Search

Introduction: Previous work conducted by our group has shown that nicotine reduces lipopolysaccharide (LPS)-induced systemic inflammatory responses and protects fetuses in pregnant Sprague-Dawley (SD) rats. In the present study, we aim to evaluate the influence of nicotine on rat placenta, including cytokine release, leukocyte infiltration, and α7 nicotinic acetylcholine receptor (α7-nAChR) expression.Methods: Placental tissues of SD rats on gestation day 14 (GD14) were obtained and cultured in the presence or absence of LPS and/or nicotine. Culture media after 24 h were analyzed for cytokines release using Luminex. Other pregnant SD rats were first pretreated with nicotine on GD14 and GD15, followed by LPS injection on GD16. Placentas were collected on GD18 for H&E staining to evaluate leukocyte density and for real-time PCR and western blotting to identify the α7-nAChR expression in different groups.Results: Nicotine suppresses LPS-stimulated placental proinflammatory cytokines (IL-1, IL-2, IL-6, TNF-α, IFN-γ) production except IL-17 in vitro, and reduces leucocytes infiltration in the placental chorionic plate caused by LPS in vivo. Moreover, LPS increases the α7-nAChR protein expression in placentas while pretreatment of nicotine inhibits it.Discussion: These data show that nicotine suppresses LPS-induced placental inflammation by inhibition of cytokine release and infiltration of leukocytes into the placenta, and regulates the increased expression of α7-nAChR in placenta after LPS treatment. Nicotine and other nicotinic agonists may be an alternative therapeutic strategy for placental inflammation. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Ginsenoside Rg1, ginsenoside Rb1 and schizandrin are main bioactive components from Panax ginseng and Schisandra chinensis. They have been found in many prescriptions of Traditional Chinese Medicines (TCM) and proven to be effective for prevention and treatment of cardiovascular disease. It is valuable to investigate their pharmacokinetic and pharmacodynamic behavior and potential synergistic effect for better drug development and clinical application. Materials and methods: Pharmacokinetic and nitric oxide (NO) release pharmacodynamic drug–drug interactions of ginsenoside Rg1, ginsenoside Rb1 and schisandrin were studied after intravenous administration of each compound with the dose of 10mg/kg and their mixture with the total dose of 10mg/kg to isoproterenol (ISO)-induced myocardial ischemia rats. Drug concentrations in serum were determined using LC–MS method. Nitrite and nitrate ( ), the predominant oxidation product of NO in serum was used as an effective marker and quantitated by the method of high-performance liquid chromatography coupled with fluorescence detection (HPLC-FL). The main pharmacokinetic parameters of T 1/2β , MRT 0−∞, V d, Cl, and AUC, and the main pharmacodynamic parameters of C max, T max and AUEC were calculated by non-compartment model. Results: The results indicated ginsenoside Rb1 and (or) schisandrin in mixture could significantly postpone the elimination of ginsenoside Rg1 in rat serum. Co-administration of three compounds markedly increased the systemic exposure level of each compound in vivo. Ginsenoside Rg1 and ginsenoside Rb1 had the effect of inducing real-time NO release in rats concentration dependently. Schisandrin had no effect of inducing real-time NO release in this study. The mixture of ginsenoside Rg1, Rb1 and schisandrin administration exhibited synergistic effect of inducing NO release in ISO treated rats. Conclusions: The result obtained from this study suggested pharmacokinetic and pharmacodynamic drug–drug interactions between ginsenoside Rg1, Rb1 and schisandrin. The study provided valuable information for drug development and clinical application of TCM. [Copyright &y& Elsevier]

Microdialysis is a powerful in vivo sampling technique for pharmacokinetic–pharmacodynamic (PK-PD) modeling of drugs in pre-clinical and clinical studies. However, the noticeable limitations of previous studies using microdialysis were that animals anesthesia in the whole experiment and the combination of microdialysis and blood sampling for drug and (or) effect detection, which can obviously influence PK and PD behavior of drugs. In this study, a simple blood microdialysis sampling system in freely-moving rats was established for simultaneous study of PK and PD of Shengmai injection (SMI) effect on inducing real-time nitric oxide (NO) release on isoproterenol (ISO) induced myocardial ischemia rats. The LC–MS/MS and HPLC with fluorescence detection (HPLC-FLD) methods were developed to determine ginsenside Rg1, Rg2, Re, Rf, Rb1, Rd and Rc, the main effective components of SMI, and NO x − , the main oxidation products of NO, in dialysates respectively. Through simultaneous determination of drug concentrations and NO efficacy levels in dialysate, the developed methods were successfully applied to set up concentration-time and effect-time profiles followed by PK-PD modeling of SMI effect on inducing NO release after intravenous administration of 10.8 mL kg −1 SMI in myocardial ischemia rats. The PK-PD modeling characterized the dose-effect relationships of SMI and behaved good prediction ability. The established blood microdialysis in freely-moving rats is an appealing technology for rational PK-PD studies when selecting suitable blood endogenous micromolecule as effect marker. [ABSTRACT FROM AUTHOR]

Abstract: One alkyl glycoside, saussurostelloside A (1), two phenolic glycosides, saussurostellosides B1 (2) and B2 (3), and 27 known compounds, including eleven flavonoids, seven phenolics, six lignans, one neolignan, one phenethyl glucoside and one fatty acid, were isolated from an ethanol extract of Saussurea stella (Asteraceae). Their structures were elucidated by NMR, MS, UV, and IR spectroscopic analysis. Of the known compounds, (+)-medioresinol-di-O-β-d-glucoside (7), picraquassioside C (10), and diosmetin-3′-O-β-d-glucoside (27) were isolated from the Asteraceae family for the first time, while (+)-pinoresinol-di-O-β-d-glucoside (6), di-O-methylcrenatin (11), protocatechuic acid (14), 1,5-di-O-caffeoylquinic acid (17), formononetin (28), and phenethyl glucoside (29) were isolated from the Saussurea genus for the first time. The anti-inflammatory activities of three new compounds (1–3), five lignans ((−)-arctiin (4), (+)-pinoresinol-4-O-β-d-glucoside (5), (+)-pinoresinol-di-O-β-d-glucoside (6), (+)-medioresinol-di-O-β-d-glucoside (7) and (+)-syringaresinol-4-O-β-d-glucoside (8)), one neolignan (picraquassioside C (10)), and one phenolic glycoside (di-O-methylcrenatin (11)) were evaluated by testing their inhibition of the release of β-glucuronidase from PAF-stimulated neutrophils. Only compound 5 showed moderate inhibition of the release of β-glucuronidase, with an inhibition ratio of 39.1%. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: The aim of this study was to determine the anti-hepatitis B effect of isochlorogenic acid A isolated from Laggera alata (Asteraceae), a traditional Chinese herbal medicine. Materials and methods: The anti-hepatitis B activity of isochlorogenic acid A was evaluated by the d-galactosamine (D-GalN)-induced HL-7702 hepatocyte damage model and the HBV-transfected HepG2.2.15 cells. Results: Isochlorogenic acid A significantly improved HL-7702 hepatocyte viability and markedly inhibited the productions of HBsAg and HBeAg. The inhibitory rates of isochlorogenic acid A on the HBsAg and HBeAg expressions were 86.9% and 72.9%, respectively. In addition, isochlorogenic acid A declined markedly the content of hepatitis B virus covalently closed circular DNA (HBV cccDNA) and induced significantly the heme oxygenase-1 (HO-1) expression in HepG2.2.15 cells. Conclusions: Isochlorogenic acid A was verified to possess the potent anti-hepatitis B activity. The anti-HBV target of isochlorogenic acid A is probably associated with blocking the translation step of the HBV replication. Overexpression of HO-1 may contribute to the anti-HBV activity of isochlorogenic acid A by reducing the stability of the HBV core protein and thus blocking the refill of nuclear HBV cccDNA. Additionally, the hepatoprotective effect of isochlorogenic acid A could be achieved by its antioxidative property and induction of HO-1. [Copyright &y& Elsevier]

Progesterone is more than a progestin. Beyond functions in cycle and pregnancy, progesterone binds with high affinity to the mineralocorticoid receptor (MR) acting as an antagonist, with obvious significance for electrolyte homeostasis, an array of MR-related functions in the circulation as well as in the CNS. Progesterone induces natriuresis at physiological concentrations. Lack of antimineralocorticoid activity with conventional progestins may account for sodium and water retention, minor elevation of blood pressure and “pill hypertension” in susceptible women on oral contraceptives. Ethinylestradiol (EE) contributes to this problem by distinct activation of the renin–angiotensin–aldosterone (RAAS) system. Drospirenone (DRSP: 6β,7β,15β,16β-dimethylene-3-oxo 17α-pregn-4-ene-21,17 carbolactone) is the first synthetic progestin with antialdosterone activity. DRSP and progesterone bind to PR in uterine (affinity of both is about 30% of R5020) and MR in kidney cytosol (affinity about 230 and 100% of aldosterone, respectively). Intrauterine administration of DRSP in silastic tubes induced maximum local progestational effects in rabbits. At systemic subcutaneous (s.c.) administration (McPhail-assay) full endometrial transformation was obtained at 1mg per animal per day. At 1–3 mg DRSP per animal per day subcutaneously, pregnancy maintenance after ovariectomy, antiovulatory activity, and antimineralocorticoid activity were seen in the respective assays in rats. The latter activity indicates about eight-fold higher potency than spironolactone. DRSP decreased blood pressure in male hypertensive rats, whereas an increase was noted under conventional progestins. DRSP also prevented hypertension and fetal growth retardation in pregnant rats after l-NAME, an inhibitor of nitric oxide synthase. DRSP has antiandrogenic activity. Feminizing effects were recorded during sexual differentiation in male fetuses at high doses. Powerful antiandrogenic effects were also seen in gonad intact and testosterone substituted castrated male rats. The antiandrogenic potency of DRSP is superior to that of spironolactone but below that of cyproterone acetate. Endometrial transformation, inhibition of ovulation, and antimineralocorticoid, i.e. natriuretic effects and mild antiandrogenic effects were recorded at the same range of oral doses (0.5–4 mg per day) in humans. Combined with EE (3 mg DRSP+30 μg EE), DRSP provides effective inhibition of ovulation and cycle control. Body weight compared to conventional oral contraceptives was reduced. DRSP (3 mg per day + 15, 20, or 30 μg ethinyl estradiol per day) prevented the mild increase of blood pressure seen under a conventional levonorgestrel-containing contraceptive and even tended to reduce pretreatment blood pressure. Studies on modulation (i.e. inhibition) of glucocorticoid effects at the MR in the CNS remain an unexplored and interesting area for research. [Copyright &y& Elsevier]

Three new flavonoids, ephedroside A (1), ephedroside B (2), ephedroside C (3), together with fifty-four known compounds 4 – 57 were isolated from the EtOH extract of the herbaceous stems of Ephedra sinica. The structures of these compounds were elucidated by spectroscopic techniques, as well as by comparison with literature data. Thirty-eight of these compounds were isolated from the genus Ephedra for the first time. The antimicrobial activities of eight compounds were tested by measuring the minimum inhibitory concentrations (MIC) against bacteria (both Gram positive and Gram negative) and fungi, and were found to be in the range of 0.105–0.926 mM. Among them, compound 2 showed the best antimicrobial activity against Pseudomonas aeruginosa with MIC value of 0.105 mM. [Display omitted] [ABSTRACT FROM AUTHOR]

This study addresses the rapid discovery of the active compounds (the original constituents and/or metabolites) of a traditional Chinese drug, Smilacis Glabrae Rhizoma (SGR). The aim of this study was to develop a new method to find out the active compounds of traditional drugs in vivo. A method was established to discover and identify the potential active compounds in drug-containing plasma from rats that were orally administered SGR extract, utilizing the relationship between the individual differences in blood drug concentrations in the rats and the resulting differences in pharmacological effect, and the method was denoted as the RID-PE method. For this method, we used high-performance liquid chromatography with a diode array detector combined with electrospray ionization ion trap time-of-flight multistage mass spectrometry (LC-MSn) to identify the compounds (the original constituents and metabolites) and to determine the peak areas of the compounds in drug-containing plasma following SGR treatment. The anti-inflammatory effect of SGR was evaluated using a carrageenan-induced inflammatory rat model. According to the percent inhibition of paw edema in each model rat (14 rats total) orally administered SGR extract, the plasma samples from the rats were sorted and divided into 7 groups. Each group consisted of two plasma samples, and their percent inhibition of paw edema were similar to each other. We performed an LC-MSn analysis on 3 plasma groups, which showed large differences in the inhibition rates, with percent inhibitions of 92.7%, 72.4% and 38.4%. The correlation coefficients (r) between the peak area of each compound and the pharmacological effect (inhibition ratio) of SGR in the three groups were analyzed using SPSS software. When the correlation coefficients of the compounds are greater than 0.8 (0.8 < r ≤1), these compounds are strongly and positively correlated with anti-inflammatory activity, making them potential anti-inflammatory active compounds. Fifty-eight potential anti-inflammatory compounds (0.8 < r ≤ 1) from SGR were discovered in model rat plasma using the RID-PE method, 47 of which were considered to be new potentially anti-inflammatory compounds. Among these compounds, four original constituents and 5 isomers of potential anti-inflammatory metabolites were validated to have significant anti-inflammatory effects, and they included astilbin, syringic acid, catechin, coumalic acid, resveratrol-3′-O-glucuronide (RG, isomer of M2 or M3), 3′-O-methyl-(+)-epicatechin-4′-O-glucuronide (CA-1, isomer of M16), 4′-O-methyl-(+)-epicatechin-3′-O-glucuronide (CA-2, isomer of M16), 4′-O-methyl-(+)-epicatechin-7-O-glucuronide (CA-3, isomer of M16) and 3′-O-methyl-(+)-epicatechin-7-O-glucuronide (CA-4, isomer of M16). In addition, four isomers (CA-1—CA-4) were reported to have anti-inflammatory effects for the first time, and CA-3 was a new compound. The RID-PE method can be used to discover and identify the active constituents and metabolites of SGR systematically and in vivo. Furthermore, these findings enhance our understanding of the metabolism and effective forms of SGR. Image 1 [ABSTRACT FROM AUTHOR]