Cystatin SN has been considered to be involved in human cancer, but its clinical significance in non-small cell lung cancer (NSCLC) has not been elucidated. The aim of this study was to evaluate the clinical value of Cystatin SN expression in patients with surgically resected NSCLCs. A retrospective analysis of 174 patients with surgically resected NSCLCs from April 2002 to March 2005 was performed with immunohistochemistry and fluorescence in situ hybridization to analyze the protein expression and amplification of Cystatin SN. The associations between Cystatin SN expression and recurrence, metastasis, and survival were investigated. In recurrence and metastasis analysis, compared with low-Cystatin SN expression NSCLCs, high expression tumors were more likely to recur and metastasize (P < 0.001). Disease-free survival (DFS) and overall survival (OS) were significantly prolonged in the low-Cystatin SN expression subgroup compared with the high-Cystatin SN expression subgroup (DFS, P < 0.001; OS, P = 0.001). A multivariate analysis confirmed that high expression of Cystatin SN was associated with poor survival (DFS, P = 0.001; OS, P = 0.006) and was an independent prognostic indicator. The present study indicates that high expression of Cystatin SN is a significant prognostic indicator of a higher rate of recurrence, metastatic risk, and poor survival in patients with surgically resected NSCLCs.
Spontaneous Ca2+ release from intracellular stores is important for various physiological and pathological processes. In cardiac muscle cells, spontaneous store overload-induced Ca2+ release (SOICR) can result in Ca2+ waves, a major cause of ventricular tachyarrhythmias (VTs) and sudden death. The molecular mechanism underlying SOICR has been a mystery for decades. Here, we show that a point mutation E4872A in the helix bundle crossing (the proposed gate) of the cardiac ryanodine receptor (RyR2) completely abolishes luminal, but not cytosolic, RyR2 Ca2+ activation. Introducing metal-binding histidines at this site converts RyR2 into a luminal Ni2+ gated channel. Mouse hearts harboring an RyR2 mutation at this site (E4872Q+/−) are resistant to store overload-induced Ca2+ waves and completely protected against Ca2+-triggered VTs. These data show that the RyR2 gate directly senses store Ca2+, explaining RyR2 store Ca2+ regulation, Ca2+ wave initiation, and Ca2+-triggered arrhythmias. This novel store-sensing gate structure is conserved in all RyRs and inositol 1,4,5-trisphosphate receptors.
The effect of different tumbling marination treatments (control group, CG; conventional static marination, SM; vacuum continuous tumbling marination, CT; vacuum intermittent tumbling marination, IT) on the quality characteristics of prepared pork chops was investigated under simulated commercial conditions. The CT treatment increased (p<0.05) the pH value, b* value, product yield, tenderness, overall flavor, sensory juiciness and overall acceptability in comparison to other treatments for prepared boneless pork chops. The CT treatment decreased (p<0.05) cooking loss, shear force value, hardness, gumminess and chewiness compared with other treatments. In addition, CT treatment effectively improved springiness and sensory color more than other treatments. However, IT treatment achieved the numerically highest (p<0.05) L* and a* values. These results suggested that CT treatment obtained the best quality characteristics of prepared pork chops and should be adopted as the optimal commercial processing method for this prepared boneless pork chops.
Tumbling; Continuous; Intermittent; Quality Characteristic; Prepared Pork Chop
Physic nut (Jatropha curcas L.) is a small perennial tree or large shrub, which is well-adapted to semi-arid regions and is considered to have potential as a crop for biofuel production. It is now regarded as an excellent model for studying biofuel plants. However, our knowledge about the molecular responses of this species to drought stress is currently limited.
In this study, genome-wide transcriptional profiles of roots and leaves of 8-week old physic nut seedlings were analyzed 1, 4 and 7 days after withholding irrigation. We observed a total of 1533 and 2900 differentially expressed genes (DEGs) in roots and leaves, respectively. Gene Ontology analysis showed that the biological processes enriched in droughted plants relative to unstressed plants were related to biosynthesis, transport, nucleobase-containing compounds, and cellular protein modification. The genes found to be up-regulated in roots were related to abscisic acid (ABA) synthesis and ABA signal transduction, and to the synthesis of raffinose. Genes related to ABA signal transduction, and to trehalose and raffinose synthesis, were up-regulated in leaves. Endoplasmic reticulum (ER) stress response genes were significantly up-regulated in leaves under drought stress, while a number of genes related to wax biosynthesis were also up-regulated in leaves. Genes related to unsaturated fatty acid biosynthesis were down-regulated and polyunsaturated fatty acids were significantly reduced in leaves 7 days after withholding irrigation. As drought stress increased, genes related to ethylene synthesis, ethylene signal transduction and chlorophyll degradation were up-regulated, and the chlorophyll content of leaves was significantly reduced by 7 days after withholding irrigation.
This study provides us with new insights to increase our understanding of the response mechanisms deployed by physic nut seedlings under drought stress. The genes and pathways identified in this study also provide much information of potential value for germplasm improvement and breeding for drought resistance.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0397-x) contains supplementary material, which is available to authorized users.
Physic nut (Jatropha curcas L.); drought stress; gene expression profiles; abscisic acid; waxes and fatty acids; endoplasmic reticulum stress response; senescence
Memantine, an NMDA receptor uncompetitive antagonist, is currently approved by the Food and Drug Administration for the treatment of moderate to severe Alzheimer’s disease. Anecdotal reports have suggested that memantine may improve neurological and cognitive symptoms of individuals with the neurodegenerative disease, fragile X-associated tremor tremor/ataxia syndrome (FXTAS); however, its efficacy and safety in this population have not been assessed in a controlled trial.
A randomized, double-blind, placebo-controlled, one-year trial in individuals with FXTAS ages 34–80 years. Primary outcome measures were the Behavioral Dyscontrol Scale (BDS) score and CATSYS intention tremor severity.
Ninety-four participants were randomized from 205 screened; of those, 43 and 45 started memantine (titrated to 10 mg twice daily) and placebo, respectively. Thirty-four participants on memantine and 36 on placebo completed the one-year endpoint assessment (n=70). Intention-to-treat analysis showed that there was no improvement with respect to intention tremor severity (memantine vs. placebo: 1.05 ± 0.73 vs. 1.89 ± 2.19, p=0.047) and BDS score (16.12 ± 5.43 vs. 15.72 ± 3.93, p=0.727) at follow-up. Post hoc analyses of participants with early FXTAS (stage ≤ 3), late FXTAS (stage > 3) and different age groups (≤ 65 years and > 65 years) also indicated no significant improvement. More frequent mild adverse events (AEs) were observed in the placebo group, while more frequent moderate AEs occurred in the memantine group (p=0.007).
This randomized, double-blind, placebo-controlled trial of memantine for individuals with FXTAS showed no benefit with respect to the selected outcome measures compared to placebo.
♦ Objectives: Peritoneal dialysis (PD) is one of the first-line modalities of renal replacement therapy in patients with end-stage renal disease. Guidelines recommended a break-in period of at least 2 weeks before full PD start. However, the optimal duration of the break-in period is still unclear. In the present study, we investigated the effect of various break-in periods on short-term outcomes in patients on PD.
♦ Methods: All patients who underwent Tenckhoff catheter implantation and initiated PD in Renji Hospital, Shanghai Jiao Tong University School of Medicine, between 1 January 2001 and 31 December 2010 were included. Patients were grouped according to the duration of their break-in period: 7 days or less (BI≤7), 8 - 14 days (BI8-14), and more than 14 days (BI>14). Kaplan-Meier curves and log-rank tests were used to compare short-term outcomes in the various groups.
♦ Results: Our study enrolled 657 patients (44.5% men), of whom 344, 137, and 176 patients were in the respective break-in groups. Compared with BI>14 patients, BI≤7 patients had a lower estimated glomerular filtration rate (5.34 ± 1.86 mL/min/1.73 m2 vs 6.55 ± 1.71 mL/min/1.73 m2, p < 0.001) and lower serum albumin (33.29 ± 5.36 g/L vs 36.64 ± 5.40 g/L, p < 0.001). The incidence of mechanical complications during the first 6 months was significantly higher in BI≤7 patients than in BI>14 patients (8.4% vs 1.7%, p = 0.004). However, we observed no significant differences between the three groups with respect to the prevalence of catheter dysfunction requiring surgical intervention (p > 0.05). Logistic regression analysis showed that BI≤7 [relative risk: 4.322; 95% confidence interval (CI): 1.278 to 14.608; p = 0.019] was an independent predictor of catheter dysfunction, but not of catheter dysfunction requiring surgical intervention (p > 0.05). Catheter dysfunction [hazard ratio (HR): 20.087; 95% CI: 7.326 to 55.074; p < 0.001] and peritonitis (HR: 4.533; 95% CI: 1.748 to 11.751; p = 0.002) were risk factors for technique failure during the first 6 months, but BI≤7 was not correlated with technique failure.
♦ Conclusions: Patients starting PD with a break-in period of less than 1 week might experience a minor increased risk of mechanical complications, but no major effect on technique survival.
Break-in period; catheter-related complications; peritonitis; technique survival
Background: Low-level laser is being evaluated for treating rheumatoid arthritis (RA). Recently, the linear polarized infrared light (Super Lizer, SL) irradiation may also be useful for RA treatment. However, the molecular mechanism underlying the effectiveness of SL on RA is unclear. It has been IL-20 may involved in RA disease progression.
Aim: To understand how SL action, we constructed the experimental model in vitro using human rheumatoid fibroblast-like synoviocyte (MH7A) and collagen induced (CIA) RA rat in vivo. We examined the effect of SL irradiation on IL-20 gene expression in MH7A and IL-20 protein production in CIA) rat joints.
Materials and methods: MH7A was cultured and challenged with IL-1ß, then examined IL-20 and IL-20R mRNA level by DNA microarray. IL-20 protein expression was examined by immunohistochemistry using a specific antibody against rat IL-20.
Result: Scatter plot analysis demonstrated that an increase in IL-20 gene expression by IL-1ß was reduced by SL irradiation, but IL-20R did not show a significant change. The Immunohistochemical analysis demonstrated a strong IL-20 staining in synovial membrane tissue of CIA rat joint, and SL irradiation significantly reduced the staining.
Discussion: Since IL-20 has been identified as an important cytokine in the pathogenesis of RA, the reduction of IL-20 expression by SL irradiation may be one of mechanisms in reduction of inflammation in RA joints by SL irradiation suggesting that SL irradiation may be useful for RA therapy.
Rheumatoid arthritis; linear polarized infrared light; IL-20
With the advances in sequencing technology and transcriptome analysis, it is estimated that up to 75 % of the human genome is transcribed into RNAs. This finding prompted intensive investigations on the biological functions of noncoding RNAs and led to very exciting discoveries of microRNAs as important players in disease pathogenesis and therapeutic applications. Research on long noncoding RNAs (lncRNAs) is in its infancy, yet a broad spectrum of biological regulations has been attributed to lncRNAs. Here, we provide a collection of detailed experimental protocols for lncRNA studies, including lncRNA immunoprecipitation, lncRNA pull-down, lncRNA northern blot analysis, lncRNA in situ hybridization, and lncRNA knockdown. We hope that the information included in this chapter can speed up research on lncRNAs biology and eventually lead to the development of clinical applications with lncRNA as novel prognostic markers and therapeutic targets.
Long noncoding RNA; RNA immunoprecipitation; RNA pull-down; In situ hybridization; Northern blot; Short hairpin RNA
Fitness costs associated with resistance to insecticides have been well documented, usually at normal temperature conditions, in many insect species. In this study, using chlorpyrifos-resistant homozygote (RR) and chlorpyrifos-susceptible homozygote (SS) of resistance ace1 allele of Plutella xylostella (DBM), we confirmed firstly that high temperature experience in pupal stage influenced phenotype of wing venation in insecticide-resistant and insecticide-susceptible Plutella xylostella, and SS DBM showed significantly higher thermal tolerance and lower damages of wing veins under heat stress than RR DBM. As compared to SS DBM, RR DBM displayed significantly lower AChE sensitivity to chlorpyrifos, higher basal GSTs activity and P450 production at 25°C, but higher inhibitions on the enzyme activities and P450 production as well as reduced resistance to chlorpyrifos under heat stress. Furthermore, RR DBM displayed significantly higher basal expressions of hsp69s, hsp72s, hsp20,hsp90,Apaf-1, and caspase-7 at 25°C, but lower induced expressions of hsps and higher induced expressions of Apaf-1,caspase-9, and caspase-7 under heat stress. These results suggest that fitness costs of chlorpyrifos resistance in DBM may partly attribute to excess consumption of energy caused by over production of detoxification enzymes and hsps when the proteins are less demanded at conducive environments but reduced expressions when they are highly demanded by the insects to combat environmental stresses, or to excess expressions of apoptotic genes under heat stress, which results in higher apoptosis. The evolutionary and ecological implications of these findings at global warming are discussed.
Caspase; fitness cost of chlorpyrifos resistance; heat shock proteins; Plutella xylostella; resistance-related enzymes; thermal tolerance
Thioredoxin domain-containing 5 (TXNDC5) is overexpressed in a number of human carcinomas. However, the involvement of TXNDC5 in gastric adenocarcinoma remains unclear. In the present study, the immunohistochemical expression and clinicopathological significance of TXNDC5 in gastric adenocarcinoma was investigated. The immunohistochemical expression of TXNDC5 was detected in 54 gastric adenocarcinoma specimens, and the correlation between TXNDC5 and the clinicopathological features was investigated. Of the 54 gastric adenocarcinoma specimens, 30 samples (55.6%) exhibited high TXNDC5 expression. In the adenocarcinoma specimens exhibiting high TXNDC5 expression, the proportion of poorly-differentiated adenocarcinomas was significantly higher than that in specimens exhibiting low TXNDC5 expression (P<0.05). Lymph node metastasis and the depth of tumor invasion in the specimens exhibiting high TXNDC5 expression were significantly higher than that in specimens exhibiting low TXNDC5 expression (P<0.05). The results of a survival analysis revealed that the prognosis of patients exhibiting high TXNDC5 expression was significantly poorer than that of patients exhibiting low TXNDC5 expression (P<0.05). Therefore, the expression of TXNDC5 may correlate with the differentiation, invasion and metastasis of gastric adenocarcinoma. Thus, TXNDC5 may be a tumor-enhancing gene that is involved in gastric cancer.
gastric cancer; thioredoxin domain-containing 5 gene; immunohistochemistry; prognosis
Papaya (Carica papaya L.) is sensitive to low temperature and easy to be subjected to chilling injury, which causes fruit ripening disorder. This study aimed to investigate the relationship between the expression of genes related to ethylene and fruit ripening disorder caused by chilling injury. Papaya fruits were firstly stored at 7°C and 12°C for 25 and 30 days, respectively, then treated with exogenous ethylene and followed by ripening at 25°C for 5 days. Chilling injury symptoms such as pulp water soaking were observed in fruit stored at 7°C on 20 days, whereas the coloration and softening were completely blocked after 25 days, Large differences in the changes in the expression levels of twenty two genes involved in ethylene were seen during 7°C-storage with chilling injury. Those genes with altered expression could be divided into three groups: the group of genes that were up-regulated, including ACS1/2/3, EIN2, EIN3s/EIL1, CTR1/2/3, and ERF1/3/4; the group of genes that were down-regulated, including ACO3, ETR1, CTR4, EBF2, and ERF2; and the group of genes that were un-regulated, including ACO1/2, ERS, and EBF1. The results also showed that pulp firmness had a significantly positive correlation with the expression of ACS2, ACO1, CTR1/4, EIN3a/b, and EBF1/2 in fruit without chilling injury. This positive correlation was changed to negative one in fruit after storage at 7°C for 25 days with chilling injury. The coloring index displayed significantly negative correlations with the expression levels of ACS2, ACO1/2, CTR4, EIN3a/b, ERF3 in fruit without chilling injury, but these correlations were changed into the positive ones in fruit after storage at 7°C for 25 days with chilling injury. All together, these results indicate that these genes may play important roles in the abnormal softening and coloration with chilling injury in papaya.
In order to investigate the prevalence of B.burgdorferi sensu lato in rodents from Jiangxi province of southeastern China. Isolation of B.burgdoferi strains and PCR-based studies were carried out in 204 mice collected from six counties of Jiangxi province in May of 2011 and 2012. The results showed the prevalence of Lyme spirochetal infection among seven species of wild and peridomestic rodents in Jiangxi. 3 strains isolated from 204 mice were all belonged to Borrelia yangze sp.nov. The study firstly showed the role of rodents in maintaining the pathogen of Lyme disease in the environment from Jiangxi province and there existed at least one genotype of Lyme spirochetes in Jiangxi.
B.burgdorferi sensu lato; rodents; Borrelia yangze sp.nov; southeastern China
As a member of the chemokine family, CXCL3 was previously known to participate in many pathophysiological events. However, whether CXCL3 stimulates trophoblast invasion as a key process of preeclampsia pathogenesis remains largely unknown. Therefore, the aim of this study was to investigate this hypothesis and determine the effect of CXCL3 on the first trimester trophoblast. Seventy gravidas were included in this study. ELISA was used to detect CXCL3 plasma levels on preeclampsia and normal pregnant groups. CXCL3 protein and mRNA levels were detected via Western blot and real-time quantitative PCR analysis after immunolocalized in human placenta. Moreover, the CXCL3 function in HTR-8/Svneo was analyzed via WST-1 assay, flow cytometry and invasion test. The plasma CXCL3 level in preeclampsia was significantly higher than that in normal pregnancy. CXCL3 expression was observed in the cytoplasm of placental trophoblasts and vascular endothelium in all groups without significant difference between maternal and fetal sides. In addition, placenta CXCL3 expression in severe preeclampsia was significantly lower than those in normal and mild PE groups. Moreover, exogenous CXCL3 can promote the proliferation and invasion of HTR-8/Svneo; however, its effect on apoptosis remains unclear. In summary, a significant abnormality of plasma CXCL3 level and placental CXCL3 expression was discovered in severe preeclampsia; CXCL3 had a function in trophoblast invasion, which indicated its participation in shallow implantation. Therefore CXCL3 might be involved in severe preeclampsia pathogenesis.
It is well-established that the development of a disease, especially cancer, is a complex process that results from the joint effects of multiple genes involved in various molecular signaling pathways. In this article, we propose methods to discover genes and molecular pathways significantly associated with clinical outcomes in cancer samples. We exploit the natural hierarchal structure of genes related to a given pathway as a group of interacting genes to conduct selection of both pathways and genes. We posit the problem in a hierarchical structured variable selection (HSVS) framework to analyze the corresponding gene expression data. HSVS methods conduct simultaneous variable selection at the pathway (group level) and the gene (within-group) level. To adapt to the overlapping group structure present in the pathway–gene hierarchy of the data, we developed an overlap-HSVS method that introduces latent partial effect variables that partition the marginal effect of the covariates and corresponding weights for a proportional shrinkage of the partial effects. Combining gene expression data with prior pathway information from the KEGG databases, we identified several gene–pathway combinations that are significantly associated with clinical outcomes of multiple myeloma. Biological discoveries support this relationship for the pathways and the corresponding genes we identified.
Bayesian variable selection; hierarchical variable selection; multiple myeloma; overlapping group
Deregulation of apoptosis is a hallmark of human cancer and contributes to therapeutic resistance. Recent advances in cancer genomics reveal a myriad of alterations in key pathways that directly or indirectly increase tumor cell survival. This review will outline the pathways of apoptosis in mammalian cells, and highlight the common alterations of apoptosis regulators found in colon cancer, the role of apoptosis and underlying mechanisms in colon cancer treatment and prevention, including recent advances on investigational agents, such as kinase inhibitors, proteasome inhibitors, HSP90 inhibitors, BH3 mimetics, TRAIL, and IAP antagonists. Topics will also include novel concepts, as well as opportunities and challenges for drug discovery and combination therapy by exploring cancer-specific genetic defects, and therefore selective induction of apoptosis in cancer cells. Although the emphasis is on colon cancer, the main theme and many of the aspects are applicable to other solid tumors.
apoptosis; colon cancer; Bcl-2 family; BH3-only protein; mitochondria; death receptor; TRAIL; EGFR; K-RAS; b-Raf; c-Myc; PI3K; IAPs; targeted therapies; sorafenib; regorafinib; vemurafenib; protesome inhibitors; Hsp90 inhibitors; autophagy; necrosis; BH3 mimetics; SMAC mimetics; NSAIDs; synthetic lethality
Malignant germ cell tumors of the ovary are very rare and account for about 2-5% of all ovarian tumors of germ origin. Most patients are adolescent and young women, approximately two-thirds of them are under 20 years of age, occasionally in postmenopausal women. But clear cell carcinoma usually occurs in older patients (median age: 57-year old), and closely related with endometriosis. Here we report a case of a 55-year old woman with right ovarian mass that discovered by B ultrasonic. Her serum levels of human chorionic gonadotropin (hCG) and α-fetoprotein (AFP) were elevated. Pathological examination revealed the tumor to be a mixed germ cell tumor (yolk sac tumor, embryonal carcinoma and mature teratoma) with clear cell carcinoma in a background of endometriosis. Immunohistochemical staining showed SALL4 and PLAP were positive in germ cell tumor area, hCG, CD30 and OCT4 were positive in epithelial-like cells and giant synctiotrophoblastic cells, AFP, AAT, CD117 and Glyp3 were positive in yolk sac component, EMA and CK7 were positive in clear cell carcinoma, CD10 was positive in endometrial cells of endometriotic area. She was treated with surgery followed by seven courses of chemotherapy. She is well and serum levels of hCG and AFP have been decreased to normal levels.
Mixed germ cell tumor; ovary; clear cell carcinoma
The present study was designed to explore the cross talk between fatty acid synthase (FASN) and HER2 (ErbB2) in ovarian cancer. A total of 60 ovarian cancer patients and 15 normal ovarian tissues were enrolled. Tissue array was conducted by using a tissue microarray instrument. Immunohistochemistry was performed to quantify the expressions of HER2 and FASN. The FASN was detected to be distributed in the cell cytoplasm and was significantly correlated with cancer grade (p = 0.000) and FIGO staging (p = 0.000). Patients with FASN overexpression in ovarian cancer tend to have a worse overall survival rate (p = 0.000). HER2 was also stained to be distributed in the cell cytoplasm associated with higher expression in high-grade cancer. It was also disclosed that FASN expression level is not correlated with HER2 status in ovarian cancer. These results for the first time indicated that a cross talk in FASN and HER2 expressions might be associated with prognosis in malignant ovarian cancer.
Fatty acid synthase; HER2; Ovarian cancer; Clinicopathological factors
In order to efficiently and accurately adjust the shearer traction speed, a novel approach based on Takagi-Sugeno (T-S) cloud inference network (CIN) and improved particle swarm optimization (IPSO) is proposed. The T-S CIN is built through the combination of cloud model and T-S fuzzy neural network. Moreover, the IPSO algorithm employs parameter automation adjustment strategy and velocity resetting to significantly improve the performance of basic PSO algorithm in global search and fine-tuning of the solutions, and the flowchart of proposed approach is designed. Furthermore, some simulation examples are carried out and comparison results indicate that the proposed method is feasible, efficient, and is outperforming others. Finally, an industrial application example of coal mining face is demonstrated to specify the effect of proposed system.
The Yes-associated protein YAP is a downstream effector of the Hippo pathway of cell cycle control which plays important roles in tumorigenesis. Hippo-mediated phosphorylation YAP, mainly at S127, inactivates YAP function. In this study, we define a mechanism for positive regulation of YAP activity that is critical for its oncogenic function. Specifically, we found that YAP is phosphorylated in vitro and in vivo by the cell cycle kinase CDK1 at T119, S289, and S367 during G2/M phase of the cell cycle. We also found that ectopic expression of a phosphomimetic YAP mutant (YAP3D, harboring T119D/S289D/S367D) was sufficient to induce mitotic defects in immortalized epithelial cells, including centrosome amplification, multipolar spindles and chromosome missegregation. Finally, we documented that mitotic phosphorylation of YAP was sufficient to promote cell migration and invasion in a manner essential for neoplastic cell transformation. In support of our findings, CDK1 inhibitors largely suppressed cell motility mediated by activated YAP-S127A but not the phosphomimetic mutant YAP3D. Collectively, our results reveal a previously unrecognized mechanism for controlling the activity of YAP that is crucial for its oncogenic function mediated by mitotic dysregulation.
YAP; Hippo pathway; mitotic phosphorylation; CDK1; mitotic defects
L-Glutamate is a major oxidative fuel for the small intestine. However, few studies have demonstrated the effect of L-glutamate on the intestinal architecture and signaling of amino acids in the small intestine. The aim of this study was to investigate the effects of dietary L-glutamate supplementation on the intestinal architecture and expressions of jejunal mucosa amino acid receptors and transporters in weaning piglets. A total of 120 weaning piglets aged 35±1 days with an average body weight at 8.91±0.45 kg were randomly allocated to two treatments with six replicates of ten piglets each, fed with diets containing 1.21% alanine, or 2% L-glutamate. L-Glutamate supplementation increased the activity of glutamate oxaloacetate transaminase (GOT) in the jejunal mucosa. Also, the mRNA expression level of jejunal mucosa glutamine synthetase (GS) was increased by L-glutamate supplementation. The height of villi in duodenal and jejunal segments, and the relative mRNA expression of occludin and zonula occludens protein-1 (ZO-1) in jejunal mucosa were increased by dietary L-glutamate supplementation. L-Glutamate supplementation increased plasma concentrations of glutamate, arginine, histidine, isoleucine, leucine, methionine, phenylalanine and threonine. L-Glutamate supplementation also increased the relative mRNA expression of the jejunal mucosa Ca2+-sensing receptor (CaR), metabotropic glutamate receptor 1 (mGluR1) and metabotropic glutamate receptor 4 (mGluR4), and neutral amino acid transporter B0-like (SLC1A5) in the jejunal mucosa. These findings suggest that dietary addition of 2% L-glutamate improves the intestinal integrity and influences the expression of amino acid receptors and transporters in the jejunum of weaning, which is beneficial for the improvement of jejunal nutrients for digestion and absorption.
Heat shock protein 90 (Hsp90) is widely overexpressed in cancer cells and believed to be essential for the maintenance of malignant phenotypes. Targeting Hsp90 by small molecules has shown promises in solid and hematological malignancies, which likely involves degradation of client oncoproteins in a cell-type specific manner. In this study, we found that structurally unrelated Hsp90 inhibitors induce DNA damage and apoptosis via p53-dependent induction of PUMA, which indirectly triggers Bax activation and mitochondrial dysfunction in colon cancer cells. Deficiency in PUMA, BAX, or p53 at lesser extent, abrogated 17AAG-induced apoptosis and mitochondrial dysfunction, and enhanced clonogenic cell survival. Furthermore, suppression of p53-dependent p21 induction or enhanced p53 activation synergized with 17AAG to induce PUMA-dependent apoptosis. Finally, PUMA was found to mediate apoptotic and therapeutic responses to the 17AAG analog 17DMAG in xenografts. These results demonstrate an important role of the p53/PUMA/Bax axis in Hsp90 inhibitor-induced killing of p53 WT cells, and have important implications for their clinical applications.
Hsp90 inhibitors; PUMA; p53; apoptosis; colon cancer
For many individuals, daily commuting activities on roadways account for a substantial proportion of total exposure, as well as peak-level exposures, to traffic-related air pollutants (TRAPS) including ultrafine particles, but the health impacts of these exposures are not well-understood. We sought to determine if exposure to TRAPs particles during commuting causes acute oxidative stress in the respiratory tract or changes in heart rate variability (HRV), a measure of autonomic activity.
We conducted a randomized, cross-over trial in which twenty-one young adults took two 1.5-hr rides in a passenger vehicle in morning rush-hour traffic. The subjects wore a powered-air-purifying respirator, and were blinded to high-efficiency particulate air (HEPA) filtration during one of the rides. At time points before and after the rides, we measured HRV and markers of oxidative stress in exhaled breath condensate (EBC) including nitrite, the sum of nitrite and nitrate, malondialdehyde, and 8-isoprostane. We used mixed linear models to evaluate the effect of exposure on EBC and HRV outcomes, adjusting for pre-exposure response levels. We used linear models to examine the effects of particle concentrations on EBC outcomes at post-exposure time points.
Mean EBC nitrite and the sum of nitrite and nitrate were increased from baseline at immediately post-exposure comparing unfiltered to filtered rides (2.11 μM vs 1.70 μM, p = 0.02 and 19.1 μM vs 10.0 μM, p = 0.02, respectively). Mean EBC malondialdehyde (MDA) concentrations were about 10% greater following the unfiltered vs. filtered exposures, although this result was not statistically significant. We found no significant associations between exposure to traffic particles and HRV outcomes at any of the time points. At immediately post-exposure, an interquartile range increase in particle number concentration was associated with statistically significant increases in nitrite (99.4%, 95% CI 32.1% to 166.7%) and nitrite + nitrate (75.7%, 95% CI 21.5% to 130.0%).
Increases in markers of oxidative stress in EBC may represent early biological responses to widespread exposures to TRAPs particles that affect passengers in vehicles on heavily trafficked roadways.
Particles; Traffic; Vehicle emissions; Oxidative stress; Heart rate variability; Exhaled breath condensate; Nitrite; Nitrate
CD133 is a cellular surface glycoprotein that has been reported as a marker for the enrichment of cancer stem cells (CSCs). However, the regulatory mechanism of CD133 remains unknown. CSCs have been proposed to contribute to radioresistance and multi-drug resistance. The elucidation of key regulators of CD133 and CSCs is critical for the development of CSC-targeted therapy. In this study, we showed that Ikarosinhibited the expression of CD133 via direct binding to the CD133 P1 promoter and repressed the tumorigenic and self-renewal capacity of CD133+ cancer stem-like cells in hepatocellular carcinoma (HCC). We found that Ikaros interacted with CtBP as a transcription repressor complex, which inhibited CD133 expression in HCC. We also demonstrated that Ikaros expression was up-regulated by ETS1 which activity was regulated by MAPKs pathway. Furthermore, decreased expression of Ikaroswas significantly associated with poor survival in HCC patients. Overall, our study identifies that Ikaros plays a role as a transcription repressor in HCC and is a new reactivated therapeutic target for the treatment of HCC. Meanwhile, our findings provide evidence that Ikaros could be an attractive inhibitor of the target gene CD133, which reactivates anticancer mechanisms in targeted CSC therapy.
Ikaros; CD133; hepatocellular carcinoma; cancer stem cells
Primary hyperuricemia, an excess of uric acid in the blood, is a major public health problem. In addition to the morbidity that is attributable to gout, hyperuricemia is also associated with metabolic syndrome, hypertension, and cardiovascular disease. This study aims to assess the genetic associations between Apolipoprotein E (APOE) polymorphisms and hyperuricemia in a Chinese population.
A total of 770 subjects (356 hyperuricemic cases and 414 normouricemic controls) were recruited from the Ningxia Hui Autonomous Region, China. A physical examination was performed and fasting blood was collected for biochemical tests, including determination of the levels of serum lipid, creatinine, and uric acid. Multi-ARMS PCR was applied to determine the APOE genotypes, followed by an investigation of the distribution of APOE genotypes and alleles frequencies in the controls and cases.
The frequencies of the APOE-ε2ε3 genotype (17.70% vs. 10.39%, P = 0.003) and the APOE-ε2 allele (10.53% vs. 5.80%, P = 0.001) were significantly higher in the hyperuricemic group than in the normouricemic group. Furthermore, male cases were more likely to have the APOE-ε2ε3 genotype and APOE-ε2 allele, compared with male controls. In both Han and Hui subjects, cases were more likely to have the APOE-ε2ε3 genotype and the APOE-ε2 allele compared with controls. Furthermore, multivariate logistic regression showed that carriers of the APOE-ε2ε3 genotype (P = 0.001, OR = 2.194) and the ε2 allele (P = 0.001, OR = 2.099) were significantly more likely to experience hyperuricemia than carriers of the ε3/ε3 genotype and the ε3 allele after adjustment for sex, body mass index (BMI), diastolic blood pressure (DBP), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), creatinine (Cr) and fasting blood glucose(FBG).
The APOE-ε2ε3 genotype and the APOE-ε2 allele are associated with serum uric acid levels in Chinese subjects, indicating that individuals carrying the APOE-ε2 allele have a higher risk of hyperuricemia than non-carriers.