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1.
Tuberculosis (Edinb) ; 143: 102413, 2023 12.
Article in English | MEDLINE | ID: mdl-37832478

ABSTRACT

INTRODUCTION: Tuberculosis (TB) poses a serious challenge to global health systems. The altered intestinal microbiota is associated with the pathogenesis of TB, but the exact links remain unclear. METHODS: 16 S rDNA sequencing was performed to comprehensively detect the changes in the intestinal microbiota of feces from active TB (ATB), latent TB infection (LTBI) and healthy controls (HC). RESULTS: The rarefaction curves demonstrated the sequencing results' validity. The alpha diversity was lowest in ATB, while highest in HC. Boxplot of beta diversity showed significant differences in every two groups. LDA Effect Size (LEfSe) Analysis revealed differences in probiotic bacteria like Romboutsia, Bifidobacterium and Lactobacillus in LTBI, and pro-inflammatory bacteria like R. gnavus, Streptococcus and Erysipelatoclostridium in ATB, corresponding to the cluster analysis. PICRUST2 analysis revealed the pentose phosphate pathway was active in ATB and LTBI (more active in ATB). The differences between the groups are statistically significant at the P<0.05 level. CONCLUSION: Our study indicated that from LTBI to ATB, some intestinal microbiota inhibit the synthesis of interferon (INF)-γ and interleukin (IL)-17, promoting the survival and spread of Mycobacterium tuberculosis (M. tb). In addition, the metabolites secreted by intestinal microbiota and dysbiosis in intestine also have an effect on the development of LTBI to ATB.


Subject(s)
Gastrointestinal Microbiome , Latent Tuberculosis , Mycobacterium tuberculosis , Tuberculosis , Humans , Mycobacterium tuberculosis/genetics , Mycobacterium tuberculosis/metabolism , Biomarkers/metabolism , Tuberculosis/microbiology , Latent Tuberculosis/diagnosis , Latent Tuberculosis/microbiology , Interferon-gamma/metabolism
2.
Infect Drug Resist ; 16: 6121-6138, 2023.
Article in English | MEDLINE | ID: mdl-37719654

ABSTRACT

Purpose: Distinguishing latent tuberculosis infection (LTBI) from active tuberculosis (ATB) is important to control the prevalence of tuberculosis; however, there is currently no effective method. The aim of this study was to discover specific metabolites through fecal untargeted metabolomics to discriminate ATB, individuals with LTBI, and healthy controls (HC) and to probe the metabolic perturbation associated with the progression of tuberculosis. Patients and Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to comprehensively detect compounds in fecal samples from HC, LTBI, and ATB patients. Differential metabolites between the two groups were screened, and their underlying biological functions were explored. Candidate metabolites were selected and enrolled in LASSO regression analysis to construct diagnostic signatures for discriminating between HC, LTBI, and ATB. A receiver operating characteristic (ROC) curve was applied to evaluate diagnostic value. A nomogram was constructed to predict the risk of progression of LTBI. Results: A total of 35 metabolites were found to exist differentially in HC, LTBI, and ATB, and eight biomarkers were selected. Three diagnostic signatures based on the eight biomarkers were constructed to distinguish between HC, LTBI, and ATB, demonstrating excellent discrimination performance in ROC analysis. A nomogram was successfully constructed to evaluate the risk of progression of LTBI to ATB. Moreover, 3,4-dimethylbenzoic acid has been shown to distinguish ATB patients with different responses to etiological tests. Conclusion: This study constructed diagnostic signatures based on fecal metabolic biomarkers that effectively discriminated HC, LTBI, and ATB, and established a predictive model to evaluate the risk of progression of LTBI to ATB. The results provide scientific evidence for establishing an accurate, sensitive, and noninvasive differential diagnosis scheme for tuberculosis.

3.
Phys Chem Chem Phys ; 24(18): 11023-11029, 2022 May 11.
Article in English | MEDLINE | ID: mdl-35470357

ABSTRACT

A new ice phase, ice XIX, was discovered in 2018, and is the second hydrogen-ordered polymorph of hydrogen-disordered ice VI. The first hydrogen-ordered polymorph of ice VI is ice XV, and ices XIX, VI, and XV comprise a unique triplet group in the ice family. However, the exact crystal structure of ice XIX has not been confirmed. We constructed four possible conformations of ice XIX using neutron diffraction data obtained by Gasser et al. We then optimized these structures and simulated their Raman scattering spectra using first-principles density functional theory. By comparing these simulated spectra with the experimental Raman scattering spectra, we were able to exclude the existence of a ferroelectric structure with the space group Cc. The other three candidate structures are in good agreement with the experimental Raman scattering data; two of them are ferroelectric structures with the space group P21; and the last one is a weak ferroelectric structure with the space group Cc. We proposed that the partially hydrogen-ordered structure of ice XIX maybe a mixing of several hydrogen-ordered structures.

4.
ACS Omega ; 7(6): 5437-5441, 2022 Feb 15.
Article in English | MEDLINE | ID: mdl-35187359

ABSTRACT

Rhenium (Re) is an extremely rare and precious element that is mainly used in the construction of aerospace components and satellite stations. However, an efficient and simple method for preparing Re has yet to be devised. To this end, we investigated the vibrational spectrum of ammonium perrhenate (NH4ReO4) using the CASTEP code based on first-principles density functional theory. We assigned the infrared (IR) absorption and Raman scattering spectra for NH4ReO4 using a dynamic process analysis of optical branch normal modes. We examined the IR-active peaks of Re-related vibrational modes in detail and found that the typical IR peak at approximately 914 cm-1 is due to the Re-O bond stretching. Thus, we posit that strong terahertz laser irradiation of NH4ReO4 at 914 cm-1 will lead to sufficient resonance absorption to cleave its Re-O bonds. This method could potentially be used to efficiently separate Re from its oxides.

5.
ACS Omega ; 7(3): 2970-2974, 2022 Jan 25.
Article in English | MEDLINE | ID: mdl-35097289

ABSTRACT

It is difficult to theoretically study the vibrational spectrum of hydrogen-disordered ice XII compared with its hydrogen-ordered counterpart, ice XIV. We constructed a 24-molecule supercell of ice XII to mimic its real structure. We focused on hydrogen bond (HB) vibrational modes in the translation band using first-principles density functional theory (DFT). Our simulated results were in good agreement with inelastic neutron scattering experiments. We found that the optical vibrational modes of HBs are composed of three main components. These are cluster vibrations in the lowest-frequency region, four-bond HB vibrations in the highest-frequency region, and two-bond modes in between. Although the experimentally recorded curve of ice XII is smooth in the translation region, our results support the proposal that two types of intrinsic HB vibrational modes are common in the ice family.

6.
Emerg Microbes Infect ; 10(1): 1739-1750, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34379047

ABSTRACT

Yellow fever virus (YFV) is a re-emerging flavivirus, which can lead to severe clinical manifestations and high mortality, with no specific antiviral therapies available. The live-attenuated yellow fever vaccine 17D (YF17D) has been widely used for over eighty years. However, the emergence of yellow fever vaccine-associated viscerotropic disease (YFL-AVD) and yellow fever vaccine-associated neurotropic disease (YFL-AND) raised non-negligible concerns. Additionally, the attenuation mechanism of YF17D is still unclear. Thus, the development of convenient models is crucial to understand the mechanisms behind YF17D attenuation and its adverse effects. In this work, we generated a reporter YF17D expressing nano-luciferase (NLuc). In vitro and in vivo characterization demonstrated that the NLuc-YF17D shared similar biological properties with its parental strain and the NLuc activity can reflect viral infectivity reliably. Combined with in vivo bioluminescence imaging, a series of mice models of YF17D infection was established, which will be useful for the evaluation of antiviral medicines and novel vaccine candidates. Especially, we demonstrated that intraperitoneally (i.p.) infection of NLuc-YF17D in type I interferon receptor-deficient mice A129 resulted in outcomes resembling YEL-AVD and YEL-AND, evidenced by viral replication in multiple organs and invasion of the central neuronal system. Finally, in vitro and in vivo assays based on this reporter virus were established to evaluate the antiviral activities of validated antiviral agents. In conclusion, the bioluminescent reporter virus described herein provides a powerful platform to study YF17D attenuation and vaccine-associated diseases as well as to develop novel countermeasures against YFV.


Subject(s)
Luminescent Measurements/methods , Yellow Fever/virology , Yellow fever virus/metabolism , Animals , Cell Line , Imaging, Three-Dimensional/methods , Luciferases/genetics , Luciferases/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Virus Replication , Yellow fever virus/genetics
7.
ACS Omega ; 6(22): 14442-14446, 2021 Jun 08.
Article in English | MEDLINE | ID: mdl-34124466

ABSTRACT

It is difficult to investigate the hydrogen-bonding dynamics of hydrogen-disordered ice VI. Here, we present a comparative method based on our previous study of its counterpart hydrogen-ordered phase, ice XV. The primitive cell of ice XV is a 10 molecule unit, and the vibrational normal modes were analyzed individually. We constructed an 80 molecule supercell of ice VI to mimic the periodic unit and performed first-principles density functional theory calculations. As the two vibrational spectra show almost identical features, we compared the molecular translation vibrations. Inspired by the phonon analysis of ice XV, we found that the vibrational modes in the translation band of ice VI are classifiable into three groups. The lowest-strength vibration modes represent vibrations between two sublattices that lack hydrogen bonding. The highest-strength vibration modes represent the vibration of four hydrogen bonds of one molecule. The middle-strength vibration modes mainly represent the molecular vibrations of only two hydrogen bonds. Although there are many overlapping stronger and middle modes, there are only two main peaks in the inelastic neutron scattering (INS) spectra. This work explains the origin of the two main peaks in the far-infrared region of ice VI and illustrates how to analyze a hydrogen-disordered ice structure.

8.
J Ethnopharmacol ; 263: 113233, 2020 Dec 05.
Article in English | MEDLINE | ID: mdl-32768638

ABSTRACT

ETHNOPHARMACOLOGY RELEVANCE: Tacrolimus is a well-known potent but expensive immunosuppressant. We previously clarified the herb-drug interaction between tacrolimus and Wuzhi tablet (WZ), a prescribed drug of ethanol extract of Schisandra sphenanthera, and showed the ideal effect of WZ on maintaining therapeutic level of tacrolimus and reducing the total drug expense. However, WZ possesses a biphasic effect on regulating CYP3A (the major metabolizing enzyme of tacrolimus), which could induce the mRNA and protein expression after long-term treatment while transiently inhibit the activity of CYP3A. In clinic, clinicians are confused about the relationship between the blood concentration of tacrolimus and the dose and the duration of pretreatment of WZ. Therefore, the effects of the pretreatment time and the dose of WZ on the pharmacokinetics of tacrolimus is urgently needed to be clarified to better combine the use of WZ and tacrolimus in clinic. AIM OF THE STUDY AND METHOD: This study aimed to investigate the effects of the pretreatment time and the dose of WZ on the pharmacokinetics of tacrolimus in rats. RESULTS AND CONCLUSIONS: After pretreated rats with WZ for 0, 0.5, 2, 6, 12 or 24 h, the area under the curve (AUC) of tacrolimus was 2.27 ± 0.59, 1.87 ± 1.14, 2.86 ± 0.64, 1.62 ± 0.70, 1.54 ± 1.06 and 1.12 ± 0.69-fold of that of the tacrolimus alone group, respectively. The ratio of AUC of tacrolimus to that of the co-administration group with 0, 62.5, 125, 250, 500 or 750 mg/kg of WZ was 1.00: 1.07: 1.44: 2.60: 2.32: 2.42, respectively. These findings suggested that WZ increased tacrolimus AUC in a pretreatment time- and dose-dependent manner. In line with the in vivo findings, WZ extract inhibited CYP3A activity in a pre-treatment time- and concentration-dependent manner in human liver microsomes. In conclusion, the pharmacokinetics of tacrolimus was significantly affected by the pretreatment time and the dose of WZ. Oral pretreatment with WZ for 0-2 h or co-dosing of 250 mg/kg of WZ most significantly increased the blood concentration of tacrolimus. These findings would be helpful for guiding the reasonable use of WZ and tacrolimus in clinic.


Subject(s)
Drugs, Chinese Herbal/administration & dosage , Herb-Drug Interactions , Plant Extracts/administration & dosage , Schisandra , Tacrolimus/administration & dosage , Animals , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/metabolism , Herb-Drug Interactions/physiology , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Plant Extracts/blood , Rats , Rats, Sprague-Dawley , Tablets , Tacrolimus/blood , Time Factors
9.
Zhongguo Zhen Jiu ; 40(3): 262-6, 2020 Mar 12.
Article in Chinese | MEDLINE | ID: mdl-32270638

ABSTRACT

OBJECTIVE: To observe the effect on postpartum pelvic girdle pain treated with the combined therapy of pelvic-sacral tendon-regulation needling technique of acupuncture and manipulative reduction and the simple manipulative therapy. METHODS: A total of 80 patients with postpartum pelvic girdle pain were randomized into an observation group and a control group, 40 cases in each one. In the control group, the manipulative reduction was simply adopted. In the observation group, on the base of the treatment as the control group, the pelvic-sacral tendon-regulation needling technique of acupuncture was applied at Mingmen (GV 4), Dachangshu (BL 25), Yaoyangguan (GV 3), Ciliao (BL 32), Zhongliao (BL 33), Huantiao (GB 30) and Yanglingquan (GB 34). In either group, the treatment was given once every two days, three times a week and 3 treatments taken as one course. Totally, 3 courses of treatment were required. The clinical therapeutic effect was compared in the patients between the two groups. The changes in the scores of the pain visual analogue scale (VAS), Oswestry dysfunction index (ODI) and Japanese Orthopaedic Association (JOA), as well as the pelvic floor distress inventory-short form 20 (PFDI-20), the pelvic floor impact questionnaire (PFIQ-7) and the sex life index (the frequency of intercourse and orgasm) were recorded in the patients of the two groups before and after treatment. RESULTS: The total effective rate was 95.0% (38/40) in the observation group, higher than 77.5% (31/40) in the control group (P<0.01). After treatment, the scores of VAS, ODI, PFDI-20 and PFIQ-7 were lower than those before treatment respectively in the patients of the two groups (P<0.01). JOA score and the sex life index were increased after treatment as compared with those before treatment in the two groups (P<0.01). The difference value of each of the above indexes in the observation group was higher than the control group (P<0.01). CONCLUSION: The combined therapy of pelvic-sacral tendon-regulation needling technique of acupuncture and manipulative reduction effectively alleviates pain and improves the muscle strength of pelvic floor muscle fibers in the patients with postpartum pelvic girdle pain. Its therapeutic effect is better than that of the simple manipulative therapy.


Subject(s)
Acupuncture Therapy , Pelvic Girdle Pain/therapy , Acupuncture Points , Female , Humans , Pelvis , Postpartum Period , Pregnancy , Sacrum , Tendons , Treatment Outcome
10.
ACS Omega ; 4(20): 18936-18941, 2019 Nov 12.
Article in English | MEDLINE | ID: mdl-31737855

ABSTRACT

The normal modes of ice IX were investigated using the CASTEP code package, which is based on density functional theory. We found that the translational modes could be divided into three categories: four-bond vibrations, which possessed the highest energy; two-bond vibrations, which possessed the medium energy; and cluster vibrations with the lowest energy. The former two categories represent monomers vibrating against neighbors and present as two distinct peaks in many ice phases recorded in inelastic neutron-scattering experiments. It is typically difficult to assign the molecular vibration peaks in the far infrared region. The method we developed to analyze the normal modes, especially in the translation band of ice IX, provided physical insights into the vibrational spectrum of ice.

11.
Molecules ; 24(17)2019 Aug 28.
Article in English | MEDLINE | ID: mdl-31466370

ABSTRACT

The vibrational spectrum of ice II was investigated using the CASTEP code based on first-principles density functional theory (DFT). Based on good agreement with inelastic neutron scattering (INS), infrared (IR), and Raman experimental data, we discuss the translation, libration, bending, and stretching band using normal modes analysis method. In the translation band, we found that the four-bond and two-bond molecular vibration modes constitute three main peaks in accordance with INS ranging from 117 to 318 cm-1. We also discovered that the lower frequencies are cluster vibrations that may overlap with acoustic phonons. Whale et al. found in ice XV that some intramolecular vibrational modes include many isolated-molecule stretches of only one O-H bond, whereas the other O-H bond does not vibrate. This phenomenon is very common in ice II, and we attribute it to local tetrahedral deformation. The pathway of combining normal mode analysis with experimental spectra leads to scientific assignments.


Subject(s)
Ice/analysis , Density Functional Theory , Hydrogen Bonding , Molecular Structure , Vibration
12.
Molecules ; 24(17)2019 Aug 27.
Article in English | MEDLINE | ID: mdl-31461964

ABSTRACT

It is always difficult to assign the peaks of a vibrational spectrum in the far-infrared region. The two distinct peaks seen in many ice phases are still a mystery to date. The normal modes of ice XV were calculated using the CASTEP code based on first-principles density functional theory. On the basis of vibrational modes analysis, we divided the translational modes into three categories: four-bond vibrations, which have the highest energy levels; two-bond vibrations, which have medium levels of energy; and relative vibrations between two sublattices, which have the lowest energy. Whale et al. found that some intramolecular stretching modes include the isolated vibration of only one O-H bond, whereas the others do not vibrate in ice XV. We verified this phenomenon in this study and attributed it to local tetrahedral deformation. Analysis of normal modes, especially in the translation and stretching band of ice XV, clarified the physical insights of the vibrational spectrum and can be used with other ice phases.


Subject(s)
Computational Biology/methods , Ice/analysis , Algorithms , Density Functional Theory , Hydrogen Bonding , Molecular Structure , Vibration
13.
J Pharm Pharmacol ; 71(6): 945-955, 2019 Jun.
Article in English | MEDLINE | ID: mdl-30873627

ABSTRACT

OBJECTIVES: This study aimed to establish a vancomycin population pharmacokinetics (PPK) model based on serum cystatin C and to optimize dosing for achieving targeted steady-state trough concentrations (Css ) of 10-15 and 15-20 mg/l. METHODS: Patients aged ≥18 years were prospectively enrolled. A vancomycin PPK model was built with glomerular filtration rate (GFR) as a renal covariate estimated by cystatin C. A new group of patients were used for external evaluation. PPK analysis and Monte Carlo simulations were performed using nonlinear mixed effect modelling programme. KEY FINDINGS: Two hundreds of patients with 514 samples were included. The final model was CL (L/h) = (5.07 × (GFR/105.5)0.524 × (AGE/48.5)-0.309 × (WT/60)0.491 ); V (l) = 46.3. Internal and external evaluations demonstrated good stability and predictability. The average probability of target attainment (PTA) of optimal dosing regimens for targeted Css achieving 10-15 and 15-20 mg/l were 51.2% and 40.6%, respectively. An average PTA ≥71% for targeted concentration of 10-20 mg/l was obtained. CONCLUSIONS: A vancomycin PPK model with cystatin C as the renal marker has good stability and predictability. The new proposed dosing regimens were predicted to achieve a good PTA.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Cystatin C/blood , Models, Biological , Vancomycin/administration & dosage , Adult , Aged , Anti-Bacterial Agents/pharmacokinetics , Dose-Response Relationship, Drug , Female , Glomerular Filtration Rate/physiology , Humans , Kidney Function Tests , Male , Middle Aged , Monte Carlo Method , Nonlinear Dynamics , Prospective Studies , Vancomycin/pharmacokinetics
14.
Yao Xue Xue Bao ; 51(5): 834-8, 2016 05.
Article in Chinese | MEDLINE | ID: mdl-29878735

ABSTRACT

The study was conducted to evaluate the pharmacokinetics of midazolam (MDZ) under different oral dosages in rats, and determine the optimum oral dosage of MDZ, a CYP3 A probe substrate in vivo. Male Sprague-Dawley rats were given a single oral dosages of MDZ at 1,2,5,10,15 or 20 mg·kg(-1). Plasma concentrations of MDZ and its major metabolite 1-hydroxyl midazolam (1-OH MDZ) were determined at different time points using a validated LC-MS/MS method. Pharmacokinetic parameters were calculated using non-compartmental model. The C(max), AUC(0-t) and AUC0(∞) of MDZ and 1-OH MDZ were linearly increased over the dose range of 1-5 mg·kg(-1) (r > 0.99), but not at the dose of 15 or 20 mg·kg(-1). The AUC/Dose at 1-10 mg·kg(-1) were not significant different, but that of 15 or 20 mg·kg(-1) were significantly higher. No significant sedative reaction was observed in all the rats at dosages of 1-5 mg·kg(-1), however loss of righting reflex was observed in rats receiving dosages of 10-20 mg·kg(-1). In conclusion, the optimized oral dose of MDZ was 1-5 mg·kg(-1) when MDZ is used as the CYP3 A probe substrate in rats.


Subject(s)
Cytochrome P-450 CYP3A , Midazolam/administration & dosage , Midazolam/pharmacokinetics , Administration, Oral , Animals , Chromatography, Liquid , Hypnotics and Sedatives/administration & dosage , Hypnotics and Sedatives/pharmacokinetics , Male , Rats , Rats, Sprague-Dawley , Tandem Mass Spectrometry
15.
Yao Xue Xue Bao ; 51(12): 1891-6, 2016 12.
Article in Chinese | MEDLINE | ID: mdl-29908561

ABSTRACT

This study was aimed to determine the hepatic and small intestinal distribution of active lignans in rats after treated with Wuzhi tablet (WZ, Schisandra sphenanthera extract) by LC-MS/MS method. Male Sprague-Dawley rats were sacrificed at 0.25, 1.5, 4, 6, 10, 24 h after an oral administration of WZ, and then hepatic and small intestinal samples were collected for analysis. The results showed that concentrations of lignans in liver and small intestine of rats were decreased with WZ pretreated time. The concentrations of all lignans in rat liver and small intestine at 0.25 h were the highest after a single oral administration. All lignans was undetectable in all tissues 24 h after oral dosing, suggesting lignans of WZ were eliminated rapidly in rats. The concentrations of schisandrin A, schisandrol B and schisantherin A in small intestine were much higher than those in the liver, suggesting the effect of WZ on the intestinal metabolism enzyme might be more potent than that on the liver. In short, the current results suggest that lignans of WZ were not accumulated in rat liver and small intestine. The concentrations of lignans of WZ in small intestine were much higher than those in liver.


Subject(s)
Drugs, Chinese Herbal/pharmacokinetics , Intestine, Small/drug effects , Liver/drug effects , Animals , Chromatography, Liquid , Cyclooctanes , Dioxoles , Intestine, Small/metabolism , Lignans , Liver/metabolism , Male , Polycyclic Compounds , Rats , Rats, Sprague-Dawley , Schisandra , Tablets , Tandem Mass Spectrometry
16.
Yao Xue Xue Bao ; 51(9): 1407-11, 2016 09.
Article in Chinese | MEDLINE | ID: mdl-29924520

ABSTRACT

The study aims to evaluate the effect of long-term pretreatment of the rat with Wuzhi tablet(WZ) on hepatic and intestinal CYP3A mRNA and protein expression and activity. Male Sprague-Dawley rats were orally administered of midazolam (2 mg·kg-1) with or without 14 days of pretreatment of WZ (0.25 g·kg-1) to determine CYP3A activity. Meanwhile, RNA and protein of rats liver and intestine samples were prepared 24 h after the last dose of 14 days of WZ treatment to determine CYP3A mRNA and protein expression. Long-term treatment of WZ increased the mRNA expression of hepatic Cyp3a1, Cyp3a9 and intestinal Cyp3a9 by 54.6%, 188.3%(P < 0.05) and 48.2%(P < 0.05), respectively; and increased the protein expression of hepatic CYP3A by 43.2%. However, after long-term treatment of WZ, the AUC of orally administered of midazolam in the WZ group was increased 29.9%(WZ pretreatment group) and 154.2%(WZ coadministered group) compared to that of control group. In conclusion, long-term treatment of WZ increased the m RNA and protein expression of CYP3A, while could inhibit the activity of CYP3A.


Subject(s)
Cytochrome P-450 CYP3A/metabolism , Drugs, Chinese Herbal/pharmacology , Midazolam/pharmacology , Animals , Intestines/enzymology , Liver/enzymology , Male , Rats , Rats, Sprague-Dawley , Tablets
17.
Biochem Biophys Res Commun ; 458(4): 836-42, 2015 Mar 20.
Article in English | MEDLINE | ID: mdl-25689717

ABSTRACT

G protein-coupled receptor 50 (GPR50), a risk factor for major depressive disorder and bipolar affective disorder, is expressed in both the developmental and adult brain. However, the function of GPR50 in the brain remains unknown. We here show GPR50 is expressed by neural progenitor cells (NPCs) in the ventricular zone of embryonic brain. Knockdown of GPR50 with a small interference RNA (siRNA) decreased self-renewal and neuronal differentiation, but not glial differentiation of NPCs. Moreover, overexpression of either full-length GPR50 or the intracellular domain of GPR50, rather than the truncated GPR50 in which the intracellular domain is deleted in, increased neuronal differentiation, indicating that GPR50 promotes neuronal differentiation of NPCs in an intracellular domain-dependent manner. We further described that the transcriptional activity of the intracellular domain of notch on Hes1 gene was repressed by overexpression of GPR50. In addition, decreased levels of transcription factor 7-like 2 (TCF7L2) mRNA was observed in GPR50 siRNA-transfected NPCs, suggesting that knockdown of GPR50 impairs wnt/ß-catenin signaling. Moreover, the mRNA levels of neurogenin (Ngn) 1, Ngn2 and cyclin D1, the target genes of notch and wnt/ß-catenin signalings, in NPCs were reduced by knockdown of GPR50. Therefore, GPR50 promotes self-renewal and neuronal differentiation of NPCs possibly through regulation of notch and wnt/ß-catenin signalings.


Subject(s)
Embryonic Stem Cells/cytology , Nerve Tissue Proteins/metabolism , Neural Stem Cells/cytology , Neurogenesis , Receptors, G-Protein-Coupled/metabolism , Receptors, Notch/metabolism , Wnt Signaling Pathway , Animals , Cells, Cultured , Embryonic Stem Cells/metabolism , Gene Expression , Gene Knockdown Techniques , Mice , Mice, Inbred C57BL , Nerve Tissue Proteins/genetics , Neural Stem Cells/metabolism , Receptors, G-Protein-Coupled/genetics , beta Catenin/metabolism
18.
Cell Biochem Biophys ; 72(1): 49-56, 2015 May.
Article in English | MEDLINE | ID: mdl-25449297

ABSTRACT

The objective of the study is to investigate the correlation between bilirubin and uric acid (UA) concentrations and symptoms of Parkinson's disease (PD) in Chinese population. A total of 425 PD patients and 460 controls were included in the current study. Patients were diagnosed by a neurologist and assessed using the Hoehn & Yahr (H&Y) scale. Venous blood samples were collected, and bilirubin and UA concentrations were analyzed. Compared to controls, indirect bilirubin (IBIL) and UA concentrations were lower in PD patients (P IBIL = 0.015, P UA = 0.000). Serum IBIL in different age subgroups and H&Y stage subgroups were also lower compared to the control group (P IBIL = 0.000, P UA = 0.000) but were not significantly different among these subgroups. Females in the control group had significantly lower serum IBIL and UA concentrations than males (P IBIL = 0.000, P UA = 0.000) and the PD group (P IBIL = 0.027, P UA = 0.000). In early PD (patients with <2-year medical history and no treatment), serum IBIL and UA concentrations were also lower than the controls (P IBIL = 0.013, P UA = 0.000). Although IBIL concentration was positively correlated with UA concentration in controls (R IBIL = 0.229, P IBIL = 0.004), this positive association was not observed in the PD group (R IBIL = -0.032, P IBIL = 0.724). Decreased levels of serum IBIL and UA were observed in PD patients. It is possible that individuals with decreased serum bilirubin and UA concentrations lack the endogenous defense system to prevent peroxynitrite and other free radicals from damaging and destroying dopaminergic cells in the substantia nigra. Our results provide a basis for further investigation into the role of bilirubin in PD.


Subject(s)
Bilirubin/blood , Parkinson Disease/blood , Uric Acid/blood , Aged , Aged, 80 and over , Antioxidants/chemistry , Asian People , Case-Control Studies , China , Dopamine/metabolism , Dose-Response Relationship, Drug , Female , Free Radicals/chemistry , Humans , Male , Middle Aged , Oxidative Stress , Parkinson Disease/ethnology , Peroxynitrous Acid/chemistry , Substantia Nigra/metabolism
19.
Phytomedicine ; 21(5): 766-72, 2014 Apr 15.
Article in English | MEDLINE | ID: mdl-24462213

ABSTRACT

We recently reported that Wuzhi tablet (WZ), a preparation of the ethanol extract of Wuweizi (Schisandra sphenanthera), had significant effects on blood concentrations of Tacrolimus (FK506) in renal transplant recipients and rats. The active lignans in WZ are schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, schisantherin A, and schisantherin B. Until now, whether the pharmacokinetics of these lignans in WZ would be affected by FK506 remained unknown. Therefore, this study aimed to investigate whether and how FK506 affected pharmacokinetics of lignans in WZ in rats and the potential roles of CYP3A and P-gp. After a single oral co-administration of FK506 and WZ, the blood concentration of lignans in WZ was decreased by FK506; furthermore, the AUC of schisantherin A, schisandrin A, schisandrol A and schisandrol B was only 64.5%, 47.2%, 55.1% and 57.4% of that of WZ alone group, respectively. Transport study in Caco-2 cells showed that these lignans were not substrates of P-gp, suggesting decreased blood concentration of lignans by FK506 was not via P-gp pathway. Metabolism study in the human recombinant CYP 3A showed that these lignans had higher affinity to CYP3A than that of FK506, and thus had a stronger CYP3A-mediated metabolism. It was concluded that the blood concentrations of these lignans were decreased and their CYP3A-mediated metabolisms were increased in the presence of FK506 since these lignans had higher affinity to CYP3A.


Subject(s)
Drugs, Chinese Herbal/pharmacokinetics , Immunosuppressive Agents/pharmacology , Lignans/pharmacokinetics , Schisandra/chemistry , Tacrolimus/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Caco-2 Cells , Cytochrome P-450 CYP3A/metabolism , Drug Interactions , Drugs, Chinese Herbal/chemistry , Humans , Lignans/analysis , Male , Random Allocation , Rats, Sprague-Dawley
20.
Drug Metab Dispos ; 42(1): 193-9, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24195812

ABSTRACT

We recently reported that Wuzhi tablet (WZ; Schisandra sphenanthera extract) can inhibit P-glycoprotein (P-gp)-mediated efflux and CYP3A-mediated metabolism of tacrolimus (FK506) and thus increase the blood concentrations of FK506. Major active lignans of WZ include schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, and schisantherin A. Whether and how these six lignans affect the pharmacokinetics of FK506 remains unclear. Therefore, this study aimed to investigate the effects of these lignans on the first-pass absorption and metabolism of FK506 and the involved mechanisms in vitro and in vivo. The results showed that whole-blood concentrations of FK506 were increased to different degrees following coadministration of the six lignans, respectively. Schisandrol B showed the strongest effect on the increase of the area under the concentration-time curve, the oral bioavailability, the gut processes affecting availability, and the hepatic availability of FK506. The reduction of intestinal first-pass effect contributed most to the increase in oral bioavailability of FK506 when coadministered with schisandrol B. In vitro transport experiment showed that schisandrin A, schisandrin B, and schisandrol B inhibited P-gp-mediated efflux of FK506. In vitro metabolism study showed that the inhibitory effect of these six lignans on FK506 metabolism was dose-dependent. In conclusion, the exposure of FK506 in rats was increased when coadministered with these lignans, and schisandrol B showed the strongest effect. Lignans of WZ inhibited P-gp-mediated efflux and CYP3A-mediated metabolism of FK506, and the reduction of intestinal first-pass affected by the lignans was the major cause of the increased FK506 oral bioavailability.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B/metabolism , Cytochrome P-450 CYP3A/metabolism , Drugs, Chinese Herbal/pharmacology , Lignans/pharmacology , Tablets/pharmacology , Tacrolimus/pharmacokinetics , Absorption , Animals , Biological Availability , Caco-2 Cells , Cell Line, Tumor , Cyclooctanes/pharmacology , Dioxoles/pharmacology , Humans , Male , Microsomes, Liver/metabolism , Polycyclic Compounds/pharmacology , Rats , Rats, Sprague-Dawley
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