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1.  Crude triterpenoid saponins from Ilex latifolia (Da Ye Dong Qing) ameliorate lipid accumulation by inhibiting SREBP expression via activation of AMPK in a non-alcoholic fatty liver disease model 
Chinese Medicine  2015;10:23.
Ilex latifolia Thunb. (Da Ye Dong Qing) is used for weight loss and for its antidiabetic effects. This study aims to investigate the beneficial effects and potential mechanisms of action of crude triterpenoid saponins (CTS) from I. latifolia in a mouse model of high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD).
Male C57BL/6 mice (n = 50), were arbitrarily divided into five groups (n = 10 in each group): a control group, HFD group, simvastatin group (10 mg/kg/day), and two CTS treatment groups (100 and 200 mg/kg/day). All mice except those in the control group were fed an HFD for 4 weeks. Animals in the treatment groups were orally administered simvastatin or CTS for 8 weeks. Oral glucose tolerance tests and insulin tolerance tests were performed. At the end of treatment, plasma lipid levels, and oxidative parameters in the liver were measured using commercial test kits. Western blotting was used to evaluate whether CTS induced AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase activation, and the expression of transcription factors and their target genes was evaluated in a quantitative PCR assay.
Compared with the HFD group, the CTS (200 mg/kg/day) treatment group showed significantly decreased plasma lipid parameters (P < 0.001, P = 0.018, and P = 0.005 for triglycerides, total cholesterol and low-density lipoprotein cholesterol, respectively), and improved insulin resistance (P = 0.006). CTS (100 and 200 mg/kg/day) supplementation also reduced hepatic lipids and protected the liver from oxidative stress by attenuating malondialdehyde content (P < 0.001 and P < 0.001, respectively) and restoring aspartate aminotransferase levels (P < 0.001 and P < 0.001, respectively). Moreover, CTS (200 mg/kg/day) reduced lipid accumulation by enhancing AMPK phosphorylation and inhibiting expression of sterol regulatory element-binding proteins (SREBPs) and their target genes SREBP-1c, SREBP-2, fatty acid synthase, and stearoyl-CoA desaturase (P = 0.013, P = 0.007, P = 0.011, and P = 0.014, respectively).
CTS from I. latifolia improved insulin resistance and liver injury in HFD-fed mice, and attenuated NAFLD via the activation of AMPK and inhibition of the gene expression of SREBPs and some of their target molecules.
PMCID: PMC4544818  PMID: 26300958
2.  Apolipoprotein E gene E2/E2 genotype is a genetic risk factor for vertebral fractures in humans: a large-scale study 
International Orthopaedics  2014;38(8):1665-1669.
Although many studies have been performed to evaluate whether or not apolipoprotein E gene (APOE) polymorphisms are differentially associated with bone mineral density (BMD) and fractures, the results have been conflicting. This large-scale study was performed to investigate whether a relationship exists between APOE polymorphisms and risk of fracture.
A hospital-based case–control study was conducted in 3,000 patients with fractures and 3,000 age- and gender-matched healthy controls. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay was applied to assess the APOE gene polymorphisms.
Patients with fractures had a significantly higher frequency of APOE E2/E2 genotype [odds ratio (OR) = 2.02, 95 % confidence interval (CI) = 1.30, 3.14; P = 0.002] than healthy controls. When stratifying by fracture type, it was found that patients with vertebral fractures had a significantly higher frequency of APOE E2/E2 genotype (OR = 2.86, 95 % CI = 1.73, 4.73; P < 0.001). No significant differences were found in nonvertebral (hip or wrist or other) fractures.
Our study suggests that APOE E2/E2 genotype is a potential genetic risk factor for vertebral fractures in humans.
PMCID: PMC4115114  PMID: 24880936
Apolipoprotein E; Fracture; Gene polymorphism; Case–control study
3.  Crude triterpenoid saponins from Anemone flaccida (Di Wu) exert anti-arthritic effects on type II collagen-induced arthritis in rats 
Chinese Medicine  2015;10:20.
Anemone flaccida Fr . Schmidt (Ranunculaceae) (Di Wu in Chinese) is used to treat punch injury and rheumatoid arthritis (RA). However, the active compounds and underlying mechanism of action mediating the anti-arthritic effects of A. flaccida remain unclear. This study aims to evaluate the underlying action mechanism of A. flaccida crude triterpenoid saponins (AFS) on RA using a type II collagen (CII)-induced arthritis (CIA) rat model, and to assess the anti-inflammatory effects of the main active compounds of AFS, namely flaccidoside II, anhuienoside E, glycoside St-I4a, hemsgiganoside B, hederasaponin B, and 3-O-α-l-rhamnopyranosyl (1 → 2)-β-d-glucopyranosyl oleanolic acid 28-O-β-d-glucopyranosyl (1 → 6)-β-d-glucopyranosyl ester.
Male Wistar rats (n = 50) were randomly separated into five groups (n = 10) and immunized by CII injection. AFS (200 or 400 mg/kg) and dexamethasone were orally administered for 30 days after establishing the model. The arthritis severity was assessed by paw volume using a plethysmometer. After 30 days of treatment, the right hind paws of the rats were obtained. Paw histology was analyzed by hematoxylin and eosin staining, and radiologic imaging was performed by micro-computed tomography. MTT assays were used to evaluate the cytotoxicity of AFS and its main compounds in RAW264.7 cells. Enzyme-linked immunosorbent assay kits were used to measure interleukin (IL)-6 and tumor necrosis factor (TNF)-α in serum and supernatants from AFS- and main AFS compound-treated RAW264.7 cells stimulated by lipopolysaccharide (LPS).
Anemone flaccida crude triterpenoid saponins inhibited redness and swelling of the right hind paw in the CIA model. Radiological and histological examinations indicated that inflammatory responses were reduced by AFS treatment. Moreover, comparing with untreated rats, serum TNF-α (P = 0.0035 and P < 0.001) and IL-6 (P = 0.0058 and P = 0.0087) were lower in AFS-treated CIA rats at the dose of 200 and 400 mg/kg/day. AFS and its main compounds, including hederasaponin B, flaccidoside II, and hemsgiganoside B, significantly inhibited TNF-α (P = 0.0022, P = 0.013, P = 0.0015, and P = 0.016) and IL-6 (P = 0.0175, P < 0.001, P < 0.001, and P < 0.001) production in LPS-treated RAW264.7 cells, respectively.
Anemone flaccida crude triterpenoid saponins and its main bioactive components, including hederasaponin B, flaccidoside II, and hemsgiganoside B, decreased pro-inflammatory cytokine levels in a CIA rat model and LPS-induced RAW264.7 cells.
PMCID: PMC4515010  PMID: 26213566
4.  Warfarin dosage adjustment strategy in Chinese population 
Background: Blood anticoagulation after heart valve replacement is a recognized difficulty all over the world. In this study, we identified the effect of amiodarone on the function of warfarin and confirmed the countermeasure by concluding the genotype distribution of vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) of the patient to predict the security dose of warfarin. Methods: Studying on the VKORC1 (-1639G>A) and CYP2C9 genotype of 271 cases on heart valve replacement in the First Affiliated Hospital of Soochow University from Jan. 2012 to Jan. 2014. Warfarin’s multivariable regression equation was taken to calculate their warfarin dosage. In the study, 80 of them were selected and divided into 4 groups according to their different warfarin dosage and their usage of amiodaron. The differences of INR values at the 5th, 8th, 11th, 14th days of operation were analyzed. Results: Among the 80 cases, VKORC1 (-1639G>A) AA types accounted for 90%, and AG types accounted for another 10%, while GG types were not found. In addition that, all of the patients (100%) had CYP2C9*1/*1 type, and CYP2C9*1/*3 had not appeared. There was significant difference in INR values between the groups who used amiodarone or not. The pharmacogenetic equation was accurate in the predicting of the warfarin dosage, so that satisfied anticoagulation efficacy had been achieved in 2 weeks after surgery. Conclusion: It is necessary for the patients to do the warfarin pharmacogenetic test to get the suitable dose before heart valve replacement. Amiodarone can enhance the anticoagulant efficacy of warfarin, so the dosages of warfarin should be reduced properly because of the medicine combination, and INR values must be monitored more frequently to make the anticoagulant process secure and efficient.
PMCID: PMC4538110  PMID: 26309674
Heart valve replacement surgery; anticoagulation; pharmacogenomic testing; warfarin; amiodarone
5.  Outflow facility efficacy of five drugs in enucleated porcine eyes by a method of constant-pressure perfusion 
This study aimed to characterize a technique that assesses the outflow facility (C) efficacy of five kinds of IOP-lowering drugs commonly used clinically in enucleated porcine Eyes. Eyes were perfused at 15 mmHg with GPBS first to establish the baseline outflow facility (C0). Then the anterior chamber contents were exchanged for GPBS with corresponding concentration eye drops (4.9×103 nM Brimonidine, 41.1 nM Latanoprost, 3.4×103 nM Levobunolol, 3.0×103 nM Brinzolamide, 8.3×103 nM Pilocarpine) in five groups (n = 6 each), while 6 eyes received GPBS alone as control. The mean stable facility obtained after drug administration (C1) was continuously recorded. The changes between C0 and C1 (ΔC = C1-C0) were analyzed. Finally, for drugs among the five experiment groups with statistical significance, the concentration was reduced 3 times, otherwise the drugs’ concentration was increased to 10 times to confirm its effectiveness further using the same methods (n = 6 each). We found that the average baseline outflow facility was 0.24±0.01 μl·min-1·mmHg-1. C increased significantly in Brimonidine and Latanoprost groups, even the concentration of Brimonidine and Latanoprost was decreased 3 times (P < 0.05). However, there was no significantly increase in Levobunolol, Brinzolamide, Pilocarpine and control group (P > 0.05), but when drugs’ concentration was increased to 10 times, the C value of Pilocarpine decreased significantly (P = 0.04). No significant washout effects in porcine eyes were observed. To conclude, outflow facility efficacy of five drugs in enucleated porcine eyes may provide a reference for clinical medicine. A constant-pressure perfusion technique should be useful to evaluate effect of pharmacologic agents or surgical manipulations on aqueous humor dynamics.
PMCID: PMC4509202  PMID: 26221257
Aqueous humor outflow facility; ocular perfusion; porcine eyes; ocular hypotensive drugs
6.  Fanconi syndrome due to prolonged use of low-dose adefovir 
Fanconi syndrome results from a generalized abnormality of the proximal tubules of the kidney and owing to phosphate depletion can cause hypophosphatemic osteomalacia. Adefovir dipivoxyl (ADV) effectively suppresses hepatitis B virus replication but exhibits nephrotoxicity when administered at a low dosage. We report two cases of Fanconi syndrome induced by ADV at 10 mg/day to call for regular screening for evidence of proximal tubular dysfunction and detailed bone metabolic investigations for prompt detection of ADV nephrotoxicity is critically important to ensure timely drug withdrawal before the development of irreversible tubulointerstitial injury.
PMCID: PMC4468461  PMID: 26110001
Adefovir; Fanconi syndrome; hypophosphatemia; nephrotoxicity
7.  Differential modulation of immune response and cytokine profiles in the bursae and spleen of chickens infected with very virulent infectious bursal disease virus 
Very virulent infectious bursal disease virus (vvIBDV) induces immunosuppression and inflammation in young birds, which subsequently leads to high mortality. In addition, infectious bursal disease (IBD) is one of the leading causes of vaccine failure on farms. Therefore, understanding the immunopathogenesis of IBDV in both the spleen and the bursae could help effective vaccine development. However, previous studies only profiled the differential expression of a limited number of cytokines, in either the spleen or the bursae of Fabricius of IBDV-infected chickens. Thus, this study aims to evaluate the in vitro and in vivo immunoregulatory effects of vvIBDV infection on macrophage-like cells, spleen and bursae of Fabricius.
The viral load was increased during the progression of the in vitro infection in the HD11 macrophage cell line and in vivo, but no significant difference was observed between the spleen and the bursae tissue. vvIBDV infection induced the expression of pro-inflammatory and Th1 cytokines, and chemokines from HD11 cells in a time- and dosage-dependent manner. Furthermore, alterations in the lymphocyte populations, cytokine and chemokine expression, were observed in the vvIBDV-infected spleens and bursae. A drastic rise was detected in numbers of macrophages and pro-inflammatory cytokine expression in the spleen, as early as 2 days post-infection (dpi). On 4 dpi, macrophage and T lymphocyte infiltration, associated with the peak expression of pro-inflammatory cytokines in the bursae tissues of infected chickens were observed. The majority of the significantly regulated pro-inflammatory cytokines and chemokines, in vvIBDV-infected spleens and bursae, were also detected in vvIBDV-infected HD11 cells. This cellular infiltration subsequently resulted in a sharp rise in nitric oxide (NO) and lipid peroxidation levels.
This study suggests that macrophage may play an important role in regulating the early expression of pro-inflammatory cytokines, first in the spleen and then in the bursae, the latter tissue undergoing macrophage infiltration at 4 dpi.
PMCID: PMC4395976  PMID: 25884204
vvIBDV; Viral load; GeXP; Real-time PCR; Pro-inflammatory cytokines; Chemokines
8.  Segmentations of MRI Images of the Female Pelvic Floor: A Study of Inter- and Intra-reader Reliability 
To describe the inter- and intra-operator reliability of segmentations of female pelvic floor structures.
Materials and Methods
Three segmentation specialists were asked to segment out the female pelvic structures in 20 MR datasets on three separate occasions. The STAPLE algorithm was used to compute inter- and intra-segmenter agreement of each organ in each dataset. STAPLE computed the sensitivity, specificity, and positive predictive values (PPV) for inter- and intra-segmenter repeatability. These parameters were analyzed using intra-class correlation analysis. Correlation of organ volume to PPV and sensitivity was also computed.
Mean PPV of the segmented organs ranged from 0.82 to 0.99, and sensitivity ranged from 33 to 96%. Intra-class correlation ranged from 0.07 to 0.98 across segmenters. Pearson correlation of volume to sensitivity were significant across organs, ranging from 0.54 to 0.91. Organs with significant correlation of PPV to volume were bladder (−0.69), levator ani (−0.68), and coccyx (−0.63).
Undirected manual segmentation of the pelvic floor organs are adequate for locating the organs, but poor at defining structural boundaries.
PMCID: PMC4364418  PMID: 21563253
segmentation; MRI; pelvic floor muscles; Intra-class correlation; positive predictive value; repeatability
9.  The application of click chemistry in the synthesis of agents with anticancer activity 
The copper(I)-catalyzed 1,3-dipolar cycloaddition between alkynes and azides (click chemistry) to form 1,2,3-triazoles is the most popular reaction due to its reliability, specificity, and biocompatibility. This reaction has the potential to shorten procedures, and render more efficient lead identification and optimization procedures in medicinal chemistry, which is a powerful modular synthetic approach toward the assembly of new molecular entities and has been applied in anticancer drugs discovery increasingly. The present review focuses mainly on the applications of this reaction in the field of synthesis of agents with anticancer activity, which are divided into four groups: topoisomerase II inhibitors, histone deacetylase inhibitors, protein tyrosine kinase inhibitors, and antimicrotubule agents.
PMCID: PMC4362898  PMID: 25792812
topoisomerase II inhibitors; histone deacetylase inhibitors; protein tyrosine kinase inhibitors; antimicrotubule agents
10.  Universal Stem-Loop Primer Method for Screening and Quantification of MicroRNA 
PLoS ONE  2014;9(12):e115293.
RT-qPCR is the accepted technique for the quantification of microRNA (miR) expression: however, stem-loop RT-PCR, the most frequently used method for quantification of miRs, is time- and reagent-consuming as well as inconvenient for scanning. We established a new method called ‘universal stem-loop primer’ (USLP) with 8 random nucleotides instead of a specific sequence at the 3′ end of the traditional stem-loop primer (TSLP), for screening miR profile and to semi-quantify expression of miRs. Peripheral blood samples were cultured with phytohaemagglutinin (PHA), and then 87 candidate miRs were scanned in cultured T cells. By USLP, our study revealed that the expression of miR-150-5p (miR-150) decreased nearly 10-fold, and miR-155-5p (miR-155) increased more than 7-fold after treated with PHA. The results of the dissociation curve and gel electrophoresis showed that the PCR production of the USLP and TSLP were specificity. The USLP method has high precision because of its low ICV (ICV<2.5%). The sensitivity of the USLP is up to 103 copies/µl miR. As compared with the TSLP, USLP saved 75% the cost of primers and 60% of the test time. The USLP method is a simple, rapid, precise, sensitive, and cost-effective approach that is suitable for screening miR profiles.
PMCID: PMC4280144  PMID: 25548906
11.  OTUB1 promotes metastasis and serves as a marker of poor prognosis in colorectal cancer 
Molecular Cancer  2014;13:258.
OTUB1 (OTU deubiquitinase, ubiquitin aldehyde binding 1) is a deubiquitinating enzyme (DUB) that belongs to the OTU (ovarian tumor) superfamily. The aim of this study was to clarify the role of OTUB1 in colorectal cancer (CRC) and to identify the mechanism underlying its function.
Two hundred and sixty CRC samples were subjected to association analysis of OTUB1 expression and clinicopathological variables using immunohistochemical (IHC) staining. Overexpression of OTUB1 was achieved in SW480 and DLD-1 cells, and downregulation of OTUB1 was employed in SW620 cells. Then, migration and invasion assays were performed, and markers of the epithelial-mesenchymal transition (EMT) were analyzed. In addition, hepatic metastasis models in mice were used to validate the function of OTUB1 in vivo.
OTUB1 was overexpressed in CRC tissues, and the expression level of OTUB1 was associated with metastasis. A high expression level of OTUB1 was also associated with poor survival, and OTUB1 served as an independent prognostic factor in multivariate analysis. OTUB1 also promoted the metastasis of CRC cell lines in vitro and in vivo by regulating EMT.
OTUB1 promotes CRC metastasis by facilitating EMT and acts as a potential distant metastasis marker and prognostic factor in CRC. Targeting OTUB1 may be helpful for the treatment of CRC.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-4598-13-258) contains supplementary material, which is available to authorized users.
PMCID: PMC4351937  PMID: 25431208
OTUB1; Colorectal cancer; Metastasis; EMT; Prognostic factor
12.  Simultaneous determination by UPLC-MS/MS of seven bioactive compounds in rat plasma after oral administration of Ginkgo biloba tablets: application to a pharmacokinetic study*  
A rapid, reliable, and sensitive method was developed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) with an electrospray ionization (ESI) source for determination of seven bioactive compounds in rat plasma after oral administration of Ginkgo biloba tablets (GBTs). The method simultaneously detects bilobalide (BB), ginkgolide A (GA), ginkgolide B (GB), ginkgolide C (GC), quercetin (QCT), kaempferol (KMF), and isorhamnetin (ISR) for pharmacokinetic study. The analytes and internal standard (IS) were extracted from rat plasma by acetidin. An MS/MS detection was conducted using multiple reaction monitoring (MRM) and operating in the negative ionization mode. The calibration curve ranges were 5–500, 5–500, 2.5–250, 1–100, 1–100, 1–100, and 1–100 ng/ml for BB, GA, GB, GC, QCT, KMF, and ISR, respectively. The mean recovery of the analytes ranged from 68.11% to 84.42%. The intra- and inter-day precisions were in the range of 2.33%–9.86% and the accuracies were between 87.67% and 108.37%. The method was used successfully in a pharmacokinetic study of GBTs. The pharmacokinetic parameters of seven compounds were analyzed using a non-compartment model. Plasma concentrations of the seven compounds were determined up to 48 h after administration, and their pharmacokinetic parameters were in agreement with previous studies.
PMCID: PMC4228506  PMID: 25367786
Ginkgo biloba tablet; Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS); Pharmacokinetics
13.  Essential oil from Zanthoxylum bungeanum Maxim. and its main components used as transdermal penetration enhancers: a comparative study*  
Our previous studies had confirmed that the essential oil from Zanthoxylum bungeanum Maxim. (Z. bungeanum oil) could effectively enhance the percutaneous permeation of drug molecules as a natural transdermal penetration enhancer. The aim of the present study is to investigate and compare the skin penetration enhancement effect of Z. bungeanum oil and its main components on traditional Chinese medicine (TCM) active components. Toxicities of Z. bungeanum oil and three selected terpene compounds (terpinen-4-ol, 1,8-cineole, and limonene) in epidermal keratinocytes (HaCaT) and dermal fibroblast (CCC-ESF-1) cell lines were measured using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Five model drugs in TCM external preparations, namely osthole (OT), tetramethylpyrazine (TMP), ferulic acid (FA), puerarin (PR), and geniposide (GP), which were selected based on their lipophilicity denoted by logK o/w, were tested using in vitro permeation studies in which vertical Franz diffusion cells and rat abdominal skin were employed. The secondary structure changes of skin stratum corneum (SC) and drug thermodynamic activities were investigated to understand their mechanisms of action using Fourier transform infrared (FTIR) spectroscopy and saturation solubility studies, respectively. It was found that Z. bungeanum oil showed lower toxicities in both HaCaT cells and CCC-ESF-1 cells compared with three terpene compounds used alone. The enhancement permeation capacities by all tested agents were in the following increasing order: terpinen-4-ol≈1,8-cineole
PMCID: PMC4228507  PMID: 25367787
Zanthoxylum bungeanum Maxim.; Essential oil; Limonene; Fourier transform infrared (FTIR) spectroscopy; Penetration enhancer; HaCaT
Ethnicity & disease  2013;23(3):310-315.
This research examines the differences in estimated odds of developing diabetes mellitus for white, black, and Mexican-Americans age 51 and over for a period of 11 years.
Design, Setting, and Participants
Longitudinal data came from 14,783 respondents of the Health and Retirement Study (1995–2006) who report being diabetes-free at the first time period. Discrete-time survival models were used to analyze ethnic variations in the probability of developing diabetes.
Main Outcome Measure
Estimated odds of developing diabetes mellitus.
The odds of newly diagnosed diabetes increased between 1995 and 2006, with 11% cumulative incidence for all study participants. The probability of incident diabetes among black Americans was 0.01 during the period of 1995/96–1998, which increased to 0.03 during 1998–2000 and remained at 0.03 throughout subsequent periods, with cumulative incidence over the 11 years at 12%. In contrast, for Mexican-Americans the probability more than doubled from 0.02 in 1995/96–1998 to 0.05 in 2004–2006, with cumulative incidence at 19%. White Americans had 11% cumulative incidence during the 11 year period.
Relative to white Americans, Mexican-Americans had significantly elevated odds of developing diabetes throughout the 11-year period of observation even after controlling for differences in demographic, socioeconomic, and time-varying health characteristics.
PMCID: PMC4106363  PMID: 23914416
Ethnic differences; diabetes mellitus incidence; discrete-time survival analysis
Ethnicity & disease  2012;22(2):175-180.
This research examines the differences in estimated risk of developing hypertension in whites, blacks, and Mexican-Americans age 50 and over for a period of 11 years.
Design, Setting, and Participants
Data came from 9,259 respondents who reported being hypertension-free at the baseline in the Health and Retirement Study with up to five time intervals (1998-2006). Discrete-time survival models were used to analyze ethnic variations in the probability of developing hypertension.
Main Outcome Measure
Estimated odds of developing hypertension.
The risk of newly diagnosed hypertension increased between 1995 and 2006 for HRS participants over age 50 years. After adjusting for demographic and health status, the probability of incident hypertension among black Americans was 0.10 during the period of 1995/96-1998, which increased steadily to 0.17 in 2004-2006, and cumulative incidence over the 11-year period at 51%. In contrast, among white Americans the risk was 0.07 during 1995/96-1998 and 0.13 in 2004-2006, with cumulative incidence at 43%. For Mexican-Americans, the probability also increased from 0.08 during 1995/96-1998 to 0.14 during 2004-2006, and cumulative incidence at 42%.
Relative to white and Mexican-Americans, black Americans had an elevated risk of incident hypertension throughout the 11-year period of observation. These variations persisted even when differences in health behaviors, socioeconomic status, demographic, and time-varying health characteristics are accounted for.
PMCID: PMC4084710  PMID: 22764639
Ethnic differences; hypertension incidence; discrete-time survival analysis
PLoS ONE  2014;9(7):e100416.
Natural products present in low quantity in herb medicines constitute an important source of chemical diversity. However, the isolation of sufficient amounts of these low abundant constituents for structural modification has been a challenge for several decades and subsequently halts research on the utilization of this important source of chemical entities for drug discovery and development. And, pro-angiogenic therapies are being explored as options to treat cardio-cerebral vascular diseases and wound healing recently. The present study investigates the pro-angiogenic potential of tanshinone derivatives produced by one-pot synthesis using zebrafish model.
Methodology/Principal Findings
In order to address the difficulty of chemical modification of low abundant constituents in herb medicines, a novel one-pot combinatorial modification was used to diversify a partially purified tanshinone mixture from Salvia miltiorrhiza. This led to the isolation of ten new imidazole-tanshinones (Compounds 1–10) and one oxazole-tanshinone (Compound 11), the structures of which were characterized by spectroscopic methods in combination with single-crystal X-ray crystallographic analysis. The angiogenesis activities of the new tanshinone derivatives were determined in an experimental model of chemical-induced blood vessels damage in zebrafish. Of all the tested new derivatives, compound 10 exhibited the most potent vascular protective and restorative activity with an EC50 value of 0.026 µM. Moreover, the mechanism underlying the pro-angiogenesis effect of 10 probably involved the VEGF/FGF-Src-MAPK and PI3K-P38 signalling pathways by gene expression analysis and a blocking assay with pathways-specific kinase inhibitors.
Taken together, our study demonstrated the more distinctive pro-angiogenic properties of 10 than other tanshinones and revealed 10 has potential for development as a pro-angiogenic agent for diseases associated with insufficient angiogenesis. Our results highlighted the great potential of adopting a newly modified one-pot approach to enhance the chemical diversity and biological activities of constituents from natural products regardless of their abundances.
PMCID: PMC4081027  PMID: 24992590
Introduction and hypothesis
This study describes pelvic organ support after childbirth.
This ancillary analysis of the Childbirth and Pelvic Symptoms Imaging Study compares pelvic organ prolapse quantification 6–12 months after childbirth among three cohorts of primiparous women: vaginal delivery with sphincter tear (n=106), vaginal delivery without sphincter tear (n=108), and cesarean without labor (n=39).
Of participants, 31.2% had stage II support. Prolapse to or beyond the hymen was present in 14% after vaginal delivery with sphincter tear (95% confidence interval 8%, 22%), 15% (9%, 24%) after vaginal delivery without sphincter tear, and 5% (1%, 17%) after cesarean without labor (p=0.23). A study of 132 women per group would be required for 80% power to test differences between 5% and 15%.
While these data provide insufficient power to dismiss a difference in pelvic organ support between modes of delivery, they add to our understanding of support following childbirth.
PMCID: PMC4064938  PMID: 19777148
Pelvic organ prolapse quantification; Uterine prolapse; Childbirth; Cesarean; Obstetrical anal sphincter laceration
The long-term ingestion of alcohol diminishes hypothalamic–pituitary–adrenal (HPA) axis reactivity in alcohol-dependent men, potentially altering future relapse risk. Although sex differences in HPA axis functioning are apparent in healthy controls, disruptions in this system have received little attention in alcohol-dependent women. In this study, we assessed the basal secretory profile of adrenocorticotropic hormone (ACTH) and cortisol, adrenocortical sensitivity in both the presence and absence of endogenous corticotropic pituitary activation, and feedback pituitary glucocorticoid sensitivity to dexamethasone.
Seven women 4- to 8-week abstinent alcohol-only dependent subjects and 10 age-matched female healthy controls were studied. All subjects were between 30 and 50 years old, not taking oral contraceptives, and were studied during the early follicular phase of their menstrual cycle. Circulating concentrations of ACTH and cortisol were measured in blood samples collected at frequent intervals from 2000 to 0800 hour. A submaximal dose of cosyntropin (0.01 μg/kg), a synthetic ACTH (1–24), was administered at 0800 hour to assess adrenocortical sensitivity. In a separate session, low-dose cosyntropin was also administered following high-dose dexamethasone (8 mg intravenous) to assess adrenocortical sensitivity in the relative absence of endogenous ACTH. In addition, the ACTH response to dexamethasone was measured to determine the pituitary glucocorticoid negative feedback. Sessions were 5 days apart, and blood draws were obtained every 5 to 10 minutes.
Mean concentrations and pulsatile characteristics of ACTH and cortisol over 12 hours were not statistically different between the 2 groups. Healthy controls had a somewhat higher (p < 0.08) net peak, but not net integrated, cortisol response to cosyntropin relative to the alcohol-dependent women. There were no significant group differences in either the ACTH or cortisol response to dexamethasone nor in the net cortisol response to cosyntropin following dexamethasone.
Significant differences in pituitary–adrenal function were not apparent between alcohol-dependent women and matched controls. Despite the small n, it appears that alcohol-dependent women do not show the same disruptions in HPA activity as alcohol-dependent men. These findings may have relevance for gender-specific treatment effectiveness.
PMCID: PMC4038906  PMID: 20331575
Adrenal Cortex; Alcoholism; Cosyntropin; Dexamethasone; Pituitary-Adrenal System; Gender; Female
Neurogenic bladder is a common complication of spinal cord injury and results in urinary bladder dysfunction through lost control of micturition, or urination. Although several treatment options exist, the efficacies of many of these treatments are unknown. In particular, electroacupuncture and bladder training have had some success as individual treatments. The aim of this study was to explore effects of electroacupuncture combined with bladder training on bladder function of patients with neurogenic bladder after spinal cord injury (SCI) above the sacral segment. Forty-two patients with neurogenic bladder after SCI were evenly divided into two groups (n=21) and given only bladder function training (control group) or electroacupuncture combined with bladder function training (treatment group). Urodynamic changes, IPSS score, and therapeutic efficacy were compared between groups pre- and post-treatment. After either treatment, patients had higher bladder volume and bladder compliance, but lower residual urine volume, bladder pressure, rectal pressure, and detrusor pressure, compared to pre-treatment (P<0.05). Compared to controls, treatment group patients had significantly increased bladder volume and bladder compliance, but significantly decreased residual urine volume, bladder pressure, rectal pressure, and detrusor pressure (P<0.05). Treatment group patients had lower IPSS scores post-treatment (P<0.05) and better therapeutic efficacy (P<0.05) than control group patients. Altogether, our results suggest that electroacupuncture combined with bladder function training can clinically improve bladder function of patients with neurogenic bladder after SCI above the sacral segment.
PMCID: PMC4073754  PMID: 24995093
Bladder function; spinal cord injury; neurogenic bladder; electroacupuncture
PLoS ONE  2014;9(3):e90664.
This study was conducted to generate knowledge useful for developing public health interventions for more effective tuberculosis control in Arkansas.
The study population included 429 culture-confirmed reported cases (January 1, 2004–December 31, 2010). Mycobacterium tuberculosis genotyping data were used to identify cases likely due to recent transmission (clustered) versus reactivation (non-clustered). Poisson regression models estimated average decline rate in incidence over time and assessed the significance of differences between subpopulations. A multinomial logistic model examined differences between clustered and non-clustered incidence.
A significant average annual percent decline was found for the overall incidence of culture-confirmed (9%; 95% CI: 5.5%, 16.9%), clustered (6%; 95% CI: 0.5%, 11.6%), and non-clustered tuberculosis cases (12%; 95% CI: 7.6%, 15.9%). However, declines varied among demographic groups. Significant declines in clustered incidence were only observed in males, non-Hispanic blacks, 65 years and older, and the rural population.
These findings suggest that the Arkansas tuberculosis control program must target both traditional and non-traditional risk groups for successful tuberculosis elimination. The present study also demonstrates that a thorough analysis of TB trends in different population subgroups of a given geographic region or state can lead to the identification of non-traditional risk factors for TB transmission. Similar studies in other low incidence populations would provide beneficial data for how to control and eventually eliminate TB in the U.S.
PMCID: PMC3949677  PMID: 24618839
The aim of this present study is to investigate the effect of Zanthoxylum bungeanum oil (essential oil from Z. bungeanum Maxim.) on cytotoxicity and the transdermal permeation of 5-fluorouracil and indomethacin. The cytotoxicity of Z. bungeanum oil on dermal fibroblasts and epidermal keratinocytes was studied using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The rat skin was employed to determine the percutaneous penetration enhancement effect of Z. bungeanum oil on hydrophilic and lipophilic model drugs, i.e., 5-fluorouracil and indomethacin. The secondary structure changes of the rat stratum corneum (SC) were determined using attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), and saturated solubilities and SC/vehicle partition coefficients of two model drugs with and without Z. bungeanum oil were also measured to understand its related mechanisms of action. It was found that the half maximal inhibitory concentration (IC50) values of Z. bungeanum oil were significantly lower in HaCaT and CCC-ESF-1 cell lines compared to the well-established and standard penetration enhancer Azone. The Z. bungeanum oil at various concentrations effectively facilitated the percutaneous penetration of two model drugs across the rat skin. In addition, the mechanisms of permeation enhancement by Z. bungeanum oil could be explained with saturated solubility, SC/vehicle partition coefficient, and secondary structure changes of SC.
PMCID: PMC3924391  PMID: 24510708
Zanthoxylum bungeanum Maxim.; Essential oil; Transdermal delivery; Penetration enhancer; HaCaT; Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR)
Hepatology (Baltimore, Md.)  2007;46(5):10.1002/hep.21923.
Malnutrition is a significant clinical problem in infants with biliary atresia. The natural history of poor growth and its potential association with early transplantation or death in children with biliary atresia was determined. Serial weight- and length-for-age z-scores were computed as part of a retrospective study of 100 infants who underwent hepatoportoenterostomy (HPE) for biliary atresia at 9 U.S. pediatric centers between 1997 and 2000. Poor outcome was defined as transplantation or death by 24 months of age (n = 46) and good outcome was defined as survival with native liver at 24 months of age with total serum bilirubin less than 6 mg/dL (n = 54). Growth velocity was significantly slower in the poor outcome group compared to the good outcome group (P < 0.001 for both weight and length). Mean weight z-scores were significantly lower by 6 months after HPE in the poor outcome group (−2.1 ± 1.4) compared to the good outcome group (−1.2 ± 1.4) (P < 0.001). In a subgroup with total bilirubin between 2 and 6 mg/dL at 3 months after HPE (n = 28), the weight z-scores at 3 months after HPE were significantly lower in the poor outcome group (−2.0 ± 1.2) compared to the good outcome group (−1.0 ± 1.2) (P = 0.04) despite similar bilirubin concentrations.
Growth failure after HPE was associated with transplantation or death by 24 months of age. The combination of intermediate bilirubin concentrations and poor mean weight z-scores 3 months after HPE was also associated with poor clinical outcome.
PMCID: PMC3881187  PMID: 17929308
To develop and test a unique, new pelvic floor surgery complication scale and compare it to an existing validated measure.
Study Design
Surgeons from two clinical trials networks rated complications based on perceived patient bother, severity, and duration of disability to develop a pelvic floor complication scale (PFCS). PFCS scores were calculated for subjects in two multicenter pelvic floor surgical trials. The PFCS and modified Clavien-Dindo scores were evaluated for associations with length of hospitalization(LOH), satisfaction, and quality-of-life (QoL) measures {Health Utilities Index(HUI), Short Form-36(SF-36), Urogenital Distress Inventory(UDI) and Incontinence Impact Questionnaire(IIQ)}.
We calculated PFCS scores for 977 subjects. Higher PFCS and Clavien-Dindo scores were similarly associated with longer LOH (p<0.01), lower satisfaction (p<0.01); lower HUI (p=0.02), lower SF-36 (p=0.02), higher UDI (p<0.01) and IIQ (p<0.01) scores at 3 months. No associations were present at 1 year.
The PFCS compares favorably to the validated modified Clavien-Dindo instrument.
PMCID: PMC3568397  PMID: 23131463
Complications; Reconstructive Pelvic Surgery; Urogynecology; Surgical Outcomes; Quality-of-life measures; Clavien-Dindo
Molecular Vision  2014;20:1557-1568.
Exendin-4 (E4), a long-acting agonist of the hormone glucagon-like peptide 1 receptor (GLP-1R), is administered to treat type II diabetes in the clinical setting and also shows a neuroprotective effect. Our previous studies demonstrated its protective effect in early experimental diabetic retinopathy (DR), but the molecular and cellular mechanisms are largely unknown. This study aimed to investigate the protective mechanism of a GLP-1R agonist E4 against early DR in Goto-Kakizaki (GK) rats.
Diabetic GK rats and control animals were randomly assigned to receive E4 or vehicle by intravitreal injection. The retinal function and retinal cell counts were evaluated using an electroretinogram and light microscopy. The expressions of retinal GLP-1R, mitochondria-dependent apoptosis-associated genes, reactive gliosis markers, and endoplasmic reticulum stress-related pathway genes were studied by western blotting and immunohistochemistry in vivo and in vitro.
E4 significantly prevented the reduction of the b-wave and oscillatory potential amplitudes and retinal cell loss and maintained the Bcl-2/Bax and Bcl-xL/Bax ratio balances in GK rats. It also downregulated the expression of glial fibrillary acidic protein and reduced retinal reactive gliosis. Similar results were found in primary rat Müller cells under high glucose culture in vitro.
E4 may protect retinal cells from diabetic attacks by activating GLP-1R, decreasing retinal cell apoptosis, and reducing retinal reactive gliosis. Thus, E4 treatment may be a novel approach for early DR.
PMCID: PMC4225140  PMID: 25489228
Chinese Medicine  2013;8:19.
This study aims to isolate the α-glucosidase inhibitory compounds from mulberry leaves (Morus atropurpurea Roxb., Moraceae) and to develop an analytical method for quantification of the compounds.
Four flavonoids, rutin (1), isoquercetin (2), kaempferol-3-O-rutinoside (3) and astragalin (4), were isolated by column chromatography from mulberry leaf water extracts (MWE). The α-glucosidase inhibitory activities of MWE and the four isolated compounds were evaluated by a microplate-based in vitro assay. The content of the isolated flavonoids in M. atropurpurea leaves purchased from different local herbal stores or collected in different locations was determined by high performance liquid chromatography.
The four flavonoids (1–4) showed α-glucosidase inhibitory activities, with rutin (1) and astragalin (4) showing high α-glucosidase inhibitory activities (IC50 values of 13.19 ± 1.10 and 15.82 ± 1.11 μM, respectively). The total contents of the four flavonoids were different among eight samples examined, ranging from 4.34 mg/g to 0.53 mg/g.
The four flavonoids in M. atropurpurea leaves could inhibit α-glucosidase activity.
PMCID: PMC4016240  PMID: 24125526

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