Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by both a chronic inflammation and tissue remodelling; as indicated by extracellular matrix protein deposition, basement membrane thickening, goblet cell hyperplasia and subepithelial edema, with reduced vessels and glands. Although remodelling is generally considered to be consequence of persistent inflammation, the chronological order and relationship between inflammation and remodelling in polyp development is still not clear. The aim of our study was therefore to investigate the pathological features prevalent in the development of nasal polyps and to elucidate the chronological order and relationship between inflammation and remodelling, by comparing specific markers of inflammation and remodelling in early stage nasal polyps confined to the middle turbinate (refer to as middle turbinate CRSwNP) obtained from 5 CRSwNP patients with bilateral polyposis, mature ethmoidal polyps from 6 CRSwNP patients, and normal nasal mucosal tissue from 6 control subjects. Middle turbinate CRSwNP demonstrated significantly more severe epithelial loss compared to mature ethmoidal polyps and normal nasal mucosa. The epithelial cell junction molecules E-cadherin, ZO-1 and occludin were also expressed in significantly lower amounts in mature ethmoidal polyps compared to healthy mucosa. Middle turbinate CRSwNP were further characterized by significantly increased numbers of subepithelial eosinophils and M2 type macrophages, with a distinct lack of collagen and deposition of fibronectin in polyp part. In contrast, the turbinate area of the middle turbinate CRSwNP was characterized by an increase in TGF-β activated myofibroblasts expressing α-SMA and vimentin, an increase in the number of pSmad2 positive cells, as well as increased deposition of collagen. These findings suggest a complex network of processes in the formation of CRSwNP; including gross epithelial damage and repair reactions, eosinophil and macrophage cell infiltration, and tissue remodelling. Furthermore, remodelling appears to occur in parallel, rather than subsequent to inflammation.
Defects in insulin secretion and reduction in β-cell mass are associated with type 2 diabetes in humans, and understanding the basis for these dysfunctions may reveal strategies for diabetes therapy. In this study, we show that pancreas-specific knockout of growth factor receptor–binding protein 10 (Grb10), which is highly expressed in pancreas and islets, leads to elevated insulin/IGF-1 signaling in islets, enhanced β-cell mass and insulin content, and increased insulin secretion in mice. Pancreas-specific disruption of Grb10 expression also improved glucose tolerance in mice fed with a high-fat diet and protected mice from streptozotocin-induced β-cell apoptosis and body weight loss. Our study has identified Grb10 as an important regulator of β-cell proliferation and demonstrated that reducing the expression level of Grb10 could provide a novel means to increase β-cell mass and reduce β-cell apoptosis. This is critical for effective therapeutic treatment of both type 1 and 2 diabetes.
Pokemon is an important proto-oncogene that plays a critical role in cellular oncogenic transformation and tumorigenesis. Anoikis, which is regulated by Bim-mediated apoptosis, is critical to cancer cell invasion and metastasis. We investigated the role of Pokemon in anoikis, and our results show that Pokemon renders liver cells resistant to anoikis via suppression of Bim transcription. We knocked-down Pokemon in human hepatoma cells QGY7703 with small interfering RNAs (siRNA). Knockdown of Pokemon alone did not significantly affect the growth and survival of QGY7703 cells but notably enhanced their sensitivity to apoptotic stress due to the presence of chemical agents or cell detachment, thereby inducing anoikis, as evidenced by flow cytometry and caspase-3 activity assays. In contrast, ectopic expression of Pokemon in HL7702 cells led to resistance to anoikis. Dual-luciferase reporter and ChIP assays illustrated that Pokemon suppressed Bim transcription via direct binding to its promoter. Our results suggest that Pokemon prevents anoikis through the suppression of Bim expression, which facilitates tumor cell invasion and metastasis. This Pokemon-Bim pathway may be an effective target for therapeutic intervention for cancer.
Pokemon; anoikis; Bim; hepatoma
Lactobacillus shenzhenensis strain LY-73T is a novel species which was first isolated from fermented goods. Here, we report the draft genome sequence of Lactobacillus shenzhenensis LY-73T.
Lysozymes are important proteins of the innate immune system for the defense against bacterial infection. We cloned and analyzed chicken-type (c-type) and goose-type (g-type) lysozymes from Asian seabass (Lates calcarifer). The deduced amino acid sequence of the c-type lysozyme contained 144 residues and possessed typical structure residues, conserved catalytic residues (Glu50 and Asp67) and a “GSTDYGIFQINS” motif. The deduced g-type lysozyme contained 187 residues and possessed a goose egg white lysozyme (GEWL) domain containing three conserved catalytic residues (Glu71, Asp84, Asp95) essential for catalytic activity. Real time quantitative PCR (qRT-PCR) revealed that the two lysozyme genes were constitutively expressed in all the examined tissues. The c-type lysozyme was most abundant in liver, while the g-type lysozyme was predominantly expressed in intestine and weakly expressed in muscle. The c-type and g-type transcripts were up-regulated in the kidney, spleen and liver in response to a challenge with Vibrio harveyi. The up-regulation of the c-type lysozyme was much stronger than that of the g-type lysozyme in kidney and spleen. The recombinant proteins of the c-type and g-type lysozymes showed lytic activities against the bacterial pathogens Vibrio harveyi and Photobacterium damselae in a dosage-dependent manner. We identified single nucleotide polymorphisms (SNPs) in the two lysozyme genes. There were significant associations of these polymorphisms with resistance to the big belly disease. These results suggest that the c- and g-type genes play an important role in resistance to bacterial pathogens in fish. The SNP markers in the two genes associated with the resistance to bacterial pathogens may facilitate the selection of Asian seabass resistant to bacterial diseases.
The antidiabetic and antiatherosclerotic effects of adiponectin make it a desirable drug target for the treatment of metabolic and cardiovascular diseases. However, the adiponectin-based drug development approach turns out to be difficult due to extremely high serum levels of this adipokine. On the other hand, a significant correlation between adiponectin multimerization and its insulin-sensitizing effects has been demonstrated, suggesting a promising alternative therapeutic strategy. Here we show that transgenic mice overexpressing disulfide bond A oxidoreductase-like protein in fat (fDsbA-L) exhibited increased levels of total and the high-molecular-weight form of adiponectin compared with wild-type (WT) littermates. The fDsbA-L mice also displayed resistance to diet-induced obesity, insulin resistance, and hepatic steatosis compared with WT control mice. The protective effects of DsbA-L overexpression on diet-induced insulin resistance, but not increased body weight and fat cell size, were significantly decreased in adiponectin-deficient fDsbA-L mice (fDsbA-L/Ad−/−). In addition, the fDsbA-L/Ad−/− mice displayed greater activity and energy expenditure compared with adiponectin knockout mice under a high-fat diet. Taken together, our results demonstrate that DsbA-L protects mice from diet-induced obesity and insulin resistance through adiponectin-dependent and independent mechanisms. In addition, upregulation of DsbA-L could be an effective therapeutic approach for the treatment of obesity and its associated metabolic disorders.
Ischemia reperfusion (IR) and cyclosporine A (CsA) injuries are unavoidable in kidney transplantation and are associated with allograft dysfunction. Herein, the effect and mechanism of a novel tissue protective peptide, helix B surface peptide (HBSP) derived from erythropoietin, were investigated in a rat model. The right kidney was subjected to 45 min ischemia, followed by left nephrectomy and 2-week reperfusion, with or without daily treatment of CsA 25 mg/kg and/or HBSP 8 nmol/kg. Blood urea nitrogen was increased by CsA but decreased by HBSP at 1 week and 2 weeks, while the same changes were revealed in urinary protein/creatinine only at 2 weeks. HBSP also significantly ameliorated tubulointerstitial damage and interstitial fibrosis, which were gradually increased by IR and CsA. In addition, apoptotic cells, infiltrated inflammatory cells, and active caspase-3+ cells were greatly reduced by HBSP in the both IR and IR + CsA groups. The 17 kD active caspase-3 protein was decreased by HBSP in the IR and IR + CsA kidneys, with decreased mRNA only in the IR + CsA kidneys. Taken together, it has been demonstrated, for the first time, that HBSP effectively improved renal function and tissue damage caused by IR and/or CsA, which might be through reducing caspase-3 activation and synthesis, apoptosis, and inflammation.
Adiponectin has been receiving a great deal of attention due to its potential therapeutic use for metabolic and cardiovascular disorders. Adiponectin expression levels and multimerization are down-regulated in obesity and up-regulated by insulin sensitizers such as thiazolidinediones (TZDs), metformin, sulfonylurea and resveratrol (RSV). The precise mechanisms underlying adiponectin up- and down-regulation remain largely unknown, but recent studies indicate that the cellular and plasma levels of adiponectin could be regulated at both transcriptional and post-transcriptional levels. At the post-translational level, TZDs and resveratrol promote adiponectin levels and multimerization via up-regulation of disulfidebond-A oxidoreductase-like protein (DsbA-L). Adiponectin levels are also stimulated by FOXO1 and AMP-activated protein kinase (AMPK), and are suppressed by PKA or silencing mediator of retinoid andthyroid hormone receptors (SMRT). Since multimerization is important not only for adiponectin function but also for stability, increasing adiponectin multimerization has become a promising drug target for the treatment of metabolic diseases and other related disorders.
Adiponectin; TZDs; Resveratrol; Metformin; DsbA-L
Previous studies have demonstrated that patients with treatment-resistant depression (TRD) and treatment-sensitive depression (TSD) differed at neural level. However, it remains unclear if these two subtypes of depression differ in the interhemispheric coordination. This study was undertaken for two purposes: (1) to explore the differences in interhemispheric coordination between these two subtypes by using the voxel-mirrored homotopic connectivity (VMHC) method; and (2) to determine if the difference of interhemispheric coordination can be used as a biomarker(s) to differentiate TRD from both TSD and healthy subjects (HS).
Twenty-three patients with TRD, 22 with TSD, and 19 HS participated in the study. Data of these participants were analyzed with the VMHC and seed-based functional connectivity (FC) approaches.
Compared to the TSD group, the TRD group showed significantly lower VMHC values in the calcarine cortex, fusiform gyrus, hippocampus, superior temporal gyrus, middle cingulum, and precentral gyrus. Lower VMHC values were also observed in the TRD group in the calcarine cortex relative to the HS group. However, the TSD group had no significant change in VMHC value in any brain region compared to the HS group. Receiver operating characteristic curves (ROC) analysis revealed that the VMHC values in the calcarine cortex had discriminatory function distinguishing patients with TRD from patients with TSD as well as those participants in the HS group.
Lower VMHC values of patients with TRD relative to those with TSD and those in the HS group in the calcarine cortex appeared to be a unique feature for patients with TRD and it may be used as an imaging biomarker to separate patients with TRD from those with TSD or HS.
To investigate the influence of the peroxisome proliferator activated receptor gamma (PPAR-γ) Pro12Ala polymorphism on the susceptibility of polycystic ovary syndrome (PCOS) and body mass index (BMI), fast insulin levels, homeostasis model assessment of insulin resistance (HOMA-IR) in PCOS patients.
PubMed, EMBASE, MEDLINE and CENTRAL databases were searched to identify eligible studies. We then conducted a meta-analysis to examine the association between Pro12Ala polymorphism and PCOS.
Seventeen eligible studies, including 2,149 patients and 2,124 controls were enrolled in this meta-analysis. Pro12Ala polymorphism was significantly associated with the susceptibility of PCOS (odds ratio [OR] 0.74, 95 % confidence interval [CI] [0.61, 0.90] for allele; OR 0.70, 95 % CI [0.57, 0.86] for genotype). In the European subgroup of PCOS, the X/Ala genotype was associated with lower BMI (mean difference [MD] −1.08, 95 % CI [−2.08, −0.09]) and fast insulin levels (MD −19.82, 95 % CI [−34.07, −5.58]). However, this polymorphism did not display an impact on HOMA-IR in PCOS patients.
Ala variant would decrease the risk of PCOS and result in lower BMI and fast insulin levels in a European population, but had no impact on HOMA-IR in PCOS patients. Further studies are required to elucidate these associations more clear.
Polycystic ovary syndrome; PPAR-γ; Meta-analysis; Body mass index; Fast insulin; Insulin sensitivity
Pokemon is an important proto-oncogene involved in various biological processes and cancer development, such as cell differentiation, tumorigenesis and metastasis. Pokemon is recognized as a transcription factor localized upstream of several oncogenes, regulating their expression. p38MAPKs act as key regulatory factors in cellular signaling pathways associated with inflammatory responses, cell proliferation, differentiation and survival. p38β, a member of p38MAPK family, is closely correlated with tumorigenesis, but the mechanism of activation remains unclear. In this study, we found overexpression of Pokemon promoted the growth, migration and invasion of HepG2 cells. However, a p38 inhibitor SB202190 efficiently attenuated the promoting effect of Pokemon in the HepG2 cells. Targeted expression or silencing of Pokemon changed cellular p38β protein level and phosphorylation of downstream ATF2 in the p38 signaling pathway. Both dual luciferase report assay and ChIP assay suggested that p38β is a novel regulatory target of the transcription factor Pokemon and positively regulated by Pokemon in hepatic cells.
Pokemon; p38β; transcription factor; hepatic cell; SB202190
Identification of differentially expressed genes (DEGs) and regulated pathways in response to stressors using a whole-genome approach is critical to understanding the mechanisms underlying stress responses. We challenged Asian seabass with lipopolysaccharide (LPS), Vibrio harveyi, high salinity and fasting, and sequenced six cDNA libraries of intestine samples using Roche 454 RNA-seq. Over 1 million reads (average size: 516 bp) were obtained. The de novo assembly obtained 83 911 unisequences with an average length of 747 bp. In total, 62.3% of the unisequences were annotated. We observed overall similar expression profiles among different challenges, while a number of DEGs and regulated pathways were identified under specific challenges. More than 1000 DEGs and over 200 regulated pathways for each stressor were identified. Thirty-seven genes were differentially expressed in response to all challenges. Our data suggest that there is a global coordination and fine-tuning of gene regulation during different challenges. In addition, we detected dramatic immune responses in intestines under different stressors. This study is the first step towards the comprehensive understanding of the mechanisms underlying stress responses and supplies significant transcriptome resources for studying biological questions in non-model fish species.
RNA-seq; intestine; stress; disease; nutrition
A new acridone derivative, 2-aminoacetamido-10-(3, 5-dimethoxy)-benzyl-9(10H)-acridone hydrochloride (named 8a) synthesized in our lab shows potent antitumor activity, but the mechanism of action remains unclear. Herein, we report the use of an UPLC/Q-TOF MS metabolomic approach to study the effects of three compounds with structures optimized step-by-step, 9(10H)-acridone (A), 10-(3,5-dimethoxy)benzyl-9(10H)-acridone (I), and 8a, on CCRF-CEM leukemia cells and to shed new light on the probable antitumor mechanism of 8a. Acquired data were processed by principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) to identify potential biomarkers. Comparing 8a-treated CCRF-CEM leukemia cells with vehicle control (DMSO), 23 distinct metabolites involved in five metabolic pathways were identified. Metabolites from glutathione (GSH) and glycerophospholipid metabolism were investigated in detail, and results showed that GSH level and the reduced/oxidized glutathione (GSH/GSSG) ratio were significantly decreased in 8a-treated cells, while L-cysteinyl-glycine (L-Cys-Gly) and glutamate were greatly increased. In glycerophospholipid metabolism, cell membrane components phosphatidylcholines (PCs) were decreased in 8a-treated cells, while the oxidative products lysophosphatidylcholines (LPCs) were significantly increased. We further found that in 8a-treated cells, the reactive oxygen species (ROS) and lipid peroxidation product malondialdehyde (MDA) were notably increased, accompanied with decrease of mitochondrial transmembrane potential, release of cytochrome C and activation of caspase-3. Taken together our results suggest that the acridone derivative 8a induces oxidative stress-mediated apoptosis in CCRF-CEM leukemia cells. The UPLC/Q-TOF MS based metabolomic approach provides novel insights into the mechanistic studies of antitumor drugs from a point distinct from traditional biological investigations.
Aquaculture is the quickest growing sector in agriculture. However, QTL for important traits have been only identified in a few aquaculture species. We conducted QTL mapping for growth traits in an Asian seabass F2 family with 359 individuals using 123 microsatellites and 22 SNPs, and performed association mapping in four populations with 881 individuals.
Twelve and nine significant QTL, as well as 14 and 10 suggestive QTL were detected for growth traits at six and nine months post hatch, respectively. These QTL explained 0.9-12.0% of the phenotypic variance. For body weight, two QTL intervals at two stages were overlapped while the others were mapped onto different positions. The IFABP-a gene located in a significant QTL interval for growth on LG5 was cloned and characterized. A SNP in exon 3 of the gene was significantly associated with growth traits in different populations.
The results of QTL mapping for growth traits suggest that growth at different stages was controlled by some common QTL and some different QTL. Positional candidate genes and association mapping suggest that the IFABP-a is a strong candidate gene for growth. Our data supply a basis for fine mapping QTL, marker-assisted selection and further detailed analysis of the functions of the IFABP-a gene in fish growth.
Single nucleotide polymorphism; Growth trait; Candidate gene; Quantitative trait locus
Here we described a paclitaxel (PTX) nanocrystals formulation using D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as the sole excipient for overcoming multidrug resistance (MDR), a key challenge in current cancer therapy. To the best of our knowledge, it is the first report on PTX nanocrystals which can reverse MDR. TPGS serves as a surfactant to stabilize the nanocrystals and a P-gp inhibitor to reverse MDR. The size and morphology of the nanocrystals were studied by transmission electron microscopy and the crystalline structure was determined by powder X-ray diffraction. In vitro drug release profile showed that the nanocrystals exhibited sustained release kinetics compared to Taxol which is the clinical paclitaxel formulation. The cytotoxicity and antitumor efficacy in xenograft models were also investigated. It is demonstrated that PTX/TPGS nanocrystals have significant advantages over Taxol in achieving better therapeutic effect in Taxol-resistant cancer cells both in vitro and in vivo, which was also confirmed by apoptosis assays. We envision that further development of this type of nanocrystals will provide a novel strategy for drug delivery and multidrug resistance treatment.
multidrug resistance; paclitaxel; nanocrystals; TPGS; cancer
Erectile dysfunction (ED) is a major complication of diabetes mellitus. Icariin has been shown to enhance erectile function through its bioactive form, icarisid II. This study investigates the effects of icarisid II on diabetic rats with ED and its potential mechanism via the assessment of advanced glycosylation end products (AGEs), autophagy, mTOR and the NO–cGMP pathway. Icarisid II was extracted from icariin by an enzymatic method. In the control and diabetic ED groups, rats were administered normal saline; in the icarisid II group, rats were administered icarisid II intragastrically. Erectile function was evaluated by measuring intracavernosal pressure/mean arterial pressure (ICP/MAP). AGE concentrations, nitric oxide synthase (NOS) activity and cGMP concentration were assessed by enzyme immunoassay. Cell proliferation was analysed using methyl thiazolyl tetrazolium assay and flow cytometry. Autophagosomes were observed by transmission electron microscopy, monodansylcadaverine staining and GFP-LC3 localisation. The expression of NOS isoforms and key proteins in autophagy were examined by western blot. Our results have shown that Icarisid II increased ICP/MAP values, the smooth muscle cell (SMC) growth curve, S phase and SMC/collagen fibril (SMC/CF) proportions and decreased Beclin 1 (P<0.05). Icarisid II significantly increased the proliferative index and p-p70S6K(Thr389) levels and decreased the numbers of autophagosomes and the levels of LC3-II (P<0.01). Icarisid II decreased AGE concentrations and increased cGMP concentration, NOS activity (P<0.05) and cNOS levels (P<0.01) in the diabetic ED group. Therefore, Icarisid II constitutes a promising compound for diabetic ED and might be involved in the upregulation of SMC proliferation and the NO–cGMP pathway and the downregulation of AGEs, autophagy and the mTOR pathway.
advanced glycosylation end products (AGEs); autophagy; cell proliferation; diabetes mellitus (DM); erectile dysfunction (ED); icariin; icarisid II; mTOR; NO–cGMP; NOS activity
Traceability through physical labels is well established, but it is not highly reliable as physical labels can be easily changed or lost. Application of DNA markers to the traceability of food plays an increasingly important role for consumer protection and confidence building. In this study, we tested the efficiency of 16 polymorphic microsatellites and their combinations for tracing 368 fish to four populations where they originated. Using the maximum likelihood and Bayesian methods, three most efficient microsatellites were required to assign over 95% of fish to the correct populations. Selection of markers based on the assignment score estimated with the software WHICHLOCI was most effective in choosing markers for individual assignment, followed by the selection based on the allele number of individual markers. By combining rapid DNA extraction, and high-throughput genotyping of selected microsatellites, it is possible to conduct routine genetic traceability with high accuracy in Asian seabass.
In aquaculture species, maintaining pedigree information and genetic variation in each generation is essential, but very difficult. In this study, we used nine microsatellites to genotype 2,520 offspring from four independent full-factorial crosses (10 males ×10 females) of Asian seabass to reconstruct pedigree and monitor the change of genetic variations. In all four crosses, over 96.8% of the offspring could be assigned to their parents, indicating the high power of the nine microsatellites for parentage assignment. This study revealed several interesting results: (1). In all four crosses, the contribution of parents to offspring was significantly uneven, and some dominant breeding fishes (i.e. brooders) were found; (2). In two mass crosses where the brooders were carefully checked for reproductive status, a majority (≥90%) of brooders contributed to offspring, whereas in another two crosses, where the brooders were randomly picked without checking reproductive status, only a few brooders (40.0–45.0%) produced offspring; (3). Females had more problems in successful spawning compared to males; and (4). In the two crosses where a few brooders produced offspring, there was a substantial loss in allelic (24.1–34.3%) and gene (20.5–25.7%) diversities in offspring, while in the other two crosses, the majority of allelic (96.8–97.0%) and gene diversities (94.8–97.1%) were maintained. These observations suggest that a routine molecular parentage analysis is required to maintain both allelic and gene diversity in breeding Asian seabass.
To gain valuable insights into the gene interaction and the complex regulation system involved in the development of insecticide resistance in mosquitoes Culex quinquefasciatus, we conducted a whole transcriptome analysis of Culex mosquitoes following permethrin selection. Gene expression profiles for the lower resistant parental mosquito strain HAmCqG0 and their permethrin-selected high resistant offspring HAmCqG8 were compared and a total of 367 and 3982 genes were found to be up- and down-regulated, respectively, in HAmCqG8, indicating that multiple genes are involved in response to permethrin selection. However, a similar overall cumulative gene expression abundance was identified between up- and down-regulated genes in HAmCqG8 mosquitoes following permethrin selection, suggesting a homeostatic response to insecticides through a balancing of the up- and down-regulation of the genes. While structural and/or cuticular structural functions were the only two enriched GO terms for down-regulated genes, the enriched GO terms obtained for the up-regulated genes occurred primarily among the catalytic and metabolic functions where they represented three functional categories: electron carrier activity, binding, and catalytic activity. Interestingly, the functional GO terms in these three functional categories were overwhelmingly overrepresented in P450s and proteases/serine proteases. The important role played by P450s in the development of insecticide resistance has been extensively studied but the function of proteases/serine proteases in resistance is less well understood. Hence, the characterization of the functions of these proteins, including their digestive, catalytic and proteinase activities; regulation of signaling transduction and protein trafficking, immunity and storage; and their precise function in the development of insecticide resistance in mosquitoes will provide new insights into how genes are interconnected and regulated in resistance.
Previous studies have found numerous brain changes in patients with major depressive disorder (MDD), but no neurological biomarker has been developed to diagnose depression or to predict responses to antidepressants. In the present study, we used multivariate pattern analysis (MVPA) to classify MDD patients with different therapeutic responses and healthy controls and to explore the diagnostic and prognostic value of structural neuroimaging data of MDD.
Eighteen patients with treatment-resistant depression (TRD), 17 patients with treatment-sensitive depression (TSD) and 17 matched healthy controls were scanned using structural MRI. Voxel-based morphometry, together with a modified MVPA technique which combined searchlight algorithm and principal component analysis (PCA), was used to classify the subjects with TRD, those with TSD and healthy controls. The results revealed that both gray matter (GM) and white matter (WM) of frontal, temporal, parietal and occipital brain regions as well as cerebellum structures had a high classification power in patients with MDD. The accuracy of the GM and WM that correctly discriminated TRD patients from TSD patients was both 82.9%. Meanwhile, the accuracy of the GM that correctly discriminated TRD or TSD patients from healthy controls were 85.7% and 82.4%, respectively; and the WM that correctly discriminated TRD or TSD patients from healthy controls were 85.7% and 91.2%, respectively.
These results suggest that structural MRI with MVPA might be a useful and reliable method to study the neuroanatomical changes to differentiate patients with MDD from healthy controls and patients with TRD from those with TSD. This method might also be useful to study potential brain regions associated with treatment response in patients with MDD.
Recent observations in in vitro and in vivo models suggest that arsenic (As) is an endocrine disruptor at environmentally-relevant levels. When exposed to As, male rats and mice show steroidogenic dysfunction that can lead to infertility. However, the possible effects of As on human male semen quality remain obscure.
We monitored the profile of As species in the urine of a reproductive-age human cohort and assessed its association with semen quality. Men (n = 96) were recruited in an infertility clinic from July 2009 to August 2010 in the Affiliated Hospital of Chongqing Institute for Population and Family Planning. Five urinary As species were analyzed by high-performance liquid chromatography coupled with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). Clinical information on the semen volume, sperm concentration and motility was employed to catalogue and evaluate semen quality according to WHO guidelines. As species concentrations in addition to other continuous variables were dichotomized by the medians and modelled as categorical variables in order to explore using the binary logistic regression possible associations between As exposure and semen quality.
Urinary concentrations (geometric mean ± SD, μg g-1 creatinine) of different As species were 7.49 (±24.8) for AsB, 20.9 (±13.7) for DMA, 2.77 (±3.33) for MMA, and 4.03 (±3.67) for Asi (AsiIII and AsiV). DMA concentrations above the median were significantly associated with below-reference sperm concentrations (P =0.02) after adjusting for age, body mass index (BMI), abstinence, smoking and drinking habits. In addition, smoking was positively associated with MMA.
Reduced parameters in human semen quality are positively associated with As exposure in a reproductive-age Chinese cohort.
Arsenic; China; Cross-sectional study; Human reproduction; Semen quality
CD4+CD25+ regulatory T cells (Tregs) do
not only influence self-antigen specific immune responses, but also dampen
the protective effect induced by a number of vaccines. The impact of CD4+CD25+
Tregs on vaccines against schistosomiasis, a neglected tropical disease that
is a major public health concern, however, has not been examined. In this
study, a DNA vaccine encoding a 26 kDa glutathione S-transferase of Schistosoma
japonicum (pVAX1-Sj26GST) was constructed and its potential effects
were evaluated by depleting CD25+ cells prior to pVAX1-Sj26GST
immunization. This work shows that removal of CD25+ cells
prior to immunization with the pVAX1-Sj26GST schistosomiasis DNA vaccine significantly
increases the proliferation of splenocytes and IgG levels. However, CD25+
cell-depleted mice immunized with pVAX1-Sj26GST show no improved protection
against S. japonicum. Furthermore, depletion of CD25+
cells causes an increase in both pro-inflammatory cytokines (e.g. IFN-γ,
GM-CSF and IL-4) and an anti-inflammatory cytokine (e.g. IL-10), with CD4+CD25-
T cells being one of the major sources of both IFN-γ and IL-10. These
findings indicate that partial CD25+ cell depletion fails
to enhance the effectiveness of the schistosome vaccine, possibly due to IL-10
production by CD4+CD25- T cells, or other cell
types, after CD25+ cell depletion during vaccination.
To assess the potential efficacy of mechano growth factor (MGF) for bone injury, we firstly investigated the effects of growth factors, including MGF, its E peptide (a short 24-amino acid C-terminal peptide, MGF-Ct24E), and insulin-like growth factor 1(IGF-1) on MC3T3-E1 osteoblast-like cell proliferation. MGF-Ct24E had the highest pro-proliferation activity among three growth factors, which was 1.4 times greater than that of IGF-1. Moreover, MGF-Ct24E promoted cell proliferation by inducing cell cycle arrest in the S and G2/M phase of the cell cycle, but also mainly by the activation of the MAPK-Erk1/2 pathway. In vivo, a 5-mm segmental bone defect in the radius of 27 rabbits was treated with MGF-Ct24E by two doses (28.5 and 57 μg /kg body weight) vs. non-growth factor injection for five consecutive days postoperatively. The cumulative rate of radiographically healed defects and histological scores of bone defect-healing revealed a statistical difference between high-dose treatment and non treatment (p < 0.01), which showed the treatment promoted defect healing. This report is the first to demonstrate that MGF-Ct24E possesses positive effects on osteoblast proliferation and bone-defect healing, suggesting a new strategy in fracture healing.
AIM: To investigate the relationship between donor liver cold preservation, lung surfactant (LS) changes and acute lung injury (ALI) after liver transplantation.
METHODS: Liver transplantation models were established using male Wistar rats. Donor livers were preserved in University of Wisconsin solution at 4 °C for different lengths of time. The effect of ammonium pyrrolidinedithiocarbamate (PDTC) on ALI was also detected. All samples were harvested after 3 h reperfusion. The severity of ALI was evaluated by lung weight/body weight ratio, lung histopathological score, serum nitric oxide (NO) and endothelin (ET)-1 levels, lung tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels. Lung surfactants (LSs) were determined by micellar electrokinetic capillary chromatography.
RESULTS: With extended donor liver cold preservation time (CPT), lung histopathological scores, serum ET-1 levels, lung weight/body weight ratio and the level of TNF-α and IL-1β in lung were increased significantly in the 180-min group compared with the sham group (3.16 ± 0.28 vs 1.12 ± 0.21, P < 0.001; 343.59 ± 53.97 vs 141.53 ± 48.48, P < 0.001; 0.00687 ± 0.00037 vs 0.00557 ± 0.00056, P < 0.001; 17.5 ± 3.0 vs 1.3 ± 0.3, P < 0.001; 10.8 ± 2.3 vs 1.8 ± 0.4, P < 0.001), but serum NO levels decreased remarkably (74.67 ± 10.01 vs 24.97 ± 3.18, P < 0.001). The expression of lung phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI) and phosphatidylserine (PS) increased when CPT was < 120 min, and decreased when CPT was > 180 min (PC: 1318.89 ± 54.79 vs 1011.18 ± 59.99, P < 0.001; PE: 1504.45 ± 119.96 vs 1340.80 ± 76.39, P = 0.0019; PI: 201.23 ± 34.82 vs 185.88 ± 17.04, P = 0.2265; PS: 300.43 ± 32.95 vs 286.55 ± 55.55, P = 0.5054). All these ALI-associated indexes could be partially reversed by PDTC treatment.
CONCLUSION: Prolonged CPT could induce or inhibit the expression of LSs at the compensation or decompensation stage, and some antioxidants (e.g., PDTC) may reverse the pathological process partially.
Liver transplantation; Acute lung injury; Organ preservation; Lung surfactants
Obesity impairs adiponectin expression, assembly, and secretion, yet the underlying mechanisms remain elusive. The aims of this study were 1) to determine the molecular mechanisms by which obesity impairs adiponectin multimerization and stability, and 2) to determine the potential role of disulfide-bond-A oxidoreductase-like protein (DsbA-L), a recently identified adiponectin interactive protein that promotes adiponectin multimerization and stability in obesity-induced endoplasmic reticulum (ER) stress and adiponectin downregulation.
RESEARCH DESIGN AND METHODS
Tauroursodeoxycholic acid (TUDCA), a chemical chaperone that alleviates ER stress, was used to study the mechanism underlying obesity-induced adiponectin downregulation in db/db mice, high-fat diet-induced obese mice, and in ER-stressed 3T3-L1 adipocytes. The cellular levels of DsbA-L were altered by RNAi-mediated suppression or adenovirus-mediated overexpression. The protective role of DsbA-L in obesity- and ER stress–induced adiponectin downregulation was characterized.
Treating db/db mice and diet-induced obese mice with TUDCA increased the cellular and serum levels of adiponectin. In addition, inducing ER stress is sufficient to downregulate adiponectin levels in 3T3-L1 adipocytes, which could be protected by treating cells with the autophagy inhibitor 3-methyladenine or by overexpression of DsbA-L.
ER stress plays a key role in obesity-induced adiponectin downregulation. In addition, DsbA-L facilitates adiponectin folding and assembly and provides a protective effect against ER stress–mediated adiponectin downregulation in obesity.