urine, the blood exposure time curve, and the radioactivity recovery rate in each tissue over time. We showed that the primary excretion route of the hydrogel was via urine (3H: about 86.4%, 14C: about 90.0%), with fewer portion through feces (3H: about 6.922%, 14C: about 8.16%). The hydrogel metabolites exhibited the highest distribution in the kidney, followed by the jejunal contents; The 3H and 14C radioactivity exposures in the remaining tissues were low. We also showed that the 3H and 14C radioactivity recovery rates in the blood were usually low (<0.10% g−1 at 12 h after implantation), even though, in theory, the hydrogel could be absorbed into the blood through the adjacent tissues. By using a combination of HPLC-MS/MS and offline radioactivity counting method, we established that the tetra-PEG-based hydrogel was mainly metabolized to lower-order PEG polymers and other low-molecular-weight substances in vivo.

Material Basis Elucidation and Quantification of Dandelion through Spectrum-Effect Relationship Study between UHPLC Fingerprint and Antioxidant Activity via Multivariate Statistical Analysis.

The excessive expression of reactive oxygen species is closely connected to many diseases. Considerable studies have demonstrated dandelion as well as its ingredients exhibited antioxidant activity. However, specific material basis reflecting the antioxidant activity has not been comprehensively investigated. In this study, a spectrum-effect relationship study on dandelion between fingerprinting and antioxidant activity was analyzed in detail, while a UHPLC quantification method developed and completely validated for simultaneous determination of active ingredients in dandelion. With the establishment of dandelion fingerprints of different regions, 24 common peaks were characterized. The classic FRAP method and ABTS methods were then used to detect their antioxidant activity. Partial least squares regression analysis, bivariate correlation analysis and grey correlation method were used to accomplish the spectrum-effect relationship. Eventually, the ingredients with antioxidant activity which could be considered as candidate quality markers of dandelion were discovered through spectrum-effect relationship analysis. The six compounds including caftaric acid, chlorogenic acid, caffeic acid, chicoric acid, isochlorogenic acid A, and isochlorogenic acid C were quantitatively determined. The developed UHPLC assay method was accurate, precise, and reliable. The study has elucidated the antioxidant material basis of dandelion and provided a scientific basis for the quality control of dandelion.

A Comprehensive Analysis of Microflora and Metabolites in the Development of Ulcerative Colitis into Colorectal Cancer Based on the Lung-Gut Correlation Theory.

The lungs and large intestine can co-regulate inflammation and immunity through the lung-gut axis, in which the transportation of the gut microbiota and metabolites is the most important communication channel. In our previous study, not only did the composition of the gut microbiota and metabolites related to inflammation change significantly during the transition from ulcerative colitis (UC) to colorectal cancer (CRC), but the lung tissues also showed corresponding inflammatory changes, which indicated that gastrointestinal diseases can lead to pulmonary diseases. In order to elucidate the mechanisms of this lung-gut axis, metabolites in bronchoalveolar lavage fluid (BALF) and lung tissues were detected using UHPLC-Q-TOF-MS/MS technology, while microbiome characterization was performed in BALF using 16S rDNA sequencing. The levels of pulmonary metabolites changed greatly during the development of UC to CRC. Among these changes, the concentrations of linoleic acid and 7-hydroxy-3-oxocholic acid gradually increased during the development of UC to CRC. In addition, the composition of the pulmonary microbiota also changed significantly, with an increase in the Proteobacteria and an obvious decrease in the Firmicutes. These changes were consistent with our previous studies of the gut. Collectively, the microbiota and metabolites identified above might be the key markers related to lung and gut diseases, which can be used as an indication of the transition of diseases from the gut to the lung and provide a scientific basis for clinical treatment.

Development of an LC-MS/MS method for simultaneous quantitative analysis of macromolecular pharmaceutical adjuvant 2-hydroxypropyl-ß-cyclodextrin and active pharmaceutical ingredients butylphthalide in rat plasma.

Hydroxypropyl-ß-cyclodextrin, which possesses a high water solubility and low hemolycity, is widely used as a solubilizer and an excipient. It had also been reported that hydroxypropyl-ß-cyclodextrin has the activity of regulating lipid homeostasis. In order to further understand the metabolism, the primary focus was to establish a quantitative method for hydroxypropyl-ß-cyclodextrin. The analytes were extracted from plasma by protein precipitation with methanol and then carried out on a Waters CORTECS T3 column in the gradient elution of pure water and methanol. Finally, liquid chromatography-tandem mass spectrometry was applied in multiple reaction monitoring mode to complete the quantitative analysis of hydroxypropyl-ß-cyclodextrin. This validated method had been successfully applied to investigate the interaction between hydroxypropyl-ß-cyclodextrin and butylphthalide in vivo by optimizing the extraction reagent, simplifying the experimental procedure, and improving the sensitivity while considering the difference of drug chemical properties. Results showed that the inclusion of hydroxypropyl-ß-cyclodextrin with butylphthalide significantly improved the pharmacokinetic behavior of free body hydroxypropyl-ß-cyclodextrin and 3-n-butylphthalide in vivo. It had been implied that the metabolism of hydroxypropyl-ß-cyclodextrin and the drug active ingredients could impact each other. It will help better application of hydroxypropyl-ß-cyclodextrin and the developed method might lay the foundation for development of hydroxypropyl-ß-cyclodextrin as a treatment drug for brain diseases.

Nephrotoxicity of Immune Checkpoint Inhibitors: A Disproportionality Analysis from 2013 to 2020.

Nephrotoxicity occasionally occurs during treatment with immune checkpoint inhibitors (ICIs). Few related studies compare the differences between these drugs. This study aimed to systematically characterize nephrotoxicity after ICI initiation. Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database. Disproportionality analysis, including information components (ICs) and reporting odds ratios (RORs), was performed to determine the potential renal toxicity of ICIs. A total of 7,204 reports of renal adverse events (AEs) were identified in the FAERS database. Renal AEs were most commonly reported for nivolumab (46.84%). Strong signals were detected in male patients combined with ICIs. In the clinical application of ICIs, attention should be paid to patients, especially male patients, with acute kidney injury, nephritis, autoimmune nephritis and other nephrotoxic AEs. The use of ICIs is likely to aggravate their condition.

An Integrated Mutually Oriented "Chemical Profiling-Pharmaceutical Effect" Strategy for Screening Discriminating Markers of Underlying Hepatoprotective Effects to Distinguish Garden-Cultivated from Mountain-Cultivated Ginseng.

Garden-cultivated Ginseng (GG) and mountain-cultivated Ginseng (MG) both belong to Panax Ginseng C. A. Meyer. However, the effective substances which can be used to distinguish GG from MG remain obscure. Therefore, the purpose of this study was to screen for discriminating markers that can assist in the correct identification of GG and MG. HPLC Q-TOF/MS and various chemometrics methods were used to analyze the chemical profiles of 13 batches of Ginseng and to explore the characteristic constituents of both GG and MG. The hepatocyte-protecting effects of GG and MG were investigated through a paclitaxel-induced liver injury model. Through a combination of correlation analysis and bioinformatic techniques, markers for differentiation between GG and MG were ascertained. A total of 40 and 41 compounds were identified in GG and MG, respectively, and 15 characteristic ingredients contributed significantly to the discrimination of GG from MG. Correlation analysis and network pharmacology were applied and ginsenosides Rg1, Re, Rb1, Rc, Rb2, and Rg3 were found to be discriminating markers of GG and MG. Six markers for the identification of GG and MG were screened out by a step-wise mutually oriented "chemical profiling-pharmaceutical effect" correlation strategy, which is of great significance for future quality assessment of Ginseng products.

Based on Multi-Activity Integrated Strategy to Screening, Characterization and Quantification of Bioactive Compounds from Red Wine.

According to French Paradox, red wine was famous for the potential effects on coronary heart disease (CHD), but the specific compounds against CHD were unclear. Therefore, screening and characterization of bioactive compounds from red wine was extremely necessary. In this paper, the multi-activity integrated strategy was developed and validated to screen, identify and quantify active compounds from red wine by using ultra high performance liquid chromatography-fraction collector (UHPLC-FC), ultra fast liquid chromatography-quadrupole-time-of-flight/mass spectrometry (UFLC-Q-TOF/MS) and bioactive analysis. UHPLC-FC was employed to separate and collect the components from red wine, which was further identified by UFLC-Q-TOF/MS to acquire their structural information. Furthermore, the active fractions were tested for antioxidant activity, inhibitory activity against thrombin and lipase activities in vitro by the activity screening kit. As the results, there were 37 fractions had antioxidant activity, 22 fractions had thrombin inhibitory activity and 28 fractions had lipase inhibitory activity. Finally, 77 active components from red wine were screened and 12 ingredients out of them were selected for quantification based on the integration of multi-activity. Collectively, the multi-activity integrated strategy was helpful for the rapid and effective discovery of bioactive components, which provided reference for exploring the health care function of food.

Application of UHPLC Fingerprints Combined with Chemical Pattern Recognition Analysis in the Differentiation of Six Rhodiola Species.

Rhodiola, especially Rhodiola crenulate and Rhodiola rosea, is an increasingly widely used traditional medicine or dietary supplement in Asian and western countries. Because of the phytochemical diversity and difference of therapeutic efficacy among Rhodiola species, it is crucial to accurately identify them. In this study, a simple and efficient method of the classification of Rhodiola crenulate, Rhodiola rosea, and their confusable species (Rhodiola serrata, Rhodiola yunnanensis, Rhodiola kirilowii and Rhodiola fastigiate) was established by UHPLC fingerprints combined with chemical pattern recognition analysis. The results showed that similarity analysis and principal component analysis (PCA) could not achieve accurate classification among the six Rhodiola species. Linear discriminant analysis (LDA) combined with stepwise feature selection exhibited effective discrimination. Seven characteristic peaks that are responsible for accurate classification were selected, and their distinguishing ability was successfully verified by partial least-squares discriminant analysis (PLS-DA) and orthogonal partial least-squares discriminant analysis (OPLS-DA), respectively. Finally, the components of these seven characteristic peaks were identified as 1-(2-Hydroxy-2-methylbutanoate) ß-D-glucopyranose, 4-O-glucosyl-p-coumaric acid, salidroside, epigallocatechin, 1,2,3,4,6-pentagalloyglucose, epigallocatechin gallate, and (+)-isolarisiresinol-4'-O-ß-D-glucopyranoside or (+)-isolarisiresinol-4-O-ß-D-glucopyranoside, respectively. The results obtained in our study provided useful information for authenticity identification and classification of Rhodiola species.

Time-dependent metabolomics study of cerebral ischemia-reperfusion and its treatment: focus on the combination of traditional Chinese medicine and Western medicine.

Cerebral ischemia is a common cerebrovascular disease with high mortality, and thrombolysis can cause more severe reperfusion injury. In clinical practice, Ginkgo biloba dispersible tablets combined with nimodipine have been widely used to reduce cerebral ischemia-reperfusion injury, but the mechanism has not been clearly elucidated. To explore this relationship, the change in metabolism between a sham operation group, a model group and an administration group was analyzed for the period after cerebral ischemia. Biochemical assays were used to assess injury extent and the therapeutic effects of different dosing regimens. A metabolomics method based on ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry was developed to screen biomarkers in plasma of rats and analyze abnormal metabolic pathways. Using statistical analysis, corticosterone, glutamine, oleic acid, isoleucine, phenylalanine and sphingomyelin (d18:1/16:0) were screened as diagnostic biomarkers. The metabolic pathways perturbed by cerebral ischemia-reperfusion involved phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, alpha-linolenic acid metabolism, retinol metabolism, alanine, aspartate and glutamate metabolism, and glycerophospholipid metabolism. Analysis of the adjustment of biomarkers at different time points showed that the best time to evaluate the efficacy of combined administration is about 6 h after administration. Both pathological characteristics and metabolomics confirmed the better effect of the combined group than the individual groups. In this study, a non-targeted metabolomics method was developed to explore the mechanism of action of the combination of traditional Chinese and Western medicine in cerebral ischemia-reperfusion treatment, providing a theoretical basis for disease prognosis and treatment options. Graphical abstract.

Metabolomic profile perturbations of serum, lung, bronchoalveolar lavage fluid, spleen and feces in LPS-induced acute lung injury rats based on HPLC-ESI-QTOF-MS.

Acute lung injury (ALI) is a clinically common and serious disease, underscoring the urgent need for clarification of its pathogenesis. According to traditional Chinese medicine (TCM) theories on the "lung-spleen-intestine axis" and its correlation with ALI, a high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS) metabolomic platform was applied to identify biomarkers from five bio-samples of control and model rats challenged with intratracheally administered lipopolysaccharide (LPS) based on multivariate mathematical statistical analysis. As a result, 19, 24, 24, 15 and 29 altered metabolites were identified in serum, lung, bronchoalveolar lavage fluid (BALF), spleen and feces samples, respectively. Metabolic pathway analysis showed that linoleic acid, sphingolipid, glycerophospholipid and bile acid metabolism pathways were mainly altered by ALI. Additionally, ROC curves were applied to assess the specificity and sensitivity of the biomarkers. ALI characteristic metabolomic spectra were then established to differentiate the control from the model group with a similarity discriminative threshold of 0.7. Additionally, to compare the metabolomic profiles of the five bio-samples and establish metabolic similarities and differences among them, correlation analysis was conducted in order to delineate an objective law of endogenous linkage along the lung-spleen-intestine axis. Therefore, this study provides insights into the mechanisms involved in ALI from a metabolomics perspective, which can be applied in characterization of the mechanism and early disease detection. Graphical abstract.

Untargeted metabolomic study on the insomnia effect of Suan-Zao-Ren decoction in the rat serum and brain using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry combined with data processing analysis.

Insomnia is a common clinical disease that can seriously damage the normal lives of sufferers. Suan-Zao-Ren decoction has been used to treat insomnia for a long time. However, the underlying molecular mechanism of Suan-Zao-Ren decoction is still not clear. In this study, the nontargeted metabolomics based on high-resolution mass spectrometry and multiple statistical approaches were initially used to investigate the changes of potential serum and brain biomarkers and metabolic pathways in the insomnia model rat. Principal component analysis-discriminate analysis indicated that the Suan-Zao-Ren decoction treatment improved the metabolic phenotype insomnia. Moreover, the heatmap analysis identified the most important biomarkers involved in insomnia. According to the pathway analysis, phenylalanine metabolism, tryptophan metabolism, and so on were recognized as the most affected metabolic pathways associated with insomnia disease. These findings provided a comprehensive understanding of the regulative effects of Suan-Zao-Ren decoction on the host metabolic phenotype of the insomnia rats. Our work demonstrated that the metabolomics approach is a promising tool that could help us to conduct the exploration of the therapeutic effects and mechanism of traditional Chinese medicines.

Determination and Comparison of Short-Chain Fatty Acids in Serum and Colon Content Samples: Alzheimer's Disease Rat as a Case Study.

Short-chain fatty acids (SCFAs) are the main microbial fermentation products from dietary fibers in the colon, and it has been speculated that they play a key role in keeping healthy in the whole-body. However, differences in SCFAs concentration in the serum and colon samples had attracted little attention. In this study, we have optimized the extract and analysis methods for the determination of ten SCFAs in both serum and colon content samples. Methanol and acetonitrile were chosen for extraction of SCFAs from serum and colon content samples, respectively. Biological samples were collected from Alzheimer's disease rats treated by extract of Schisandra chinensis (Turcz.) Baill (SC-extract) were taken as research objects. The results showed that, the relative peak intensities of SCFAs in the colon content from all groups were quite similar, and the trend was identical in the serum samples. Compared with the values in humans, the ratio of ten SCFAs in rat's colon was similar, while the percent of acetate in rat's serum was significantly higher. For therapy of Alzheimer's disease (AD), SC-extract decreased the concentration of butyrate, 3-Methyvalerate, and caproate in the serum samples towards the trend of normal rats. This study may help our understanding of how SCFAs are transported across colonic epithelium in healthy and diseased organisms.

A Novel Strategy for Targeted Lipidomics Based on LC-Tandem-MS Parameters Prediction, Quantification, and Multiple Statistical Data Mining: Evaluation of Lysophosphatidylcholines as Potential Cancer Biomarkers.

Lipid quantification is the ultimate goal in lipidomics studies challenged by the availability of standard compounds. A novel strategy for targeted lipidomics based on LC-MS/MS parameters prediction and multivariate statistical analysis was developed for the quantitation of lysophosphatidylcholines (LPCs) in this study. Multiple linear regression models were established with the acyl chain length and number of double bonds after the prediction correlation coefficients ( R2pred) were evaluated. Then related analytical parameters including collision energy, declustering potential, retention time, and response factor were successfully predicted for any given LPC. With this "model-prediction" strategy, sensitivity, accuracy, and coverage of targeted lipidomics were improved significantly, and 60 LPCs were determined simultaneously in plasma for the first time. An integrated evaluation method for multi-indexes, logistic regression-ROC analysis was also proposed after biomarkers were identified by Student's t test, univariate ROC curve, and PLS-DA. Then the developed workflow was successfully used to discover and evaluate multi-LPCs indexes (a set of LPCs biomarkers with the best discriminating ability) for differentiating lung, breast, colorectal, and gastric cancer from controls, and among different types of cancer. Finally, the multi-LPCs index for lung cancer was compared with the plasma before and after treatment to test its utility. The novel targeted lipidomics methodology for LPCs was expected to provide a new insight into quantitative lipidomics and further clinical application.

The internal link of serum steroid hormones levels in insomnia, depression, and Alzheimer's disease rats: Is there an effective way to distinguish among these three diseases based on potential biomarkers?

Insomnia, depression, and Alzheimer's disease are all neurodegenerative diseases and are associated with the levels of steroid hormones. To investigate the internal connection and difference of steroid hormones among these three diseases and distinguish them from the perspective of biomarkers, an easy, quick, and efficient high-performance liquid chromatography with tandem mass spectrometry method was established and validated to determine six steroid hormones simultaneously in rat serum. The separation was accomplished on a SHIM-PACK XR-ODS chromatographic column with 0.1% v/v formic acid and methanol as the mobile phase and the detection was performed with electrospray ionization source in the positive ion mode. Based on the concentrations of steroid hormones, all the groups could be distinguished obviously from each other by using partial least square discriminant analysis. Meanwhile, 11-deoxycortisol, corticosterone, and cortisol were identified as potential biomarkers and 100% of samples were classified correctly by Bayes' discriminant function. These biomarkers were further screened by one-way analysis of variance and cortisol was significantly different among all these groups. Bayes' discriminant function was also built by cortisol and the classification accuracy was 87.2%. This workflow including determination of steroid hormones and discrimination among three neurological diseases would provide a basis for further clinical studies.

Combination of schisandrin and nootkatone exerts neuroprotective effect in Alzheimer's disease mice model.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases which seriously affect the quality of life of the elderly. Schisandrin (SCH) and nootkatone (NKT) are the two marked active components in ASHP. In this study, the effects of Alpinia oxyphylla-Schisandra chinensis herb pair (ASHP) as well as its bioactive components on cognitive deficiency and dementia were revealed via Aß1-42-induced AD in mouse. Morris water maze test showed that acute administration of ASHP and SCH + NKT treatments had higher discrimination index in the object recognition task, more quadrant dwell time and shorter escape latency compared with those in the Morris water maze. The levels of TNF-α, IL-1ß and IL-6 were decreased after ASHP and SCH + NKT treatment. The inflammatory response was attenuated by inhibiting TLR4/ NF-κB/ NLRP3 pathway. In addition, ASHP and SCH + NKT treatments significantly restored the activities of superoxide dismutase (SOD), glutathione S-transferase (GST), cyclooxygenase-2 (COX-2), total antioxidant capacity (T-AOC) and inducible nitric oxide syntheses (iNOS), and the levels of glutathione (GSH), malondialdehyde (MDA) and nitric oxide (NO). The histopathological changes of hippocampus were noticeably improved after ASHP and SCH + NKT treatments. These findings demonstrate that ASHP as well as its bioactive components exerted a protective effects on cognitive disorder, inflammatory reaction and oxidative stress.

Intracerebroventricular injection of resveratrol ameliorated Aß-induced learning and cognitive decline in mice.

Resveratrol (RSV) is a natural plant polyphenol compound which consists in red grape skins and wine in general. Plenty of previous studies have shown that resveratrol has neuroprotective effects. The primary object of this research was to study the effects of RSV on improving the cognitive function and neurodegeneration in the mouse model of Alzheimer's disease induced by Aß1-42, and the possible mechanism about targeting on Sirt1, which results in attenuating inflammatory response and mitochondrial dysfunction. We established the AD model of intracerebroventricular (i.c.v.) injection of Aß1-42 and it was observed that the significant decrease in alternately of Y Maze and the quadrant dwell time percentage of Morris water maze test. Furthermore, there were significant upregulations of AMPK/ PGC-1α and downregulations of NF-κB/ IL-1ß/ NLRP3 signaling pathways in the hippocampus and prefrontal cortex in AD mice. The treatments with RSV and Donepezil could significantly ameliorate all the behavioral and biochemical changes induced by Aß1-42. It also noticeably improved the histopathological changes in the hippocampus and cortex. The results suggested that RSV might protect against cognitive deficits and neurodegeneration induced by Aß1-42, and serve as a potential agent in treatment of AD.

A UFLC-MS/MS method for the simultaneous determination of eight bioactive constituents from red wine and dealcoholized red wine in rat plasma: Application to a comparative pharmacokinetic study.

To explore whether alcohol has an effect on the pharmacokinetic behavior of phenolic acids, the main bioactive constituents in red wine, a highly sensitive and simple ultra-fast liquid chromatography coupled with triple quadrupole mass spectrometry (UFLC-MS/MS) method was developed for simultaneous quantitation of eight phenolic acids in plasma samples. Plasma samples were extracted by liquid-liquid extraction and the chromatographic separation was achieved on a Zorbax SB-C18 column within 7.0 min. Results of the validated method revealed that all of the calibration curves displayed good linear regression (r > 0.99). The intra- and inter-day precisions of the analytes were <14.0% and accuracies ranged from -8.5 to 7.3%. The extraction recoveries of the analytes were from 71.2 to 110.2% and the matrix effects ranged from 86.2 to 105.5%. The stability of these compounds under various conditions satisfied the requirements of biological sample measurement. The method was successfully applied to a comparative pharmacokinetic study of phenolic acids in rat plasma. For gallic acid and gentisic acid, the parameters AUC0-t and AUC0-∞ increased remarkably (p < 0.05) after oral administration of red wine, which suggested that alcohol might enhance their absorption. This is the first report to compare the pharmacokinetic behavior of phenolic acids in red wine and dealcoholized red wine.

Schisandrae Chinensis Fructus inhibits behavioral deficits induced by sleep deprivation and chronic unpredictable mild stress via increased signaling of brain-derived neurotrophic factor.

The present study was undertaken to explore the interactions between sleep deprivation (SD) and Schisandrae Chinensis Fructus (SCF) treatment in the antidepressant-like effects. We observed that SD aggravated the anxiety-like behavior induced by chronic unpredictable mild stress (CUMS) in the elevated plus maze test. However, the forced swimming test and sucrose preference test showed that SD (12 hr) alleviated the depressive symptoms and SD (72 hr) has the opposite effects. Administration of SCF showed a promising therapeutic effect on depression and anxiety induced by CUMS and SD. Moreover, SCF could potential strengthen the antidepressant-like effects of SD (12 hr) according to the behavioral tests. In addition, the BDNF level in hippocampus was elevated by SD (12 hr) and SCF treatment and together with the upregulation of TrkB/CREB/ERK and PI3K/AKT/GSK3ß/mTOR signaling pathways. Besides, the protein levels of p70S6K and PSD95, which are downstream targets of mTOR, also increased by the treatment. These results indicated that the antidepressant-like effect of SCF in the CUMS depends on the activation of BDNF and the modulation of TrkB/CREB/ERK and PI3K/AKT/GSK3ß/mTOR signaling cascades, and SD (12 hr) shared a common etiology consisting of complex bidirectional interactions with SCF.