Diterpene synthases from plants are key enzymes in diterpene biosynthesis, which catalyzed the initial cyclization cascade of (E, E, E,)-geranylgeranyl pyrophosphate, and generated diverse carbon skeletons. Recent research show that the structural and stereo chemical differences lead to diverse natural diterpene compounds of plants. The structures of diterpene synthases play a crucial role in cyclization function. This article mainly reviews the mechanisms, functional characteristics, and structural information of diterpene synthases according to the crystal structures and functions.

Oxcarbazepine (OXC) is a common antiepileptic drugs. In this study, one hundred and eighty four epilepsy patients with 196 observations of oxcarbazepine's active metabolite, 10, 11-dihydro-10-monohydroxy carbazepine (MHD) were collected prospectively from routine clinical monitoring. Nonlinear mixed effect modeling was employed to develop a population pharmacokinetic model of oxcarbazepine in Chinese patients with epilepsy to investigate the impact of gender, age, weight, co-medications and genetic polymorphisms of UGT2B7 c.802T > C, ABCC2 c.1249G > A, ABCC 23972C > T on pharmacokinetic characteristics of OXC. The population estimate of apparent clearance (CL/F) and apparent volume of distribution (V/F) was 1.84 L·h⁻¹ and 275 L, respectively. Gender and UGT2B7 c.802T > C affected the clearance rate of MHD significantly. The established model was:CL/F=1.84×0.848^UGT2B7×1.17^GENDER. Where the genotype of UGT2B7 c.802T > C was CC, UGT2B7=0, otherwise UGT2B7=1. When the patient was male, GENDER=1, otherwise GENDER=0. The final model was evaluated by normalized predictive distribution error (NPDE) and bootstrap method. The model was stable and reliable, which offers a powerful approach for rational use of OXC in epilepsy patients.

Flavonol glycoside is in clinical trials for treatment of hyperlipidemia. An accurate and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of flavonol glycoside (M0), aglycone (M1) and glucuronide conjugate (M2) in rat plasma. d₆-Flavonol glycoside was used as internal standard (IS). After extraction from the plasma by protein precipitation, the analytes and internal standard were separated on a XDB C₁₈ column (50 mm×4.6 mm, 1.8 μm) using a gradient elution procedure. The mobile phase consisted of methanol and water (0.2% formic acid) at a flow rate of 0.6 mL·min^-1. The total run time was 4.5 min. Positive electrospray ionization was performed using multiple reaction monitoring (MRM) with transitions of m/z 461.3 → m/z 299.1 for M0, m/z 299.1 → m/z 283.1 for M1, m/z 475.0 → m/z 299.1 for M2, and m/z 467.3 → m/z 305.1 for d₆-flavonol glycoside. The method was validated and successfully applied to the pharmacokinetics study of flavonol glycoside in SD rats which were given flavonol glycoside (30 mg·kg^-1) by gavage. The C_max of M0 is (341 ±106) ng·mL^-1 and AUC_0-t is (1 960 ±725) h·ng·mL^-1, while the C_max of M2 is (1 720 ±843) ng·mL^-1and AUC_0-t is (8 510 ±2 920) h·ng·mL^-1. The results suggest that flavonol glycoside existed mainly in the form of M0 and M2 in rats. After flavonol glycoside being hydrolyzed by the intestinal flora, it was absorbed in the form of aglycone and further metabolized to M2 after the first-pass effect. In this paper, the main metabolites of flavonol glycoside in rat plasma were determined for the first time, which provided a basis for the design of clinical pharmacokinetic experiment.

Microneedles is an efficient, safe and novel transdermal drug delivery technology that has attracted much attention in recent decades. Microneedles could break through the skin's stratum corneum barrier and have an especially significant effect on the transdermal delivery of water-soluble small molecules and biological macromolecules. In this paper, a rapid onset local anesthetic preparation of lidocaine hydrochloride was prepared based on dissolving microneedles, and related quality evaluations were carried out. The key quality indicators of prepared lidocaine hydrochloride dissolving microneedles such as drug loading amount, appearance morphology, mechanical properties, skin penetration performance, in vitro dissolution performance and local anesthetic efficacy were investigated with HPLC, SEM, texture analyzer, organic staining, histological section, in vitro dissolution test and pharmacodynamics experiments respectively. The drug loading of the dissolving microneedles array reached 68.19 ±1.55 mg, and the needle tip contained 3.57 ±0.21 mg. The microneedles has good needle shape and sufficient mechanical strength to penetrate into the skin, which is a prerequisite for the successful administration of the preparation. The in vitro dissolution time was 28.28 ±1.12 s. When applied to guinea pig back acupuncture model which was modified by guinea pig intradermal papules model, although the efficacy maintenance time was shorter than that of compound lidocaine cream, dissolving microneedles can be activated within 1 min, which was much faster than compound lidocaine cream. It is possible to increase the duration of drug efficacy by increasing the density of microneedles and preparing microneedles for sustained and controlled release in future studies. Lidocaine hydrochloride dissolving microneedles and its evaluation methods for local anesthesia were established systematically here for the first time. The rapid effect of anesthesia with lidocaine hydrochloride dissolving microneedles on the skin was worthy of further investigation.

The study was designed to establish an LC-MS/MS method for the simultaneous determination of scutellarin and its major metabolite isoscutellarin in rat tissues and plasma, and to investigate the effect of different route of administration on the tissue distribution of scutellarin and its metabolite in rats. Rats were treated both intravenously and intragastrically with 20 and 80 mg·kg^-1 scutellarin, respectively. Blood and tissues were collected at predetermined intervals. The concentrations of scutellarin and isoscutellarin were determined by a validated LC-MS/MS method. The method was linear in concentration ranges of 10.0/5.00 - 5 000/2 500 ng·mL^-1 for scutellarin/isoscutellarin in the rat plasma and 30.0/15.0 - 10 000/5 000 ng·g^-1 in tissues with acceptable accuracy and precision. Data obtained after an intravenous administration of scutellarin to rats showed that the drug was distributed predominantly into the small intestine, bladder and kidney. The exposures of the metabolite isoscutellarin in plasma and tissue were both less than 5%of the parent drug. After an intragastric administration, stomach wall and small intestine were the preferred sites for scutellarin disposition, followed by bladder, adrenal gland and lung at concentrations significantly higher than its plasma concentration. The plasma exposure of isoscutellarin was higher than that of the parent drug, but its tissue exposure was significantly lower than that of scutellarin. The method established in this study was successfully applied to characterization of the tissue profiles of scutellarin and its metabolite in rats. The route of administration has a marked impact on the disposition of scutellarin and its metabolite in rats. Ratios of the tissue to plasma concentrations after intragastric administration were obviously higher than those after intravenous administration. Scutellarin could pass the blood-brain barrier in a marked extent, but isoscutellarin was not detected in the rat brain, which may be attributed to the fact that scutellarin is a higher-affinity substrate for OATP than isoscutellarin.

Present study was designed to investigate the effects and underlying antioxidant mechanism of klotho overexpression through an intracerebroventricular injection of a lentiviral vector that encoded murine klotho (LV-KL) on cerebral ischemia injury. Four weeks after the injection of lentivirus into the lateral ventricle of C57Balc/6J mice, a mouse model of global cerebral ischemia-reperfusion was established by bilateral common carotid artery occlusion (2VO). Klotho overexpression significantly improved neurobehavioral deficits and increased the number of survival neurons in the hippocampal CA1 and caudate putamen subregions. The overexpression also decreased malondialdehyde (MDA) content in brain, while mitochondrial manganese- superoxide dismutase (Mn-SOD) and catalase (CAT) expression in brain were increased. Moreover, klotho overexpression decreased Akt and forkhead box class O1 phosphorylation. These findings suggest that klotho may compensate for its aging-related decline to provide a promising therapeutic approach for the acute ischemic stroke during aging.

This study was aimed to investigate the effects of six Schisandra lignans of Wuzhi tablet (WZ, a preparation of ethanol extract of Schisandra sphenanthera) on the pharmacokinetic process of digoxin (DG, a classical P-gp substrate) after intravenous and oral administration in rats. The effect of Schisandra lignans on the transportion of DG in Caco-2 cells was further elucidated. Our data showed that the plasma concentrations of DG were increased to different extent following co-administration of schisandrin A, schisandrin B, schisandrol B and schisantherin A, respectively. Schisandrol B showed the most potent effect among the six lignans. However, schisandrin C and schisandrol A showed little effect on pharmacokinetic of DG. Schisandrol B led to 99.0% (P < 0.05) and 109.2% (P < 0.05) increase in the AUC after orally or intravenously administered of DG, suggesting that co-administration of schisandrol B induced a more potent effect on increasing hepatic bioavailability of DG than that of intestinal. Furthermore, in vitro transport experiment showed that schisandrin A, schisandrin B, schisandrol B and schisantherin A inhibited P-gp-mediated efflux of DG, suggested that these lignans inhibited the P-gp-mediated efflux of DG. In conclusion, the exposure of DG in rats was increased when co-administered with Schisandra lignans, and schisandrol B showed the strongest effect. The dramatic increase in oral bioavailability of digoxin in the presence of schisandrol B may be due to the inhibition of hepatic/renal P-gp activity.

The rheological properties of six compound gels that consists of kappa carrageenan (KC) and another excipient such as konjac gum were explored through comparison of their viscosity measured by the rotation method. The gel fluid type was dependent on the rheological curve fitted by the power-law equation. The effect of concentration on the viscosity of different compound gels was investigated by establishing the linear equation between their viscosity and concentration, the slope of which was used to determine the relation between viscosity and concentration of different compound gels. The viscous flow activation energy (E_η) was calculated by the Arrhenius equation, which was able to investigate the effect of temperature on their viscosity. The interaction between monomer and compound gels was also studied by measuring their viscosity. The results showed that six compound gels were pseudoplastic fluid. Among all compound gels, the KC-xanthan gum (KC-XG) solution exhibited the most obvious shear thinning, the strongest pseudoplasticity, while the smallest E_η, resulting in the best thermal stability of viscosity. Furthermore, the concentration of KC-sodium hyaluronate (KC-HA-Na) solution affected its viscosity significantly. The viscosity of six compound gels was greater than the summation of the two kinds of monomer gels, which suggests that there is a synergistic-viscosity interaction between KC and another excipient.

IDO1 (indoleamine 2, 3-dioxygenase 1) is one of the most significant checkpoint in tumor immunology. Numerous studies indicates that IDO1 is abnormally expressed in breast cancer, colorectal cancer, liver cancer and other tumor tissues, participating in tumor immune escape through multiple pathways. This review is prepared to elucidate the biological function of IDO1, highlight its pivotal role in tumor evasion, and summarize IDO1 inhibitors in the clinical trials.

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder including mainly ulcerative colitis (UC) and Crohn's disease (CD). In China, IBD has become a common disease of the digestive system with an dramatic increase in incidence in recent years. The pathogenesis of IBD is not yet clear, and no drugs can completely cure IBD. Compared with monoclonal antibody drugs, small molecule drugs have the advantages of low cost, easy development as oral agents, and absence of immunogenicity. This review summarizes the recent research and development of small molecule immunosuppressants for IBD.