G Protein Coupled Receptors (GPCRs) are critically regulated by β-arrestins (βarrs), which not only desensitize G protein signaling but also initiate a G protein independent wave of signaling1-5. A recent surge of structural data on a number of GPCRs, including the β2 adrenergic receptor (β2AR)-G protein complex, has provided novel insights into the structural basis of receptor activation6-11. Lacking however has been complementary information on recruitment of βarrs to activated GPCRs primarily due to challenges in obtaining stable receptor-βarr complexes for structural studies. Here, we devised a strategy for forming and purifying a functional β2AR-βarr1 complex that allowed us to visualize its architecture by single particle negative stain electron microscopy (EM) and to characterize the interactions between β2AR and βarr1 using hydrogen-deuterium exchange mass spectrometry (HDXMS) and chemical cross-linking. EM 2D averages and 3D reconstructions reveal bimodal binding of βarr1 to the β2AR, involving two separate sets of interactions, one with the phosphorylated carboxy-terminus of the receptor and the other with its seven-transmembrane core. Areas of reduced HDX together with identification of cross-linked residues suggest engagement of the finger loop of βarr1 with the seven-transmembrane core of the receptor. In contrast, focal areas of increased HDX indicate regions of increased dynamics in both N and C domains of βarr1 when coupled to the β2AR. A molecular model of the β2AR-βarr signaling complex was made by docking activated βarr1 and β2AR crystal structures into the EM map densities with constraints provided by HDXMS and cross-linking, allowing us to obtain valuable insights into the overall architecture of a receptor-arrestin complex. The dynamic and structural information presented herein provides a framework for better understanding the basis of GPCR regulation by arrestins.
A lipid emulsion composed of soybean oil (long-chain triglycerides, LCT), medium-chain triglycerides (MCT) and n-3 poly-unsaturated fatty acids (PUFAs) was evaluated for immune-modulation efficacy, safety, and tolerance in patients undergoing major surgery for gastric and colorectal cancer.
In a prospective, randomized, double-blind study, 99 patients with gastric and colorectal cancer receiving elective surgery were recruited and randomly assigned to either the study group, receiving the n-3 PUFAs enriched intravenous fat emulsion (IVFE), or the control group, receiving a lipid emulsion comprised of soybean oil and MCTs (0.8 – 1.5 g · kg-1 · day-1) as part of total parenteral nutrition (TPN) regimen from surgery (day -1) up to post-operative day 7. Safety and efficacy parameters were assessed on day -1 and post-operative visits on day 1, 3, and 7. Adverse events were documented daily and compared between the groups.
Pro-inflammatory markers, laboratory parameters, and adverse events did not differ prominently between the 2 groups, with the exception of net changes (day 7 minus day -1) of free fatty acids (FFAs), triglyceride, and high-density lipoprotein (HDL). Net decrease of FFAs was remarkably higher in the study group, while the net increase of triglyceride and decrease of HDL was significantly lower.
The n-3 PUFA-enriched IVFE showed improvements in lipid metabolism. In respect of efficacy, safety and tolerance both IVFE were comparable. In patients with severe stress, there is an inflammation-attenuating effect of n-3 PUFAs. Further, adequately powered clinical trials will be necessary to address this question in postsurgical GI cancer patients.
Lipid emulsion; n-3 fatty acids; LCT/MCT; Fish oils; Gastric cancer; Colorectal cancer
In the People’s Republic of China, both western medicine (WM) and traditional Chinese medicine (TCM) are the main treatment and rehabilitation options for cancer patients. This study aimed to explore cancer survivors’ perspectives and experience of treatment and rehabilitation, in order to promote patient-centered activities of treatment and rehabilitation.
Using a qualitative research approach, 68 cancer survivors were recruited from eight community cancer rehabilitation organizations in Shanghai, People’s Republic of China. Eight focus group interviews were conducted. All these interviews were transcribed verbatim, and the data were analyzed by theme analysis.
WM was the main choice in treatment phase though study participants noted more side effects. TCM was primarily used in the recovery phase. The lack of communication between doctors and cancer patients appears to affect treatment adherence and impair the doctor–patient relationship. WM was expensive for diagnostic procedures and treatment, while the cumulative costs of frequent use of TCM in the long rehabilitation period were also high. Both treatment options created significant perceived economic burden on patients. Conflicting information about dietary supplements tended to make cancer survivors confused.
Improving the communication between doctors and cancer patients helps to ameliorate cancer patient adherence and the effect of treatments. It is essential to educate cancer patients about the effect and cost of both WM and traditional TCM. Meanwhile, marketing management and guidance to consumers regarding use of dietary supplements in the cancer rehabilitation field are also necessary.
preference; adherence; cancer survivor education; focus group interview
AIM: To assess the diagnostic value of serum interleukin-8 (IL-8) in the detection of colorectal cancer (CRC).
METHODS: An original study was conducted to explore the potential value of IL-8 in CRC diagnosis. Receiver operating characteristic (ROC) analysis was performed and the area under the curve (AUC) value was calculated. PUBMED and EMBASE were searched (to October, 2013), supplemented with manual screening for relevant publications. Meta-analysis methods were applied to pool sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratios and to construct a summary receiver-operating characteristic (sROC) curve. Heterogeneity across studies was checked by the I2 test and Deek’s funnel plot method was applied to test publication bias.
RESULTS: In our original study, serum IL-8 yielded an AUC of 0.742 [95%CI: 0.635-0.849]. The sensitivity and specificity were 85.42% and 54.05%, respectively, at a cut-off value of 5.39. In this meta-analysis, we included five studies with 668 CRC patients and 374 controls and one study in our own center with 48 CRC patients and 37 controls. The pooled sensitivity and specificity of IL-8 were 0.69 (95%CI: 0.42-0.87) and 0.85 (95%CI: 0.68-0.94) for CRC detection. Besides, the area under the sROC curve was 0.86 (95%CI: 0.82-0.88). Subgroup analysis suggested that there was no heterogeneity in the Asian subgroup but some in the European subgroup. In addition, no publication bias was found according to the Deek’s funnel plot asymmetry test.
CONCLUSION: Serum IL-8 is a promising biomarker for CRC detection and may become a clinically useful tool to identify high-risk patients.
Interleukin-8; Colorectal cancer; Diagnostic value; Case-control study; Meta-analysis
China has become the world’s largest producer and consumer of tobacco and lung cancer is China’s leading cause of cancer deaths. The large majority of Chinese smokers are men. Tobacco consumption is of particular concern among China’s internal floating (or migrant) population, which has become a permanent feature of Chinese society, because this population is very large (over 100 million persons) and it has a high prevalence of smoking. Considering additionally that like the general population of China, the smoking prevalence rate of women from this group is quite low, we therefore aimed to explore smoking-related knowledge, attitudes and behaviours among male smokers in the floating population to help inform the development of effective smoking cessation interventions in this important target group in China.
We interviewed 39 floating population male smokers in six focus groups and performed a qualitative content analysis of the interviews.
Most participants knew that smoking is risky to health but they knew little about why. Habit and social participation were key drivers of smoking. Smoking was regarded as a core component of their identity by the urban residents. Some participants had tried to stop smoking but none reported having ever been educated about smoking.
Smoking cessation interventions for China’s male floating population would need to incorporate comprehensive education and information about why smoking is dangerous and the benefits of stopping.
Floating population; Smoking; China; Qualitative study
The aim of the present study was to investigate the association between O6-methylguanine-DNA methyltransferase (MGMT) gene expression levels, and DNA methylation status and histone modifications in laryngeal squamous cell carcinoma (LSCC). Chromatin immunoprecipitation, methylation-specific polymerase chain reaction (PCR), and reverse transcription-quantitative PCR were performed to analyze histone modifications, DNA methylation status and mRNA expression levels in the promoter region of the MGMT gene in laryngeal carcinoma HEp-2 cells, as well as in 50 paired healthy and LSCC tissue samples. The present study demonstrated that treatment of HEp-2 cells with 5-aza-2′-deoxycytidine (Aza), a DNA methyltransferase inhibitor, significantly upregulated MGMT mRNA expression levels, reduced MGMT DNA methylation, reduced MGMT histone H3 lysine 9 (H3K9) di-methylation, and increased MGMT histone H3 lysine 4 di-methylation without a significant change in H3K9 acetylation. Trichostatin A (TSA), a histone deacetylase inhibitor, marginally upregulated MGMT mRNA expression levels without affecting the DNA methylation status, or H3K9 or H3K4 di-methylation, however, TSA treatment caused a significant increase in H3K9 acetylation. Furthermore, Aza and TSA combination treatment produced a synergistic effect. In the LSCC samples, the rate of DNA methylation in the MGMT gene was 54%, compared with 24% in the healthy control group (P<0.05). Therefore, data from the present study indicates that MGMT may serve as a novel therapeutic target in the treatment of LSCC.
laryngeal carcinoma; O6-methylguanine-DNA methyltransferase gene; DNA methylation; histone modification; 5-aza-2′-deoxycytidine; trichostatin A
Osteoarthritis (OA) is the most common form of arthritis and has become an increasingly important public-health problem. However, the pathogenesis of OA is still unclear. In recent years, its correlation with mtDNA haplogroups attracts much attention. We aimed to perform a meta-analysis to investigate the association between mtDNA haplogroups and OA.
Published English or Chinese literature from PubMed, Web of Science, SDOS, and CNKI was retrieved up until April 15, 2014. Case-control or cohort studies that detected the frequency of mtDNA haplogroups in OA patients and controls were included. The quality of the included studies was evaluated by the Newcastle-Ottawa Scale (NOS) assessment. A meta-analysis was conducted to calculate pooled odds ratio (OR) with 95% confidence interval (CI) through the random or fixed effect model, which was selected based on the between-study heterogeneity assessed by Q test and I2 test. Subgroup analysis was performed to explore the origin of heterogeneity.
A total of 6 case-control studies (10590 cases and 7161 controls) with an average NOS score of 6.9 were involved. For the analysis between mtDNA haplogroup J and OA, random model was selected due to high heterogeneity. No significant association was found initially (OR = 0.73, 95%CI: 0.52–1.03), however, once any study from UK population was removed the association emerged. Further subgroup analysis demonstrated that there was a significant association in Spain population (OR = 0.57, 95%CI: 0.46–0.71), but not in UK population. Also, subgroup analysis revealed that there was a significant correlation between cluster TJ and OA in Spain population (OR = 0.70, 95%CI: 0.58–0.84), although not in UK population. No significant correlation was found between haplogroup T/cluster HV/cluster KU and OA.
Our current meta-analysis suggests that mtDNA haplogroup J and cluster TJ correlate with the risk of OA in Spanish population, but the associations in other populations require further investigation.
The occurrence, bleeding, and treatment of internal mammary artery (IMA) injury after blunt chest trauma have not been well described in the literature. We reviewed articles published from July 1977 to February 2014 describing IMA injury after blunt chest trauma in 49 patients. There was a predominant incidence in males and on the left side. Blunt trauma to the IMA can cause anterior mediastinal hematoma, hemothorax, pseudoaneurysm, arteriovenous fistula, and extra-pleural hematoma. Of the 49 patients studied, 20 underwent embolization, 22 underwent surgical operation, 4 were managed by clinical observation, and 3 had undescribed treatment. Different parts and extents of IMA injury, adjacent vein injury, as well as the integrity of the pleura determined differences in bleeding modality. Prompt diagnosis, complete hemostasis, aggressive resuscitation, and multidisciplinary teams are recommended for patients with IMA injury.
Internal mammary artery injury; Blunt chest trauma; Bleeding; Treatment
Due to increased awareness and interest in the biomedical implant field as a result of an aging population, research in the field of implantable devices has grown rapidly in the last few decades. Among the biomedical implants, metallic implant materials have been widely used to replace disordered bony tissues in orthopedic and orthodontic surgeries. The clinical success of implants is closely related to their early osseointegration (ie, the direct structural and functional connection between living bone and the surface of a load-bearing artificial implant), which relies heavily on the surface condition of the implant. Electrochemical techniques for modifying biomedical implants are relatively simple, cost-effective, and appropriate for implants with complex shapes. Recently, metal oxide nanotubular arrays via electrochemical anodization have become an attractive technique to build up on metallic implants to enhance the biocompatibility and bioactivity. This article will thoroughly review the relevance of electrochemical anodization techniques for the modification of metallic implant surfaces in nanoscale, and cover the electrochemical anodization techniques used in the development of the types of nanotubular/nanoporous modification achievable via electrochemical approaches, which hold tremendous potential for bio-implant applications. In vitro and in vivo studies using metallic oxide nanotubes are also presented, revealing the potential of nanotubes in biomedical applications. Finally, an outlook of future growth of research in metallic oxide nanotubular arrays is provided. This article will therefore provide researchers with an in-depth understanding of electrochemical anodization modification and provide guidance regarding the design and tuning of new materials to achieve a desired performance and reliable biocompatibility.
nanotubular arrays; anodization; implant; bioactivity; in vitro; in vivo
The blood-brain barrier (BBB) is critical to the health of the central nervous system (CNS). The possibility that 5-hydroxytryptamine (5-HT) participates in the alteration of the BBB has been previously demonstrated. Tryptophan hydroxylase 2 (TPH2) is a unique genetic enzyme isoform that catalyzes the rate-limiting step in the biosynthesis of 5-HT in the CNS; however, its role in the permeability changes of the BBB remains unclear. In the present study, TPH2-knockout mice were utilized in the assessment of BBB disruption, as measured by the Evans Blue (EB) extravasation or fluorescein isothiocyanate-albumin leakage assay in the brain. EB was not found to be retained in the brain in the TPH2-knockout mice or the wild-type controls. The results of the study demonstrate that TPH2 knockout has no effect on BBB permeability, indicating that TPH2 and the 5-HT system in the CNS are not sufficient to influence the BBB leakage.
blood-brain barrier; tryptophan hydroxylase 2; 5-hydroxytryptamine
The dopamine system, which is involved in drug dependence, can be damaged by opioid abuse. However, current clinical medicines cannot reverse these damages in the brain, which are believed to be a key reason for the high relapse rate after abstinence treatment. This study aimed to investigate the effects of An-jun-ning (AJN), a commercial traditional Chinese medicine formula used for the treatment of opioid addiction, on the dopamine system in morphine-dependent rats and to explore the possible mechanism underlying its therapeutic effects.
The morphine dependence model was obtained through injections of morphine at increasing doses for 8 days. The AJN pre-treatment group was administered AJN 30 min before each morphine administration, and the AJN post-treatment groups were treated with AJN for 10 days after withdrawal. Spontaneous withdrawal symptoms (wet dog shakes, and episodes of writhing) were observed after withdrawal. Autoradiography study and/or immunohistochemical staining were used to examine the levels of dopamine transporter (DAT), dopamine D2 receptor (D2R) and tyrosine hydroxylase (TH).
(1) Pre-treatment with AJN attenuates wet dog shakes and episodes of writhing to approximately 50% or less of those observed in the morphine group (p < 0.01). (2) AJN post-treatment dose-dependently reduced the number of wet dog shakes (p < 0.01), and the episodes of writhing (p < 0.01). (3) Pre-treatment with AJN effectively interdicted the morphine-induced decreases in the levels of DAT, D2R, and TH in the striatum (p < 0.01) such that they remained at nearly normal levels. (4) Post-treatment with AJN restored DAT and D2R to the normal levels (p < 0.01) and the level of TH to 87% of normal in the striatum.
AJN can effectively alleviate opioid withdrawal symptoms and preserve or restore the DAT, D2R, and TH levels in the striatum. The mechanism underlying the effect of AJN on withdrawal symptoms may be related to the modulation of the dopamine system by AJN. These results suggest that AJN may help to prevent relapse in opioid dependence treatment.
Morphine dependence; Dopamine transporter; Dopamine D2receptor; Tyrosine hydroxylase; An-jun-ning
In the title compound, C17H21ClNO4P·C3H7NO, the dihedral angle formed by the aromatic rings is 83.98 (7)°. In the crystal, O—H⋯O, N—H⋯O and C—H⋯O hydrogen bonds link the molecules into double layers parallel to (011).
crystal structure; hydrogen bond; phosphonate
To our knowledge, the mechanism underlying the high transfection efficiency of alkylated low-molecular-weight polyethylenimine (PEI) is not yet well understood. In this work, we grafted branched PEI (molecular weight of 1,800 Da; bPEI1800) with lauryl chains (C12), and found that bPEI1800-C12 was structurally similar to gemini surfactant and could similarly assemble into micelle-like particles. Stability, cellular uptake, and lysosome escape ability of bPEI1800-C12/DNA polyplexes were all greatly enhanced after C12 grafting. bPEI1800-C12/DNA polyplexes exhibited significantly higher transfection efficiency than Lipofectamine™ 2000 in the presence of serum. Bioluminescence imaging showed that systemic injection of bPEI1800-C12/DNA polyplexes resulted in intensive luciferase expression in vivo and bioluminescence signals that could be detected even in the head. Altogether, the high transfection efficacy of bPEI1800-C12 was because bPEI1800-C12, being an analog of gemini surfactant, facilitated lysosome escape and induced the coil–globule transition of DNA to assemble into a highly organized micelle-like structure that showed high stability.
self-organization; alkylation; luciferase; bioluminescence imaging
To study the associations between lysyl oxidase-like 1 (LOXL1) polymorphisms and primary open angle glaucoma (POAG) remain inconsistent. In this study, we have performed a meta-analysis to investigate the association of LOXL1 polymorphisms with POAG risk.
Published literature from PubMed and other databases were retrieved. All studies evaluating the association between LOXL1 polymorphisms (rs2165241, rs1048661, rs3825942) and POAG risk were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model.
Twelve studies were identified as eligible articles, with thirteen (2098 cases and 16 473 controls), thirteen (1795 cases and 2916 controls) and sixteen population cohorts (2456 cases and 2846 controls) for the association of rs2165241, rs1048661 and rs3825942 with POAG risk respectively. Overall analyses showed no association between each LOXL1 polymorphism and POAG risk, and the negative associations were remained when the subjects were stratified as Caucasian and Asian. The heterozygote of rs2165241 was associated with reduced POAG risk in hospital-based populations (TC vs CC: OR, 0.79, 95%CI: 0.63-0.99), and rs1048661 was associated with increased POAG risk in hospital-based populations in a dominant model (TT vs CC+CT: OR, 1.23, 95%CI: 1.01-1.50); however, these associations were not found in population-based subjects.
This meta-analysis suggests that LOXL1 polymorphisms are not associated with POAG risk. Given the limited sample size, the associations of LOXL1 polymorphisms with POAG risk in hospital-based populations await further investigation.
glaucoma; gene polymorphism; meta-analysis; lysyl oxidase-like 1
AIM: To evaluate the value of positron emission tomography (PET)/computerized tomography (CT) in surveillance of colorectal cancer (CRC) patients with different carcinoembryonic antigen (CEA) concentrations.
METHODS: One hundred and six postoperative CRC patients who had suspected recurrence or metastasis and received fluorodeoxyglucose (FDG) PET/CT within one week were included in this study. The final diagnosis was confirmed by histological examination or clinical follow-up over at least six months.
RESULTS: The sensitivity, specificity, and accuracy of FDG PET/CT were 95.2%, 82.6%, and 92.5%, and 94.8%, 81.4% and 92.8%, respectively, in the case- and lesion-based analyses. The sensitivity and accuracy of FDG PET/CT significantly differed from CT in both analyses (χ2 = 8.186, P = 0.004; χ2 =6.201, P = 0.013; χ2 =13.445, P = 0.000; χ2 =11.194, P = 0.001). In the lesion-based analysis, the sensitivity, specificity, and accuracy of FDG PET/CT in the abnormal CEA group were 97.8%, 82.6%, and 95.6%, compared with 81.3%, 80%, and 80.6% for patients with normal CEA levels. In case-based analysis, the sensitivity, specificity, and accuracy of FDG PET/CT were 97.2%, 77.8%, and 95% in abnormal CEA group. Only in lesion-based analysis, the sensitivity and accuracy of FDG PET/CT in the abnormal CEA group were significantly superior to those in the normal CEA group (χ2 =6.432, P = 0.011; χ2 =7.837, P = 0.005). FDG PET/CT changed the management in 45.8% of patients with positive scans.
CONCLUSION: FDG PET/CT showed superior diagnostic value and is an advisable option in surveillance of postoperative CRC patients with a vague diagnosis.
Colorectal cancer; Carcinoembryonic antigen; Fluorodeoxyglucose positron emission tomography/computed tomography; Recurrence; Metastasis
Abnormal lipids is one of the critical risk factors for myocardial infarction (MI), however the role of genetic variants in lipid metabolism-related genes on MI pathogenesis still requires further investigation. We herein genotyped three SNPs (LRP6 rs2302685, LDLRAP1 rs6687605, SOAT1 rs13306731) in lipid metabolism-related genes, aimed to shed light on the influence of these SNPs on individual susceptibility to MI.
Genotyping of the three SNPs (rs2302685, rs6687605 and rs13306731) was performed in 285 MI cases and 650 control subjects using polymerase chain reaction–ligation detection reaction (PCR–LDR) method. The association of these SNPs with MI and lipid profiles was performed with SPSS software.
Multivariate logistic regression analysis showed that C allele (OR = 1.62, P = 0.039) and the combined CT/CC genotype (OR = 1.67, P = 0.035) of LRP6 rs2302685 were associated with increased MI risk, while the other two SNPs had no significant effect. Further stratified analysis uncovered a more evident association with MI risk among younger subjects (≤60 years old). Fascinatingly, CT/CC genotype of rs2302685 conferred increased LDL-C levels compared to TT genotype (3.0 mmol/L vs 2.72 mmol/L) in younger subjects.
Our data provides the first evidence that LRP6 rs2302685 polymorphism is associated with an increased risk of MI in Chinese subjects, and the association is more evident among younger individuals, which probably due to the elevated LDL-C levels.
LRP6; Single nucleotide polymorphism; Myocardial infarction; Risk
CD146, a cell adhesion molecule, is found in normal and tumor tissues. The level of its expression has been found to directly correlate with tumor progression and metastatic potential. The objective of this study was to investigate the expression of CD146 in esophageal squamous cell carcinoma (ESCC) and its correlation with clinicopathological parameters. Tumor specimens were collected from 63 patients with ESCC who underwent complete resection. We analyzed the CD146 expression levels in ESCC by immunohistochemistry. The expression of CD146 was detected and it was observed to correlate with clinicopathological parameters. Sixty-three cases of normal squamous mucosa were included for comparison. CD146 expression was identified in 46.0% (29/63) of the ESCC samples, and no positive (weak to moderate or moderate to strong) expression was found in the normal squamous epithelium samples (χ2=27.248; P<0.0001). CD146 expression was associated with lymph node metastasis (χ2=5.117; P=0.024) and advanced clinical stage (χ2=4.661; P=0.031). CD146 expression was one of the significant predictors of survival (hazard ratio, 2.838; 95% confidence interval 1.102–7.305). The overexpression of the CD146 gene was one of the important phenotypes and characteristics in ESCC carcinomatous change. We found that CD146 expression was associated with lymph node metastasis and advanced clinical stage, and was an indicator of poor prognosis in ESCC patients. CD146 may prove to be an important tumor marker for the individualized treatment for ESCC.
CD146; esophageal squamous cell cancer; clinicopathological characteristics; immunohistochemistry
Sparganosis mansoni is a parasitic disease caused by the larva of Spirometra mansoni. It occurs worldwide, but only a few patients show pulmonary involvement. Here, we present a case of pulmonary sparganosis mansoni in a non-endemic region. A 32-year-old Chinese woman presented with intermittent bloody phlegm, peripheral blood eosinophilia, and migratory patch shadows in both lungs. She had been misdiagnosed with eosinophilic pneumonia. She had a history of eating raw frogs, and the sparganum mansoni antibody was positive in both her blood and bronchoalveolar lavage fluid. Several sparganum mansoni were found in a frog sample that the patient provided. Consequently, she was diagnosed with pulmonary sparganosis mansoni. After two oral courses of praziquantel were administered, her symptoms and radiological lesions improved significantly. To our knowledge, this is the first case of pulmonary sparganosis mansoni occuring in Shanghai. Oral praziquantel is effective for the treatment of sparganosis mansoni, although its course of therapy may need to be repeated.
Lung; sparganosis mansoni; diagnosis; treatment
To evaluation the doxorubicin (DOX)-loaded pH-sensitive polymeric micelle release from tumor blood vessels into tumor interstitium using an animal vessel visibility model, the so-called dorsal skin-fold window chamber model.
DOX-loaded pH-sensitive polyHis-b-PEG micelles and DOX-loaded pH-insensitive PLLA-b-PEG micelles were prepared. The uptake of the micelles by MDA-MB-231 breast cancer cells in vitro and in vivo was examined using flow cytometry. The pharmacokinetic parameters of the micelles were determined in SD rats after intravenous injection of a DOX dose (6 mg/kg). The release of the micelles from tumor vasculature and the antitumor efficacy were evaluated in MDA-MB-231 breast cancer xenografted in nude mice using a dorsal skin-fold window chamber.
The effective elimination half-life t1/2 of the pH-sensitive, pH-insensitive polymeric micelles and DOX-PBS in rats were 11.3 h, 9.4 h, and 2.1 h, respectively. Intravital microscopy in MDA-MB-231 breast cancer xenografted in nude mice showed that the pH-sensitive polymeric micelles rapidly extravasated from the tumor blood vessels, and DOX carried by the pH-sensitive micelles was preferentially released at the tumor site as compared to the pH-insensitive polymeric micelles. Furthermore, the pH-sensitive polymeric micelles exhibited significant greater efficacy in inhibition of tumor growth in the nude mice.
When DOX is loaded into pH-sensitive polymeric micelles, the acidity in tumor interstitium causes the destabilization of the micelles and triggers drug release, resulting in high local concentrations within the tumor, thus more effectively inhibiting the tumor growth in vivo.
anticancer drug; doxorubicin; nanoparticle; polymeric micelle; drug release; pharmacokinetics; pH; dorsal skin-fold window chamber model
Sarcoidosis is a chronic inflammatory disease with a systemic granulomatous disorder affecting multiple organs including the eye. Both CD4+ T cell and macrophage have been linked to the pathogenesis of the disease.
The expression of IL-17RC was measured using FACS,immunohistochemistry and real-time PCR. Serum level of IL-17 was detected using ELISA.
An elevated expression of IL-17RC on CD8+ T cells in peripheral blood was found in patients with ocular sarcoidosis as compared to healthy controls. Interestingly, we found a significant increase in the serum level of IL-17 in patients with ocular sarcoidosis as compared to healthy controls, which may be responsible for the induction of IL-17RC on CD8+ cells. In addition, IL-17RC appeared only in the retinal tissue of the patient with clinically active sarcoidosis.
Our results suggested a potential involvement of IL-17RC+CD8+ T cells in pathogenesis of ocular sarcoidosis.
Ocular sarcoidosis; IL-17RC; CD8
Hypertrophic scars are fibroproliferative disorders of excessive wound healing after skin injury. Vascular endothelial growth factor (VEGF)-induced angiogenesis plays a major role in fibrogenesis and hypertrophic scar formation. Over recent years, there has been a major interest in homeobox gene regulation of VEGF-VEGFR mediated angiogenesis in dermal tissue. In the current study, we investigated the role of homeobox genes in the epidermis, for their role in angiogenesis, with a focus on epidermal-mesenchymal interactions. As epidermal stem cells (ESCs) have a central role in epidermal homeostasis, we tested the hypothesis that these cells play a key role in the pathogenesis of hypertrophic scars through the HOXA9-VEGF/VEGFR signaling pathways. We found significant differences in the expression of homeobox A9 in hyperplastic scar tissue during different phases of development. These differences coincided with similar regulations in VEGF expression and with the distribution of ESCs. HOXA9 is expressed in cultured human ESCs in vitro. Antisense suppression of HOXA9 expression was found to suppress VEGF levels in ESCs. Together these findings indicate that homeobox A9 regulates the expression of VEGF in ESCs.
Epidermal stem cells (ESCs); homeobox genes; vascular endothelial growth factor (VEGF); angiogenesis
Background. Migration of T cells into the colon plays a major role in the pathogenesis in inflammatory bowel disease. This study investigated the effects of glutamine (Gln) supplementation on chemokine receptors and adhesion molecules expressed by T cells in mice with dextran sulfate sodium- (DSS-) induced colitis. Methods. C57BL/6 mice were fed either a standard diet or a Gln diet replacing 25% of the total nitrogen. After being fed the diets for 5 days, half of the mice from both groups were given 1.5% DSS in drinking water to induce colitis. Mice were killed after 5 days of DSS exposure. Results. DSS colitis resulted in higher expression levels of P-selectin glycoprotein ligand- (PSGL-) 1, leukocyte function-associated antigen- (LFA-) 1, and C-C chemokine receptor type 9 (CCR9) by T helper (Th) and cytotoxic T (Tc) cells, and mRNA levels of endothelial adhesion molecules in colons were upregulated. Gln supplementation decreased expressions of PSGL-1, LFA-1, and CCR9 by Th cells. Colonic gene expressions of endothelial adhesion molecules were also lower in Gln-colitis mice. Histological finding showed that colon infiltrating Th cells were less in the DSS group with Gln administration. Conclusions. Gln supplementation may ameliorate the inflammation of colitis possibly via suppression of T cell migration.
There is limited understanding of the effect of dietary components on the absorption of ginsenosides and their metabolites into the blood.
This study investigated the pharmacokinetics of the ginseng extract and its main constituent ginsenoside Rb1 in rats with or without pretreatment with a prebiotic fiber, NUTRIOSE, by liquid chromatography tandem mass spectrometry. When ginsenoside Rb1 was incubated with rat feces, its main metabolite was ginsenoside Rd.
When the intestinal microbiota of rat feces were cultured in vitro, their ginsenoside Rd-forming activities were significantly induced by NUTRIOSE. When ginsenoside Rb1 was orally administered to rats, the maximum plasma concentration (Cmax) and area under the plasma drug concentration–time curve (AUC) for the main metabolite, ginsenoside Rd, were 72.4 ± 31.6 ng/mL and 663.9 ± 285.3 μg·h/mL, respectively. When the ginseng extract (2,000 mg/kg) was orally administered, Cmax and AUC for ginsenoside Rd were 906.5 ± 330.2 ng/mL and 11,377.3 ± 4,470.2 μg·h/mL, respectively. When ginseng extract was orally administered to rats fed NUTRIOSE containing diets (2.5%, 5%, or 10%), Cmax and AUC were increased in the NUTRIOSE receiving groups in a dose-dependent manner.
These findings reveal that intestinal microflora promote metabolic conversion of ginsenoside Rb1 and ginseng extract to ginsenoside Rd and promote its absorption into the blood in rats. Its conversion may be induced by prebiotic diets such as NUTRIOSE.
ginsenoside Rb1; ginsenoside Rd; NUTRIOSE; Panax ginseng; pharmacokinetic
Many reports have claimed associations between diagonal earlobe crease (DELC) and coronary artery disease (CAD), but data in Chinese populations are limited.
This cohort study investigated 449 consecutive Chinese, 250 cases with CAD and 199 without CAD, who were certified by coronary artery angiography in our center. Characteristic differences and the relation of DELC to CAD were assessed by Chi-square and t tests. The multivariate regression was performed to adjust for confounders and ROCs mode were used to detect its predicting performance for CAD.
The prevalence of DELC was 46.2% in those without CAD and 75.2% in those with CAD (P < .001). Subjects with DELC had more stenostic vessels and higher prevalence of both any and significant coronary artery stenosis than those without DELC (P < .001). The sensitivity, specificity and positive and negative predictive values for DELC to diagnose CAD in the whole population were 0.752, 0.538, 0.671 and 0.633. The higher sensitivity and positive predictive values (ppv) were found in male, the lowest sensitivity and the highest ppv in the <45 years old group, and the lowest specificity and ppv in the >75 years old group. After adjusting for other variables including age, gender and traditional risk factors, DELC remained a positive predictor for CAD (OR, 3.408; 95% CI 2.235-5.196; P < 0.001), but not for hypertension, diabetes mellitus, hypercholesterolemia and hypertriglyceridemia. ROC analysis showed the area under the curve was 0.645 (95% CI 0.593-0.697, p < 0.001).
The study showed a significant association between DELC and CAD independent of established risk factors in Chinese.
Diagonal earlobe crease; Coronary artery disease; Chinese ethnics; Coronary artery angiography; Han Chinese
Resveratrol (3,4′,5-trihydroxystilbene) is a naturally derived phytoalexin stilbene isolated from grapes and other plants, playing an important role in human health and is well known for its extensive bioactivities, such as antioxidation, anti-inflammatory, anticancer. In addition to resveratrol, scientists also pay attention to resveratrol oligomers, derivatives of resveratrol, which are characterized by the polymerization of two to eight, or even more resveratrol units, and are the largest group of oligomeric stilbenes. Resveratrol oligomers have multiple beneficial properties, of which some are superior in activity, stability, and selectivity compared with resveratrol. The complicated structures and diverse biological activities are of significant interest for drug research and development and may provide promising prospects as cancer preventive and therapeutical agents. This review presents an overview on preventive or anticancer properties of resveratrol oligomers.