The nerve growth factor (NGF) is a growth factor that belongs to the neurotrophin family. NGF has two structurally different receptors, the p75 neurotrophin receptor (p75NTR) and the tropomyosin-related kinase A (TrkA). Interaction of NGF with its receptors regulates a variety of physiological processes of neuronal system. Recent studies have shown that NGF and its receptors were involved in the regulation of tumourigenesis by either supporting or suppressing tumor growth depending on the tumor types. This review summarizes the current views of NGF and its receptors in tumorigenesis and cancer pain.
Human enterovirus 71 (EV71) is the major etiological agent of hand, foot and mouth disease (HFMD), which is a common infectious disease in young children. Studies in the past have shown that reversed transcription loop-mediated isothermal amplification (RT-LAMP) was a rapid approach for the detection of EV71 in HFMD. This meta-analysis study is to evaluate the diagnostic role of RT-LAMP in detecting EV71 infection. A comprehensive literature research of PubMed, Embase, Wan Fang Data, and Chinese National Knowledge Infrastructure databases was conducted on articles aiming at the diagnostic performance of RT-LAMP in EV71 detection published before February 10, 2014. Data from selected studies were pooled to yield the summary sensitivity, specificity, positive and negative likelihood ratio (PLR, NLR), diagnostic odds ratio (DOR), and receiver operating characteristic (SROC) curve by using STATA VERSION 12.0 software. Ten studies including a total of 907 clinical samples were of high quality in this meta-analysis. Overall, the pooled sensitivity, specificity, PLR, NLR, DOR, and the area under the SROC curve was 0.99 (0.97, 1.00), 0.97 (0.94, 1.00), 5.90 (95% CI: 3.90-8.94), 0.20 (95% CI: 0.14-0.29), and 1.00 (95% CI: 0.99-1.00), respectively. The univariate analysis of potential variables showed some changes in the diagnostic performance, but none of the differences reached statistical significance. Despite inter-study variability, the test performance of RT-LAMP was consistent with real-time RT-PCR in detecting EV71. This meta-analysis suggests that RT-LAMP is a useful diagnostic tool with high sensitivity and specificity for detecting EV71.
Streptococcus suis is a pathogen of zoonotic diseases. Moreover, the emergence of fluoro-quinolones (FQs) resistance in this pathogen has severe consequences for pigs and human health. In this study, the molecular mechanism of FQs resistance in S. suis type 2 (SS2) sensitive strains isolated from pigs was assessed after in vitro induction of resistance against the most frequently used FQs: ciprofloxacin, norfloxacin, and enrofloxacin. Proteome analysis, sequencing and real-time RT-PCR results strongly established an overexpression of an ABC transporter protein (other than SatAB) and topoisomerase mutations in GyrA (Ser81Arg), GyrB (Glu354Lys), and ParC (Ser79Phe) in contributing to high level ciprofloxacin resistance in SS2. Due to the overexpression of the ABC transporter, intracellular ciprofloxacin concentrations were significantly lower in the resistant strains than those of sensitive strains after 20, 35, and 60 min exposures to ciprofloxacin (p < 0.05). It was concluded that improper use of FQs is one of the main causes of the emergence of this zoonotic pathogen as a multiresistant organism against commonly used antibiotics. The existence of an efflux-like protein is an incentive to find new drug targets to avoid the spread of FQs-resistant S. suis isolates in pigs and the human population.
Tropomyosin-related kinase B (TrkB) is a functional signal molecule that correlates with cell survival and epithelial-mesenchymal transition (EMT), which is essential for the invasiveness of malignant cancer cells. While a truncated isoform of TrkB has a dominant negative effect, full-length TrkB with its tyrosine kinase domain is predicted to play a role in cancer progression. Because ovarian clear cell adenocarcinoma (CCA) shows worse prognosis compared to other cancer types, we investigated the correlation between TrkB isoforms and the progression of CCA. Ovarian adenocarcinoma and benign tumor samples were obtained from Tokai University Hospital and Juntendo University Hospital. These samples were examined for the TrkB expression of isotype-specific proteins and mRNAs by immunohistochemistry and domain-specific semi-quantitative reverse transcription polymerase chain reaction. While TrkB mRNA expression was detected in all of the ovarian tissues and TrkB protein expression was predominant in ovarian cancer tissues, the number of tissues expressing the tyrosine kinase-truncated isoforms (T-Shc or T1) decreased according to the clinical stage of CCA. Irregular isoforms were also observed in some CCA samples. The decrease in T-Shc and T1 were less obvious in mucinous adenocarcinoma and not observed in serous or endometrioid adenocarcinoma. Decreased expression of the truncated isoforms (T-Shc and T1) was associated with CCA progression. These results demonstrate that irregular expression of TrkB isoforms is a characteristic of CCA tissues. The unique TrkB expression profile may be useful for the diagnosis of CCA subtypes.
Ankyrin repeat and SOCS box containing 4 (ASB4) involves in physiological process of ubiquitin-mediated proteasomal degradation. Our previous study demonstrated high expression of ASB4 in hepatocellular carcinoma (HCC) cell lines. This study further reveals its clinical implications and tumorigenic properties in HCC. Analysis of 217 HCC gene expression profiles followed by validation in a separate cohort of 50 cases illustrated high ASB4 in HCC. Among the 50 cases, 54% of tumors exhibited more than 2-fold up-regulation of ASB4. Elevated ASB4 associated with low serum level of a HCC serological marker alpha-fetoprotein (AFP), postulating of its use to differentiate AFP-negative HCC. Suppression of ASB4 in PLC and MHCC97-L HCC cells hindered the cell migration and invasion. Reciprocally, enhanced migration rate was measured when ASB4 was ectopically expressed in Hep3B HCC cells. Cross comparison of results derived from in silico predictions of seed-matched sequences and by analyzing human HCC databases with matched microRNA and gene expression profiles, microRNA-200 (miR-200) family members including miR-200a and miR-200b were predicted to regulate ASB4 expression in HCC. MiR-200a showed inversed expression level with ASB4 in several of studied HCC cell lines. Dual luciferase reporter assay confirmed the presence of miR-200a binding site on the 3’ untranslated region of ASB4. Reduced ASB4 level was noticed under the influence of miR-200a mimic treatment, for which this mimic-induced effect was neutralized with miR-200a inhibitor. In conclusion, this study demonstrates for the first time on the involvement of ASB4 in HCC and that its level is regulated by miR-200a.
This study aimed to investigate whether valproic acid (VPA) pretreatment enhances the therapeutic effectiveness of mesenchymal stem cells derived from bone marrow (BMSCs) transplanted into rats with an acute spinal cord injury (SCI). BMSCs were pretreated with VPA before transplantation and then intravenously injected 1 week after SCI. Before transplantation, levels of CXC chemokine receptor 4 (CXCR4) expression in BMSCs were tested using quantitative real-time PCR and Western blotting. Stromal derived factor-1 (SDF-1), the unique ligand of CXCR4, was quantified using RT-PCR and immunofluorescence. The locomotor function of rats with an SCI was evaluated using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale. Fluorescence microscopy and hematoxylin-eosin (HE) staining were also performed to evaluate pathophysiological changes after transplantation. On day 7 after SCI, the level of SDF-1 expression peaked. CXCR4 expression increased significantly in BMSCs pretreated with VPA. After intravenous transplantation, BrdU-labeled BMSCs were noted at the spinal injury site, and this was especially true for BMSCs pretreated with VPA. More significant functional improvement was observed in rats receiving BMSCs pretreated with VPA than in other groups of rats. AMD3100 partially inhibited improvement. This study demonstrates that pretreatment with VPA before transplantation enhances the therapeutic benefits of BMSCs in terms of greater cell migration and better neurological outcomes after traumatic SCI. The mechanism of this enhancement may be related to the SDF-1/CXCR4 axis. Therefore, pretreatment of BMSCs with VPA warrants further study in relation to the treatment of traumatic SCI.
Fish oil containing n-3 polyunsaturated fatty acids (n-3 PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is known to prevent the progression of nephropathy and retard the progression of kidney disease. This study sought to investigate the underlying mechanisms of EPA and DHA in terms of peroxisome proliferator-activated receptor γ (PPARγ), integrin-linked kinase (ILK), and integrin β1 expression in glomerular mesangial cells (GMCs) because of their critical roles in the development and progression of nephropathy. Lipopolysaccharide (LPS) significantly reduced the expression of PPARγand increased the expression of ILK at the mRNA level and at the protein level in GMCs as indicated by real-time PCR and Western blotting. In addition, LPS increased integrin β1 expression in GMCs at the mRNA level. Treatment with EPA and DHA significantly increased the expression of PPARγ and decreased the expression of ILK and integrin β1 in GMCs. These data suggest that the renoprotective effects of EPA and DHA may be related to their potential to increase the expression of PPARγ and decrease the expression of ILK and integrin β1.
Granzyme 3 (Gr3) is known as a tryptase-type member of the granzyme family and exists in the granules of immunocompetent cells. Granule proteases including granzymes, are transported into the cytoplasm of tumor cells or virus-infected cells by perforin function, degrade cytoplasmic or nuclear proteins and subsequently cause the death of the target cells. Recently, although several substrates of Gr3 in vivo have been reported, these hydrolyzed sites were unclear or lacked consistency. Our previous study investigated the optimal amino acid triplet (P3-P2-P1) as a substrate for Gr3 using a limited combination of amino acids at the P2 and P3 positions. In the present study, new fluorescence resonance energy transfer (FRET) substrate libraries to screen P2 and P3 positions were synthesized, respectively. Using these substrate libraries, the optimal amino acid triplet was shown to be Tyr-Phe-Arg as a substrate for human Gr3. Moreover, kinetic analyses also showed that the synthetic substrate FRETS-YFR had the lowest Km value for human Gr3. A substantial number of membrane proteins possessed the triplet Tyr-Phe-Arg and some of them might be in vivo substrates for Gr3. The results might also be a great help for preparing specific inhibitors to manipulate Gr3 activity both in vitro and in vivo.
Different diets consumed by individuals of different ethnicities, gender, and age may cause changes in blood pressure. The current study sought to investigate changes in blood pressures after consumption of a high-carbohydrate (high-CHO) diet by healthy Chinese adolescents. As a population, the Chinese consume a diet with a high carbohydrate content and they have a low incidence of hypertension and coronary artery disease. Dietary data were collected using a 3-day diet diary. Subjects were 672 high school students who were divided into a high-CHO diet group (≥ 55% carbohydrates) and a non-high-CHO diet group (< 55% carbohydrates, < 40% fats). Plasma glucose levels, heart rate, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured. Body mass index (BMI), waist-to-hip ratio (WHR), pulse pressure (PP), and mean arterial pressure (MAP) were calculated. Results indicated that males had a higher BMI, glucose level, SBP, DBP, PP, and MAP than females. When diet was taken into account, males in the non-high-CHO diet group had a higher SBP and PP than females. Males in the high-CHO diet group had a higher glucose level than females. Males in the high-CHO diet group had a lower SBP (p = 0.004) and PP (p = 0.002) than males in the non-high-CHO diet group and females in the high-CHO diet group had a lower glucose level (p = 0.003) than females in the non-high-CHO diet group. After adjusting for age, BMI, WHR, heart rate, the total daily energy intake, and the intake of vitamin C, calcium, sodium, potassium and magnesium, significant differences in SBP and PP were noted in males. These results indicate that male adolescents consuming a high-CHO diet had a lower SBP and PP than males consuming a non-high-CHO diet.