The Pretreatment of Xiaoqinglong Decoction Alleviates Inflammation and Oxidative Damage and Up-Regulates Angiotensin-Converting Enzyme 2 in Lipopolysaccharide-Induced Septic Acute Lung Injury Rats.

Xiaoqinglong decoction (XQLD), a classic prescription of Traditional Chinese Medicine, has already been used clinically to cure acute lung injury (ALI), but its mechanism remains unclear. This subject aimed to explore the preventive role of XQLD in septic ALI rats besides its effects on angiotensin-converting enzyme (ACE)2 and its downstream factors. After, respectively, administrated with different concentrations of XQLD (6.25 g/kg/d, 12.5 g/kg/d, 25 g/kg/d) for 5 days and dexamethasone (DEX, 1 mg/kg) for 0.5 h, the rat models of ALI were established by intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) for 24 h. All rats were evaluated by lung function test, arterial blood gas analysis, morphological observation, lung wet/dry (W/D) ratio, and the lung injury score. The levels of malonaldehyde (MDA), superoxide dismutase (SOD), interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and angiotensin (Ang) (1-7) in the lung were measured through biochemical and ELISA kits. The expressions of angiotensin-converting enzyme (ACE)2, mitochondrial assembly receptor (MasR), and nuclear factor (NF)-κB in lung tissue were detected by qRT-PCR and western blotting. Positive reaction cells of MasR were observed by immunohistochemistry. The results show that XQLD significantly ameliorated septic lung injury including edema and hemorrhage, as well as improved pulmonary function and arterial blood gas. Furthermore, XQLD markedly decreased the levels of IL-1ß, TNF-α, MDA, and NF-κB while increased the levels of SOD, Ang (1-7), ACE2, and MasR in septic ALI rats. Pearson correlation showed that the expressions of ACE2 were inversely related to IL-1ß, TNF-α, MDA, and NF-κB and positively correlated with SOD contents. Our data indicated that XQLD pretreatment alleviated inflammation and oxidative damage in septic ALI rats, which might be related to the up-regulation of ACE2-Ang (1-7)-MasR axis and inhibition of the NF-κB pathway.

Habitual fish oil supplementation and incident chronic obstructive pulmonary disease: Data from a prospective cohort study.

BACKGROUND: Fish oil is one of the most popular supplements in the UK and other developed countries. However, the relationship between fish oil use and chronic obstructive pulmonary disease (COPD) is unclear. OBJECTIVE: To prospectively examine the association of habitual fish oil supplementation with incident COPD risk and to evaluate potential effect modification by genetic predisposition. METHODS: This study included 484,414 participants (mean and standard deviation [SD] age: 56.5 [8.1] years) from the UK Biobank who completed a touchscreen questionnaire on habitual fish oil supplement use between 2006 and 2010 and were followed up through 2018. Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) with adjustment for sociodemographic and lifestyle behaviours, health conditions, and other potential confounding factors. A weighted genetic risk score (GRS) for COPD was derived from 112 validated single nucleotide polymorphisms. RESULTS: During a median follow-up of 9.0 years, 8860 incident COPD events were recorded. A total of 31.4% (152,230) of the study participants reported habitual fish oil supplementation at baseline. Habitual fish oil supplementation was significantly associated with a lower risk of incident COPD (adjusted HR: 0.88; 95% CI: 0.84-0.93). The association with COPD did not differ by GRS strata (P for interaction = 0.880). The results from subgroup and sensitivity analyses supported the robustness of our findings. CONCLUSIONS: Our findings suggest that habitual fish oil supplementation is associated with a lower risk of incident COPD, irrespective of genetic predisposition.

[Toxicokinetics of emodin-8-O-ß-D-glucoside in rats in vivo].

This study aims to establish an ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) method for the determination of emodin-8-O-ß-D-glucoside(EG) and its metabolites in plasma, and to investigate the toxicokinetics(TK) behavior of them in rats. To be specific, the TK of EG and its metabolites from the first to the last administration in the repeated dose toxicity study was determined, and the kinetic parameters were calculated. The exposure of EG prototype and metabolites in rat plasma after oral administration of different doses of EG was evaluated. The result showed that the prototype of EG and its metabolites aloe-emodin-8-O-ß-D-glucoside, emodin, aloe-emodin, and hydroxyemodin could be detected in rats after oral administration of high-, medium-, and low-dose EG. The area under the curve(AUC) of the prototype and metabolites after the first and last administration was in positive correlation with the dose. The time to the maximum concentration(T_(max)) of EG and metabolites in the three administration groups was <6 h, and the longest in vivo residence time was 12 h. The T_(max) and in vivo residence time of EG were prolonged with the increase in the dose. The metabolites emodin, aloe-emodin, and hydroxyemodin all had two peaks. Both hydroxyemodin and aloe-emodin exhibited increased plasma exposure, slow metabolism, and accumulation in vivo. In addition, aloe-emodin-8-O-ß-D-glucoside and emodin disappeared with the increase in dose, suggesting the change of the metabolic pathway of EG in vivo in the case of high-dose administration. The mechanism of high-dose EG in vivo needs to be further explored. This study preliminarily elucidates the TK behavior of EG in rats, which is expected to support clinical drug use.

[Influence of coexisting components in Coptidis Rhizoma on excretion of magnoflorine in rat bile, urine, and feces].

Magnoflorine is an important aporphine alkaloid in Coptidis Rhizoma. As reported previously, coexisting components in Coptidis Rhizoma can change the pharmacokinetic characteristics of magnoflorine. To illustrate the interactional links of magnoflorine with its coexisting components in Coptidis Rhizoma, the present study investigated the influence of coexisting components in Coptidis Rhizoma on the excretion of magnoflorine in rat bile, urine, and feces. The rats were dosed with magnoflorine(30 mg·kg~(-1)) and water decoction of Coptidis Rhizoma(equivalent to 30 mg·kg~(-1) magnoflorine) via intragastric administration, and magnoflorine(10 mg·kg~(-1)) by intravenous administration, respectively, and the excretion of magnoflorine in rat bile, urine, and feces in 24 h was observed. The excretion rates of magnoflorine in bile and urine in 24 h were 0.90% and 37.11% respectively after intravenous administration of magnoflorine, which suggested that urination was the main excretive way of magnoflorine. The excretion rates of magnoflorine in feces were 8.77% and 6.18% respectively after intragastric administration of magnoflorine and water decoction of Coptidis Rhizoma, which indicated that defecation was the main excretion route of magnoflorine. The cumulative excretion rates of magnoflorine in the bile, urine, and feces in the Coptidis Rhizoma water decoction group were 77.78%, 79.44%, and 70.47% of those in the magnoflorine group. The results showed that the cumulative excretion rates of magnoflorine in rat bile, urine, and feces were not high, suggesting that magnoflorine was metabolized significantly in rats. The coexisting components of Coptidis Rhizoma could inhibit the excretion of magnoflorine in rat bile, urine, and feces, which was consistent with the decrease in the elimination rate of magnoflorine in the pharmacokinetics of Coptidis Rhizoma water decoction. It indicated interactions between drugs. This study is expected to provide references for the development of magnoflorine-containing new drugs and rational clinical medication of Coptidis Rhizoma.

[Effect of electroacupuncture on pulmonary neuroendocrine cells and secretion of neuroactive substances in lung of COPD rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Zusanli" (ST36) and "Feishu" (BL13) on the activation and secretion of calcitonin gene-related peptide (CGRP) and 5-hydroxytryptamine (5-HT) of pulmonary neuroendocrine cells (PNECs) and inflammatory response in rats with chronic obstructive pulmonary disease (COPD), so as to explore its underlying mechanisms in treating COPD. METHODS: Male SD rats were randomly divided into normal control, COPD model and EA groups, with 7 rats in each group. The COPD model was established by forced inhale of cigarette smoke for 1 h in a self-made box (1 m×1 m×1 m in volume), twice daily for 12 weeks. EA (4 Hz/20 Hz, 1-3 mA) was applied at bilateral ST36 and BL13 acupoints for 30 min, once a day for 14 consecutive days. The pulmonary function including the forced vital capacity (FVC), forced expiratory volume at 0.1 second (FEV0.1), FEV0.3, FEV0.1/FVC and FEV0.3/FVC was detected using a lung function analyzer for small animals. The lung tissue was sampled for observing histopathological changes by using H.E. staining, for observing expression and distribution of PNECs by Grimelius silver staining, and for detecting the immunoactivity (integrated optical density) of CGRP and 5-HT by using immunohistochemistry. The contents of CGRP, 5-HT, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and transforming growth factor-ß1 (TGF-ß1) in the bronchoalveolar lavage fluid (BALF) and lung tissue were detected by ELISA, and the correlations between TNF-α and CGRP, IL-1ß and CGRP, TNF-α and 5-HT, and IL-1ß and 5-HT levels were analyzed. The mRNA and protein expression levels of nerve fiber markers of CGRP and purinergic receptor P2X ligand gated ion channel 3 (P2X3) which dominate PNECs in the lung tissue were detected by real-time fluorescence quantitative PCR and Western blot, respectively. RESULTS: Compared with the normal control group, the levels of FVC, FEV0.1, FEV0.3, and the ratios of FEV0.1/FVC and FEV0.3/FVC were significantly decreased (P<0.05, P<0.01), while the immunoactivity of PNECs, CGRP and 5-HT, the contents of CGRP, 5-HT, TNF-α, IL-1ß and TGF-ß1 in the BALF and lung tissue, and the expression levels of CGRP and P2X3 mRNAs and proteins in the lung tissue significantly increased in the COPD model group (P<0.01, P<0.05). Following EA intervention, both the increased and decreased levels of all the indexes mentioned above were reversed (P<0.05, P<0.01) except FEV0.3. H.E. staining showed severe deformed bronchial lumen with thickened wall and alveolar septum, and obvious inflammatory cell infiltration and reduced number of alveolar lumen fusion in the COPD model group, which was mild in the EA group. A positive correlation was found between TNF-α and CGRP, IL-1ß and CGRP, TNF-α and 5-HT,IL-1ß and 5-HT levels in both BALF and lung tissues (P<0.01). CONCLUSION: EA at ST36 and BL13 can improve lung function and reduce inflammatory response in COPD rats, which may be related to its function in inhibiting the activation of PNECs and release of neuroactive substances.

[Effect of Suanzaoren Decoction on molecular levels of bile acids in serum, liver, and ileum of insomnia mice].

To explore the mechanism of Suanzaoren Decoction in the treatment of insomnia from endogenous bile acid regulation, the present study investigated the hepatoprotective effect of Suanzaoren Decoction and the molecular changes of bile acids in the serum, liver, and ileum of insomnia model mice and Suanzaoren Decoction treated mice. The insomnia model in mice was established by the sleep deprivation method. After Suanzaoren Decoction(48.96 mg·kg~(-1)·d~(-1)) intervention by gavage for 7 days, the related indicators, such as water consumption, food intake, body weight, aspartate aminotransferase(AST), alanine transaminase(ALT), and total bile acid(TBA) were detected, and the pathological changes of the liver and ileum were observed. The molecular levels and distribution of 23 bile acids in the serum, liver, and ileum were analyzed by UPLC-MS/MS combined with principal component analysis(PCA) and partial least squares discriminant analysis(PLS-DA). The results showed that Suanzaoren Decoction could improve the decreased water consumption and food intake, weight loss, and increased AST and ALT in the model group, and effectively reverse the injury and inflammation in the liver and ileum. The bile acids in the liver of the insomnia model mice were in the stage of decompensation, and the bile acids in the serum, liver, and ileum of the mice decreased or increased. Suanzaoren Decoction could regulate the anomaly of some bile acids back to normal. Seven bile acids including glycoursodeoxycholic acid(GUDCA), glycodesoxycholic acid(GDCA), tauro-α-MCA(T-α-MCA), α-MCA, taurodeoxycholate(TDCA), T-ß-MCA, and LCA were screened out as the main discriminant components by PLS-DA. It is concluded that Suanzaoren Decoction possesses the hepatoprotective effect and bile acids could serve as the biochemical indicators to evaluate the drug efficacy in the treatment of abnormal liver functions caused by insomnia. The mechanism of Suanzao-ren Decoction in soothing the liver, resolving depression, tranquilizing the mind, and improving sleep may be related to the molecular regulation of bile acid signals.

[Study on bile acid metabolism of sleep-deprived mice regulated by Jiaotai Pills based on LC-MS].

To investigate the changes of bile acid(BA) levels in mice with sleep deprivation and the regulatory effect of Jiaotai Pills(JTP) on bile acid metabolism, this study established an ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) method for simultaneous determination of 23 BAs in mice. A total of 24 ICR mice were randomized into normal group, model group, and JTP group. Mice in the model group and JTP group were deprived of sleep at 20 h·d~(-1) by sleep deprivation apparatus for 8 consecutive days. Mice in the JTP group were given(ig, qd) JTP 3.3 g·kg~(-1) and those in the normal group and model group received(ig) the same volume of purified water. UPLC conditions are as follows: Waters ACQUITY UPLC BEH C_(18) column(2.1 mm×100 mm, 1.7 µm), gradient elution with the mobile phase of 0.1% formic acid in water-methanol. MS conditions are as below: negative-ion electrospray ionization, multiple reaction monitoring(MRM). Thereby, the content of 23 BAs in serum, liver, and ileum was determined and methodological investigation of the method was performed. The results showed that 23 BAs could be accurately determined within 15 min and the correlation coefficients were all higher than 0.99. The precision, accuracy, specificity, reproducibility, matrix effect, and recovery of BAs all met the requirement. The levels of BAs were significantly increased in the serum, liver, and ileum of sleep-deprived mice, but JTP can significantly reduce the levels. The UPLC-MS/MS method is simple, rapid, and accurate, which can be used for the determination of 23 BAs in biological samples, and JTP can adjust the elevated BA levels of sleep-deprived mice.

[Evaluation of Astragali Radix quality grade based on appearance characteristics and internal ingredients].

This study is to provide the basis of establishing a quality evaluation system, based on the differences in appearance and internal components of Astragali Radix from different sources. The diameter of 18 batches of Astragali Radix, the content of alcohol(water) extract and 7 kinds of flavonoids were determined. The peak area ratio of flavonoid aglycon to aglycone was calculated. PCA and CA were carried out by synthesizing various indexes. The results of PCA and CA showed that Astragali Radix was obviously clustered into three types. Alcohol extract, formononetin/formosan glycosides,(pilose isoflavones+astragalus flavonoid A)/pilose isoflavone glucoside are the most significant differences in the variable importance projection index(VIP) of Astragali Radix. Combining the diameter, alcohol(water) extract, flavonoid aglycon to aglycone peak area ratio can provide an analysis method for the establishment of the grade evaluation system of Astragali Radix.

Jiaotai Pill () Alleviates Insomnia through Regulating Monoamine and Organic Cation Transporters in Rats.

OBJECTIVE: To reveal the effect and mechanism of Jiaotai Pill (, JTP) on insomniac rats. METHODS: The insomniac model was established by intraperitoneal injection of p-chlorophenylalanine (PCPA). In behavioral experiments, rats were divided into control, insomniac model, JTP [3.3 g/(kg•d)], and diazepam [4 mg/(kg•d)] groups. The treatment effect of JTP was evaluated by weight measurement (increasement of body weight), open field test (number of crossings) and forced swimming test (immobility time). A high performance liquid chromatography-electrochemical detection (HPLC-ECD) method was built to determine the concentration of monoamine transmitters in hypothalamus and peripheral organs from normal, model, JTP, citalopram [30 mg/(kg•d)], maprotiline [40 mg/(kg•d)] and bupropion [40 mg/(kg•d)] groups. Expressions of serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) were analyzed by quantitative polymerase chain reaction (qPCR) and Western blot in normal, model and JTP groups. A high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS/MS) method was established to determine the pharmacokinetics, urine cumulative excretion of metformin in vivo, and tissue slice uptake in vitro, which were applied to assess the activity of organic cation transporters (OCTs) in hypothalamus and peripheral organs. RESULTS: Compared with the insomniac model group, the body weight and spontaneous locomotor were increased, and the immobility time was decreased after treatment with JTP (P<0.01). Both serotonin and dopamine contents in hypothalamus and peripheral organs were increased (P<0.01). The norepinephrine content was increased in peripheral organs and decreased in hypothalamus (P<0.05 or P<0.01). At the same time, SERT, DAT, OCT1, OCT2, and OCT3 were down-regulated in hypothalamus and peripheral organs (P<0.05). NET was down-regulated in peripheral organs and up-regulated in hypothalamus (P<0.05 or P<0.01). Moreover, the activity of OCTs in hypothalamus and peripheral organs was inhibited (P<0.05). CONCLUSION: JTP alleviates insomnia through regulation of monoaminergic system and OCTs in hypothalamus and peripheral organs.

Rescue effects of Se-enriched rice on physiological and biochemical characteristics in cadmium poisoning mice.

Cadmium (Cd) is an element injurious for human health and is possibly toxic to organisms at minor concentrations. While some of other trace metallic elements have antagonistic features to it. One of them is the interaction between selenium (Se) and Cd in plant different organs. Literature review disclosed that the intake of Se to some extent can reduce the accumulation of Cd in plants, while the research on of trace metallic elements (Cd) and Se-enriched food (rice) in the living body has rarely been reported. This study intended to explore whether there was a mitigating effect of Se-enriched rice on mice poisoned with Cd. A mouse model of low-dose and high-dose Cd poisoning was established (supplemented with cadmium chloride(CdCl2·2½H20)), followed by feeding two groups (1) Se-enriched rice and (2) setting an equal amount of inorganic Se group. After that, the impact of Se-enriched rice on the antioxidant activity was evaluated. The Se-enriched diet enhanced the total antioxidant capacity (T-AOC), superoxide dismutase (SOD), and enzyme activities of GSH peroxidase (GSH-Px) in mice livers and kidney whereas significantly decreased the malondialdehyde (MDA) contents. Moreover, the degree of physiological damage in mice with low cadmium poisoning was significantly alleviated, and the expression of antioxidant genes (Nrf-2, GPX1, TrxR2, TNF-2) was increased. In conclusion, the Se-enriched diet has a positive effect on the biological effects in mice, and it can be used as a daily diet to resist damage to the body's low Cd state and support enzymatic antioxidant systems by eliminating oxidative injury.

[Regulatory effect of Jiaotai Pills on central and peripheral neurotransmitters in rats with heart-kidney imbalance insomnia].

To explore the pathogenesis of heart and kidney imbalance insomnia and the regulatory effect of Jiaotai Pills, in order to study the changes of central and peripheral neurotransmitters in rat. Insomnia rats with heart and kidney imbalance were induced through intraperitoneal injection with p-chlorophenylalanine(PCPA, 400 mg·kg~(-1)·d~(-1)), and the model rats were intragastrically administrated with Jiaotai Pills(3.3 g·kg~(-1)·d~(-1)) for 7 days. Nine neurotransmitters were determined by UPLC-MS/MS and principal component analysis(PCA) method in serum, urine, brain, heart, liver, kidney and adrenal gland of rats. The results showed that the ratio of 5-HT and 5-HIAA in platelet of insomnia rats was significantly lower than that in the normal group, and Jiaotai Pills had a significant up-regulatory or down-regulatory effect. Compared with the normal group, the changed neurotransmitters in blood of insomnia rats were 5-HIAA, E, NE, DA, Glu and ACH, and except ACH, the changes of 7 kinds of neurotransmitters in urine were more significant, Jiaotai Pills had a significant up-regulatory or down-regulatory effect. Compared with the normal group, all of the 8 neurotransmitters in insomnia rats except HVA were changed. Jiaotai Pills could regulate the neurotransmitters in each tissue of insomnia rats, especially in brain, liver and adrenal gland. In conclusion, insomnia is caused by not only a change of neurotransmitters in brain, but also a series of changes in peripheral tissues. It indicates that insomnia is a systematic imbalance of neurotransmitters. Jiaotai Pills not only regulates the central nervous system, but also has a certain protective effect on other organs, reflecting the multi-target and systematic effect of Jiaotai Pills in the treatment of insomnia.

Associations of habitual fish oil supplementation with cardiovascular outcomes and all cause mortality: evidence from a large population based cohort study.

OBJECTIVES: To evaluate the associations of habitual fish oil supplementation with cardiovascular disease (CVD) and mortality in a large prospective cohort. DESIGN: Population based, prospective cohort study. SETTING: UK Biobank. PARTICIPANTS: A total of 427 678 men and women aged between 40 and 69 who had no CVD or cancer at baseline were enrolled between 2006 and 2010 and followed up to the end of 2018. MAIN EXPOSURE: All participants answered questions on the habitual use of supplements, including fish oil. MAIN OUTCOME MEASURES: All cause mortality, CVD mortality, and CVD events. RESULTS: At baseline, 133 438 (31.2%) of the 427 678 participants reported habitual use of fish oil supplements. The multivariable adjusted hazard ratios for habitual users of fish oil versus non-users were 0.87 (95% confidence interval 0.83 to 0.90) for all cause mortality, 0.84 (0.78 to 0.91) for CVD mortality, and 0.93 (0.90 to 0.96) for incident CVD events. For CVD events, the association seemed to be stronger among those with prevalent hypertension (P for interaction=0.005). CONCLUSIONS: Habitual use of fish oil seems to be associated with a lower risk of all cause and CVD mortality and to provide a marginal benefit against CVD events among the general population.

[Simultaneous rapid detection of eight neurotransmitters in rat tissues,blood and urine samples by UPLC-MS/MS].

Ultra performance liquid chromatography-tandem mass spectrometry( UPLC-MS/MS) was used to establish the simultaneous determination method of eight neurotransmitters in brain,liver,kidney,adrenal gland,serum and urine,including serotonin,5-hydroxyindole acetic acid,epinephrine,norepinephrine,dopamine,glutamic acid,γ-aminobutyric acid,and acetylcholine,and then investigate the distribution characteristics of neurotransmitters in rat tissues,blood and urine. Waters ACQUITY UPLC BEH C_(18) column( 2. 1 mm×100 mm,1. 7 µm) was used,with 0. 3% formic acid solution-acetonitrile as the mobile phase for gradient elution.Multiple reaction monitoring( MRM) scanning method under positive mode by atmospheric pressure electrospray ion source( ESI) was also performed to establish the detection method of neurotransmitters for methodological research. The plasma,urine and tissues of normal rats were pre-treated including homogenization,centrifuging,and protein removal,then the 2 µL supernatant was injected for analysis. The results showed that eight kinds of neurotransmitters could be accurately determined within 7 min,with linear correlation coefficients all greater than 0. 99. This method showed high accuracy and good precision,with specificity,stability,extraction recovery and matrix effects all complying with the biological sample analysis requirements. The most abundant transmitters in the brain,liver,kidney,kidney gland,blood and urine were γ-aminobutyric acid,glutamic acid,glutamic acid,adrenaline,glutamic acid and dopamine.The method is sensitive,rapid,precise,accurate and specific,and can be used for simultaneous quantitative analysis of eight neurotransmitters in biological samples. The investigation of the distribution ratio of transmitters in rats is of important significance to disease prevention and treatment.

The oral bioavailability, excretion and cytochrome P450 inhibition properties of epiberberine: an in vivo and in vitro evaluation.

Epiberberine (EPI) is a novel and potentially effective therapeutic and preventive agent for diabetes and cardiovascular disease. To evaluate its potential value for drug development, a specific, sensitive and robust high-performance liquid chromatography-tandem mass spectrometry assay for the determination of EPI in rat biological samples was established. This assay was used to study the pharmacokinetics, bioavailability and excretion of EPI in rats after oral administration. In addition, a cocktail method was used to compare the inhibition characteristics of EPI on cytochrome P450 (CYP450) isoforms in human liver microsomes (HLMs) and rat liver microsomes (RLMs). The results demonstrated that EPI was rapidly absorbed and metabolized after oral administration (10, 54 or 81 mg/kg) in rats, with Tmax of 0.37-0.42 h and T1/2 of 0.49-2.73 h. The Cmax and area under the curve values for EPI increased proportionally with the dose, and the oral absolute bioavailability was 14.46%. EPI was excreted mainly in bile and feces, and after its oral administration to rats, EPI was eliminated predominantly by the kidneys. A comparison of the current half-maximal inhibitory concentration and Ki values revealed that EPI demonstrated an obvious inhibitory effect on CYP2C9 and CYP2D6. Furthermore, its effect was stronger in HLM than in RLM, more likely to be a result of noncompetitive inhibition.

[Study on mechanism of hepatotoxicity of Ploygoni Multiflori Caulis based on function inhibition of bilirubin-associated transporters in idiosyncratic rat].

To explore the possible mechanism of liver injury, the effects of Ploygoni Multiflori Caulis and its extractive on the function of bilirubin-associated transporters were investigated in normal (N) and idiosyncratic (LPS) rats (M). The normal and LPS rats were respectively administrated powder of Ploygoni Multiflori Caulis, its extractive and same volume of 0.5% CMC-Na solution for 7 d. BSP, a substrate of the transporters of Oatp1a1 and Oatp1b2 was selected, and its pharmacokinetic parameters of intravenous injection were determined to examined the activity these transporters. Meanwhile the mRNA expressions of transporters were detected. Compared with N-blank control group, besides M-powder group, the Cmax has no significantly different from other groups, t1/2, AUC0-t and AUC0-∞ were significantly increased, and CL were significantly decreased. However, compared with N- blank control group, AST and ALT decreased significantly. The expression of Oatp1a1, Oatp1b2 and MRP2 mRNA was significantly decreased (P<0.05), but there was no act synergistically when Ploygoni Multiflori Caulis and extractive were combined with LPS. The function of Oatp1a1, Oatp1b2 and MRP2 in rats were significantly inhibited by Ploygoni Multiflori Caulis and extractive, which may be an important cause of hepatotoxicity.

[Changes in amino acid profiling in spontaneously hypertensive rats and regulatory effect of extract from Coreopsis tinctoria].

To compare the amino acid metabolic profiling in urine of spontaneously hypertensive rats (SHR) and normal Wistar rats, and investigate the regulatory effect of extract from Coreopsis tinctoria on blood pressure and amino acid metabolic profiling in SHR. Right aged SHR and Wistar rats were housed to fit the new environment for 2 weeks. After that, their systolic pressure(SBP), diastolic pressure(DBP) were measured and urine was collected. Amino acids profiles for SHR and Wistar rats were acquired by using AQC precolumn derivatization HPLC-fluorescence method, and then partial least squares discriminant analysis(PLS-DA) was applied to facilitate differentiation and determine metabolic differences between collected samples from two groups of rats. Consequently, 40 SHR were randomly divided into 5 groups: model group, high, middle, low dosage groups of C. tinctoria extract (3.2, 1.6,0.8 g•kg⁻¹), and captopril group (4 mg•kg⁻¹). They were treated for 4 weeks by ig administration, and then their urine samples were collected to determine the amino acid metabolic profiling in various groups. After treatment for 4 weeks, as compared with Wistar group, serine, alanine, tyrosine, and cystine in the amino acid metabolic profiling were significantly increased in SHR group. As compared with SHR model group, threonine and methionine were decreased significantly in captopril group (P<0.01); amino acid metabolism was changed to different degrees in high, middle, and low dosage groups of C. tinctoria extract, and the threonine in low dose group was significantly decreased (P<0.01); serine and threonine were decreased (P<0.05), and valine, methionine and lysine were significantly decreased (P<0.01) in middle dose group; threonine, valine, methionine and lysine were significantly decreased in large dose group (P<0.01). The results showed that middle and high doses of extract from C. tinctoria could significantly improve disturbance of amino acid metabolism, help to further clarify the drug property research of C. tinctoria, and provide data support for amino acid metabolic pathway abnormalities in hypertension patients.

[Effects of Acupuncture Stimulation of Bilateral "Hegu" (LI 4) and "Taichong" (LR 3) on Learning-memory Ability, Hippocampal AP 42 Expression and Inflammatory Cytokines in Rats with Alzheimer's Disease].

OBJECTIVE: To observe the effect of acupuncture stimulation of bilateral "Hegu" (LI 4) and "Taichong" (LR 3, the so-called "Four Gate Points") on learning-memory ability, hippocampal interleukin-1 (IL-1) P and IL-2 and amyloid beta (Abeta) 42 levels in Alzheimer's disease (AD) rats,so as to reveal its underlying mechanism in improving AD. METHODS: Male SD rats were randomly divided into sham operation, model, medication and acupuncture groups (n = 12 rats in each group). The AD model was created by microinjection of streptozotocin (10 pL, 3 mg/kg) into the lateral ventricle (repeated the microinjection once two days later). Bilateral LR 3 and LI 4 were punctured with filiform needles and stimulated manually, once a day, 6 days a week for 4 weeks. The rats of the medication group were intragastric perfusion of Donepezil HOI (0.045 mg/kg), once a day for 4 weeks. The learning-memory ability was detected by Morris water maze swimming tests. The immunoactivity of hippocampal Abeta 42 was detected by immunohistochemistry, and the contents of IL-1 P and IL-2 in the hippocampus tissue were determined by ELISA. RESULTS: After modeling, the average escape latency of Morris water navigation task was significantly increased, and the target-platform crossing times of space probe trials were significantly reduced in the model group (P<0.05), suggesting a g-memory ability. After acupuncture intervention, the increased escape latency and the decreased target-platform crossing times were reversed, suggesting an improvement of the learning-memory. The hippocampal Abeta 42 immunoactivity and IL-1 beta content were significantly higher in the model group than in the sham operation group (P<0.05), but the hippocampal IL-2 content was markedly decreased in the model group (P<0. 05). Following the interventions, the increased Abeta 42 expression and IL-1 beta contents, and the decreased IL-2 contents in the hippocampus were also reversed in both the acupuncture and medication groups (P<0.05). CONCLUSION: Acupuncture may improve learning-memory ability in AD rats, which may be associated with its effects in reducing hippocampal Abeta13 42 expression and IL-1beta content and in up-regulating IL-2 level.

Effects of Beverages on Alcohol Metabolism: Potential Health Benefits and Harmful Impacts.

Nonalcoholic beverages are usually consumed accompanying alcoholic drinks, and their effects on alcohol metabolism are unclear in vivo. In this study, the effects of 20 nonalcoholic beverages on alcohol metabolism and liver injury caused by alcohol were evaluated in mice. Kunming mice were orally fed with alcohol (52%, v/v) and beverages. The concentrations of ethanol and acetaldehyde in blood as well as the activities of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in liver were assessed to indicate alcohol metabolism. The levels of aspartate aminotransferase (AST) and alanine transaminase (ALT) in serum as well as the levels of malonaldehyde (MDA) and superoxide dismutase (SOD) in liver were measured to reflect the alcohol-induced liver injury. The results showed that the treatment of soda water, green tea and honey chrysanthemum tea could accelerate ethanol metabolism and prevent liver injuries caused by alcohol when companied with excessive alcohol drinking. They might be potential dietary supplements for the alleviation of harmful effects from excessive alcohol consumption. On the contrary, some beverages such as fresh orange juice and red bull are not advised to drink when companied with alcohol consumption due to their adverse effects on ethanol induced liver injury.

Natural Products for the Prevention and Treatment of Hangover and Alcohol Use Disorder.

Alcoholic beverages such as beer, wine and spirits are widely consumed around the world. However, alcohol and its metabolite acetaldehyde are toxic and harmful to human beings. Chronic alcohol use disorder or occasional binge drinking can cause a wide range of health problems, such as hangover, liver damage and cancer. Some natural products such as traditional herbs, fruits, and vegetables might be potential dietary supplements or medicinal products for the prevention and treatment of the problems caused by excessive alcohol consumption. The aim of this review is to provide an overview of effective natural products for the prevention and treatment of hangover and alcohol use disorder, and special emphasis is paid to the possible functional component(s) and related mechanism(s) of action.

[In vitro effects of Genkwa Flos chloroform extract on activity of human liver microsomes UGTs and UGT1A1].

To predict the mechanism of liver injury induced by Genkwa Flos, we investigated the effect of chloroform extract on UGTs and UGT1A1 activities of the liver microsomes in rat and human. In the present study, 4-nitrophenol(4-NP) and ß-estradiol were elected as substrates to determine activities of UGTs and UGT1A1 by UV and HPLC. The results showed that there were 1.00% of apigenin, 6.40% of hydroxygenkwanin and 18.38% of genkwanin in chloroform extract; and total diterpene mass fraction was 31.40%. Compared with the control group, chloroform extract could significantly inhibit the activity of UGTs in rat liver microsomes(RLM) system, while the inhibitory effect was not obvious in human liver microsomes(HLM) system. UGT1A1 activity was inhibited by chloroform extract in rat liver microsomes and human liver microsomes (based on genkwanin, IC50=8.76, 10.36 µmol•L⁻¹). The inhibition types were non-competitive inhibition(RLM) and uncompetitive inhibition(HLM). In conclusion, the results indicated that chloroform extract showed different inhibitory effects on UGTs and UGT1A1 activity, which may be one of the mechanisms of liver injury induced by Genkwa Flos.