Polymorphisms in immunity-related GTPase family M (IRGM) gene may be associated with inflammatory bowel disease (IBD) by affecting autophagy. However, the genetic association studies on three common variants in IRGM gene (rs13361189, rs4958847 and rs10065172) have shown inconsistent results.
Methodology/ Principal Findings
The PubMed and Embase were searched up to June 5, 2013 for studies on the association between three IRGM polymorphisms and IBD risk. Data were extracted and the odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Finally, we performed a meta-analysis of 25 eligible studies in 3 SNPs located at IRGM gene by using a total of 20590 IBD cases and 27670 controls. The analysis showed modest significant association for the rs13361189, rs4958847 and rs10065172 variants in Crohn’s disease (CD): the risk estimates for the allele contrast were OR=1.306 (1.200-1.420), p=5.2×10-10, OR=1.182 (1.082-1.290), p=0.0002, and OR=1.248 (1.057-1.473), p=0.009 respectively (still significant when the p value was Bonferroni adjusted to 0.017). When stratified by ethnicity, significantly increased CD risk was observed in Europeans, but not in Asians. Conversely, there was no association of rs13361189 or rs4958847 variant with risk of ulcerative colitis (UC).
These results indicated that autophagy gene-IRGM polymorphisms appear to confer susceptibility to CD but not UC, especially in Europeans. Our data may provide further understanding of the role of autophagy in the pathogenesis of CD.
An EST sequence, designated JnRAP2-like, was isolated from tissue at the heartwood/sapwood transition zone (TZ) in black walnut (Juglans nigra L). The deduced amino acid sequence of JnRAP2-like protein consists of a single AP2-containing domain with significant similarity to conserved AP2/ERF DNA-binding domains in other species. Based on multiple sequence alignment, JnRAP2-like appears to be an ortholog of RAP2.6L (At5g13330), which encodes an ethylene response element binding protein in Arabidopsis thaliana. Real-time PCR revealed that the JnRAP2-like was expressed most abundantly in TZ of trees harvested in fall when compared with other xylem tissues harvested in the fall or summer. Independent transgenic lines over-expressing JnRAP2-like in Arabidopsis developed dramatic ethylene-related phenotypes when treated with 50 µM methyl jasmonate (MeJA). Taken together, these results indicated that JnRAP2-like may participate in the integration of ethylene and jasmonate signals in the xylem and other tissues. Given the role of ethylene in heartwood formation, it is possible JnRAP2-like expression in the transition zone is part of the signal transduction pathway leading to heartwood formation in black walnut.
AIM: To investigate the effects of photodynamic therapy with quantum dots-arginine-glycine-aspartic acid (RGD) probe as photosensitizer on the proliferation and apoptosis of pancreatic carcinoma cells.
METHODS: Construction of quantum dots-RGD probe as photosensitizer for integrin-targeted photodynamic therapy was accomplished. After cells were treated with photodynamic therapy (PDT), the proliferation of SW1990 cells were measured by methyl thiazolyl tetrazolium assay. Morphologic changes, cell cycle retardance and apoptosis were observed under fluoroscope and flow cytometry. The expression of myeloid cell leukemia-1 (Mcl-1), protein kinase B (Akt) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA were detected by reverse transcription-polymerase chain reaction. The amount of reactive oxygen species were also evaluated by fluorescence probe.
RESULTS: The photodynamic therapy with quantum dots-RGD probe as photosensitizer significantly inhibited cell proliferation (P < 0.01). Apoptotic cells and morphologic changes could be found under optical microscope. The FCM revealed PDT group had more significant cell apoptosis rate compared to control cells (F = 130.617, P < 0.01) and cell cycle G0/G1 and S retardance (P < 0.05) compared to control cells. The expression of Mcl-1 and Akt mRNA were down-regulated, while expression of TRAIL mRNA was up-regulated after cells treated with PDT. PDT group had more significant number of cells producing reactive oxygen species compared to control cells (F = 3262.559, P < 0.01).
CONCLUSION: The photodynamic therapy with quantum dots-RGD probe as photosensitizer significantly inhibits cell proliferation and increases apoptosis in SW1990 cells.
Pancreatic carcinoma; Targeted probe; Photodynamic therapy; Apoptosis; Reactive oxygen species
TLR3 is known to respond to dsRNA from viruses, apoptotic cells, and/or necrotic cells. Dying cells are a rich source of ligands that can activate TLRs, such as TLR3. TLR3 expressed in the liver is likely to be a mediator of innate activation and inflammation in the liver. The importance of this function of TLR3 during acute hepatitis has not previously been fully explored. We used the mouse model of Con A-induced hepatitis and observed a novel role for TLR3 in hepatocyte damage in the absence of an exogenous viral stimulus. Interestingly, TLR3 expression in liver mononuclear cells and sinus endothelial cells was up-regulated after Con A injection and TLR3−/− mice were protected from Con A-induced hepatitis. Moreover, splenocytes from TLR3−/− mice proliferated less to Con A stimulation in the presence of RNA derived from damaged liver tissue compared with wild-type (WT) mice. To determine the relative contribution of TLR3 expression by hematopoietic cells or nonhematopoietic to liver damage during Con A-induced hepatitis, we generated bone marrow chimeric mice. TLR3−/− mice engrafted with WT hematopoietic cells were protected in a similar manner to WT mice reconstituted with TLR3−/− bone marrow, indicating that TLR3 signaling in both nonhematopoietic and hematopoietic cells plays an important role in mediating liver damage. In summary, our data suggest that TLR3 signaling is necessary for Con A-induced liver damage in vivo and that TLR3 regulates inflammation and the adaptive T cell immune response in the absence of viral infection.
During plant embryogenesis, once the suspensor organ of the plant embryo has fulfilled its role, it is removed by programmed cell death (PCD). The pro-death cathepsin protease NtCP14 initiates this PCD, but is inhibited by the cystatin NtCYS until the suspensor function is fulfilled.
Plant zygote divides asymmetrically into an apical cell that develops into the embryo proper and a basal cell that generates the suspensor, a vital organ functioning as a conduit of nutrients and growth factors to the embryo proper. After the suspensor has fulfilled its function, it is removed by programmed cell death (PCD) at the late stages of embryogenesis. The molecular trigger of this PCD is unknown. Here we use tobacco (Nicotiana tabacum) embryogenesis as a model system to demonstrate that the mechanism triggering suspensor PCD is based on the antagonistic action of two proteins: a protease inhibitor, cystatin NtCYS, and its target, cathepsin H-like protease NtCP14. NtCYS is expressed in the basal cell of the proembryo, where encoded cystatin binds to and inhibits NtCP14, thereby preventing precocious onset of PCD. The anti-cell death effect of NtCYS is transcriptionally regulated and is repressed at the 32-celled embryo stage, leading to increased NtCP14 activity and initiation of PCD. Silencing of NtCYS or overexpression of NtCP14 induces precocious cell death in the basal cell lineage causing embryonic arrest and seed abortion. Conversely, overexpression of NtCYS or silencing of NtCP14 leads to profound delay of suspensor PCD. Our results demonstrate that NtCYS-mediated inhibition of NtCP14 protease acts as a bipartite molecular module to control initiation of PCD in the basal cell lineage of plant embryos.
Similar to animals, plants eliminate tissues and organs that have transient function via programmed cell death (PCD). This is especially apparent during plant embryogenesis, when a plant zygote divides into an apical cell, which develops into a mature embryo, and a basal cell, which generates a single organ called the suspensor. During early seed development, the suspensor connects the embryo to the surrounding seed tissues and transports the nutrients and hormones required for its early development. Once its functions are fulfilled, the suspensor is subsequently eliminated by PCD. In this study, we answer a long-standing question in the field by elucidating the mechanism that is responsible for initiating suspensor PCD at a specific time during embryogenesis. Our findings show that in tobacco plant embryos, suspensor PCD is controlled by two antagonistically acting proteins—the pro-death cathepsin protease NtCP14 and its inhibitor cystatin NtCYS, which co-localize to the basal-most cell of the suspensor. High expression levels of NtCYS during early embryogenesis confer suspensor growth and viability by suppressing NtCP14 activity. When the suspensor ceases to grow, NtCYS expression is downregulated, leading to increased NtCP14 activity and to the initiation of PCD. The genetic modulation of this NtCYS/NtCP14 expression ratio either delays or hastens suspensor PCD, demonstrating its indispensable role in plant embryo development.
Isocitrate dehydrogenase isoforms 1 and 2 (IDH1 and IDH2) mutations have received considerable attention since the discovery of their relation with human gliomas. The predictive value of IDH1 and IDH2 mutations in gliomas remains controversial. Here, we present the results of a meta-analysis of the associations between IDH mutations and both progression-free survival (PFS) and overall survival (OS) in gliomas. The interrelationship between the IDH mutations and MGMT promoter hypermethylation, EGFR amplification, codeletion of chromosomes 1p/19q and TP53 gene mutation were also revealed.
Methodology and Principal Findings
An electronic literature search of public databases (PubMed, Embase databases) was performed. In total, 10 articles, including 12 studies in English, with 2,190 total cases were included in the meta-analysis. The IDH mutations were frequent in WHO grade II and III glioma (59.5%) and secondary glioblastomas (63.4%) and were less frequent in primary glioblastomas (7.13%). Our study provides evidence that IDH mutations are tightly associated with MGMT promoter hypermethylation (P<0.001), 1p/19q codeletion (P<0.001) and TP53 gene mutation (P<0.001) but are mutually exclusive with EGFR amplification (P<0.001). This meta-analysis showed that the combined hazard ratio (HR) estimate for overall survival and progression-free survival in patients with IDH mutations was 0.33 (95% CI: 0.25–0.42) and 0.38 (95% CI: 0.21–0.68), compared with glioma patients whose tumours harboured the wild-type IDH. Subgroup analyses based on tumour grade also revealed that the presence of IDH mutations was associated with a better outcome.
Our study suggests that IDH mutations, which are closely linked to the genomic profile of gliomas, are potential prognostic biomarkers for gliomas.
Different forest types exert essential impacts on soil physical-chemical characteristics by dominant tree species producing diverse litters and root exudates, thereby further regulating size and activity of soil microbial communities. However, the study accuracy is usually restricted by differences in climate, soil type and forest age. Our objective is to precisely quantify soil microbial biomass, basal respiration and enzyme activity of five natural secondary forest (NSF) types with the same stand age and soil type in a small climate region and to evaluate relationship between soil microbial and physical-chemical characters. We determined soil physical-chemical indices and used the chloroform fumigation-extraction method, alkali absorption method and titration or colorimetry to obtain the microbial data. Our results showed that soil physical-chemical characters remarkably differed among the NSFs. Microbial biomass carbon (Cmic) was the highest in wilson spruce soils, while microbial biomass nitrogen (Nmic) was the highest in sharptooth oak soils. Moreover, the highest basal respiration was found in the spruce soils, but mixed, Chinese pine and spruce stands exhibited a higher soil qCO2. The spruce soils had the highest Cmic/Nmic ratio, the greatest Nmic/TN and Cmic/Corg ratios were found in the oak soils. Additionally, the spruce soils had the maximum invertase activity and the minimum urease and catalase activities, but the maximum urease and catalase activities were found in the mixed stand. The Pearson correlation and principle component analyses revealed that the soils of spruce and oak stands obviously discriminated from other NSFs, whereas the others were similar. This suggested that the forest types affected soil microbial properties significantly due to differences in soil physical-chemical features.
The aim of this study was to assess the effectiveness of neuroendoscopy compared with non-neuroendoscopic procedures for treating patients with arachnoid membrane cysts in the lateral ventricles.
The medical records of 28 patients with arachnoid membrane cysts in the lateral ventricles who were treated with neuroendoscopy and 39 such patients treated with non-neuroendoscopic techniques using classic treatment procedures were reviewed. The neuroendoscopic approach combined craniotomy, corticectomy, lesion resection and cyst ventriculostomy or cyst cisternostomy to restore normal cerebrospinal fluid circulation. The non-neuroendoscopic techniques included craniotomy, corticectomy, and lesion resection performed under a microscope. Clinical outcomes of symptoms and cyst size change on imaging were compared between the two treatment groups during follow-up (range: 1–5 years).
Patients in the neuroendoscopy group had significantly less blood loss (P < 0.001) and shorter operative time (P < 0.001), better marked improvement in symptoms (64.3% vs. 5.1%, respectively), and a higher total resection rate (92.9% vs. 66.7%; P = 0.011) compared with the patients in the non-neuroendoscopy group. In the neuroendoscopy group there was no cyst recurrence whereas in the non-neuroendoscopy group 8 (20.5%) patients had cyst recurrence. However, all patients in the neuroendoscopy group had postoperative transient fever and 8 (28.6%) patients had subdural fluid accumulation which was treated and subsequently resolved during follow-up. These symptoms did not occur in the non-neuroendoscopy group.
We found that neuroendoscopic therapy for arachnoid cysts in the lateral ventricles was more efficacious than non-neuroendoscopic methods. Our results indicate that neuroendoscopy may produce better clinical outcomes than non-neuroendoscopic procedures in treating patients with arachnoid cysts in the lateral ventricles.
Neuroendoscope; Lateral ventricle; Arachnoid cyst; Intracranial lesion
Marek's disease virus (MDV) Chinese strain GX0101, isolated in 2001 from a vaccinated flock of layer chickens with severe tumors, was the first reported recombinant MDV field strain with one reticuloendotheliosis virus (REV) long terminal repeat (LTR) insert. GX0101 belongs to very virulent MDV (vvMDV) but has higher horizontal transmission ability than the vvMDV strain Md5. The complete genome sequence of GX0101 is 178,101 nucleotides (nt) and contains only one REV-LTR insert at a site 267 nt upstream of the sorf2 gene. Moreover, GX0101 has 5 repeats of a 217-nt fragment in its terminal repeat short (TRS) region and 3 repeats in internal repeat short (IRS) region, compared to the other 10 strains with only 1 or 2 repeats in both TRS and IRS.
Genetic variations in DNA double-strand break repair genes can influence the ability of a cell to repair damaged DNA and alter an individual’s susceptibility to cancer. We studied whether polymorphisms in DNA double-strand break repair genes are associated with an increased risk of glioma development.
We genotyped 10 potentially functional single nucleotide polymorphisms (SNPs) in 7 DNA double-strand break repair pathway genes (XRCC3, BRCA2, RAG1, XRCC5, LIG4, XRCC4 and ATM) in a case–control study including 384 glioma patients and 384 cancer-free controls in a Chinese Han population. Genotypes were determined using the OpenArray platform.
In the single-locus analysis there was a significant association between gliomas and the LIG4 rs1805388 (Ex2 +54C>T, Thr9Ile) TT genotype (adjusted OR, 3.27; 95% CI, 1.87-5.71), as well as the TC genotype (adjusted OR, 1.62; 95% CI, 1.20-2.18). We also found that the homozygous variant genotype (GG) of XRCC4 rs1805377 (IVS7-1A>G, splice-site) was associated with a significantly increased risk of gliomas (OR, 1.77; 95% CI, 1.12-2.80). Interestingly, we detected a significant additive and multiplicative interaction effect between the LIG4 rs1805388 and XRCC4 rs1805377 polymorphisms with an increasing risk of gliomas. When we stratified our analysis by smoking status, LIG4 rs1805388 was associated with an increased glioma risk among smokers.
These results indicate for the first time that LIG4 rs1805388 and XRCC4 rs1805377, alone or in combination, are associated with a risk of gliomas.
DNA double-strand breaks (DSBs); Single nucleotide polymorphisms (SNPs); Glioma; Susceptibility
Lipocalin-2 (LCN2) is induced in conditions of obesity and Type 2 diabetes (T2DM). IFNγ and TNFα induce LCN2 expression in adipocytes in a manner that is dependent on transcription. The effects of these cytokines are additive. IFNγ induced STAT1 and TNFα induced NF-κB play a role in the induction of LCN2. In the LCN2 promoter, one NF-κB binding site and four STAT1 binding sites were identified by in silico and in vitro approaches. MAPK (ERKs 1 and 2) activation was required for the IFNγ and TNFα induction of LCN2 expression, but did not affect the nuclear translocation or DNA binding activity of STAT1 or NF-κB. The NF-κB binding site and the STAT1 binding sites we identified in vitro were confirmed by in vivo studies. Transfection of a LCN2 promoter/luciferase reporter construct confirmed acute activation by IFNγ and TNFα. Our studies identify mechanisms involved in the actions of cytokines secreted from immune cells in adipose tissue that induce LCN2 expression in conditions of obesity and T2DM.
Lipocalin-2; STAT1; NF-κB; ERKs; Adipocyte; TNFα; IFNγ
The aim of this study was to evaluate the efficacy and safety of percutaneous microwave coagulation therapy (PMCT) followed by 125I seed brachytherapy for VX2 liver cancer in rabbits. Eighty New Zealand rabbits were injected with suspensions of VX2 tumor cells to create an animal model. The rabbits were randomly divided into 4 groups (n=20); the control, PMCT, 125I seed brachytherapy and combination groups. Group A was treated with PMCT at 40 W for 120 sec, group B was treated with 125I seed brachytherapy and group C was treated with PMCT followed by 125I seed brachytherapy. Group D were not treated and served as the control group. At 21 days after treatment, the rabbits were sacrificed for pathological assessment. The complete tumor necrosis rate was 19 out of 20 tumors (95%) in group C, 6 (30%) in group A, 0 (0%) in group B and 0 (0%) in the control group. The complete tumor necrosis rate was observed to be significantly different between groups C and A, and between groups C and B (P<0.01). No intraheptic metastasis occurred in group C, compared with an incidence of 7 (35%) in group A, 2 (10%) in group B and 20 (100%) in the control group. Between groups C and A, and between groups C and D, the intraheptic metastasis rate was statistically significant (P<0.01). PMCT followed by 125I seed brachytherapy increased the rate of carcinoma necrosis and decreased carcinoma metastasis in the VX2 rabbit model. This combined treatment is a safe, effective and minimally invasive therapeutic option for liver cancer.
liver cancer; microwave; 125I seed; computed tomography; animal model
Neuropeptide S (NPS) is a newly identified neuromodulator located in the brainstem and regulates various biological functions by selectively activating the NPS receptors (NPSR). High level expression of NPSR mRNA in the olfactory cortex suggests that NPS-NPSR system might be involved in the regulation of olfactory function. The present study was undertaken to investigate the effects of intracerebroventricular (i.c.v.) injection of NPS or co-injection of NPSR antagonist on the olfactory behaviors, food intake, and c-Fos expression in olfactory cortex in mice. In addition, dual-immunofluorescence was employed to identify NPS-induced Fos immunereactive (-ir) neurons that also bear NPSR. NPS (0.1–1 nmol) i.c.v. injection significantly reduced the latency to find the buried food, and increased olfactory differentiation of different odors and the total sniffing time spent in olfactory habituation/dishabituation tasks. NPS facilitated olfactory ability most at the dose of 0.5 nmol, which could be blocked by co-injection of 40 nmol NPSR antagonist [D-Val5]NPS. NPS administration dose-dependently inhibited food intake in fasted mice. Ex-vivo c-Fos and NPSR immunohistochemistry in the olfactory cortex revealed that, as compared with vehicle-treated mice, NPS markedly enhanced c-Fos expression in the anterior olfactory nucleus (AON), piriform cortex (Pir), ventral tenia tecta (VTT), the anterior cortical amygdaloid nucleus (ACo) and lateral entorhinal cortex (LEnt). The percentage of Fos-ir neurons that also express NPSR were 88.5% and 98.1% in the AON and Pir, respectively. The present findings demonstrated that NPS, via selective activation of the neurons bearing NPSR in the olfactory cortex, facilitates olfactory function in mice.
Adipocytes play important roles in lipid storage, energy homeostasis and whole body insulin sensitivity. Studies in the last two decades have identified the hormones and cytokines that activate specific STATs in adipocytes in vitro and in vivo. Five of the seven STAT family members are expressed in adipocyte (STATs 1, 3, 5A, 5B and 6). Many transcription factors, including STATs, have been shown to play an important role in adipose tissue development and function. This review will summarize the importance of adipocytes, indicate the cytokines and hormones that utilize the JAK-STAT signaling pathway in fat cells and focus on the identification of STAT target genes in mature adipocytes. To date, specific target genes have been identified for STATs, 1, 5A and 5B, but not for STATs 3 and 6.
adipocytes; STAT; adipocyte; adipose tissue; transcription
Primary Fallopian tube carcinoma (PFTC) is a rare but highly aggressive disease. Currently, treatments are similar to those used in epithelial ovarian carcinoma (EOC), however, there are distinct differences between the two diseases. PFTC tends to recur in the retroperitoneal nodes and distant sites more often than EOC. Limited literature with regard to effective agents in platinum-resistant and -refractory (Pt-R) disease exists, particularly after two lines of consecutive treatment. In this case report, a 47-year-old female with PFTC exhibited recurrence in the liver after postoperative chemotherapy. The patient received paclitaxel and cisplatin combination as first-line chemotherapy and topotecan as a second-line treatment, which is considered platinum-refractory. After the second-line treatment failed, this patient received a gemcitabine plus cisplatin combination as third-line chemotherapy for a total of 6 cycles. The liver metastases regressed rapidly and completely. The patient’s progression-free survival (PFS) was 10 months and overall survival (OS) was 45 months. In conclusion, gemcitabine and cisplatin combination is an effective regimen for refractory PFTC even after the failure of two previous lines of consecutive chemotherapy and this warrants further independent investigation.
primary Fallopian tube carcinoma; gemcitabine; refractory; complete remission
Our previous study reported that both glycoproteins gB and gH of the herpesvirus Marek's disease virus (MDV) contain eleven potential heptad repeat domains. These domains overlap with α-helix-enriched hydrophobic regions, including the gH-derived HR1 (gHH1) and HR3 (gHH3) and gB-derived HR1 (gBH1) regions, which demonstrate effective antiviral activity, with 50% inhibitory concentrations (IC50) of less than 12 µM. Plaque formation and chicken embryo infection assays confirmed these results. In this study, biochemical and biophysical analyses detected potential interactions between these peptides. gHH1, gHH3, and gBH1 were found to interact with each other in pairs. The complex formed by gHH3 and gBH1 showed the most stable interaction at a molar ratio of 1:3, the binding between gHH1 and gBH1 was relatively weak, and no interaction was observed between the three HR peptides. These results indicate that gHH3 and gBH1 are likely the key contributors to the interaction between gB and gH. Furthermore, each HR peptide from herpesvirus glycoproteins did not effectively inhibit virus infection compared with peptides from a class I enveloped virus. In this report, the HR mimic peptide modified with a double glutamic acid (EE) or a double lysine (KK) at the non-interactive sites (i.e., solvent-accessible sites) did not noticeably affect the antiviral activity compared with the wild-type HR peptide, whereas tandem peptides from gH-derived gHH1 and gB-derived gBH1 (i.e., gBH1-Linker-gHH1) produced efficient antiviral effects, unlike the individual peptides. The proposed interpretation of inhibition of entry has been addressed. Our results support the hypothesis that the interaction domain between glycoproteins gH and gB is a critical target in the design of inhibitors of herpesvirus infection.
SMC1A (structural maintenance of chromosomes 1A), which encodes a structural subunit of the cohesin protein complex, is necessary for the process of sister chromatid cohesion during the cell cycle. Mutation and deregulation of SMC1A are highly relevant to diverse human diseases, including Cornelia de Lange syndrome and malignant carcinomas. In order to further investigate the role of SMC1A in the oncogenesis of lung cancer, SMC1A-specific short hairpin RNA (shRNA)-expressing lentivirus (Lv-shSMC1A) was constructed and used to infect A549 and H1299 cells. SMC1A mRNA and protein expression levels were downregulated in A549 and H1299 cells as demonstrated by real-time PCR and western blot assays. We found that SMC1A inhibition resulted in significantly impaired proliferation and colony formation as well as reduced invasiveness of tumor cells. Notably, Lv-shSMC1A-infected cancer cells exhibited a greater proportion of cells in the G0/G1 phase, but a lower proportion of S phase cells, compared to the parent or Lv-shCon infected cancer cells. Moreover, a greater proportion of sub-G1 apoptotic cells was observed in Lv-shSMC1A-infected cells. These results suggest that SMC1A is a novel proliferation regulator that promotes the growth of lung cancer cells, and that down-regulation of SMC1A expression induces growth suppression of A549 and H1299 cells via G1/S cell cycle phase arrest and apoptosis pathways. Therefore, SMC1A may serve as a new molecular target for lung cancer therapy.
SMC1A; proliferation; shRNA; lung cancer
Interferon-γ (IFN-γ) is regarded as a potent antitumor agent, but its clinical application is limited by its short half-life and significant side effects. In this paper, we tried to develop IFN-γ gene therapy by a replication defective adenovirus encoding the human IFN-γ (Ad-IFNγ), and evaluate the antitumoral effects of Ad-IFNγ on nasopharyngeal carcinoma (NPC) cell lines in vitro and in xenografts model.
The mRNA levels of human IFN-γ in Ad-IFNγ-infected NPC cells were detected by reverse transcription-polymerase chain reaction (RT-PCR), and IFN-γ protein concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in the culture supernatants of NPC cells and tumor tissues and bloods of nude mice treated with Ad-IFNγ. The effects of Ad-IFNγ on NPC cell proliferation was determined using MTT assay, cell cycle distribution was determined by flow cytometry analysis for DNA content, and cells apoptosis were analyzed by Annexin V-FITC/7-AAD binding assay and hoechst 33342/PI double staining. The anti-tumor effects and toxicity of Ad-IFNγ were evaluated in BALB/c nude mice carrying NPC xenografts.
The results demonstrated that Ad-IFNγ efficiently expressed human IFN-γ protein in NPC cell lines in vitro and in vivo. Ad-IFNγ infection resulted in antiproliferative effects on NPC cells by inducing G1 phase arrest and cell apoptosis. Intratumoral administration of Ad-IFNγ significantly inhibited the growth of CNE-2 and C666-1 cell xenografts in nude mice, while no significant toxicity was observed.
These findings indicate IFN-γ gene therapy mediated by replication defective adenoviral vector is likely a promising approach in the treatment of nasopharyngeal carcinoma.
Gene therapy; Interferon-γ; Nasopharyngeal carcinoma; Adenoviral vector
The extrapontine myelinolysis of osmotic demyelination syndrome (ODS) is a well-known but uncommon disorder of the central nervous system. Although the mechanism is not fully understood and the treatment is controversial, hyponatremia is probably considered to be the main pathophysiological basis. There are few reports of ODS caused by a sellar lesion. Here we present a case of suprasellar arachnoid cyst that developed extrapontine myelinolysis of ODS after a neuroendoscopic treatment procedure. It is suggested that patients with suprasellar lesions are at risk of developing extrapontine myelinolysis of ODS and correction of hyponatremia in these cases should be closely monitored.
The oxidative stress mechanism is of particular interest in the pathogenesis of glioma, given the high rate of oxygen metabolism in the brain. Potential links between polymorphisms of antioxidant genes and glioma risk are currently unknown. We therefore investigated the association between polymorphisms in antioxidant genes and glioma risk.
We examined 16 single nucleotide polymorphisms (SNPs) of 9 antioxidant genes (GPX1, CAT, PON1, NQO1, SOD2/MnSOD, SOD3, and NOS1*2*3) in 384 glioma and 384 control cases in a Chinese hospital-based case–control study. Genotypes were determined using the OpenArray platform, which employs the chip-based Taq-Man genotyping technology. The adjusted odds ratio (OR) and 95% confidence interval (CI) were estimated using unconditional logistic regression.
Using single-locus analysis, we identified four SNPs (SOD2 V16A, SOD3 T58A, GPX1 -46 C/T, and NOS1 3’-UTR) that were significantly associated with the risk of glioma development. To assess the cumulative effects, we performed a combined unfavourable genotype analysis. Compared with the reference group that exhibited no unfavourable genotypes, the medium- and high-risk groups exhibited a 1.86-fold (95% CI, 1.30-2.67) and a 4.86-fold (95% CI, 1.33-17.71) increased risk of glioma, respectively (P-value for the trend < 0.001).
These data suggest that genetic variations in oxidative stress genes might contribute to the aetiology of glioma.
Oxidative stress; Single nucleotide polymorphism; Glioma; SOD2; SOD3; GPX1; NOS1
In the recent years, China's auto industry develops rapidly, thus bringing a series of burdens to society and environment. This paper uses Logistic model to simulate the future trend of China's vehicle population and finds that China's auto industry would come into high speed development time during 2020–2050. Moreover, this paper predicts vehicles' fuel consumption and exhaust emissions (CO, HC, NOx, and PM) and quantificationally evaluates related industry policies. It can be concluded that (1) by 2020, China should develop at least 47 million medium/heavy hybrid cars to prevent the growth of vehicle fuel consumption; (2) China should take the more stringent vehicle emission standard V over 2017–2021 to hold back the growth of exhaust emissions; (3) developing new energy vehicles is the most effective measure to ease the pressure brought by auto industry.
E2Fs are a family of transcription factors that regulate proliferation, differentiation and apoptosis in many cell types. E2F-1 is the prototypical E2F and the family member that has most often been implicated in also mediating apoptosis. To better understand the role of E2F-1 in mediating cardiomyocyte injury we initially analyzed E2F family member expression after ischemia/reperfusion (I/R) in vivo or simulated ischemia in vitro. I/R injury in vivo caused a 3.4-fold increase specifically in E2F-1 protein levels. Expression of other E2F family members did not change. To establish the role of E2F-1 in I/R we examined the response of germline deleted E2F-1 mice to I/R injury. Infarct size as a percentage of the area at risk was decreased 39.8% in E2F-1−/− mice compared to E2F-1+/+ controls. Interestingly, expression of classic, E2F-1 apoptotic target genes was not altered in E2F-1 null cardiomyocytes after I/R. However, upregulation of the primary member of the Forkhead family of transcription factors, FoxO-1a, was attenuated. Consistent, with a role for FoxO-1a as an important target of E2F-1 in I/R, a number of proapoptotic FoxO-1a target genes were also altered. These results suggest that E2F-1 and FoxO-1a belong to a complex transcriptional network that may modulate myocardial cell death during I/R injury.
ABCC6 genetic deficiency underlies Pseudoxanthoma elasticum (PXE) in humans, characterized by ectopic calcification, and early cardiac disease. The spectrum of PXE has been noted in Abcc6 deficient mice, including dystrophic cardiac calcification. We tested the role of Abcc6 in response to cardiac ischemia-reperfusion (I/R) injury.
Methods and results
To determine the role of Abcc6 in cardio-protection we induced ischemic injury in mice in vivo by occluding the left anterior descending artery (30min) followed by reperfusion (48hrs). Infarct size was increased in Abcc6 deficient mice compared to wild type controls. Additionally, an Abcc6 transgene significantly reduced infarct size on the background of a naturally occurring Abcc6 deficiency. There were no differences in cardiac calcification following I/R, but increased cardiac apoptosis was noted in Abcc6 deficient mice. Previous studies have implicated the BMP signaling pathway in directing calcification, and here we show the BMP responsive transcription factors, pSmad1/5/8 were increased in hearts of Abcc6 mice. Consistent with this finding, BMP4 and BMP9 were increased, and ALK2 and Endoglin were down-regulated in cardiac extracts from Abcc6 deficient mice versus controls.
These data identify Abcc6 as a novel modulator of cardiac myocyte survival after I/R. This cardio-protective mechanism may involve inhibition of the BMP signaling pathway, which modulates apoptosis.
ABCC6; Pseudoxanthoma elasticum; BMP signaling; apoptosis; cardiac ischemia-reperfusion (I/R)
Paeoniflorin (PF), the principal component of Paeoniae Radix prescribed in traditional Chinese medicine, has been reported to exhibit many pharmacological effects including protection against ischemic injury. However, the mechanisms underlying the protective effects of PF on cerebral ischemia are still under investigation. The present study showed that PF treatment for 14 days could significantly inhibit transient middle cerebral artery occlusion (MCAO)-induced over-activation of astrocytes and microglia, and prevented up-regulations of pro-inflamamtory mediators (TNFα, IL-1β, iNOS, COX2 and 5-LOX) in plasma and brain. Further study demonstrated that chronic treatment with PF suppressed the activations of JNK and p38 MAPK, but enhanced ERK activation. And PF could reverse ischemia-induced activation of NF-κB signaling pathway. Moreover, our in vitro study revealed that PF treatment protected against TNFα-induced cell apoptosis and neuronal loss. Taken together, the present study demonstrates that PF produces a delayed protection in the ischemia-injured rats via inhibiting MAPKs/NF-κB mediated peripheral and cerebral inflammatory response. Our study reveals that PF might be a potential neuroprotective agent for stroke.
To investigate the effects of inflammation on perfusion regulation and brain volumes in type 2 diabetes.
RESEARCH DESIGN AND METHODS
A total of 147 subjects (71 diabetic and 76 nondiabetic, aged 65.2 ± 8 years) were studied using 3T anatomical and continuous arterial spin labeling magnetic resonance imaging. Analysis focused on the relationship between serum soluble vascular and intercellular adhesion molecules (sVCAM and sICAM, respectively, both markers of endothelial integrity), regional vasoreactivity, and tissue volumes.
Diabetic subjects had greater vasoconstriction reactivity, more atrophy, depression, and slower walking. Adhesion molecules were specifically related to gray matter atrophy (P = 0.04) and altered vasoreactivity (P = 0.03) in the diabetic and control groups. Regionally, sVCAM and sICAM were linked to exaggerated vasoconstriction, blunted vasodilatation, and increased cortical atrophy in the frontal, temporal, and parietal lobes (P = 0.04–0.003). sICAM correlated with worse functionality.
Diabetes is associated with cortical atrophy, vasoconstriction, and worse performance. Adhesion molecules, as markers of vascular health, have been indicated to contribute to altered vasoregulation and atrophy.