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Bladder cancer (BCa) is the most common tumor of the urinary system. Chronic inflammation in the papillary urothelial neoplasm of low malignant potential (PUNLMP) may contribute to carcinogenesis, including that of BCa, via poorly understood mechanisms. In this study, we show that the lymphotoxin β receptor (LTβR) is upregulated in BCa via activation of the canonical and non-canonical nuclear factor-κB (NF-κB) pathways. The mRNA expression of LTβR in 81 BCa, 10 chronic cystitis and 23 healthy bladder mucosa tissues was investigated by reverse transcription-fluorescent quantitative polymerase chain reaction (RT-FQ-PCR), and protein expression was studied in 73 BCa, 30 cystitis and 15 healthy paraffin-embedded tissue sections by immunohistochemistry. Both LTβR mRNA and protein were upregulated in BCa and cystitis compared to the healthy group (P<0.05). The mRNA level of the downstream NF-κB canonical pathway p65 gene and of the non-canonical pathway RelB gene were higher in the BCa and cystitis groups compared to the healthy one. The level of phosphorylated p65 (p-p65) protein of the canonical NF-κB pathway and that of p52, a protein of the non-canonical NF-κB pathway, were also higher in the BCa and cystitis group compared to the healthy group. The levels of these proteins significantly correlated to the pathological grade, clinical stage and lymph node metastasis of BCa patients (P<0.05). In addition, there was a positive correlation between LTβR and NF-κB pathway proteins. Thus, LTβR signaling may be involved in promoting BCa through the NF-κB pathway, and which may represent the molecular link between inflammation and BCa. [ABSTRACT FROM AUTHOR]

In recent years, microRNAs (miRNAs) were found to play critical roles in many important biological processes. On the other hand, the rapid development of genome-wide association studies (GWAS) help identify potential genetic variants associated with the disease phenotypic variance. Therefore, we suggested a combined analysis of microRNA expression profiling with genome-wide Single Nucleotide Polymorphism (SNP) genotyping to identify potential disease-related biomarkers. Considering functional SNPs in miRNA genes or target sites might be important signals associated with human complex diseases, we constructed a miRNA-miRNA synergistic network related to coronary artery disease (CAD) by performing a genome-wide scan for SNPs in human miRNA 3′ -untranslated regions (UTRs) target sites and computed potential SNP cooperation effects contributing to disease based on potential miRNA-SNP interactions reported recently. Furthermore, we identified some potential CAD-related miRNAs by analyzing the constructed miRNAmiRNA synergistic network. As a result, the predicted miRNA-miRNA network and miRNA clusters were validated by significantly high interaction effects of CAD-related miRNAs. Accurate classification performances were obtained for all of the identified miRNA clusters, and the sensitivity and specificity were all more than 90%. The network topological analysis confirmed some novel CAD-related miRNAs identified recently by experiments. Our method might help to understand miRNA function and CAD disease, as well as to explore the novel mechanisms involved. [ABSTRACT FROM AUTHOR]

To evaluate the effect of melatonin supplementation in maturation medium for human 'rescue IVM' and investigate differences in transcriptomic profile of blastocysts developed from oocytes matured in vitro with/without melatonin treatment and in vivo, a total of 314 GV oocytes and 320 MI oocytes were collected from 200 patients younger than 35 years old undergoing ICSI cycle. The oocytes were randomly distributed in the control group (no melatonin) and four other groups of varying melatonin concentrations (10-11, 10-9, 10-7, 10-5 mol/l). Gene profiling was performed on blastocysts developed from in vivo maturation oocytes (in vivo group), and in vitro maturation (IVM) oocytes with an optimal concentration of melatonin treatment (IVM-anti group) or without melatonin (IVM group). The ratio of high quality blastocysts was significantly higher in the groups treated with 10-5 mol/l melatonin compared with others groups. The large-scale analysis of the transcriptome revealed significant differences in mRNA expression levels. In each group, nine blastocysts were selected for gene expression profiling. The differentially expressed genes were involved in cysteine and methionine metabolism, regulation of apoptotic process, mineral absorption, steroid hormone biosynthesis, Wnt signaling, p53 signaling pathway and other functions. The findings indicated that the IVM procedure may potentially affect DNA methylation and the canonical Wnt signaling pathway. Exogenous melatonin positively influenced quality of blastocysts, which may be mediated via upregulation of p53 signaling and correcting DNA methylation changes caused by 'rescue IVM'. However, this study reflected what was generally referred to as 'rescue IVM' and was not a true reflection of clinical IVM techniques. Therefore, melatonin required further investigation as a promising supplement for use in IVM. [ABSTRACT FROM AUTHOR]

The caudal-type homeobox 1 (CDX1) transcription factor is a member of the caudal-related homeobox transcription factor gene family and has been reported to be down-regulated in a variety of cancers. However, the expression status and significance of CDX1 in hepatocellular carcinoma (HCC) is still controversial, and little is known about the role of CDX1 in HCC-In our previous study, we investigated the expression and clinical significance of CDX1 in HCC samples from 313 HCC patients. We found CDX1 was strikingly down-regulated in HCC samples. CDX1 expression was associated with poor differentiation (P= 0.002), and patients with low CDX1 expression had a significantly poorer prognosis. A subgroup analysis revealed a difference in prognosis between groups with low and high CDX1 expression among patients who had tumors <5 cm in size and who were alpha-fetoprotein (AFP) negative. Moreover, low expression was more frequently observed in the early recurrence group (within 2 years, P = 0.002). In addition, multivariate Cox regression analysis indicated that the CDX1 expression level, tumor size, presence of hepatitis B e antigen (HBeAg), vascular invasion, and presence of hepatitis B surface antigen (HBsAg) were independent risk factors for HCC recurrence, and the CDX1 expression level, tumor size, tumor number, and presence of HBsAg were independent predictor of overall survival of HCC patients. In conclusion, the downregulation of CDX1 is associated with poor prognosis; and it may serve as a novel predictor of the prognosis of HCC patients after curative resection. [ABSTRACT FROM AUTHOR]

The caudal-type homeobox 1 (CDX1) transcription factor is a member of the caudal-related homeobox transcription factor gene family and has been reported to be down-regulated in a variety of cancers. However, the expression status and significance of CDX1 in hepatocellular carcinoma (HCC) is still controversial, and little is known about the role of CDX1 in HCC$In our previous study, we investigated the expression and clinical significance of CDX1 in HCC samples from 313 HCC patients. We found CDX1 was strikingly down-regulated in HCC samples. CDX1 expression was associated with poor differentiation (P = 0.002), and patients with low CDX1 expression had a significantly poorer prognosis. A subgroup analysis revealed a difference in prognosis between groups with low and high CDX1 expression among patients who had tumors <5 cm in size and who were alpha-fetoprotein (AFP) negative. Moreover, low expression was more frequently observed in the early recurrence group (within 2 years, P = 0.002). In addition, multivariate Cox regression analysis indicated that the CDX1 expression level, tumor size, presence of hepatitis B e antigen (HBeAg), vascular invasion, and presence of hepatitis B surface antigen (HBsAg) were independent risk factors for HCC recurrence, and the CDX1 expression level, tumor size, tumor number, and presence of HBsAg were independent predictor of overall survival of HCC patients. In conclusion, the downregulation of CDX1 is associated with poor prognosis; and it may serve as a novel predictor of the prognosis of HCC patients after curative resection. [ABSTRACT FROM AUTHOR]

Background: This study aimed to explore the responses to the interleukin-6 (IL-6)/soluble interleukin-6 receptor (sIL-6R) complex in peritumoral endothelial cells (PECs) and tumor endothelial cells (TECs), as well as determine the signaling pathways in the angiogenesis of hepatocellular carcinoma (HCC).Methods: The expression of IL-6, IL-6R, gp130, CD68, HIF-1α, and microvessel density (MVD) were assessed with an orthotopic xenograft model in nude mice. ECs were incubated under hypoxic conditions to detect IL-6 and gp130. The proliferation of PECs and TECs in the presence of IL-6 and sIL-6R, as well as the expression of gp130, JAK2/STAT3, PI3K/AKT in endothelial cells were measured.Results: Peritumoral IL-6, IL-6R, gp130, CD68, and HIF-1α expression, as well as MVD, gradually increased during tumor growth. Hypoxia could directly induce IL-6 expression, but not gp130 in PECs. The co-culture of IL-6/sIL-6R induced much higher PEC proliferation and gp130 expression, as well as the elevated phosphorylation of JAK2 and STAT3, however not the phosphorylation of PI3K and AKT.Conclusions: PECs exhibited higher proliferation in response to IL-6/sIL-6R co-treatment compared with TECs in HCC via the up-regulation of gp130 /JAK2/STAT3. PEC and its associated peritumoral angiogenesis microenvironment may be a potential novel target for anti-angiogenic treatment. [ABSTRACT FROM AUTHOR]

T cell activation causes the translocation of NF-kB dimers from the cytoplasm into the nucleus where NF-kB regulates inflammatory and immune response genes. Cbl-b is a negative regulator of T cell activation. However, the correlation between NF-kB activity and Cbl-b expression remains unclear. We showed that IKBαΔN-Tg T cells exhibited less NF-kB activity but higher levels of Cbl-b when compared with wild-type T cells. Furthermore, ursolic acid suppressed NF-kB activation and inhibited the downregulation of Cbl-b in wild-type T cells. NF-KBp65 specifically bound to an 11-bp NF-kB consensus sequence (gcaggaagtcc) in the Cbl-b promoter. Binding of NF-kB to this sequence suppressed Cbl-b transcription, thereby resulting in the negative regulation of Cbl-b expression. In addition, Cbl-b knockout led to the loss of cardiac allograft tolerance in IKBαΔN-Tg mice. These results indicated that NF-kB downregulated Cbl-b by binding and suppressing Cbl-b promoter in T cell activation. Our findings provide a novel role for NF-kB signaling in T cell activation. [ABSTRACT FROM AUTHOR]

Complex diseases result from molecular changes induced by multiple genetic factors and the environment. To derive a systems view of how genetic loci interact in the context of tissue-specific molecular networks, we constructed an F2 intercross comprised of .500 mice from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mouse strains made genetically obese by the Leptinob/ob mutation (Lepob). High-density genotypes, diabetes-related clinical traits, and whole- transcriptome expression profiling in five tissues (white adipose, liver, pancreatic islets, hypothalamus, and gastrocnemius muscle) were determined for all mice. We performed an integrative analysis to investigate the inter-relationship among genetic factors, expression traits, and plasma insulin, a hallmark diabetes trait. Among five tissues under study, there are extensive protein--protein interactions between genes responding to different loci in adipose and pancreatic islets that potentially jointly participated in the regulation of plasma insulin. We developed a novel ranking scheme based on cross- loci protein-protein network topology and gene expression to assess each gene's potential to regulate plasma insulin. Unique candidate genes were identified in adipose tissue and islets. In islets, the Alzheimer's gene App was identified as a top candidate regulator. Islets from 17-week-old, but not 10-week-old, App knockout mice showed increased insulin secretion in response to glucose or a membrane-permeant cAMP analog, in agreement with the predictions of the network model. Our result provides a novel hypothesis on the mechanism for the connection between two aging-related diseases: Alzheimer's disease and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Progranulin (PGRN) is a widely expressed secreted protein that is linked to inflammation. In humans, PGRN haploinsufficiency is a major inherited cause of frontotemporal dementia (FTD), but how PGRN deficiency causes neurodegeneration is unknown. Here we show that loss of PGRN results in increased neuron loss in response to injury in the CNS. When exposed acutely to l-methyl-4-(2'-methylphenyl)-l,2,3,6-tetrahydrophine (MPTP), mice lacking PGRN (Grn-/-) showed more neuron loss and increased microgliosis compared with wild-type mice. The exacerbated neuron loss was due not to selective vulnerability of Grn-/-neurons to MPTP, but rather to an increased microglial inflammatory response. Consistent with this, conditional mutants lacking PGRN in microglia exhibited MPTP-induced phenotypes similar to Grn-/- mice. Selective depletion of PGRN from microglia in mixed cortical cultures resulted in increased death of wild-type neurons in the absence of injury. Furthermore, Grn-/- microglia treated with LPS/IFN-γ exhibited an amplified inflamma-tory response, and conditioned media from these microglia promoted death of cultured neurons. Our results indicate that PGRN deficiency leads to dysregulated microglial activation and thereby contributes to increased neuron loss with injury. These findings suggest that PGRN deficiency may cause increased neuron loss in other forms of CNS injury accompanied by neuroinflammation. [ABSTRACT FROM AUTHOR]

CD36, a class-B scavenger receptor involved in multiple functions, including inflammatory signaling, may also contribute to ischemic brain injury through yet unidentified mechanisms. We investigated whether CD36 participates in the molecular events underlying the inflammatory reaction that accompanies cerebral ischemia and may contribute to the tissue damage. We found that activation of nuclear factor-κB, a transcription factor that coordinates postischemic gene expression, is attenuated in CD36-null mice subjected to middle cerebral artery occlusion. The infiltration of neutrophils and the glial reaction induced by cerebral ischemia were suppressed. Treatment with an inhibitor of inducible nitric oxide synthase, an enzyme that contributes to the tissue damage, reduced ischemic brain injury in wild-type mice, but not in CD36 nulls. In contrast to cerebral ischemia, the molecular and cellular inflammatory changes induced by intracerebroventricular injection of interleukin-1β were not attenuated in CD36-null mice. The findings unveil a novel role of CD36 in early molecular events leading to nuclear factor-κB activation and postischemic inflammation. Inhibition of CD36 signaling may be a valuable therapeutic approach to counteract the deleterious effects of postischemic inflammation. [ABSTRACT FROM AUTHOR]

[Objective] By the observation of dosage-effect relationship of Astragalus and Salvia's effective components in E-cadherin Expression of UUO rat, an analysis of the effect on renal tubular epithelial cells was made and pathological changes of renal tubule interstitial fibrosis under different concentrations of Astragalus-Salviandrugs were observed and compared.[Methods] Forty SD rats were randomly classified into five groups : normal group, model group, Astragalus-Salviandrug granules compatibility (1: 1) low dosage group (hereinafter referred to as the low dosage group), middle dosage group and high dosage group. Double distiiled water gavage was given to norma group and model group, rather 14 d therapy of relevant drug gavage to other groups to test serum creatinine (Scr), blood urea nitrogen (BUN) and 24 h urine protein content and to observe the renal pathology and collagen deposition with light microscope. The immunohistochemical method was used to detect E-cadherin chages in renal tissue. [Results]The renal function, pathological damage, coHagen deposition and immunohistochemical results of diferent groups of kidney was the most obvious in module group and the least in high dosage group. [Conclusions] Astragalus-Salviandrugs have a certain protective effect on renal function of UUO rats and renal tubular function. Furthermore, with the dosage increased, the effect is more obvious, whose mechaism may be correlated with the gradual enhancement of E-cadherin expression; there exists dosage-effect relationship of Astragalus-Salvia's effecttve components in E-cadherin expression of UUO rats, with the most obvious effect of high dosage group. [ABSTRACT FROM AUTHOR]