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This study establishes and optimizes the physiologically based pharmacokinetics (PBPK) model for dapagliflozin, predicts the drug distribution into relevant tissues, and calculates the inhibitory effect on the sodium-glucose cotransporters (SGLTs) in the intestine and renal proximal tubule. Based on literature data, a PBPK model for oral administration in healthy adults was established and the predicted blood concentration-time curve characteristics, the main pharmacokinetic parameters (PK), and drug excretion in urine were compared with the published data. To verify and optimize the model and verify the accuracy of the tissue distribution and concentration predictions, a pharmacodynamics model (PD) was established. Urine glucose excretion (UGE) was simulated at the corresponding times. The characteristics of the drug-time curve predicted by the model are similar to those of the measured curve, and the ratio of the main PK parameters to the measured values is within a two-fold range; the accuracy of the established PBPK model is good. The maximal inhibition obtained with 10 mg of dapagliflozin on the duodenum and jejunum segment sodium-glucose co-transporter 1 (SGLT1s) was 1.6%-4.7%, and the inhibition rate of the sodium-glucose co-transporter 2 (SGLT2s) in the proximal tubule of the kidney was as high as 99.9%. At a dose of 10 mg, dapagliflozin delayed intestinal glucose absorption while occupying most of the sites (99.9%) of the renal sodium-glucose cotransporter 2 and inhibiting its glucose reabsorption. This physiological-pharmacokinetic model for dapagliflozin in healthy adults can provide meaningful guidance for exploring pharmacological mechanisms and potential toxicity of gliflozin by simulating drug distribution in different tissues.
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Objective@#To evaluate the predictive performance of anthropometric indices for metabolic syndrome (MetS) among Chinese adolescents with different nutritional status.@*Methods@#We recruited 9,513 adolescents aged 10-18 years from seven provinces in China during September 2014. Anthropometric indices and blood pressure were measured at recruitment, and blood samples were collected for determining fasting plasma glucose and lipid profile. Receiver operating characteristic (ROC) analyses were used to assess the predictive performance of anthropometric indices, including body mass index (BMI) percentile, waist circumference percentile, waist-height ratio, and waist-hip ratio.@*Results@#Overall, the four anthropometric indices showed good accuracy for predicting MetS with areas under ROC curves (AUCs) ranging from 0.86 to 0.94; similar AUCs ranging from 0.73 to 0.99 were observed for participants with normal weight. The performance of all four indices was poor in overweight and obese participants, with AUCs ranging from 0.66 to 0.77 and from 0.60 to 0.67, respectively. Waist circumference showed relatively better performance in all the subgroup analyses.@*Conclusions@#We suggest using anthropometric indices with the cutoff values presented here for predicting MetS in the overall and normal-weight adolescent population, but not in the overweight and obese adolescent population where more specific screening tests are required.
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Adolescent , Child , Female , Humans , Male , Asian People , Body Weights and Measures , China , Cross-Sectional Studies , Metabolic Syndrome/diagnosis , Nutritional Status , Randomized Controlled Trials as TopicABSTRACT
Prunella vulgaris(PV) is an edible and traditional medicinal herb which has a wide range application in fighting inflammation and oxidative stress, and protecting liver. Now it has been used to treat various types of liver diseases and has significant clinical efficacy. This study aims to investigate the effects of PV on ethanol-induced oxidative stress injury in rats and its metabolic mechanism. The rats were divided into control group, model group, PV group, and VC group. The liver protection of PV was identified by measuring pharmacological indexes such as antioxidant and anti-inflammatory activity. The metabolic mechanism of long-term ethanol exposure and the metabolic regulation mechanism of PV treatment were studied by LS-MS metabonomics. The pharmacological investigation indicated that ethanol could significantly decrease the contents of SOD, GSH-Px, CAT and other antioxidant enzymes in liver and increase the content of MDA. At the same time, PV could significantly reduce the contents of inflammatory factors(TNF-α, IL-6 and IL-1β) and liver function markers(ALT, AST, ALP) in serum. What's more, long-term ethanol exposure could significantly cause liver injury, while PV could protect liver. Metabolomics based on multiple statistical analyses showed that long-term ethanol exposure could cause significant metabolic disorder, and fatty acids, phospholipids, carnitines and sterols were the main biomarkers. Meanwhile, pathway analysis and enrichment analysis showed that the β oxidation of branched fatty acids was the main influencing pathway. Also, PV could improve metabolic disorder of liver injury induced by ethanol, and amino acids, fatty acids, and phospholi-pids were the main biomarkers in PV treatment. Metabolic pathway analysis showed that PV mainly regulated metabolic disorder of ethanol-induced liver injury through phenylalanine, tyrosine and tryptophan biosynthetic pathways. This study could provide a new perspective on the hepatoprotective effect of natural medicines, such as PV.
Subject(s)
Animals , Rats , Antioxidants/metabolism , Ethanol/toxicity , Liver/metabolism , Metabolomics , Oxidative Stress , PrunellaABSTRACT
Objective:To evaluate the effects of different output pressures of extracorporeal shock wave therapy (ESWT) on triceps surae spasticity after stroke, and to explore the electrophysiologic mechanism involved. Methods:From January, 2015 to December, 2017, 90 hemiplegic stroke patients with triceps surae spasticity were randomly assigned into control group (n = 30), treatment group 1 (n = 30) and treatment group 2 (n = 30). All the patients accepted routine medicine and rehabilitation, while the treatment groups 1 and 2 received ESWT of 1.5 bar and 2.0 bar in addition, respectively, for four weeks. They were assessed with Composite Spasticity Scale (CSS), passive range of motion (PROM), 10-meter walk test (10MWT), and H reflex latency and the Hmax/Mmax ratio before and after treatment, and the two treatment groups were assessed with Visual Analogue Scale (VAS) immediately after ESWT. Results:All the groups improved in scores of CSS, PROM and 10MWT after treatment (t > 7.261, P < 0.001), and improved more in scores of CSS and 10MWT in the two treatment groups than in the control group (P < 0.05), and the 10MWT was less in the treatment group 2 than in the treatment group 1 (P < 0.05). H reflex latency lengthened (t > 15.025, P < 0.001) and Hmax/Mmax ratio decreased (t > 14.850, P < 0.001) after treatment in the two treatment groups, and the H reflex latency was longer in the two treatment groups than in the control group (P < 0.01). There was no significant difference in VAS between the two treatment groups (t = 0.735, P > 0.05). Conclusion:ESWT of both 2.0 bar and 1.5 bar can improve triceps surae spasticity after stroke, and ESWT of 2.0 bar may more benefit the ability of walking. Further study is needed to explore the involved electrophysiologic mechanism.
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Objective:To evaluate the effects of different output pressures of extracorporeal shock wave therapy (ESWT) on triceps surae spasticity after stroke, and to explore the electrophysiologic mechanism involved. Methods:From January, 2015 to December, 2017, 90 hemiplegic stroke patients with triceps surae spasticity were randomly assigned into control group (n = 30), treatment group 1 (n = 30) and treatment group 2 (n = 30). All the patients accepted routine medicine and rehabilitation, while the treatment groups 1 and 2 received ESWT of 1.5 bar and 2.0 bar in addition, respectively, for four weeks. They were assessed with Composite Spasticity Scale (CSS), passive range of motion (PROM), 10-meter walk test (10MWT), and H reflex latency and the Hmax/Mmax ratio before and after treatment, and the two treatment groups were assessed with Visual Analogue Scale (VAS) immediately after ESWT. Results:All the groups improved in scores of CSS, PROM and 10MWT after treatment (t > 7.261, P < 0.001), and improved more in scores of CSS and 10MWT in the two treatment groups than in the control group (P < 0.05), and the 10MWT was less in the treatment group 2 than in the treatment group 1 (P < 0.05). H reflex latency lengthened (t > 15.025, P < 0.001) and Hmax/Mmax ratio decreased (t > 14.850, P < 0.001) after treatment in the two treatment groups, and the H reflex latency was longer in the two treatment groups than in the control group (P < 0.01). There was no significant difference in VAS between the two treatment groups (t = 0.735, P > 0.05). Conclusion:ESWT of both 2.0 bar and 1.5 bar can improve triceps surae spasticity after stroke, and ESWT of 2.0 bar may more benefit the ability of walking. Further study is needed to explore the involved electrophysiologic mechanism.
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OBJECTIVE To investigate toll-like receptor 4(TLR4)-related the regulation of Ornithog-alum caudatum extract(OCE)on inflammatory responses in lipopolysaccharide(LPS)activated macro-phages.METHODS Primary peritoneal macrophage,Raw 264.7,and THP-1 were incubated in 96-well plate for 24 h and treated with OCE of the concentration of 0-400 μg/ml for 4h.The viability of cells was measured by MTT assay.Specific concentrations of OCE were added into the medium of primary peri-toneal macrophage, Raw 264.7, and THP-1, respectively, then following with lipopolysaccharides (LPS). Cells were harvested and the total cellular protein and nuclear protein were extracted, and the protein content was determined using BCA protein assay Kit.The expressions of TLR4,inducible nitric oxide synthase(iNOS),cyclooxygenase 2(COX-2),α-inhibitor of NF-κB(IκB-α)and nuclear factor-κB (NF-κB)were assayed by Western blot.The expressions of interleukin-1α(IL-1α),interleukin-1β(IL-1β), interleukin-18(IL-18),and tumor necrosis factor-α(TNF-α)were measured by RT-PCR.RESULTS The results of MTT showed that OCE has no cytotoxicity in Raw 264.7 cells between 1.56 μg/ml and 400 μg/ml. Compared with normal group,the expressions of TLR4,iNOS,COX-2,NF-κB and IL-1α,IL-1β,IL-18, TNF-α,the level of nitric oxide(NO)were significantly increased by LPS stimulation,while OCE pretreat-ment reduced these increase induced by LPS. However, OCE pretreatment reversed the reduction of IκB-α after LPS stimulation.CONCLUSION OCE might suppress TLR4 expression and block the inflamma-tion process of NF-κB and iNOS,further decrease the expression of COX-2 and inhibit the release of inflammatory factors.
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<p><b>Background</b>The effectiveness of the combination of electroacupuncture (EA) and behavioral training (BT) for mid/advanced cerebral infarction (M/ACI) and related mechanisms remains unclear. This study aimed to investigate the combined effects on the learning-memory ability and event-related potential P300 in rats with M/ACI.</p><p><b>Methods</b>Eighty rats with M/ACI were divided into Group Model (M), Group EA, Group BT, and Group EA-BT (n = 20) according to the random number with five healthy rats in Group Control (CON). On the 6 week after modeling, EA, BT, and EA-BT were given to Group EA, Group BT, and Group EA-BT, respectively, whereas Group M and Group CON were not given any intervention. Y-maze test and P300 were recorded before and after the intervention.</p><p><b>Results</b>After intervention, the P300 latency was lower and the amplitude was higher in the Group EA-BT, Group EA, and Group BT than before (for latency, t = -7.638, -4.334, and -5.916; for amplitude, t = 8.125, 3.846, and 5.238; P < 0.01), with Group EA-BT superior to Group EA (for latency, t = -3.708; for amplitude, t = 3.653; P < 0.01) and Group BT (for latency, t = -2.067; for amplitude, t = 2.816; P < 0.05), with no significant difference between Group BT and EA (for latency, t = -1.439; for amplitude, t = 1.075; P > 0.05). While the performances of Y-maze tests in the Group EA-BT, Group EA, and Group BT were all better than before (t = 10.359, 4.520, and 7.791, P < 0.01), with Group EA-BT better than Group EA (t = 5.627, P < 0.01) and Group BT (t = 2.913, P < 0.01) respectively, and Group BT better than Group EA (t = 2.912, P < 0.01).</p><p><b>Conclusion</b>EA or BT can affect P300 in rats with M/ACI, and the combination of these two methods can significantly improve the learning-memory ability.</p>
Subject(s)
Animals , Humans , Rats , Acupuncture Points , Cerebral Infarction , Disease Models, Animal , Electroacupuncture , Evoked Potentials , Rats, Inbred ACI , Rats, Sprague-DawleyABSTRACT
Flavonoids have attracted much attention due to their good anti-inflammatory, anti-oxidation and anti-tumor effects. At present, the extraction of flavonoids is mainly based on organic solvent, while the researches on the use of green and safe solvents are quite limited. Therefore, in the present study, different types of deep eutectic solvents (DESs) were applied to investigate their effect on extraction of flavonoids and optimize the process, also investigate the recovery efficiency of DESs and evaluate the recovery method for total flavonoids. The extraction yield of the total flavonoids acted as the comprehensive evaluation indexes, and a central composite design (CCD) of response surface methodology (RSM) was employed to further optimize the alcohol-based DES extraction conditions. The results showed that the optimized extraction conditions were as follows: water-DES ratio of 27%, solid-liquid ratio of 15 mL·g⁻¹, extraction temperature of 83 °C and extraction time of 42 min in ChCl-glycerol at 1:4 ratio. Under these conditions, the mean experimental value of the extraction yield (75.05 mg·g⁻¹) corresponded well with the predicted value (77.86 mg·g⁻¹). Moreover, these experimental results showed more advantages such as in higher efficiency, economy and environmental protection as compared with previously reported conventional extraction methods. In addition，the recovery yield of the total flavonoids from the DESs extraction solution achieved 97.88% by using AB-8 macroporous resin, and 88.12% desorption ratio can be achieved by 100% ethanol with 5 times resin content. After the above treated DESs were collected, the extraction yield with the same method reached 95.23%, indicating that the method of macroporous resin can be used for efficient and simple recovery and reuse. This study suggests that DESs can be used as a kind of sustainable and efficient natural extraction solvents for extraction of flavonoids from Prunella vulgaris.
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Prunellae Spica is a perennial edible and medicinal plant, rich in antioxidant substances. Total flavonoids (TFC), Phenolics (TPC), triterpenoids (TSC), polysaccharides (PC) and their antioxidant capacities (by the FRAP, DPPH and ABTS⁺ methods) of ethyl acetate fraction, n-butanol fraction and other fractions of aqueous extract from Prunellae Spica were investigated in this study. Then the multivariate statistical method was adopted to analyze the relationship between the multiple pharmaceutical ingredients and antioxidant capacities of Prunellae Spica. The results showed that ethyl acetate fraction had relatively high concentration of TFC (0.61±0.10) g·g⁻¹DW, TPC (0.52±0.09) g·g⁻¹DW, and TSC (0.21±0.03) g·g⁻¹DW, with high scavenging capacity of DPPH (3.1±0.38) mmol·L⁻¹·g⁻¹DW and FRAP (2.56±0.35) mmol·L⁻¹·g⁻¹DW. Hierarchical clustering analysis (HCA) and principal component analysis (PCA) results indicated the information from chemical compositions and antioxidant capacity can represent the "differences" of different fractions. Canonical correlation analysis (CCorA) revealed a high positive correlation between the amounts of multiple chemical compositions and the antioxidant capacities (r=0.970 0), and the first canonical variate had been reached. Moreover, ABTS⁺ method showed a low response to the compositions of different fractions, so this method may not be suitable for evaluation of Prunellae Spica antioxidant capacities, while DPPH evaluation method was more suitable for TSC and TPC. The results of this study have important reference significance for the evaluation method on antioxidant activity of Prunellae Spica in the field of food or medicine as well as for the development of related extracts.
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Antioxidants , Flavonoids , Phenols , Plant ExtractsABSTRACT
Objective To investigate the expression of retinoic acid receptors (RARs) subtypes RAR-α, RAR-β, RAR-γ and retinal dehydrogenases 1(Ra/dh1), Raldh2 in the mouse embryonic hematopoiesis, so as to discuss the role of different RAR subtypes in embryonic hematopoiesis. Methods The yolk sac (YS) at embryonic day 9. 5 (E9. 5), aortagonad- mesonephros (AGM) region at E10. 5 and E11. 5, fetal liver (FL) at E13. 5, E14. 5 and E17. 5 were harvested from the pregnant mice. The bonemarrow (BM) was also harvested from adult mice. The mRNA levels of RAR-α, RAR-β, RAR-γ, Raldh1 and Raldh2 at the above four different hematopoietic sites were assessed by quantitative reverse transcription polymerase chain reaction (RT PCR). Results The mRNA levels of RAR-α, RAR-β, RAR-γ, RaldhX and Raldh2 at E9. 5 YS, E11. 5 AGM regions and BM were significantly higher than those in other relevant hematopoietic tissues (P<0. 01). Compared with the E10. 5 AGM region, E11. 5 AGM region had significantly increasedmRNA levels of RAR-α, RAR-β, RAR-γ, Raldh1 and Raldh2 (P<0. 01), but the mRNA levels of these genes in FL at E13. 5-E17. 5 were not significantly different. Conclusion The expressions of RAR-α, RAR-β, RAR-γ, Raldh1 and Raldh2 in YS, AGM regions and BM are consistent with the situation of colony forming unit erythroid (CFU-E), suggesting that retinoic acid is closely related to the formation of hematopoiesis in the YS, AGM region and BM in mouse, but has less correlation with the FL in mouse.
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To establish the fingerprints of Xiasangju granules (with sugar and non-sugar forms) by HPLC, and provide reference for their identification and effective quality control. High performance liquid chromatography (HPLC) method was used to collect the fingerprints of 20 batches of non-sugar Xiasangju granules and 34 batches of sugar type Xiasangju granules. Their main different components were classified and screened by mode identification methods (principal component analysis, PCA, and orthogonal partial least squares discriminate analysis, OPLS-DA). The principal components were identified by comparing with reference standards. The fingerprints of Xiasangju granules (sugar type and non-sugar type) were established. PCA could not fully classify the two types of granules, while OPLS-DA could obviously classify these two different types of Xiasangju granules. Six components showed greatest difference between two types of granules, including salviaflaside, luteoloside and linarin. The developed mode identification method is helpful to control the overall quality of Xiasangju granules, and it provides an effective approach to quality evaluation.
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Traditional Chinese medicine (TCM) has a good reputation for preventing or healing diseases in clinic due to its higher efficacy, minor toxicity and abundant resources. Screening bioactive components in TCMs is not only crucial for clarifying their action mechanisms, but also the basis of their safety and quality control. TCM is characterized by multiple components, multiple targets and multiple mechanisms, however the complex composition of TCM makes it difficult to study the therapeutic material basis which has become the bottleneck in the process of its modernization and internationalization. Recently, with the rapid development of modern technologies and the unceasing progress of various disciplines, multidisciplinary approach, such as analytical chemistry, chemistry of TCM, pharmacology, cell biology, systems biology and bioinformatics has been successfully applied to the study of TCM. Multidisciplinary approach realizes the communication and interaction of multi-discipline, and accelerates the research and development of TCM. This review summarizes the application of multidisciplinary approach which may have certain potential of bringing new thoughts to TCM research and provide references for screening and identification of therapeutic material basis of TCMs.
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Humans , Chemistry, Pharmaceutical , Computational Biology , Drugs, Chinese Herbal , Chemistry , Therapeutic Uses , Medicine, Chinese Traditional , Phototherapy , Systems BiologyABSTRACT
<p><b>BACKGROUND</b>Population based epidemiologic study on the main diseases and birth status of liveborn neonates remains scarce in China, especially in rural areas where a large number of neonates are born. The aim of this study was to establish an epidemiological basis of live births in Julu County, a representative of the northern and mid-western parts of China in terms of demography, disease pattern and women and children's health care infrastructure.</p><p><b>METHODS</b>The perinatal data of all live births were prospectively collected in three participating county-level hospitals from September 1, 2007 to August 30, 2008.</p><p><b>RESULTS</b>There were 5822 live births in these hospitals. Among all live births, 53.7% were male and 4.5% were born prematurely. Mean (SD) birth weight (BW) was (3348 ± 503) g. The low (< 2500 g) and very low BW (< 1500 g) infants accounted for 3.8% and 0.5% of the total births, with 6.5% as small for gestational age and 2.8% as multi-births. Cesarean section rate was 30.2%, of which 68.6% were elective. There were 745 infants (12.8% of the live births) admitted to local neonatal wards within 7 days of postnatal life, in which 48.3% and 19.3% were due to perinatal asphyxia and prematurity, respectively. The incidences of perinatal aspiration syndrome, transient tachypnea and respiratory distress syndrome were 4.9%, 0.6% and 0.5%, respectively. Neonatal mortality was 7.6‰ (44/5822), with 16 in delivery room and 28 in neonatal ward before discharge.</p><p><b>CONCLUSIONS</b>This study provided a population-based perinatal data of live births and neonatal mortality in a northern China county with limited resources. Neonatal disorders related to perinatal asphyxia remain a serious clinical problem, which calls for sustained education of advanced neonatal resuscitation and improvement in the quality of perinatal-neonatal care.</p>
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Female , Humans , Infant, Newborn , Male , Asphyxia Neonatorum , Epidemiology , Birth Weight , China , Epidemiology , Infant Mortality , Infant, Newborn, Diseases , Epidemiology , Therapeutics , Prospective Studies , Respiratory Distress Syndrome, Newborn , Epidemiology , TherapeuticsABSTRACT
<p><b>OBJECTIVE</b>To study the potential effect of gene-environment interaction between glutathione S-transferase T1 (GSTT1) and serum organochlorines residues on the risk of breast cancer in women, in China.</p><p><b>METHODS</b>70 newly diagnosed female breast cancer patients and 30 controls from September 2006 to October 2007 were interviewed using the same questionnaire to obtain information regarding exposure to those risks. Organochlorine residues level in serum was measured by gas chromatography (GC). Genotypes of GSTT1 polymorphisms were analyzed by multiplex allele-specific polymerase chain reaction (PCR). Interaction indexes (gamma) were calculated to determine the type of gene-environment interaction.</p><p><b>RESULTS</b>After adjusting the confounding factors, results showed that interaction existed in genetic polymorphisms of GSTT1 and dichlorodiphenyltrichloroethane (DDT)/hexachlorocyclohexane (HCH) residues, with interaction indexes (gamma) value as 1.352 and 1.528.</p><p><b>CONCLUSION</b>Genetic and environmental hazard factors had a co-effect on the development of breast cancer while genetic polymorphisms of GSTT1 and DDT/HCH expressed an interaction to breast cancer.</p>