Reactive oxygen species (ROS) induce chemokines responsible for the recruitment of inflammatory cells to sites of injury or infection. Here we show that the plasma membrane Ca 2+ -permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. In human U937 monocytes, hydrogen peroxide (H 2 O 2 ) evokes Ca 2+ influx through TRPM2 to activate Ca 2+ -dependent tyrosine kinase Pyk2 and amplify Erk signaling via Ras GTPase. This elicits nuclear translocation of nuclear factor-κB essential for the production of the chemokine interleukin-8 (CXCL8). In monocytes from Trpm2-deficient mice, H 2 O 2 -induced Ca 2+ influx and production of the macrophage inflammatory protein-2 (CXCL2), the mouse CXCL8 functional homolog, were impaired. In the dextran sulfate sodium-induced colitis inflammation model, CXCL2 expression, neutrophil infiltration and ulceration were attenuated by Trpm2 disruption. Thus, TRPM2 Ca 2+ influx controls the ROS-induced signaling cascade responsible for chemokine production, which aggravates inflammation. We propose functional inhibition of TRPM2 channels as a new therapeutic strategy for treating inflammatory diseases.
Human plasma contains at least three forms of adiponectin: a trimer, a hexamer, and a high-molecular-weight (HMW) multimer. We purified HMW adiponectin from human plasma using its affinity to gelatin and obtained monoclonal antibodies against it. On Western blot analysis, the reactivity of these monoclonal antibodies was shown to be restricted to a non-heat-denatured form of adiponectin molecules. On heating, the collagen-like domain of adiponectin molecules became denatured, and thus the trimer form could not be maintained. From these, monoclonal antibodies against HMW adiponectin were suggested to react with the intact trimer of adiponectin. With these monoclonal antibodies, we developed a sandwich ELISA system for quantifying adiponectin in human serum. Its specificity was verified by analysis of serum fractions separated by gel-filtration chromatography, and our ELISA system was found to be HMW adiponectinspecific. With this novel ELISA, the HMW adiponectin concentrations were 8.4 6 5.5 mg/ml (mean 6 SD) in healthy women and 6.2 6 3.6 mg/ml in healthy men. Also, serum with a lower HMW adiponectin concentration was shown to have a lower HMW ratio (i.e., HMW adiponectin/total adiponectin).-Nakano, Y., S. Tajima, A. Yoshimi, H. Akiyama, M. Tsushima, T. Tanioka, T. Negoro, M. Tomita, and T. Tobe. A novel enzyme-linked immunosorbent assay specific for high-molecular-weight adiponectin. Adiponectin is an adipocyte-specific secretory protein that is highly and specifically expressed in adipose tissue (1-3). Adiponectin includes a collagen-like domain, and in this domain, three adiponectin peptides form one stable trimer and the trimers further multimerize to form "bouquet" forms (Fig. 1). In human plasma, adiponectin was found to circulate as a trimer, a hexamer, and a highmolecular-weight (HMW) multimer, and we purified the HMW adiponectin of 420 kDa from human serum using gelatin-Cellulofine and previously reported it as the gelatin binding protein of 28 kDa (GBP28) in 1996 (4).Plasma adiponectin levels are reported to be decreased in obese individuals, to be negatively correlated with visceral fat accumulation, and to be significantly lower in type 2 diabetic patients with coronary artery disease (5-7). Adiponectin mRNA levels are significantly reduced in omental adipose tissue of obese patients with type 2 diabetes compared with lean and obese normoglycemic subjects, and although less pronounced, the levels are also reduced in subcutaneous adipose tissue of type 2 diabetic patients (8). Plasma adiponectin concentrations in patients with acute coronary syndrome, both acute myocardial infarction and unstable angina pectoris, are significantly lower than those in patients with stable angina pectoris and in controls, and a low adiponectin concentration is correlated independently with the development of an acute coronary disease (9). Plasma adiponectin levels are an inverse predictor of the cardiovascular outcome in patients with end-stage renal disease (10). Tietge et al. (11) reported that plasma adipon...
Focal and degenerative lesions of articular cartilage greatly reduce the patient’s quality of life. Various therapies including surgical treatment have been developed, but a definitive therapy is not yet known. Several cell therapy products have already been developed and are available in the market. In this study, we examined the clinical research trends related to cell therapy products in the cartilage repair field based on data obtained from the ClinicalTrial.gov website. Although this website does not provide comprehensive results of clinical trials, it offers information on prospective clinical trials, including work in progress, and thus allows for chronological analysis of the data. We selected 203 studies related to the field of cartilage regeneration from ClinicalTrial.gov. The results showed a shift in the clinical translational trend in utilized cells from cartilage- and bone marrow- to adipose tissue-based cells. Whereas the studies that used cartilage as the cell source included many phase III trials, fewer studies using bone marrow and adipose tissue cells progressed to phase III, suggesting that most clinical developments using the latter sources have not been successful so far. One product covered the entire period from the start of phase I to the completion of phase III, with a time to completion of more than 100 months. Translational trends in autologous chondrocyte implantation were also discussed. The use of ClinicalTrials.gov as the sole data source can yield a perspective view of the global clinical translational trends, which has been difficult to observe up to this point.
We isolated the cDNA encoding a novel member of the human fibroblast growth factor (FGF) family from the lung. The cDNA encodes a protein of 208 amino acids with high sequence homology (95.6%) to rat FGF-10, indicating that the protein is human FGF-10. Human FGF-10 as well as rat FGF-10 has a hydrophobic amino terminus (ϳ40 amino acids), which may serve as a signal sequence. The apparent evolutionary relationships of human FGFs indicate that FGF-10 is closest to FGF-7. Chromosomal localization of the human FGF-10 gene was examined by in situ hybridization. The gene was found to map to the 5p12-p13 region. Human FGF-10 (amino acids 40 to 208 with a methionine residue at the amino terminus) was produced in Escherichia coli and purified from the cell lysate. Recombinant human FGF-10 (ϳ19 kDa) showed mitogenic activity for fetal rat keratinizing epidermal cells, but essentially no activity for NIH/3T3 cells, fibroblasts. The specificity of mitogenic activity of FGF-10 is similar to that of FGF-7 but distinct from that of bFGF. In structure and biological activity, FGF-10 is similar to FGF-7.
These findings indicate that neutrophil TRPM2 is implicated in the exacerbation of myocardial reperfusion injury. Accumulation of neutrophils in the reperfused area mediated by TRPM2 activation is likely to play a crucial role in myocardial I/R injury.
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