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Sample records for factor beta type

  1. [Functional analysis of transforming growth factor-beta type II dominant negative receptor].

    Science.gov (United States)

    Takarada, M

    1996-06-01

    The transforming growth factor-beta (TGF-beta) is a multifunctional homodimeric protein with an apparent molecular weight of 25 KDa. TGF-beta transduces signals by forming heteromeric complexes of their type-I (T beta R-I) and type-II (T beta R-II) serin/threonine kinase receptors. TGF-beta binds first to T beta R-II receptor, and then the ligand in this complex is recognized by T beta R-I, resulting in formation of a heteromeric receptor complex composed of T beta R-I and T beta R-II. Once received, T beta R-I becomes phosphorylated in the GS domain by the associated constitutively active T beta R-II and transmits the downstream signal. It has been reported that formation of the heteromeric complex is indispensible at least in epithelial cells for growth inhibition and extracellular matrix production induced by TGF-beta. In this study, the functional role of T beta R-II for the TGF-beta-induced signals in osteoblastic cells was investigated by using a dominant negative type of T beta R-II mutant receptors (T beta RIIDNR). ROS 17/2.8 and MG 63 cells were found to express T beta R-I, T beta R-II, and T beta R-III, and their cell growth was inhibited by TGF-beta, whereas alkaline phosphatase activity was stimulated. Cells that were stably transfected with the T beta RIIDNR plasmid showed decreased response to TGF-beta during growth and alkaline phosphatase activity. These results indicate that the intracellular serine/threonine kinase domain of T beta R-II is essential for signal transduction of the TGF-beta-induced alkaline phosphatase activity as well as growth inhibition.

  2. BAT3 interacts with transforming growth factor-beta (TGF-beta) receptors and enhances TGF-beta1-induced type I collagen expression in mesangial cells.

    Science.gov (United States)

    Kwak, Joon Hyeok; Kim, Sung Il; Kim, Jin Kuk; Choi, Mary E

    2008-07-11

    Transforming growth factor-beta1 (TGF-beta1) plays essential roles in a wide array of cellular processes, such as in development and the pathogenesis of tissue fibrosis, including that associated with progressive kidney diseases. Tight regulation of its signaling pathways is critical, and proteins that associate with the TGF-beta receptors may exert positive or negative regulatory effects on TGF-beta signaling. In the present study we employed a yeast-based two-hybrid screening system to identify BAT3 (HLA-B-associated transcript 3) as a TGF-beta receptor-interacting protein. Analysis of endogenously expressed BAT3 in various tissues including the kidney reveals the existence of approximately 140-kDa full-length protein as well as truncated forms of BAT3 whose expression is developmentally regulated. Endogenous BAT3 protein interacts with TGF-beta receptors type I and type II in renal mesangial cells. Functional assays show that expression of full-length BAT3 results in enhancement of TGF-beta1-stimulated transcriptional activation of p3TP-Lux reporter, and these effects require the presence of functional TGF-beta signaling receptors as demonstrated in R-1B and DR-26 mutant cells. Moreover, expression of full-length BAT3, but not C-terminal truncated mutant of BAT3, enhanced TGF-beta1-induced type I collagen expression in mesangial cells, whereas knock down of BAT3 protein expression by small interfering RNA suppressed the expression of type I collagen induced by TGF-beta1. Our findings suggest that BAT3, a TGF-beta receptor-interacting protein, is capable of modulating TGF-beta signaling and acts as a positive regulator of TGF-beta1 stimulation of type I collagen expression in mesangial cells.

  3. A new method for high yield purification of type beta transforming growth factor from human platelets

    NARCIS (Netherlands)

    Eijnden-van Raaij, A.J.M. van den; Koornneef, I.; Zoelen, E.J.J. van

    1988-01-01

    A new method was developed for the purification of type beta transforming growth factor from human platelets. This method is a three-step procedure including gel filtration, weak cation exchange HPLC and reverse phase HPLC. All steps are carried out at low pH using exclusively volatile acidic buffer

  4. Enhanced expression of the type II transforming growth factor beta receptor in human pancreatic cancer cells without alteration of type III receptor expression.

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    Friess, H; Yamanaka, Y; Büchler, M; Berger, H G; Kobrin, M S; Baldwin, R L; Korc, M

    1993-06-15

    We have recently found that human pancreatic adenocarcinomas exhibit strong immunostaining for the three mammalian transforming growth factor beta (TGF-beta) isoforms. These important growth-regulating polypeptides bind to a number of proteins, including the type I TGF-beta receptor (T beta R-I), type II TGF-beta receptor (T beta R-II), and the type III TGF-beta receptor (T beta R-III). In the present study we sought to determine whether T beta R-II and T beta R-III expression is altered in pancreatic cancer. Northern blot analysis indicated that, by comparison with the normal pancreas, pancreatic adenocarcinomas exhibited a 4.6-fold increase (P beta R-II. In contrast, mRNA levels encoding T beta R-III were not increased. In situ hybridization showed that T beta R-II mRNA was expressed in the majority of cancer cells, whereas mRNA grains encoding T beta R-III were detectable in only a few cancer cells and were present mainly in the surrounding stroma. These findings suggest that enhanced levels of T beta R-II may have a role in regulating human pancreatic cancer cell growth, while T beta R-III may function in the extracellular matrix.

  5. Factors associated with beta-cell dysfunction in type 2 diabetes: the BETADECLINE study.

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    Giuseppina T Russo

    Full Text Available AIMS: Beta-cell dysfunction is an early event in the natural history of type 2 diabetes. However, its progression is variable and potentially influenced by several clinical factors. We report the baseline data of the BetaDecline study, an Italian prospective multicenter study on clinical predictors of beta-cell dysfunction in type 2 diabetes. MATERIALS AND METHODS: Clinical, lifestyle, and laboratory data, including circulating levels of inflammatory markers and non-esterified fatty acids, were collected in 507 type 2 diabetic outpatients on stable treatment with oral hypoglycemic drugs or diet for more than 1 year. Beta-cell dysfunction was evaluated by calculating the proinsulin/insulin ratio (P/I. RESULTS: At baseline, the subjects in the upper PI/I ratio quartile were more likely to be men and receiving secretagogue drugs; they also showed a borderline longer diabetes duration (P = 0.06 and higher serum levels of glycated hemoglobin (HbA1c, fasting blood glucose, and triglycerides. An inverse trend across all PI/I quartiles was noted for BMI and serum levels of total cholesterol (T-C, LDL-C, HDL-C and C reactive protein (CRP, and with homeostatic model assessment (HOMA-B and HOMA of insulin resistance (HOMA-IR values (P<0.05 for all. At multivariate analysis, the risk of having a P/I ratio in the upper quartile was higher in the subjects on secretagogue drugs (odds ratio [OR] 4.2; 95% confidence interval [CI], 2.6-6.9 and in the males (OR 1.8; 95% CI, 1.1-2.9. CONCLUSIONS: In the BetaDecline study population, baseline higher PI/I values, a marker of beta-cell dysfunction, were more frequent in men and in patients on secretagogues drugs. Follow-up of this cohort will allow the identification of clinical predictors of beta-cell failure in type 2 diabetic outpatients.

  6. Effect of human papillomavirus type 16 E6 and E7 oncogenes on the activity of the transforming growth factor-beta2 (TGF-beta2) promoter.

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    Murvai, M; Borbély, A A; Kónya, J; Gergely, L; Veress, G

    2004-12-01

    The effect of the human papillomavirus type 16 (HPV 16) E6 and E7 proteins was studied on the transcriptional activity of the human transforming growth factor beta2 (TGF-beta) promoter in different cell lines. Luciferase tests were performed after co-transfection of cells with TGF-beta2 reporter constructs and HPV 16 E6 or E7 expression vectors. HPV 16 E7, but not E6 significantly repressed TGF-beta2 promoter activity in NIH/3T3 cells, which have wild-type p53 and pRb proteins. The repressive effect of HPV 16 E7 on the transcriptional activity of the TGF-beta2 promoter could be localized to the promoter region -528 to -251 relative to the transcriptional start site. Ability of E7 to bind pRb was necessary to inhibit the TGF-beta2 promoter. Over-expression of the transcription factor E2F-1 had an effect on the TGF-beta2 promoter similar to that of E7, which may indicate that HPV 16 E7 represses the TGF-beta2 promoter by releasing E2F from pRb.

  7. Correlation of fibrosis and transforming growth factor-beta type 2 levels in the eye.

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    Connor, T B; Roberts, A B; Sporn, M B; Danielpour, D; Dart, L L; Michels, R G; de Bustros, S; Enger, C; Kato, H; Lansing, M

    1989-05-01

    Approximately 1 out of every 10 eyes undergoing surgery for retinal detachment develops excessive intraocular fibrosis that can lead to traction retinal detachment and ultimate blindness. This disease process has been termed proliferative vitreoretinopathy (PVR). The ability to monitor and grade this fibrotic response accurately within the eye as well as the ability to aspirate vitreous cavity fluid bathing the fibrotic tissue makes this an ideal setting in which to investigate the development of fibrosis. Although laboratory studies have recently shown that transforming growth factor-beta (TGF-beta) can enhance fibrosis, little clinical evidence is yet available correlating the level of this or other growth factors with the degree of fibrosis in a clinical setting. We have found that vitreous aspirates from eyes with intraocular fibrosis associated with PVR have more than three times the amount of TGF-beta (1,200 +/- 300 pM [SEM]) found in eyes with uncomplicated retinal detachments without intraocular fibrosis (360 +/- 91 pM [SEM]). Using an in vitro assay, 84-100% of the TGF-beta activity could be blocked with specific antibodies against TGF-beta 2, whereas only 10-21% could be blocked by specific antibodies against TGF-beta 1. TGF-beta 1 was used in an animal model of traction retinal detachment. Since beta 1 and beta 2 have essentially identical biologic effects and only human beta 1 was available in quantities required, beta 1 was chosen for these in vivo studies. The injection of TGF-beta1 plus fibronectin (FN) but not TGF-beta1 alone into the vitreous cavity of rabbits resulted in the increased formation of intraocular fibrosis and traction retinal detachments as compared to control eyes. In previous studies, intravitreal FN levels were also found to be elevated in eyes with intraocular fibrosis.

  8. Absence of transforming growth factor-beta type II receptor is associated with poorer prognosis in HER2-negative breast tumours

    DEFF Research Database (Denmark)

    Paiva, C E; Drigo, S A; Rosa, F E;

    2010-01-01

    BACKGROUND: The clinical relevance of transforming growth factor-beta (TGF-beta)-signalling pathway in breast carcinomas (BCs) remained elusive. This study aimed to evaluate the prognostic value of TGF-beta1 and transforming growth factor-beta type II receptor (TGF-betaRII) expression levels...... in tumour cells and their association with the established biomarkers in BC. PATIENTS AND METHODS: In 324 BC from patients with long-term follow-up, the TGF-beta1 and TGF-betaRII transcript and protein expression levels were assessed. RESULTS: TGF-beta1 and TGF-betaRII down-expression was significantly...... associated with BC. Negative TGF-beta1 and TGF-betaRII protein status was associated with the development of distant metastasis (P = 0.003 and P = 0.029, respectively). In multivariate analysis, TGF-beta1-positive tumours were associated with increased disease-free survival (DFS) [hazard ratio (HR) = 0...

  9. Inactivation of the transforming growth factor beta type II receptor in human small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Hougaard, S; Nørgaard, P; Abrahamsen, N;

    1999-01-01

    Transforming growth factor beta (TGF-beta) exerts a growth inhibitory effect on many cell types through binding to two types of receptors, the type I and II receptors. Resistance to TGF-beta due to lack of type II receptor (RII) has been described in some cancer types including small cell lung...... cancer (SCLC). The purpose of this study was to examine the cause of absent RII expression in SCLC cell lines. Northern blot analysis showed that RII RNA expression was very weak in 16 of 21 cell lines. To investigate if the absence of RII transcript was due to mutations, we screened the poly-A tract...... for mutations, but no mutations were detected. Additional screening for mutations of the RII gene revealed a GG to TT base substitution in one cell line, which did not express RII. This mutation generates a stop codon resulting in predicted synthesis of a truncated RII of 219 amino acids. The nature...

  10. Hyperosmolarity enhanced susceptibility to renal tubular fibrosis by modulating catabolism of type I transforming growth factor-beta receptors.

    Science.gov (United States)

    Chiang, Tai-An; Yang, Yu-Lin; Yang, Ya-Ying; Hu, Min-Hsiu; Wu, Pei-Fen; Liu, Shu-Fen; Huang, Ruay-Ming; Liao, Tung-Nan; Hung, Chien-Ya; Hung, Tsung-Jen; Lee, Tao-Chen

    2010-03-01

    Hyperosmolarity plays an essential role in the pathogenesis of diabetic tubular fibrosis. However, the mechanism of the involvement of hyperosmolarity remains unclear. In this study, mannitol was used to evaluate the effects of hyperosmolarity on a renal distal tubule cell line (MDCK). We investigated transforming growth factor-beta receptors and their downstream fibrogenic signal proteins. We show that hyperosmolarity significantly enhances the susceptibility to exogenous transforming growth factor (TGF)-beta1, as mannitol (27.5 mM) significantly enhanced the TGF-beta1-induced increase in fibronectin levels compared with control experiments (5.5 mM). Specifically, hyperosmolarity induced tyrosine phosphorylation on TGF-beta RII at 336 residues in a time (0-24 h) and dose (5.5-38.5 mM) dependent manner. In addition, hyperosmolarity increased the level of TGF-beta RI in a dose- and time-course dependent manner. These observations may be closely related to decreased catabolism of TGF-beta RI. Hyperosmolarity significantly downregulated the expression of an inhibitory Smad (Smad7), decreased the level of Smurf 1, and reduced ubiquitination of TGF-beta RI. In addition, through the use of cycloheximide and the proteasome inhibitor MG132, we showed that hyperosmolarity significantly increased the half-life and inhibited the protein level of TGF-beta RI by polyubiquitination and proteasomal degradation. Taken together, our data suggest that hyperosmolarity enhances cellular susceptibility to renal tubular fibrosis by activating the Smad7 pathway and increasing the stability of type I TGF-beta receptors by retarding proteasomal degradation of TGF-beta RI. This study clarifies the mechanism underlying hyperosmotic-induced renal fibrosis in renal distal tubule cells. (c) 2010 Wiley-Liss, Inc.

  11. Cell-specific delivery of a transforming growth factor-beta type I receptor kinase inhibitor to proximal tubular cells for the treatment of renal fibrosis

    NARCIS (Netherlands)

    Prakash, Jai; de Borst, Martin H.; van Loenen - Weemaes, Annemiek M.; Lacombe, Marie; Opdam, Frank; van Goor, Harry; Meijer, Dirk K. F.; Moolenaar, Frits; Poelstra, Klaas; Kok, Robbert J.

    2008-01-01

    Purpose. Activation of tubular epithelial cells by transforming growth factor-beta (TGF-beta) plays an important role in the pathogenesis of renal tubulointerstitial fibrosis. We developed a renally accumulating conjugate of a TGF-beta type-I receptor kinase inhibitor (TKI) and evaluated its

  12. Hepatocyte Growth Factor Suppresses Transforming Growth Factor-Beta-1 and Type III Collagen in Human Primary Renal Fibroblasts

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    Shan Mou

    2009-11-01

    Full Text Available Tubulointerstitial changes in the diabetic kidney correlate closely with renal fibrosis, and transforming growth factor-beta-1 (TGF-β1 is thought to play a key role in this process. In contrast, hepatocyte growth factor (HGF has shown therapeutic effects on injured renal tubules in animal models. This study was undertaken to test the hypothesis that the preventive effects of HGF may result from interventions in TGF-β1-mediated signaling and collagen III secretion. We examined the expression of HGF/HGF receptor (c-Met and TGF-β1 in renal fibroblasts at multiple time points. The effects of recombinant human HGF on TGF-β1 expression were studied by RT-PCR and Western blotting, and the levels of collagen III were measured by ELISA. In the high-glucose condition, the expression of HGF and c-Met in renal fibroblasts was detected as early as 6 hours following cell culture while the level of TGF-β1 peaked at 96 hours. The addition of recombinant human HGF to the culture media dose-dependently inhibited TGF-β1 mRNA expression and reduced collagen III secretion by 34%. These results indicate that, during hyperglycemia, HGF inhibits TGF-β1 signaling and type III collagen activation in interstitial fibroblasts. Furthermore, we should recognize that changes in the balance between HGF and TGF-β1 might be decisive in the pathogenesis of chronic renal fibrosis. Therefore, administration of HGF to restore this balance may offer a novel therapeutic intervention in managing renal fibrogenesis in diabetic nephropathy.

  13. Cloning the promoter for transforming growth factor-beta type III receptor. Basal and conditional expression in fetal rat osteoblasts

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    Ji, C.; Chen, Y.; McCarthy, T. L.; Centrella, M.

    1999-01-01

    Transforming growth factor-beta binds to three high affinity cell surface molecules that directly or indirectly regulate its biological effects. The type III receptor (TRIII) is a proteoglycan that lacks significant intracellular signaling or enzymatic motifs but may facilitate transforming growth factor-beta binding to other receptors, stabilize multimeric receptor complexes, or segregate growth factor from activating receptors. Because various agents or events that regulate osteoblast function rapidly modulate TRIII expression, we cloned the 5' region of the rat TRIII gene to assess possible control elements. DNA fragments from this region directed high reporter gene expression in osteoblasts. Sequencing showed no consensus TATA or CCAAT boxes, whereas several nuclear factors binding sequences within the 3' region of the promoter co-mapped with multiple transcription initiation sites, DNase I footprints, gel mobility shift analysis, or loss of activity by deletion or mutation. An upstream enhancer was evident 5' proximal to nucleotide -979, and a silencer region occurred between nucleotides -2014 and -2194. Glucocorticoid sensitivity mapped between nucleotides -687 and -253, whereas bone morphogenetic protein 2 sensitivity co-mapped within the silencer region. Thus, the TRIII promoter contains cooperative basal elements and dispersed growth factor- and hormone-sensitive regulatory regions that can control TRIII expression by osteoblasts.

  14. Bone morphogenetic protein-2 antagonizes renal interstitial fibrosis by promoting catabolism of type I transforming growth factor-beta receptors.

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    Yang, Yu-Lin; Liu, Yi-Shiuan; Chuang, Lea-Yea; Guh, Jinn-Yuh; Lee, Tao-Chen; Liao, Tung-Nan; Hung, Min-Yuan; Chiang, Tai-An

    2009-02-01

    TGF-beta is a therapeutic target for renal fibrosis. Scientists have long sought ways to antagonize TGF-beta to ameliorate diabetic nephropathy. Bone morphogenetic protein (BMP-2) is a member of the TGF-beta superfamily and is highly regulated in the kidney. Thus, the role of BMP-2 was investigated in NRK-49F cells (rat fibroblasts). We showed that TGF-beta1 induces an increase in fibronectin. Treatment with exogenous BMP-2 or pCMV-BMP-2 significantly reversed the TGF-beta1-induced increase in fibronectin concomitant with a significant decrease in type I TGF-beta receptors (TGF-beta RI). Moreover, BMP-2 significantly shortened the half-life of TGF-beta RI. These results are related to proteosomal activation because MG132, a proteasome inhibitor, abolished BMP-2-mediated degradation of TGF-beta RI. This was confirmed because BMP-2 time course dependently enhanced the ubiquitination level of TGF-beta RI. In addition, Smads would seem to be involved in the interaction of BMP-2 and TGF-beta. We demonstrated that BMP-2 significantly reversed the TGF-beta1-induced increase in pSmad2/3 and reversed the TGF-beta1-induced decrease in inhibitory Smad7. Most importantly, Smad7 small interfering RNA abolished the BMP-2-induced decrease in TGF-beta RI. We evaluated the clinical efficacy of BMP-2 using unilateral ureteral obstruction rats. BMP-2 was administered ip for 7 d. In the unilateral ureteral obstruction kidneys, interstitial fibrosis was prominent. However, treatment with BMP-2 dramatically reduced Masson's trichrome staining (collagen) in the interstitial and tubular areas of the kidneys concomitantly with a reduction in TGF-beta RI. These results suggest that BMP-2 acts as a novel fibrosis antagonizing cytokine partly by down-regulating TGF-beta RI and Smads.

  15. Release of transforming growth factor beta 1 and platelet derived growth factor type AB from canine platelet gels obtained by the tube method and activated with calcium salts

    OpenAIRE

    RF Silva; GC Santana; FOP Leme; JU Carmona; CMF Rezende

    2013-01-01

    The objectives of this study were: 1) to measure the concentrations of transforming growth factor beta 1 (TGF-β1) and platelet-derived growth factor type AB (PDGF-AB) in plasma and platelet gel (PG) activated with calcium salts (gluconate or chloride) in dogs, and 2) to determine correlations between cell results and growth factors (GF) concentrations. Blood samples were collected from fourteen Brazilian Fila dogs. EDTA was used to obtain whole blood and plasma while ACD-A solution was used t...

  16. Expression of transforming growth factor-beta receptors types II and III within various cells in the rat periodontium.

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    Gao, J; Symons, A L; Bartold, P M

    1999-02-01

    This study reports the immunohistochemical localization of TGF-beta receptor type II (T beta R-II) and type III (T beta R-III) in cells of the forming periodontal ligament (PDL) in rat first molar roots. Mandibular periodontium was obtained from 3, 6 and 12-wk-old rats. This represented tissue from the initial, pre-mature and post-mature stages of root and periodontal development, respectively. Mandibular bone chips and molar roots were used to isolate osteoblasts, fibroblasts and cementoblasts. Cells were obtained using a 2-step trypsinization and explant technique, and cultured in Dulbecco's modification of Eagle's medium (DMEM) under routine cell culture conditions. Cells were cultured on coverslips for the purpose of detecting TGF-beta receptors, and compared with whole tissue sections using the same detection method. Cells which stained positively for T beta R-II and T beta R-III on both paraffin sections and cultured cell slides were counted. Both receptors were expressed in the various periodontal tissue compartments. PDL fibroblasts, cementoblasts and osteoblasts were stained positively for T beta R-II and T beta R-III. Endothelial cells were noted to be positive for T beta R-II only. T beta R-II was more widely distributed in cells than T beta R-III, but T beta R-III was extensively localized in the extracellular matrix. Both receptors were expressed on the cell membrane and also localized in the cytoplasm. The findings for paraffin sections were consistent with the immunohistochemical staining of cultured cells. The percentage of cells which stained positively for T beta R-II was greater (approximately 85%) than that for T beta R-III (approximately 60%) in all major types of the PDL cells on both paraffin sections and cultured cell slides. Extensive location of TGF-beta receptors in both cells and extracellular matrix suggests that several binding sites are available for TGF-beta s to interact with target cells during development and following maturation

  17. Transforming growth factor-beta induced by live or ultraviolet-inactivated equid herpes virus type-1 mediates immunosuppression in the horse.

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    Charan, S; Palmer, K; Chester, P; Mire-Sluis, A R; Meager, A; Edington, N

    1997-04-01

    Up to 21 days after exposure to live or ultraviolet-inactivated equid herpesvirus type-1 (EHV-1) autologous serum from ponies caused an immunosuppressive effect if incorporated into T-cell proliferation assays to EHV-1. The suppressive factor in the sera of ponies also inhibited T-cell response to phytohaemagglutinin. Increased levels of circulating activated transforming growth factor-beta 1 (TGF-beta 1) were detected, and the suppressive activity of the serum could be reversed by antibody to TGF-beta 1. In a challenge experiment the ponies which exhibited circulating TGF-beta 1 activity succumbed to infection while the ones with similar magnitudes of T-cell responses, but no TGF-beta 1 activity, were protected. A definition of this immunosuppressive mechanism and its mode of induction must be central to the design of vaccines and to an understanding of the pathogenesis of EHV-1.

  18. Transforming growth factor beta activity in urine of patients with type 2 diabetes and diabetic nephropathy

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    Rivarola E.W.R.

    1999-01-01

    Full Text Available Diabetic nephropathy (DN is characterized structurally by progressive mesangial deposition of extracellular matrix (ECM. Transforming growth factor-ß (TGF-ß is considered to be one of the major cytokines involved in the regulation of ECM synthesis and degradation. Several studies suggest that an increase in urinary TGF-ß levels may reflect an enhanced production of this polypeptide by the kidney cells. We evaluated TGF-ß in occasional urine samples from 14 normal individuals and 23 patients with type 2 diabetes (13 with persistent proteinuria >500 mg/24 h, DN, 6 with microalbuminuria, DMMA, and 4 with normal urinary albumin excretion, DMN by enzyme immunoassay. An increase in the rate of urinary TGF-ß excretion (pg/mg UCreat. was observed in patients with DN (296.07 ± 330.77 (P<0.001 compared to normal individuals (17.04 ± 18.56 (Kruskal-Wallis nonparametric analysis of variance; however, this increase was not observed in patients with DMMA (25.13 ± 11.30 or in DMN (18.16 ± 11.82. There was a positive correlation between the rate of urinary TGF-ß excretion and proteinuria (r = 0.70, a = 0.05 (Pearson's analysis, one of the parameters of disease progression.

  19. Extracellular matrix sub-types and mechanical stretch impact human cardiac fibroblast responses to transforming growth factor beta.

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    Watson, Chris J; Phelan, Dermot; Collier, Patrick; Horgan, Stephen; Glezeva, Nadia; Cooke, Gordon; Xu, Maojia; Ledwidge, Mark; McDonald, Kenneth; Baugh, John A

    2014-06-01

    Understanding the impact of extracellular matrix sub-types and mechanical stretch on cardiac fibroblast activity is required to help unravel the pathophysiology of myocardial fibrotic diseases. Therefore, the purpose of this study was to investigate pro-fibrotic responses of primary human cardiac fibroblast cells exposed to different extracellular matrix components, including collagen sub-types I, III, IV, VI and laminin. The impact of mechanical cyclical stretch and treatment with transforming growth factor beta 1 (TGFβ1) on collagen 1, collagen 3 and alpha smooth muscle actin mRNA expression on different matrices was assessed using quantitative real-time PCR. Our results revealed that all of the matrices studied not only affected the expression of pro-fibrotic genes in primary human cardiac fibroblast cells at rest but also affected their response to TGFβ1. In addition, differential cellular responses to mechanical cyclical stretch were observed depending on the type of matrix the cells were adhered to. These findings may give insight into the impact of selective pathological deposition of extracellular matrix proteins within different disease states and how these could impact the fibrotic environment.

  20. Tumor necrosis factor-alpha upregulates 11beta-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-beta in HepG2 cells.

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    Ignatova, Irena D; Kostadinova, Radina M; Goldring, Christopher E; Nawrocki, Andrea R; Frey, Felix J; Frey, Brigitte M

    2009-02-01

    The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the conversion of inactive to active glucocorticoids. 11beta-HSD1 plays a crucial role in the pathogenesis of obesity and controls glucocorticoid actions in inflammation. Several studies have demonstrated that TNF-alpha increases 11beta-HSD1 mRNA and activity in various cell models. Here, we demonstrate that mRNA and activity of 11beta-HSD1 is increased in liver tissue from transgenic mice overexpressing TNF-alpha, indicating that this effect also occurs in vivo. To dissect the molecular mechanism of this increase, we investigated basal and TNF-alpha-induced transcription of the 11beta-HSD1 gene (HSD11B1) in HepG2 cells. We found that TNF-alpha acts via p38 MAPK pathway. Transient transfections with variable lengths of human HSD11B1 promoter revealed highest activity with or without TNF-alpha in the proximal promoter region (-180 to +74). Cotransfection with human CCAAT/enhancer binding protein-alpha (C/EBPalpha) and C/EBPbeta-LAP expression vectors activated the HSD11B1 promoter with the strongest effect within the same region. Gel shift and RNA interference assays revealed the involvement of mainly C/EBPalpha, but also C/EBPbeta, in basal and only of C/EBPbeta in the TNF-alpha-induced HSD11B1 expression. Chromatin immunoprecipitation assay confirmed in vivo the increased abundance of C/EBPbeta on the proximal HSD11B1 promoter upon TNF-alpha treatment. In conclusion, C/EBPalpha and C/EBPbeta control basal transcription, and TNF-alpha upregulates 11beta-HSD1, most likely by p38 MAPK-mediated increased binding of C/EBPbeta to the human HSD11B1 promoter. To our knowledge, this is the first study showing involvement of p38 MAPK in the TNF-alpha-mediated 11beta-HSD1 regulation, and that TNF-alpha stimulates enzyme activity in vivo.

  1. Transforming growth factor-beta modulates plasminogen activator activity and plasminogen activator inhibitor type-1 expression in human keratinocytes in vitro.

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    Wikner, N E; Elder, J T; Persichitte, K A; Mink, P; Clark, R A

    1990-11-01

    Transforming growth factor beta (TGF-beta) is a multifunctional mediator with effects on cellular growth, differentiation, and extracellular matrix (ECM) metabolism. Because TGF-beta stimulates fibronectin expression in cultured human keratinocytes, we wished to determine whether it might also affect ECM degradation through the plasminogen activator (PA)-plasminogen activator inhibitor (PAI) system. Immunofluorescence of human keratinocytes using a monospecific antiserum to type 1 PAI (PAI-1) showed enhanced cellular and ECM staining when they were cultured in the presence of TGF-beta. The antiserum also identified an Mr 50,000 protein in conditioned media that was markedly enhanced by TGF-beta. A corresponding stimulation of PAI-1 mRNA was demonstrated by quantitative RNA blot analysis. Total plasminogen activating activity of conditioned medium was markedly decreased by TGF-beta. Zymography showed this to be at least partially due to decreased secreted urokinase activity. TGF-beta may play an important role in stabilizing the provisional matrix synthesized by keratinocytes in healing wounds.

  2. Characterization of novel transforming growth factor-beta type I receptors found in malignant pleural effusion tumor cells

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    Leu Sy-Jye C

    2007-08-01

    Full Text Available Abstract Background Tumors expressing a transforming growth factor-beta type I receptor (TβRI mutant with sequence deletions in a nine-alanine (9A stretch of the signal peptide are reported to be highly associated with disease progression. Expression of this mutant could interfere with endogenous TGFβ signaling in the cell. However, little is known about the importance of the remaining part of the signal peptide on the cellular function of TβRI. Results We cloned and identified four new in-frame deletion variants of TβRI, designated DM1 to DM4, in pleural effusion-derived tumor cells. Intriguingly, DM1 and DM2, with a small region truncated in the putative signal peptide of TβRI, had a serious defect in their protein expression compared with that of the wild-type receptor. Using serial deletion mutagenesis, we characterized a region encoded by nucleotides 16–51 as a key element controlling TβRI protein expression. Consistently, both DM1 and DM2 have this peptide deleted. Experiments using cycloheximde and MG132 further confirmed its indispensable role for the protein stability of TβRI. In contrast, truncation of the 9A-stretch itself or a region downstream to the stretch barely affected TβRI expression. However, variants lacking a region C-terminal to the stretch completely lost their capability to conduct TGFβ-induced transcriptional activation. Intriguingly, expression of DM3 in a cell sensitive to TGFβ made it significantly refractory to TGFβ-mediated growth inhibition. The effect of DM3 was to ablate the apoptotic event induced by TGFβ. Conclusion We identified four new transcript variants of TβRI in malignant effusion tumor cells and characterized two key elements controlling its protein stability and transcriptional activation. Expression of one of variants bestowed cancer cells with a growth advantage in the presence of TGFβ. These results highlight the potential roles of some naturally occurring TβRI variants on the

  3. Cell-specific delivery of a transforming growth factor-beta type I receptor kinase inhibitor to proximal tubular cells for the treatment of renal fibrosis.

    Science.gov (United States)

    Prakash, Jai; de Borst, Martin H; van Loenen-Weemaes, Annemiek M; Lacombe, Marie; Opdam, Frank; van Goor, Harry; Meijer, Dirk K F; Moolenaar, Frits; Poelstra, Klaas; Kok, Robbert J

    2008-10-01

    Activation of tubular epithelial cells by transforming growth factor-beta (TGF-beta) plays an important role in the pathogenesis of renal tubulointerstitial fibrosis. We developed a renally accumulating conjugate of a TGF-beta type-I receptor kinase inhibitor (TKI) and evaluated its efficacy in vitro and in vivo. TKI was conjugated to the protein Lysozyme (LZM) via a platinum-based linker. TKI-LZM was evaluated in human tubular cells (HK-2) for its anti-fibrotic activity. Plasma, kidney and urine drug levels after a single intravenous dose of TKI-LZM in rats were determined by HPLC or immunodetection. Anti-fibrotic effects of TKI-LZM were examined in the unilateral ureteral obstruction (UUO) model. TKI-LZM conjugate was successfully synthesized at an 1:1 drug/carrier ratio, and inhibited TGF-beta1-induced procollagen-1alpha1 gene expression in HK-2 cells. In vivo, TKI-LZM accumulated rapidly in tubular cells and provided a local depot for 3 days. Interestingly, a single dose of TKI-LZM inhibited the activation of tubular cells and fibroblasts in UUO rats and reduced renal inflammation. In contrast, free TKI at an equimolar (low) dosage exhibited little effects. Inhibition of TGF-beta signaling by local drug delivery is a promising antifibrotic strategy, and demonstrated the important role of tubular activation in renal fibrosis.

  4. Studies of the variability of the hepatocyte nuclear factor-1beta (HNF-1beta / TCF2) and the dimerization cofactor of HNF-1 (DcoH / PCBD) genes in relation to type 2 diabetes mellitus and beta-cell function

    DEFF Research Database (Denmark)

    Ek, J; Grarup, N; Urhammer, S A

    2001-01-01

    , and 46 type 2 diabetic patients with an impaired beta-cell function by combined single-strand conformation polymorphism (SSCP) and heteroduplex analysis. Analysis of the promoter and nine exons including intron-exon boundaries of the HNF-1beta gene revealed one novel silent polymorphism and three...... previously reported intronic variants. The silent polymorphism (I91I) was found in one patient with late-onset type 2 diabetes. One of the intronic variant (IVS6+26T-->C) was examined further. Among 584 type 2 diabetic patients the allelic frequency was 13.1% (11.2-15.0%) compared to 11.6% (8.6-14.5%) in 229...... comprising the DCoH gene revealed a previously described A-->G polymorphism located in the 3' untranslated region, which was not investigated further. In conclusion, mutations in HNF-1beta and DCoH are not a major cause of MODY or late onset type 2 diabetes in Danish Caucasian subjects....

  5. Expression and Regulation of Corticotropin-Releasing Factor Receptor Type 2 beta in Developing and Mature Mouse Skeletal Muscle

    NARCIS (Netherlands)

    Kuperman, Yael; Issler, Orna; Vaughan, Joan; Bilezikjian, Louise; Vale, Wylie; Chen, Alon

    2011-01-01

    Corticotropin-releasing factor receptor type 2 (CRFR2) is highly expressed in skeletal muscle (SM) tissue where it is suggested to inhibit interactions between insulin signaling pathway components affecting whole-body glucose homeostasis. However, little is known about factors regulating SM CRFR2 ex

  6. Different expression of mu-opiate receptor in chronic and acute wounds and the effect of beta-endorphin on transforming growth factor beta type II receptor and cytokeratin 16 expression.

    Science.gov (United States)

    Bigliardi, P L; Sumanovski, L T; Büchner, S; Rufli, T; Bigliardi-Qi, M

    2003-01-01

    There is evidence that neuropeptides, especially the opiate receptor agonists, are involved in wound healing. We have previously observed that beta-endorphin, the endogenous ligand for the mu-opiate receptor, stimulates the expression of cytokeratin 16 in a dose-dependent manner in human skin organ cultures. Cytokeratin 16 is expressed in hyperproliferative epidermis such as psoriasis and wound healing. Therefore we were interested to study whether epidermal mu-opiate receptor expression is changed at the wound margins in acute and chronic wounds. Using classical and confocal microscopy, we were able to compare the expression level of mu-opiate receptors and the influence of beta-endorphin on transforming growth factor beta type II receptor in organ culture. Our results show indeed a significantly decreased expression of mu-opiate receptors on keratinocytes close to the wound margin of chronic wounds compared to acute wounds. Additionally beta-endorphin upregulates the expression of transforming growth factor beta type II receptor in human skin organ cultures. These results suggest a crucial role of opioid peptides not only in pain control but also in wound healing. Opioid peptides have already been used in animal models in treatment of wounds; they induce fibroblast proliferation and growth of capillaries, and accelerate the maturation of granulation tissue and the epithelization of the defect. Furthermore opioid peptides may fine-tune pain and the inflammatory response while healing takes place. This new knowledge could potentially be used to design new locally applied drugs to improve the healing of painful chronic wounds.

  7. [Transforming growth factor-beta controls pathogenesis of Crohn disease].

    Science.gov (United States)

    Friess, H; di Mola, F F; Egger, B; Scheuren, A; Kleeff, J; Zimmermann, A; Büchler, M W

    1998-01-01

    The pathogenetic mechanisms which contribute to the progression of Crohn's disease are still not known. Transforming growth factor-beta (TGF-beta) and its subtypes are multifunctional polypeptides which regulate immunological processes as well as the synthesis of the extracellular matrix and fibrogenesis. In the present study, Crohn's disease tissue samples of 18 patients undergoing intestinal resection were analyzed by Northern blot analysis, in situ hybridization and immunostaining for TGF-beta 1-3 and the TGF-beta receptors type I-III (T beta R-I, T beta R-II, T beta R-III). There was a marked overexpression of TGF-beta 1, TGF-beta 3 and T beta R-II in 94% of the Crohn's disease tissue samples. TGF-beta 2 and T beta R-I ALK5 and T beta R-III were enhanced in 72%, 72% and 82% of the Crohn tissue samples, respectively. In situ hybridization and immunostaining revealed that there was frequent coexpression of TGF-beta with its signaling receptors. Our data indicate that TGF-beta and their receptors seem to be involved in the pathogenesis of Crohn's disease. Their enhanced expression might contribute to the increase in extracellular matrix resulting in fibrosis and subsequently in intestinal obstruction.

  8. Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes.

    Science.gov (United States)

    Cauchi, Stéphane; Meyre, David; Dina, Christian; Choquet, Hélène; Samson, Chantal; Gallina, Sophie; Balkau, Beverley; Charpentier, Guillaume; Pattou, François; Stetsyuk, Volodymyr; Scharfmann, Raphaël; Staels, Bart; Frühbeck, Gema; Froguel, Philippe

    2006-10-01

    Recently, the transcription factor 7-like 2 (TCF7L2) gene has been associated with type 2 diabetes in subjects of European origin in the DeCode study. We genotyped the two most associated variants (rs7903146 and rs12255372) in 2,367 French type 2 diabetic subjects and in 2,499 control subjects. Both the T-allele of rs7903146 and the T-allele of rs12255372 significantly increase type 2 diabetes risk with an allelic odds ratio (OR) of 1.69 (95% CI 1.55-1.83) (P = 6.0 x 10(-35)) and 1.60 (1.47-1.74) (P = 7.6 x 10(-28)), respectively. In nonobese type 2 diabetic subjects (BMI risk allele associates with decreased BMI and earlier age at diagnosis in the type 2 diabetic subjects (P = 8.0 x 10(-3) and P = 3.8 x 10(-4), respectively), which is supported by quantitative family-based association tests. TCF7L2 is expressed in most human tissues, including mature pancreatic beta-cells, with the exception of the skeletal muscle. In the subcutaneous and omental fat from obese type 2 diabetic subjects, TCF7L2 expression significantly decreased compared with obese normoglycemic individuals. During rat fetal beta-cell differentiation, TCF7L2 expression pattern mimics the key marker NGN3 (neurogenin 3), suggesting a role in islet development. These data provide evidence that TCF7L2 is a major determinant of type 2 diabetes risk in European populations and suggests that this transcription factor plays a key role in glucose homeostasis.

  9. Transforming growth factor type beta (TGF-β) requires reactive oxygen species to induce skeletal muscle atrophy.

    Science.gov (United States)

    Abrigo, Johanna; Rivera, Juan Carlos; Simon, Felipe; Cabrera, Daniel; Cabello-Verrugio, Claudio

    2016-05-01

    Transforming growth factor beta 1 (TGF-β1) is a classical modulator of skeletal muscle and regulates several processes, such as myogenesis, regeneration, and muscle function in skeletal muscle diseases. Skeletal muscle atrophy, characterised by the loss of muscle strength and mass, is one of the pathological conditions regulated by TGF-β. Atrophy also results in increased myosin heavy chain (MHC) degradation and the expression of two muscle-specific E3 ubiquitin ligases, atrogin-1 and MuRF-1. Reactive oxygen species (ROS) are modulators of muscle wasting, and NAD(P)H oxidase (NOX) is one of the main sources of ROS. While it was recently found that TGF-β1 induces atrophy in skeletal muscle, the underlying mechanism is not fully understood. In this study, the role of NOX-derived ROS in skeletal muscle atrophy induced by TGF-β was assessed. TGF-β1 induced an atrophic effect in C2C12 myotubes, as evidenced by decreased myotube diameter and MHC levels, together with increased MuRF-1 levels. Concomitantly, TGF-β increased NOX-induced ROS contents. Interestingly, NOX inhibition through apocynin and the antioxidant treatment with N-acetyl cysteine (NAC) decreased increased ROS levels in myotubes. Additionally, both apocynin and NAC completely prevented the decreased MHC, decreased myotube diameter, and increased MuRF-1 induced by TGF-β. Injection of TGF-β1 into the tibialis anterior muscle induced atrophy, as observed by decreased fibre diameter and MHC levels, together with increased MuRF-1 levels. Likewise, TGF-β increased the ROS contents in the smaller fibres of skeletal muscle. Additionally, the administration of NAC to mice prevented all atrophic effects and the increase in ROS induced by TGF-β in the tibialis anterior. This is the first study to report that TGF-β has an atrophic effect dependent on NOX-induced ROS in skeletal muscle.

  10. Transforming growth factor-beta1 induces transforming growth factor-beta1 and transforming growth factor-beta receptor messenger RNAs and reduces complement C1qB messenger RNA in rat brain microglia.

    Science.gov (United States)

    Morgan, T E; Rozovsky, I; Sarkar, D K; Young-Chan, C S; Nichols, N R; Laping, N J; Finch, C E

    2000-01-01

    Transforming growth factor-beta1 is a multifunctional peptide with increased expression during Alzheimer's disease and other neurodegenerative conditions which involve inflammatory mechanisms. We examined the autoregulation of transforming growth factor-beta1 and transforming growth factor-beta receptors and the effects of transforming growth factor-beta1 on complement C1q in brains of adult Fischer 344 male rats and in primary glial cultures. Perforant path transection by entorhinal cortex lesioning was used as a model for the hippocampal deafferentation of Alzheimer's disease. In the hippocampus ipsilateral to the lesion, transforming growth factor-beta1 peptide was increased >100-fold; the messenger RNAs encoding transforming growth factor-beta1, transforming growth factor-beta type I and type II receptors were also increased, but to a smaller degree. In this acute lesion paradigm, microglia are the main cell type containing transforming growth factor-beta1, transforming growth factor-beta type I and II receptor messenger RNAs, shown by immunocytochemistry in combination with in situ hybridization. Autoregulation of the transforming growth factor-beta1 system was examined by intraventricular infusion of transforming growth factor-beta1 peptide, which increased hippocampal transforming growth factor-beta1 messenger RNA levels in a dose-dependent fashion. Similarly, transforming growth factor-beta1 increased levels of transforming growth factor-beta1 messenger RNA and transforming growth factor-beta type II receptor messenger RNA (IC(50), 5pM) and increased release of transforming growth factor-beta1 peptide from primary microglia cultures. Interactions of transforming growth factor-beta1 with complement system gene expression are also indicated, because transforming growth factor-beta1 decreased C1qB messenger RNA in the cortex and hippocampus, after intraventricular infusion, and in cultured glia. These indications of autocrine regulation of transforming growth

  11. Growth suppression by transforming growth factor beta 1 of human small-cell lung cancer cell lines is associated with expression of the type II receptor

    DEFF Research Database (Denmark)

    Nørgaard, P; Damstrup, L; Rygaard, K;

    1994-01-01

    was observed in two cell lines expressing only type III receptor and in TGF-beta-r negative cell lines. In two cell lines expressing all three receptor types, growth suppression was accompanied by morphological changes. To evaluate the possible involvement of the retinoblastoma protein (pRb) in mediating...... the growth-suppressive effect of TGF-beta 1, the expression of functional pRb, as characterised by nuclear localisation, was examined by immunocytochemistry. Nuclear association of pRb was only seen in two of the five TGF-beta 1-responsive cell lines. These results indicate that in SCLC pRb is not required...

  12. High processed meat consumption is a risk factor of type 2 diabetes in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study.

    Science.gov (United States)

    Männistö, Satu; Kontto, Jukka; Kataja-Tuomola, Merja; Albanes, Demetrius; Virtamo, Jarmo

    2010-06-01

    Relatively small lifestyle modifications related to weight reduction, physical activity and diet have been shown to decrease the risk of type 2 diabetes. Connected with diet, low consumption of meat has been suggested as a protective factor of diabetes. The aim of the present study was to examine the association between the consumption of total meat or the specific types of meats and the risk of type 2 diabetes. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention cohort included middle-aged male smokers. Up to 12 years of follow-up, 1098 incident cases of diabetes were diagnosed from 24 845 participants through the nationwide register. Food consumption was assessed by a validated FFQ. In the age- and intervention group-adjusted model, high total meat consumption was a risk factor of type 2 diabetes (relative risk (RR) 1.50, 95 % CI 1.23, 1.82, highest v. lowest quintile). The result was similar after adjustment for environmental factors and foods related to diabetes and meat consumption. The RR of type 2 diabetes was 1.37 for processed meat (95 % CI 1.11, 1.71) in the multivariate model. The results were explained more by intakes of Na than by intakes of SFA, protein, cholesterol, haeme Fe, Mg and nitrate, and were not modified by obesity. No association was found between red meat, poultry and the risk of type 2 diabetes. In conclusion, reduction of the consumption of processed meat may help prevent the global epidemic of type 2 diabetes. It seems like Na of processed meat may explain the association.

  13. Transforming Growth Factor Beta-Based Therapies, a Potential Modulator of the Immune Response in Type 1 Diabetes?

    Directory of Open Access Journals (Sweden)

    E. Allison Green

    2015-11-01

    Full Text Available Immunobiological interventions are proving to be an exciting new area for mobilising the immune response towards certain tumours. In contrast, classical immunotherapeutic interventions aimed at dampening the autoimmune response to host tissue have been less successful; this is particularly evident for Type 1 diabetes (T1D. In part, the failure to control autoimmunity in T1D relates to the complexity of the immune response to β cells. To resolve this dilemma, immunologists are turning to immunobiological agents that were initially deemed too high risk for therapeutic use due to their potential to inadvertently promote autoimmunity or induce deleterious side effects. Two of these immunobiological mediators under consideration are transforming growth factor β (TGFβ and tolerogenic dendritic cells (DCs, both of which have shown robust control of the anti-islet response in animal models of T1D, the latter also recently documented to be acceptable for trialling in patients with T1D. In this review, both the challenges of translating immunobiological therapies discovered in animal models of T1D to man and the potential of TGFβ and tolerogenic DCs in the T1D setting will be discussed.

  14. Purification, crystallization and preliminary X-ray diffraction of wild-type and mutant recombinant human transforming growth factor beta-induced protein (TGFBIp).

    Science.gov (United States)

    Runager, Kasper; García-Castellanos, Raquel; Valnickova, Zuzana; Kristensen, Torsten; Nielsen, Niels Chr; Klintworth, Gordon K; Gomis-Rüth, F Xavier; Enghild, Jan J

    2009-03-01

    Transforming growth factor beta-induced protein (TGFBIp) has been linked to several corneal dystrophies as certain point mutations in the protein may give rise to a progressive accumulation of insoluble protein material in the human cornea. Little is known about the biological functions of this extracellular protein, which is expressed in various tissues throughout the human body. However, it has been found to interact with a number of extracellular matrix macromolecules such as collagens and proteoglycans. Structural information about TGFBIp might prove to be a valuable tool in the elucidation of its function and its role in corneal dystrophies caused by mutations in the TGFBI gene. A simple method for the purification of wild-type and mutant forms of recombinant human TGFBIp from human cells under native conditions is presented here. Moreover, the crystallization and preliminary X-ray analysis of TGFBIp are reported.

  15. Rat testicular germ cells and sertoli cells release different types of bioactive transforming growth factor beta in vitro

    NARCIS (Netherlands)

    B.L. Haagmans (Bart); J.W. Hoogerbrugge (Jos); A.P.N. Themmen (Axel); K.J. Teerds (Katja)

    2003-01-01

    textabstractSeveral in vivo studies have reported the presence of immunoreactive transforming growth factor-β's (TGF-β's) in testicular cells at defined stages of their differentiation. The most pronounced changes in TGF-β1 and TGF-β2 immunoreactivity occurred during spermatogenesis. In the present

  16. Serum Concentrations of Transforming Growth Factor-Beta 1 in Predicting the Occurrence of Diabetic Retinopathy in Juvenile Patients with Type 1 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Katarzyna Zorena

    2013-01-01

    Full Text Available In the present study, we have decided to evaluate if serum transforming growth factor-beta 1 (TGF-β1 concentrations may have diagnostic value in predicting the occurrence of diabetic retinopathy (DR in juvenile patients with type 1 diabetes mellitus (T1DM. The study included 81 children and adolescents with T1DM and 19 control subjects. All study participants had biochemical parameters examined, underwent an eye examination, and 24-hour blood pressure monitoring. Moreover, serum concentrations of TGF-β1 were measured. The group of patients with T1DM and nonproliferative diabetic retinopathy (NPDR had statistically significant higher serum levels of TGF-β1 (P=0.001 as compared to T1DM patients without retinopathy as well as the healthy control subject. The threshold serum TGF-β1 concentrations which had a discriminative ability to predict the presence of DR were calculated using the receiver operating characteristic (ROC curves analysis and amounted to 443 pg/ml. The area under the ROC curve (AUCROC was 0.80, and its population value was in the range of 0.66 to 0.94. The sensitivity and specificity were calculated to be 72% and 88%, respectively. Our results suggest that TGF-β1 serum concentrations may be an additional parameter in predicting the occurrence of DR in juvenile patients with T1DM.

  17. Angiotensin-(1-7 Prevents Skeletal Muscle Atrophy Induced by Transforming Growth Factor Type Beta (TGF-β via Mas Receptor Activation

    Directory of Open Access Journals (Sweden)

    Johanna Ábrigo

    2016-11-01

    Full Text Available Background: Transforming growth factor type beta 1 (TGF-β1 produces skeletal muscle atrophy. Angiotensin-(1-7 (Ang-(1-7, through the Mas receptor, prevents the skeletal muscle atrophy induced by sepsis, immobilization, or angiotensin II (Ang-II. However, the effect of Ang-(1-7 on muscle wasting induced by TGF-β1 is unknown. Aim: To evaluate whether Ang-(1-7/Mas receptor axis could prevent the skeletal muscle atrophy induced by TGF-β1. Methods: This study assessed the atrophic effect of TGF-β1 in C2C12 myotubes and mice in absence or presence of Ang-(1-7, and the receptor participation using A779, an antagonist of the Mas receptor. The levels of myosin heavy chain (MHC, polyubiquitination, and MuRF-1 were detected by western blot. Myotube diameter was also evaluated. In vivo analysis included the muscle strength, fibre diameter, MHC and MuRF-1 levels by western blot, and ROS levels by DCF probe detection. Results: The results showed that Ang-(1-7 prevented the increase in MuRF-1 and polyubiquitined protein levels, the decrease of MHC levels, the myotubes/fibre diameter diminution, and the increased production of reactive oxygen species (ROS induced by TGF-β1. Utilizing A779 inhibited the anti-atrophic effect of Ang-(1-7. Conclusion: The preventive effect of Ang-(1-7 on skeletal muscle atrophy induced by TGF-β1 is produced through inhibition of ROS production and proteasomal degradation of MHC.

  18. Insulin-like growth factors and pancreas beta cells.

    NARCIS (Netherlands)

    Haeften, T.W. van; Twickler, M.

    2004-01-01

    Abstract Insulin-like growth factors (IGFs) have been implicated in normal growth, and especially foetal pancreas beta-cell development. As low birth weight has been implicated in the development of obesity and type 2 diabetes, much research has evolved into the importance of IGF and their signallin

  19. Insulin-like growth factors and pancreas beta cells

    NARCIS (Netherlands)

    van Haeften, TW; Twickler, TB

    2004-01-01

    Insulin-like growth factors (IGFs) have been implicated in normal growth, and especially foetal pancreas beta-cell development. As low birth weight has been implicated in the development of obesity and type 2 diabetes, much research has evolved into the importance of IGF and their signalling pathway

  20. Expression of transforming growth factor beta (TGF beta) receptors and expression of TGF beta 1, TGF beta 2 and TGF beta 3 in human small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Damstrup, L; Rygaard, K; Spang-Thomsen, M;

    1993-01-01

    A panel of 21 small cell lung cancer cell (SCLC) lines were examined for the presence of Transforming growth factor beta receptors (TGF beta-r) and the expression of TGF beta mRNAs. By the radioreceptor assay we found high affinity receptors to be expressed in six cell lines. scatchard analysis...... of the binding data demonstrated that the cells bound between 4.5 and 27.5 fmol mg-1 protein with a KD ranging from 16 to 40 pM. TGF beta 1 binding to the receptors was confirmed by cross-linking TGF beta 1 to the TGF beta-r. Three classes of TGF beta-r were demonstrated, type I and type II receptors with M......(r) = 65,000 and 90,000 and the betaglycan (type III) with M(r) = 280,000. Northern blotting showed expression of TGF beta 1 mRNA in ten, TGF beta 2 mRNA in two and TGF beta 3 mRNA in seven cell lines. Our results provide, for the first time, evidence that a large proportion of a broad panel of SCLC cell...

  1. Role of Flightless-I (Drosophila) homolog in the transcription activation of type I collagen gene mediated by transforming growth factor beta

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Mi-Sun; Jeong, Kwang Won, E-mail: kwjeong@gachon.ac.kr

    2014-11-21

    Highlights: • FLII activates TGFβ-mediated expression of COL1A2 gene. • TGFβ induces the association of FLII with SMAD3 and BRG1 in A549 cells. • FLII is required for the recruitment of SWI/SNF complex and chromatin accessibility to COL1A2 promoter. - Abstract: Flightless-I (Drosophila) homolog (FLII) is a nuclear receptor coactivator that is known to interact with other transcriptional regulators such as the SWI/SNF complex, an ATP-dependent chromatin-remodeling complex, at the promoter or enhancer region of estrogen receptor (ER)-α target genes. However, little is known about the role of FLII during transcription initiation in the transforming growth factor beta (TGFβ)/SMAD-dependent signaling pathway. Here, we demonstrate that FLII functions as a coactivator in the expression of type I collagen gene induced by TGFβ in A549 cells. FLII activates the reporter gene driven by COL1A2 promoter in a dose-dependent manner. Co-expression of GRIP1, CARM1, or p300 did not show any synergistic activation of transcription. Furthermore, the level of COL1A2 expression correlated with the endogenous level of FLII mRNA level. Depletion of FLII resulted in a reduction of TGFβ-induced expression of COL1A2 gene. In contrast, over-expression of FLII caused an increase in the endogenous expression of COL1A2. We also showed that FLII is associated with Brahma-related gene 1 (BRG1) as well as SMAD in A549 cells. Notably, the recruitment of BRG1 to the COL1A2 promoter region was decreased in FLII-depleted A549 cells, suggesting that FLII is required for TGFβ-induced chromatin remodeling, which is carried out by the SWI/SNF complex. Furthermore, formaldehyde-assisted isolation of regulatory elements (FAIRE)-quantitative polymerase chain reaction (qPCR) experiments revealed that depletion of FLII caused a reduction in chromatin accessibility at the COL1A2 promoter. These results suggest that FLII plays a critical role in TGFβ/SMAD-mediated transcription of the COL1A2 gene

  2. Incisional wound healing in transforming growth factor-beta1 null mice.

    Science.gov (United States)

    Koch, R M; Roche, N S; Parks, W T; Ashcroft, G S; Letterio, J J; Roberts, A B

    2000-01-01

    Expression of endogenous transforming growth factor-beta1 is reduced in many animal models of impaired wound healing, and addition of exogenous transforming growth factor-beta has been shown to improve healing. To test the hypothesis that endogenous transforming growth factor-beta1 is essential for normal wound repair, we have studied wound healing in mice in which the transforming growth factor-beta1 gene has been deleted by homologous recombination. No perceptible differences were observed in wounds made in 3-10-day-old neonatal transforming growth factor-beta1 null mice compared to wild-type littermates. To preclude interference from maternally transferred transforming growth factor-beta1, cutaneous wounds were also made on the backs of 30-day-old transforming growth factor-beta1 null and littermate control mice treated with rapamycin, which extends their lifetime and suppresses the inflammatory response characteristic of the transforming growth factor-beta1 null mice. Again, no impairment in healing was seen in transforming growth factor-beta1 null mice. Instead these wounds showed an overall reduction in the amount of granulation tissue and an increased rate of epithelialization compared to littermate controls. Our data suggest that release of transforming growth factor-beta1 from degranulating platelets or secretion by infiltrating macrophages and fibroblasts is not critical to initiation or progression of tissue repair and that endogenous transforming growth factor-beta1 may actually function to increase inflammation and retard wound closure.

  3. Changes of transforming growth factor beta 1 in patients with type 2 diabetes and diabetic nephropathy: A PRISMA-compliant systematic review and meta-analysis.

    Science.gov (United States)

    Qiao, Yong-Chao; Chen, Yin-Ling; Pan, Yan-Hong; Ling, Wei; Tian, Fang; Zhang, Xiao-Xi; Zhao, Hai-Lu

    2017-04-01

    The existing evidence indicates increased levels of transforming growth factor beta 1 (TGF-β1) in patients with type 2 diabetes mellitus (T2DM) and those with type 2 diabetic nephropathy (T2DN); yet no meta-analysis displays a reliable result. Here we conducted a meta-analysis to evaluate characteristic changes of TGF-β1 in T2DM and diabetic nephropathy. A systematic search was conducted for eligible studies, which reported the association of TGF-β1 withT2DM and T2DN patients, in PubMed, Wangfang, Chinese-Cqvip, and China National Knowledge Infrastructure database, from February 1, 1991 to December 15, 2015. The association of serum and urine TGF-β1 in T2DM and T2DN patients should be evaluated in case-control studies. The Newcastle-Ottawa Scale was used to access the quality of the included studies, and pooling data were synthesized as standard mean difference (SMD) and 95% confidence interval (CI). The collected data were synthesized according to Cochrane Handbook for Systematic Reviews criteria. Subgroup analysis was conducted by albuminuria and ethnicity. Regression analysis and sensitivity analysis were used to explore the sources of heterogeneity. Publication bias was judged by the Egger test. Sixty-three case-control studies of 364 T2DM patients (1604 T2DN patients) and 2100 healthy controls were included for meta-analysis. Compared with the controls, the cases had increased TGF-β1 levels in both serum (T2DM: SMD 1.78 μg/L; 95% CI 0.98-2.59, P < .001; T2DN: SMD 4.70 μg/L, 95% CI 3.55-5.85, P < .001) and urine samples (T2DM: SMD 1.27 pg/mg.creatinine, 95% CI 0.16-2.38, P < .001; SMD 1.19 ng/L, 95% CI 0.77-1.62, P < .001; T2DN: SMD 3.14 pg/mg.creatinine, 95% CI 2.15-4.13, P < .001; SMD 4.50 ng/L, 95% CI 3.16-5.83, P < .001). The increase of serum TGF-β1 persisted in patients with either microalbuminuria or macroalbuminuria (all P < .001) in Chinese and non-Chinese population. High heterogeneity exists in some

  4. High value of the radiobiological parameter Dq correlates to expression of the transforming growth factor beta type II receptor in a panel of small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Hougaard, S; Krarup, M; Nørgaard, P;

    1998-01-01

    Our panel of SCLC cell lines have previously been examined for their radiobiological characteristics and sensitivity to treatment with TGF beta 1. In this study we examined the possible correlations between radiobiological parameters and the expression of the TGF beta type II receptor (TGF beta-r...... role for the repair of radiation induced DNA damage in SCLC....

  5. The Int7G24A variant of transforming growth factor-beta receptor type I is a risk factor for colorectal cancer in the male Spanish population: a case-control study

    Directory of Open Access Journals (Sweden)

    Lázaro Rafael

    2009-11-01

    Full Text Available Abstract Background The Int7G24A variant of transforming growth factor-beta receptor type I (TGFBR1 has been shown to increase the risk for kidney, ovarian, bladder, lung and breast cancers. Its role in colorectal cancer (CRC has not been established. The aims of this study were to assess the association of TGFBR1*Int7G24A variant with CRC occurrence, patient age, gender, tumour location and stage. Methods We performed a case-control study with 504 cases of sporadic CRC; and 504 non-cancerous age, gender and ethnically matched controls. Genotyping analysis was performed using allelic discrimination assay by real time PCR. Results The Int7G24A variant was associated with increased CRC incidence in an additive model of inheritance (P for trend = 0.005. No significant differences were found between Int7G24A genotypes and tumour location or stage. Interestingly, the association of the Int7G24A variant with CRC risk was significant in men (odds ratio 4.10 with 95% confidence intervals 1.41-11.85 for homozygous individuals; P for trend = 0.00023, but not in women. We also observed an increase in susceptibility to CRC for individuals aged less than 70 years. Conclusion Our data suggest that the Int7G24A variant represents a risk factor for CRC in the male Spanish population.

  6. Preclinical Toxicology Studies of Recombinant Human Platelet-Derived Growth Factor-BB Either Alone or in Combination with Beta-Tricalcium Phosphate and Type I Collagen

    Directory of Open Access Journals (Sweden)

    Conan S. Young

    2010-01-01

    Full Text Available Human platelet-derived growth factor-BB (hPDGF-BB is a basic polypeptide growth factor released from platelets at the injury site. It is a multifunctional molecule that regulates DNA synthesis and cell division and induces biological effects that are implicated in tissue repair, atherosclerosis, inflammatory responses, and neoplastic diseases. This paper is an overview of the toxicology data generated from a broad testing platform to determine bone, soft tissue, and systemic responses following administration of rhPDGF-BB. Moreover, the systemic and local toxicity of recombinant human PDGF-BB (rhPDGF-BB in combination with either beta-tricalcium phosphate (β-TCP or collagen combined with β-TCP was studied to determine dermal sensitization, irritation, intramuscular tissue responses, pyrogenicity, genotoxicity, and hemolytic properties. All data strongly suggest that rhPDGF-BB either alone or in combination with β-TCP or collagen with β-TCP is biocompatible and has neither systemic nor local toxicity, supporting its safe use in enhancing wound healing in patients.

  7. Regulating the beta cell mass as a strategy for type-2 diabetes treatment.

    Science.gov (United States)

    Song, Imane; Muller, Christo; Louw, Johan; Bouwens, Luc

    2015-01-01

    The incidence of type 2 diabetes (T2D) increases dramatically worldwide and has created an enormous health care burden. Obesity, dyslipidemia and insulin resistance are major risk factors for the development of T2D, but the major factor leading to the disease is failure of the insulin-producing beta cell mass to compensate for increasing insulin demands of the body. Progression of the disease further diminishes the beta cell mass as a result of lipotoxicity and glucotoxicity for which beta cells are particularly sensitive. Hence, treatment aiming to prevent beta cell loss or increase the number of beta cells could inhibit diabetes progression or lead to restoration of normal metabolism. Whereas current and new antidiabetic drugs are mainly targeting insulin secretion and action or glucose uptake, newer interventions must be found that prevent beta cell loss or increase beta cell number. The targets for this are beta cell proliferation, neogenesis and survival. This review examines major evidence from animal experiments suggesting that it is feasible to regulate the beta cell mass by bioactive compounds like growth factors, cytokines, hormones, phytochemicals and small molecules. Often the mode of action remains unclear due to inadequate methods to assess the effects of the compounds on the beta cell dynamics. Furthermore, a major challenge is to identify compounds with sufficient specificity in order to avoid unwanted effects on other cell types. Provided such safety issues can be solved, this may provide a curative approach for diabetes treatment.

  8. Genes involved in the transforming growth factor beta signalling pathway and the risk of intracranial aneurysms

    NARCIS (Netherlands)

    Ruigrok, Y. M.; Tan, S.; Medic, J.; Rinkel, G. J. E.; Wijmenga, C.

    2008-01-01

    Background and purpose: The 19q13.3 locus for intracranial aneurysms (IA) partly overlaps with the 19q13 locus for abdominal aortic aneurysms (AAA). A common genetic risk factor located in this locus for the two aneurysm types seems plausible. The transforming growth factor beta (TGF-beta) signallin

  9. Expression of transforming growth factor-beta (TGF-beta) receptors, TGF-beta 1 and TGF-beta 2 production and autocrine growth control in osteosarcoma cells.

    Science.gov (United States)

    Kloen, P; Jennings, C L; Gebhardt, M C; Springfield, D S; Mankin, H J

    1994-08-01

    Transforming growth factor-beta (TGF-beta) is a polypeptide with multiple physiological functions. Isoforms of this growth factor have important roles in control of the cell cycle, in regulation of cell-cell interactions and in growth and development. Malignant transformation has been shown to be associated with increased expression of TGF-beta. Since bone is the largest storage site and producer of TGF-beta, we speculated on the existence of an autocrine mechanism in osteosarcoma, a malignant bone tumor. Expression of TGF-beta cell surface receptors, effects on growth of TGF-beta and TGF-beta antibodies and production of 2 TGF-beta isoforms were studied in a panel of 7 osteosarcoma cell lines. In contrast to most previous reports on the effects of TGF-beta on osteosarcoma cell growth, we found a mitogenic effect of TGF-beta 1 in 4 of 7 osteosarcoma cell lines. Receptor profiles for TGF-beta were aberrant in 5 of the 7 cell lines tested, and production of TGF-beta 1 and TGF-beta 2 varied among cell lines. Addition of anti-TGF-beta antagonized the effects of endogenous TGF-beta. Our results suggest a potential role of TGF-beta in autocrine growth control of osteosarcoma cells.

  10. Role of IL-1beta in type 2 diabetes

    DEFF Research Database (Denmark)

    Dinarello, Charles A; Donath, Marc Y; Mandrup-Poulsen, Thomas

    2010-01-01

    To understand the role of inflammation as the fundamental cause of type 2 diabetes and specifically to examine the contribution of IL-1beta.......To understand the role of inflammation as the fundamental cause of type 2 diabetes and specifically to examine the contribution of IL-1beta....

  11. A polymorphism within the connective tissue growth factor (CTGF) gene has no effect on non-invasive markers of beta-cell area and risk of type 2 diabetes.

    Science.gov (United States)

    Pivovarova, Olga; Fisher, Eva; Dudziak, Katarzyna; Ilkavets, Iryna; Dooley, Steven; Slominsky, Petr; Limborska, Svetlana; Weickert, Martin O; Spranger, Joachim; Fritsche, Andreas; Boeing, Heiner; Pfeiffer, Andreas F H; Rudovich, Natalia

    2011-01-01

    Chromosomal locus 6q23 is strongly linked to type 2 diabetes (T2DM) and related features including insulin secretion in various ethnic populations. Connective tissue growth factor (CTGF) gene is an interesting T2DM candidate gene in this chromosome region. CTGF is a key mediator of progressive pancreatic fibrosis up-regulated in type 2 diabetes. In contrast, CTGF inactivation in mice compromises islet cell proliferation during embryogenesis. The aim of our study was to investigate an impact of CTGF genetic variation on pancreatic beta-cell function and T2DM pathogenesis. We studied the effect of a common CTGF polymorphism rs9493150 on the risk of the T2DM development in three independent German cohorts. Specifically, the association between CTGF polymorphism and non-invasive markers of beta-cell area derived from oral glucose tolerance test was studied in subjects without diabetes. Neither in the Metabolic Syndrome Berlin Potsdam (MESYBEPO) study (n=1026) (OR=0.637, CI (0.387-1.050); p=0.077) nor in the European Prospective Investigation into Cancer and Nutrition-Potsdam (EPIC-Potsdam) (n=3049) cohort (RR=0.77 CI (0.49-1.20), p=0.249 for the recessive homozygote in general model), a significant association with increased diabetes risk was observed. The risk allele of rs9493150 had also no effect on markers of beta-cell area in the combined analysis of the MESYBEPO and Tübingen Family Study (n=1826). In conclusion, the polymorphism rs9493150 in the 5'-untranslated region of the CTGF gene has no association with T2DM risk and surrogate markers of beta-cell area.

  12. A Polymorphism Within the Connective Tissue Growth Factor (CTGF Gene has No Effect on Non-Invasive Markers of Beta-Cell Area and Risk of Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Olga Pivovarova

    2011-01-01

    Full Text Available Chromosomal locus 6q23 is strongly linked to type 2 diabetes (T2DM and related features including insulin secretion in various ethnic populations. Connective tissue growth factor (CTGF gene is an interesting T2DM candidate gene in this chromosome region. CTGF is a key mediator of progressive pancreatic fibrosis up-regulated in type 2 diabetes. In contrast, CTGF inactivation in mice compromises islet cell proliferation during embryogenesis. The aim of our study was to investigate an impact of CTGF genetic variation on pancreatic beta-cell function and T2DM pathogenesis. We studied the effect of a common CTGF polymorphism rs9493150 on the risk of the T2DM development in three independent German cohorts. Specifically, the association between CTGF polymorphism and non-invasive markers of beta-cell area derived from oral glucose tolerance test was studied in subjects without diabetes. Neither in the Metabolic Syndrome Berlin Potsdam (MESYBEPO study (n = 1026 (OR = 0.637, CI (0.387–1.050; p = 0.077 nor in the European Prospective Investigation into Cancer and Nutrition-Potsdam (EPIC-Potsdam (n = 3049 cohort (RR = 0.77 CI (0.49–1.20, p = 0.249 for the recessive homozygote in general model, a significant association with increased diabetes risk was observed. The risk allele of rs9493150 had also no effect on markers of beta-cell area in the combined analysis of the MESYBEPO and Tübingen Family Study (n = 1826. In conclusion, the polymorphism rs9493150 in the 5’-untranslated region of the CTGF gene has no association with T2DM risk and surrogate markers of beta-cell area.

  13. 11beta-hydroxysteroid dehydrogenase type 1 inhibitors for metabolic syndrome.

    Science.gov (United States)

    Schnackenberg, Christine G

    2008-03-01

    The metabolic syndrome is a constellation of interrelated metabolic risk factors that appear to promote the development of diabetes and cardiovascular disease. These risk factors include abdominal obesity, insulin resistance, hypertension and dyslipidemia. 11beta-Hydroxysteroid dehydrogenase (11beta-HSD) catalyzes the interconversion of glucocorticoids through the activity of two isozymes: type 1 (11beta-HSD1) and type 2 (11beta-HSD2). 11beta-HSD1 converts inactive glucocorticoid to the active form, whereas 11beta-HSD2 converts active glucocorticoid to the inactive form. It is well established that reduced 11beta-HSD2 activity causes hypertension and electrolyte abnormalities. More recently, the pathophysiological role of 11beta-HSD1 has been explored and studies suggest that increased 11beta-HSD1 activity within target tissues may promote insulin resistance, obesity, hypertension and dyslipidemia. This review will discuss the evidence that inhibition of 11beta-HSD1 may be therapeutic in the treatment of the metabolic syndrome.

  14. Factors influencing beta-amylase activity in sorghum malt

    CSIR Research Space (South Africa)

    Taylor, JRN

    1993-09-01

    Full Text Available An investigation into factors influencing beta-amylase activity in sorghum malt confirmed that ungerminated sorghum grain exhibited essentially no beta-amylase activity. Malted sorghum had beta-amylase activity less than 25% of the level in barley...

  15. The disintegrin and metalloproteinase ADAM12 contributes to TGF-beta signaling through interaction with the type II receptor

    DEFF Research Database (Denmark)

    Atfi, Azeddine; Dumont, Emmanuelle; Colland, Frédéric;

    2007-01-01

    Transforming growth factor-beta (TGF-beta) regulates a wide variety of biological processes through two types of Ser/Thr transmembrane receptors: the TGF-beta type I receptor and the TGF-beta type II receptor (TbetaRII). Upon ligand binding, TGF-beta type I receptor activated by TbetaRII propagates...... signals to Smad proteins, which mediate the activation of TGF-beta target genes. In this study, we identify ADAM12 (a disintegrin and metalloproteinase 12) as a component of the TGF-beta signaling pathway that acts through association with TbetaRII. We found that ADAM12 functions by a mechanism...... independent of its protease activity to facilitate the activation of TGF-beta signaling, including the phosphorylation of Smad2, association of Smad2 with Smad4, and transcriptional activation. Furthermore, ADAM12 induces the accumulation of TbetaRII in early endosomal vesicles and stabilizes the Tbeta...

  16. Transforming growth factor-beta type 1 receptor (ALK5) and Smad proteins mediate TIMP-1 and collagen synthesis in experimental intestinal fibrosis.

    Science.gov (United States)

    Medina, Carlos; Santos-Martinez, Maria Jose; Santana, Alfredo; Paz-Cabrera, Maria Cristina; Johnston, Michael J; Mourelle, Marisabel; Salas, Antonio; Guarner, Francisco

    2011-08-01

    Transforming growth factor β (TGF-β) is known to play a key role in intestinal fibrosis; however, the underlying mechanisms are not well understood. TGF-β signal transduction is through TGF-β receptors, including the TGF-β type 1 receptor. Most cell types contain a TGF-β type 1 receptor form known as activin receptor-like kinase 5 (ALK5), which propagates the signal to the nucleus through the phosphorylation of Smad2 and Smad3 proteins. Therefore, we assessed the effect of the disruption of TGF-β/ALK5/Smad signalling by an ALK5 inhibitor (SD-208) in two experimental animal models of intestinal fibrosis: anaerobic bacteria- and trinitrobenzensulphonic acid-induced colitis. In addition, isolated myofibroblasts were pretreated with SD-208 and exposed to recombinant TGF-β1. Finally, myofibroblasts were transfected with ALK5, Smad2, and Smad3-specific siRNA. Up-regulation of ALK5 and TIMP-1, phosphorylation of Smad2 and Smad3 proteins, and increased intestinal wall collagen deposition were found in both experimental animal models. These effects were decreased by SD-208. TGF-β1 treatment also induced phosphorylation of Smad2 and Smad3 and up-regulation of ALK5 protein, TIMP-1, and α2 type 1 collagen gene expression in isolated myofibroblasts. Again these effects were inhibited by SD-208. Also, ALK5, Smad2, and Smad3 siRNA abolished the induction of TIMP-1 and α2 type 1 collagen. Our findings provide evidence that the TGF-β/ALK5/Smad pathway participates in the pathogenesis of experimental intestinal fibrosis. These data show promise for the development of an effective therapeutic intervention in this condition.

  17. Transforming growth factor-beta as a differentiating factor for cultured smooth muscle cells.

    Science.gov (United States)

    Gawaziuk, J P; X; Sheikh, F; Cheng, Z-Q; Cattini, P A; Stephens, N L

    2007-10-01

    The aim of the present study was to determine whether the development of supercontractile smooth muscle cells, contributing to the nonspecific hyperreactivity of airways in asthmatic patients, is due to transforming growth factor (TGF)-beta. In cultured smooth muscle cells starved by removal of 10% foetal bovine serum for 7 days, growth arrest was seen; 30% became elongated and demonstrated super contractility. Study of conditioned medium suggested that the differentiating factor was TGF-beta. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) was carried out on conditioned medium from the arrested cells. Two protein bands were identified as matrix metalloproteinase (MMP)-2 and TGF-beta1. To determine second messenger signalling by SMAD2, Western blotting and confocal microscopy were employed. Conditioned medium from arrested cultures showed the presence of MMP-2 and TGF-beta1, as revealed by SDS-PAGE; 68- and 25-kDa bands were seen. Differentiation was confirmed by upregulation of marker proteins, smooth muscle type myosin heavy chain and myosin light chain kinase. Confirmation was obtained by downregulating these proteins with decorin treatment, which reduces the levels of active TGF-beta and an adenoviral dominant-negative vector coding for a mutated type II TGF-beta-receptor. Activation of second messenger signalling was demonstrated immunocytochemically by the presence of phosphorylated SMAD2 and SMAD4. Transforming growth factor-beta is likely to be the differentiating factor responsible for the development of these supercontractile smooth muscle cells. The development of such cells in vivo after cessation of an asthmatic attack could contribute to the nonspecific hyperreactivity of airways seen in patients.

  18. 21beta-Hydroxy-oleanane-type triterpenes from Hippocratea excelsa.

    Science.gov (United States)

    Cáceres-Castillo, David; Mena-Rejón, Gonzalo J; Cedillo-Rivera, Roberto; Quijano, Leovigildo

    2008-02-01

    Stem bark of Hippocratea excelsa afforded six pentacyclic triterpenes, five oleanane and one ursane types. They were identified as 11beta,21beta-dihydroxy-olean-12-ene-3-one (2), 3alpha,11alpha,21beta-trihydroxy-olean-12-ene (3), 3alpha,21beta-dihydroxy-11alpha-methoxy-olean-12-ene (4), 3alpha,21beta-dihydroxy-olean-9(11),12-diene (5), 3alpha,21beta-dihydroxy-olean-12-ene (6) and 3alpha,21beta-dihydroxy-11alpha-methoxy-urs-12-ene, isolated as its diacetate derivative (7), as well as 3alpha,21beta-dihydroxy-olean-12-ene (1) previously isolated from the root bark. The known alpha- and beta-amyrin, oleanoic and ursolic acids, trans-polyisoprene, and the ubiquitous beta-sitosterol were also isolated. Structures were elucidated on the basis of spectroscopic analyses, including homo- and heteronuclear correlation NMR experiments (COSY, ROESY, HSQC and HMBC) and comparison with literature data. The antigiardial activity of compounds 2-5 was not significant.

  19. Changes of regulatory T cells, transforming growth factor-beta and interleukin-10 in patients with type 1 diabetes mellitus: A systematic review and meta-analysis.

    Science.gov (United States)

    Qiao, Yong-Chao; Shen, Jian; Hong, Xue-Zhi; Liang, Ling; Bo, Chao-Sheng; Sui, Yi; Zhao, Hai-Lu

    2016-09-01

    Regulatory T lymphocyte cells (Treg) associated with interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) have implicated in the development of type 1 diabetes mellitus (T1DM), yet the existing evidence remains unclear. Hereby we performed a systematic review and meta-analysis to characterize the changes in T1DM patients. A total of 1407 T1DM patients and 1373 healthy controls from 40 case-control studies were eventually included in the pooling analysis. Compared with the controls, T1DM patients had decreased frequency of CD4(+)CD25(+)Treg (p=0.0003), CD4(+)CD25(+)Foxp3(+)Treg (p=0.020), and the level of TGF-β (p=0.030). Decrease in IL-10 (p=0.14) was not significant. All the changes remained significant when the studies with low NOS scores and publication bias were excluded. In conclusion, peripheral Treg and serum TGF-β are reduced in type 1 diabetes mellitus whereas changes in serum IL-10 are not significant. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Role of TGF-beta1 in relation to exercise-induced type I collagen synthesis in human tendinous tissue

    DEFF Research Database (Denmark)

    Heinemeier, Katja; Langberg, Henning; Olesen, Jens L

    2003-01-01

    Mechanical loading of tissue is known to influence local collagen synthesis, and microdialysis studies indicate that mechanical loading of human tendon during exercise elevates tendinous type I collagen production. Transforming growth factor-beta1 (TGF-beta1), a potent stimulator of type I collag...... to exercise, suggest a role for TGF-beta1 in mechanical regulation of local collagen type I synthesis in tendon-related connective tissue in vivo....

  1. Deletion of the mitochondrial flavoprotein apoptosis inducing factor (AIF induces beta-cell apoptosis and impairs beta-cell mass.

    Directory of Open Access Journals (Sweden)

    Fabienne T Schulthess

    Full Text Available BACKGROUND: Apoptosis is a hallmark of beta-cell death in both type 1 and type 2 diabetes mellitus. Understanding how apoptosis contributes to beta-cell turnover may lead to strategies to prevent progression of diabetes. A key mediator of apoptosis, mitochondrial function, and cell survival is apoptosis inducing factor (AIF. In the present study, we investigated the role of AIF on beta-cell mass and survival using the Harlequin (Hq mutant mice, which are hypomorphic for AIF. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemical evaluation of pancreata from Hq mutant mice displayed much smaller islets compared to wild-type mice (WT. Analysis of beta-cell mass in these mice revealed a greater than 4-fold reduction in beta-cell mass together with an 8-fold increase in beta-cell apoptosis. Analysis of cell cycle dynamics, using BrdU pulse as a marker for cells in S-phase, did not detect significant differences in the frequency of beta-cells in S-phase. In contrast, double staining for phosphorylated Histone H3 and insulin showed a 3-fold increase in beta-cells in the G2 phase in Hq mutant mice, but no differences in M-phase compared to WT mice. This suggests that the beta-cells from Hq mutant mice are arrested in the G2 phase and are unlikely to complete the cell cycle. beta-cells from Hq mutant mice display increased sensitivity to hydrogen peroxide-induced apoptosis, which was confirmed in human islets in which AIF was depleted by siRNA. AIF deficiency had no effect on glucose stimulated insulin secretion, but the impaired effect of hydrogen peroxide on beta-cell function was potentiated. CONCLUSIONS/SIGNIFICANCE: Our results indicate that AIF is essential for maintaining beta-cell mass and for oxidative stress response. A decrease in the oxidative phosphorylation capacity may counteract the development of diabetes, despite its deleterious effects on beta-cell survival.

  2. Time course, distribution and cell types of induction of transforming growth factor betas following middle cerebral artery occlusion in the rat brain.

    Directory of Open Access Journals (Sweden)

    Gabriella Pál

    Full Text Available Transforming growth factor-βs (TGF-β1-3 are cytokines that regulate the proliferation, differentiation, and survival of various cell types. The present study describes the induction of TGF-β1-3 in the rat after focal ischemia at 3 h, 24 h, 72 h and 1 month after transient (1 h or permanent (24 h middle cerebral artery occlusion (MCAO using in situ hybridization histochemistry and quantitative analysis. Double labeling with different markers was used to identify the localization of TGF-β mRNA relative to the penumbra and glial scar, and the types of cells expressing TGF-βs. TGF-β1 expression increased 3 h after MCAO in the penumbra and was further elevated 24 h after MCAO. TGF-β1 was present mostly in microglial cells but also in some astrocytes. By 72 h and 1 month after the occlusion, TGF-β1 mRNA-expressing cells also appeared in microglia within the ischemic core and in the glial scar. In contrast, TGF-β2 mRNA level was increased in neurons but not in astrocytes or microglial cells in layers II, III, and V of the ipsilateral cerebral cortex 24 h after MCAO. TGF-β3 was not induced in cells around the penumbra. Its expression increased in only a few cells in layer II of the cerebral cortex 24 h after MCAO. The levels of TGF-β2 and -β3 decreased at subsequent time points. Permanent MCAO further elevated the levels of all 3 subtypes of TGF-βs suggesting that reperfusion is not a major factor in their induction. TGF-β1 did not co-localize with either Fos or ATF-3, while the co-localization of TGF-β2 with Fos but not with ATF-3 suggests that cortical spreading depolarization, but not damage to neural processes, might be the mechanism of induction for TGF-β2. The results imply that endogenous TGF-βs are induced by different mechanisms following an ischemic attack in the brain suggesting that they are involved in distinct spatially and temporally regulated inflammatory and neuroprotective processes.

  3. Transforming growth factor-beta, but not ciliary neurotrophic factor, inhibits DNA synthesis of adrenal medullary cells in vitro

    DEFF Research Database (Denmark)

    Wolf, N; Krohn, K; Bieger, S;

    1999-01-01

    by the neuroendocrine chromaffin cells, which also express the transforming growth factor-beta receptor type II. In contrast to the developmentally related sympathetic neurons, chromaffin cells continue to proliferate throughout postnatal life. Using 5-bromo-2'-deoxyuridine pulse labeling and tyrosine hydroxylase...... regulator of chromaffin cell division.......Transforming growth factor-betas are members of a superfamily of multifunctional cytokines regulating cell growth and differentiation. Their functions in neural and endocrine cells are not well understood. We show here that transforming growth factor-betas are synthesized, stored and released...

  4. Beta cell proliferation and growth factors

    DEFF Research Database (Denmark)

    Nielsen, Jens Høiriis; Svensson, C; Møldrup, Annette

    1999-01-01

    Formation of new beta cells can take place by two pathways: replication of already differentiated beta cells or neogenesis from putative islet stem cells. Under physiological conditions both processes are most pronounced during the fetal and neonatal development of the pancreas. In adulthood little...... increase in the beta cell number seems to occur. In pregnancy, however, a marked hyperplasia of the beta cells is observed both in rodents and man. Increased mitotic activity has been seen both in vivo and in vitro in islets exposed to placental lactogen (PL), prolactin (PRL) and growth hormone (GH......). Receptors for both GH and PRL are expressed in islet cells and are upregulated during pregnancy. By mutational analysis we have identified different functional domains of the cytoplasmic part of the GH receptor. Thus the mitotic signaling only requires the membrane proximal part of the receptor...

  5. Factors Influencing Beta-Thalassemia Awareness in Western India

    OpenAIRE

    Ashwin P Patel; Prakash H Parmar; Rupesh B Patel; Nikhil M Trivedi; Nileshkumar A Bhartiya

    2016-01-01

    "Context: Beta-thalassemia is highly prevalent in western India. Our organization runs a screening and prevention program to create awareness and reduce the incidence of homozygous beta-thalassemia cases. Aims: The study was designed to evaluate factors influencing awareness about Beta-thalassemia. Methodology: This cross sectional survey was conducted at six colleges, two medical clinics, and a thalassemia transfusion centre. It involved 398 adults ( and #8805;18 years).The survey form...

  6. Factors Influencing Beta-Thalassemia Awareness in Western India

    OpenAIRE

    Ashwin P Patel; Prakash H Parmar; Rupesh B Patel; Nikhil M Trivedi; Nileshkumar A Bhartiya

    2016-01-01

    "Context: Beta-thalassemia is highly prevalent in western India. Our organization runs a screening and prevention program to create awareness and reduce the incidence of homozygous beta-thalassemia cases. Aims: The study was designed to evaluate factors influencing awareness about Beta-thalassemia. Methodology: This cross sectional survey was conducted at six colleges, two medical clinics, and a thalassemia transfusion centre. It involved 398 adults ( and #8805;18 years).The survey form...

  7. Plasma transforming growth factor beta levels in breast cancer patients

    NARCIS (Netherlands)

    Sminia, P; Barten, AD; Van Waarde, MAWH; Vujaskovic, Z; Van Tienhoven, G

    1998-01-01

    We investigated whether the concentration of circulating transforming growth factor beta (TGF beta) yields diagnostic value in breast cancer. Blood was collected from twenty stage I and II breast cancer patients both prior to treatment and after surgical excision of the tumour. Both latent and activ

  8. 11beta-hydroxysteroid dehydrogenase type 1 and obesity.

    Science.gov (United States)

    Morton, Nicholas M; Seckl, Jonathan R

    2008-01-01

    The metabolic syndrome consists of a constellation of co-associated metabolic abnormalities such as insulin resistance, type 2 diabetes, dyslipidaemia, hypertension and visceral obesity. For many years endocrinologists have noted the striking resemblance between this disease state and that associated with Cushing's syndrome. However, in the metabolic syndrome plasma cortisol levels tend to be normal or lower than in normal individuals. Nevertheless there is strong evidence that glucocorticoid action underlies metabolic disease, largely from rodent obesity models where removing glucocorticoids reverses obesity and its metabolic abnormalities. The apparent paradox of similar metabolic defects - despite the opposing plasma glucocorticoid profiles of Cushing's and idiopathic metabolic syndrome - remained intriguing until the discovery that intracellular glucocorticoid reactivation was elevated in adipose tissue of obese rodents and humans. The enzyme that mediates this activation, conversion of cortisone (11-dehydrocorticosterone in rodents) to cortisol (corticosterone in rodents), locally within tissues is 11beta -hydroxysteroid dehydrogenase type 1 (11beta -HSD1). In order to determine whether elevated tissue 11beta -HSD1 contributed to obesity and metabolic disease, transgenic mice overexpressing 11beta -HSD1 in adipose tissue or liver were made. Adipose-selective 11beta -HSD1 transgenic mice exhibited elevated intra-adipose and portal, but not systemic corticosterone levels, abdominal obesity, hyperglycaemia, insulin resistance, dyslipidaemia and hypertension. In contrast, transgenic overexpression of 11beta -HSD1 in liver yielded an attenuated metabolic syndrome with mild insulin resistance, dyslipidaemia, hypertension and fatty liver, but not obesity or glucose intolerance. Together with early data using non-selective 11beta -HSD1 inhibitors to insulin sensitise humans, this corroborated the notion that the enzyme may be a good therapeutic target in the treatment

  9. Induction of nuclear factor-kappaB and its downstream genes by TNF-alpha and IL-1beta has a pro-apoptotic role in pancreatic beta cells

    DEFF Research Database (Denmark)

    Ortis, F; Pirot, P; Naamane, N

    2008-01-01

    AIMS/HYPOTHESIS: IL-1beta and TNF-alpha contribute to pancreatic beta cell death in type 1 diabetes. Both cytokines activate the transcription factor nuclear factor-kappaB (NF-kappaB), but recent observations suggest that NF-kappaB blockade prevents IL-1beta + IFN-gamma- but not TNF-alpha + IFN-g...

  10. Transforming growth factor-beta (TGF-beta) and programmed cell death in the vertebrate retina.

    Science.gov (United States)

    Duenker, Nicole

    2005-01-01

    Programmed cell death (PCD) is a precisely regulated phenomenon essential for the homeostasis of multicellular organisms. Developmental systems, particularly the nervous system, have provided key observations supporting the physiological role of PCD. We have recently shown that transforming growth factor-beta (TGF-beta) plays an important role in mediating ontogenetic PCD in the nervous system. As part of the central nervous system the developing retina serves as an ideal model system for investigating apoptotic processes during neurogenesis in vivo as it is easily accessible experimentally and less complex due to its limited number of different neurons. This review summarizes data indicating a pivotal role of TGF-beta in mediating PCD in the vertebrate retina. The following topics are discussed: expression of TGF-beta isoforms and receptors in the vertebrate retina, the TGF-beta signaling pathway, functions and molecular mechanisms of PCD in the nervous system, TGF-beta-mediated retinal apoptosis in vitro and in vivo, and interactions of TGF-beta with other pro- and anti-apoptotic factors.

  11. Factors affecting drug adsorption on beta zeolites.

    Science.gov (United States)

    Pasti, Luisa; Sarti, Elena; Cavazzini, Alberto; Marchetti, Nicola; Dondi, Francesco; Martucci, Annalisa

    2013-05-01

    The adsorption behaviour of three commonly used drugs, namely ketoprofen, hydrochlorothiazide and atenolol, from diluted aqueous solutions on beta zeolites with different SiO2/Al2O3 ratio (i.e. 25, 38 and 360) was investigated by changing the ionic strength and the pH, before and after thermal treatment of the adsorbents. The selective adsorption of drugs was confirmed by thermogravimetry and X-ray diffraction. The adsorption capacity of beta zeolites was strongly dependent on both the solution pH and the alumina content of the adsorbent. Such a remarkable difference was interpreted as a function of the interactions between drug molecules and zeolite surface functional groups. Atenolol was readily adsorbed on the less hydrophobic zeolite, under pH conditions in which electrostatic interactions were predominant. On the other hand, ketoprofen adsorption was mainly driven by hydrophobic interactions. For undissociated molecules the adsorption capability increased with the increase of hydrophobicity.

  12. LASIK surgery of granular corneal dystrophy type 2 patients leads to accumulation and differential proteolytic processing of transforming growth factor beta-induced protein (TGFBIp)

    DEFF Research Database (Denmark)

    Poulsen, Ebbe Toftgaard; Nielsen, Nadia Sukusu; Jensen, Morten Mørk;

    2016-01-01

    at position 124 in mature TGFBIp leads to granular corneal dystrophy type 2 (GCD2). Homozygous GCD2 cases develop massive protein accumulation early in life whereas heterozygous GCD2 cases become affected much later and generally with a much less severe outcome. However, if heterozygous GCD2 patients undergo...... laser-assisted in situ keratomileusis (LASIK) surgery protein accumulation is accelerated and they develop massive protein accumulations a few years after surgery. Here, we present the protein profile of aggregate-containing corneal tissue from GCD2 patients with a history of LASIK surgery using LC......-MS/MS. Label-free quantification of corneal extracellular matrix proteins showed accumulation of TGFBIp. This was supported by 2DE and immunoblotting against TGFBIp that revealed the accumulation of full-length TGFBIp. In addition, a high molecular weight TGFBIp complex was more apparent in GCD2 patients after...

  13. Imaging of beta-Cell Mass and Insulitis in Insulin-Dependent (Type 1) Diabetes Mellitus

    NARCIS (Netherlands)

    Di Gialleonardo, Valentina; de Vries, Erik F. J.; Di Girolamo, Marco; Quintero, Ana M.; Dierckx, Rudi A. J. O.; Signore, Alberto

    2012-01-01

    Insulin-dependent (type 1) diabetes mellitus is a metabolic disease with a complex multifactorial etiology and a poorly understood pathogenesis. Genetic and environmental factors cause an autoimmune reaction against pancreatic beta-cells, called insulitis, confirmed in pancreatic samples obtained at

  14. An effective method to accurately calculate the phase space factors for $\\beta^- \\beta^-$ decay

    CERN Document Server

    Neacsu, Andrei

    2015-01-01

    Accurate calculations of the electron phase space factors are necessary for reliable predictions of double-beta decay rates, and for the analysis of the associated electron angular and energy distributions. We present an effective method to calculate these phase space factors that takes into account the distorted Coulomb field of the daughter nucleus, yet allows one to easily calculate the phase space factors with good accuracy relative to the most exact methods available in the recent literature.

  15. Transforming growth factor-beta stimulates the expression of fibronectin by human keratinocytes.

    Science.gov (United States)

    Wikner, N E; Persichitte, K A; Baskin, J B; Nielsen, L D; Clark, R A

    1988-09-01

    Transforming growth factor beta (TGF-beta) is a 25-kD protein which has regulatory activity over a variety of cell types. It is distinct from epidermal growth factor (EGF) and EGF analogs, and exerts its action via a distinct receptor. Its effect on proliferation or differentiation can be positive or negative depending on the cell type and the presence of other growth factors. It also modulates the expression of cellular products. TGF-beta causes fibroblasts to increase their production of the extracellular matrix components, fibronectin and collagen. Human keratinocytes (HK) are known to have TGF-beta receptors. We wished to study the effect of TGF-beta on the production of extracellular matrix proteins by human keratinocytes in culture. Human keratinocytes were grown in serum-free defined medium (MCDB-153) to about 70% confluence. Following a 16-h incubation in medium lacking EGF and TGF-beta, cells were incubated for 12 h in medium containing varying concentrations of EGF and TGF-beta. Cells were then labeled with 35S-methionine for 10 h in the same conditions. Labeled proteins from the medium were analyzed by SDS-PAGE and autoradiography. TGF-beta at 10 ng/ml induced a sixfold increase in the secretion of fibronectin, as well as an unidentified 50-kD protein. Thrombospondin production was also increased, but not over a generalized twofold increase in the production of all other proteins. EGF, at 10 ng/ml, caused a smaller additive effect. TGF-beta may be an important stimulator of extracellular matrix production by human keratinocytes.

  16. IM-1662 Attenuates Radiation-Induced Fibroblast Differentiation through Restoration of TGF-beta type III Receptor

    Energy Technology Data Exchange (ETDEWEB)

    Park, Sa Rah; Ahn, Ji Yeon; Kim, Mi Hyoung; Lim, Min Jin; Lee, Sae Loom; Yun, Yeon Sook; Song, Jie Young [Korea Institue of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2010-05-15

    Although pulmonary fibrosis occurs 5-20% of lung cancer patients who underwent radiotherapy, clinically standard treatment for fibrotic disease has not been developed yet. Among fibrosis mediating factors such as transforming growth factor-beta (TGF-beta), connective tissue growth factor (CTGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), interleukin-13 (IL-13), IL-4, interferon-gamma (IFN-gamma), and tumor necrosis factor (TNF-alpha), TGF-beta is considered as a critical mediator in normal wound healing as well as pathological fibrogenic processes. The TGF-beta transmits signals either directly or indirectly through types I, II and III (TbetaRI, II, and III) receptor complexes and activates downstream Smad signaling. The type III TGF-beta receptor (TbetaRIII or betaglycan) is a transmembrane proteoglycan without a functional kinase domain, and is regarded as a co-receptor to increase the affinity of ligand binding to TbetaRII. In addition, TbetaRIII act as a regulator in cell migration, invasion and cell growth in cancer models. However, in contrast to a great number of studies about TGF-beta ligand and TbetaRII signaling, the relationship between TGF-beta and TbetaRIII (or betaglycan) remains largely unknown. In this study, we searched for a new compound which inhibited TGF-beta responses using cell-based chemical screening and investigated the effects of the novel compound on radiation induced myofibroblast differentiation. We suggest that a novel small molecule, pyrazolopyrimidine compound IM-1662, can act as an anti-fibrotic agent through inhibiting expression of TGF-beta receptor type I and type II whereas, preserving the levels of TbetaRIII which seems to act as a negative regulator in TGF-beta signaling

  17. 11 beta-hydroxysteroid dehydrogenase type 1 promotes differentiation of 3T3-L1 preadipocyte

    Institute of Scientific and Technical Information of China (English)

    Yun LIU; Yan SUN; Ting ZHU; Yu XIE; Jing YU; Wen-lan SUN; Guo-xian DING; Gang HU

    2007-01-01

    Aim: To investigate the relationship between 11 beta-hydroxysteroid dehydroge-nase type 1 (1 lbeta-HSD1), a potential link between obesity and type 2 diabetes,and preadipocyte differentiation. Methods: Mouse 11beta-HSD1 siRNA plasmids were transfected into 3T3-L1 preadipocytes (a cell line derived from mouse Swiss3T3 cells that were isolated from mouse embryo), for examination of the effect of targeted 11 beta-HSD1 inhibition on differentiation of 3T3-L1 cells. Dif-ferentiation was stimulated with 3-isobutyl-1-methyxanthine, insulin, and dexamethasone. The transcription level of the genes was detected by real-time PCR. Results: Lipid accumulation was significantly inhibited in cells transfected with mouse 11beta-HSD1 siRNA compared with non-transfected 3T3-L1 cells.Fewer lipid droplets were detected in the transfected cells both prior to stimulation and after stimulation with differentiation-inducing reagents. The expression of adipocyte differentiation-associated markers such as lipoprotein lipase and fatty acid synthetase were downregulated in the transfected cells. Similarly, the expres-sion of preadipocyte factor-1, an inhibitor of adipocyte differentiation, was downregulated upon stimulation of differentiation and had no changes in the transfected cells. Conclusion: 11 beta-HSD1 can promote preadipocyte differentiation. Based on this, we propose that 11 beta-HSD1 may be an important candidate mediator of obesity and obesity-induced insulin resistance.

  18. Inhibition of human and rat 11beta-hydroxysteroid dehydrogenase type 1 by 18beta-glycyrrhetinic acid derivatives.

    Science.gov (United States)

    Su, Xiangdong; Vicker, Nigel; Lawrence, Harshani; Smith, Andrew; Purohit, Atul; Reed, Michael J; Potter, Barry V L

    2007-05-01

    11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) plays an important role in regulating the cortisol availability to bind to corticosteroid receptors within specific tissue. Recent advances in understanding the molecular mechanisms of metabolic syndrome indicate that elevation of cortisol levels within specific tissues through the action of 11beta-HSD1 could contribute to the pathogenesis of this disease. Therefore, selective inhibitors of 11beta-HSD1 have been investigated as potential treatments for metabolic diseases, such as diabetes mellitus type 2 or obesity. Here we report the discovery and synthesis of some 18beta-glycyrrhetinic acid (18beta-GA) derivatives (2-5) and their inhibitory activities against rat hepatic11beta-HSD1 and rat renal 11beta-HSD2. Once the selectivity over the rat type 2 enzyme was established, these compounds' ability to inhibit human 11beta-HSD1 was also evaluated using both radioimmunoassay (RIA) and homogeneous time resolved fluorescence (HTRF) methods. The 11-modified 18beta-GA derivatives 2 and 3 with apparent selectivity for rat 11beta-HSD1 showed a high percentage inhibition for human microsomal 11beta-HSD1 at 10 microM and exhibited IC50 values of 400 and 1100 nM, respectively. The side chain modified 18beta-GA derivatives 4 and 5, although showing selectivity for rat 11beta-HSD1 inhibited human microsomal 11beta-HSD1 with IC50 values in the low micromolar range.

  19. Expression of transforming growth factor-beta (TGF-beta) isoforms in osteosarcomas: TGF-beta3 is related to disease progression.

    Science.gov (United States)

    Kloen, P; Gebhardt, M C; Perez-Atayde, A; Rosenberg, A E; Springfield, D S; Gold, L I; Mankin, H J

    1997-12-15

    Transforming growth factor-beta (TGF-beta) is a multipotent growth factor affecting development, homeostasis, and tissue repair. In addition, increased expression of TGF-beta has been reported in different malignancies, suggesting a role for this growth factor in tumorigenesis. Using immunohistochemistry, the expression, prevalence, and distribution of TGF-beta isoforms were evaluated in 25 high grade human osteosarcomas. The Cox proportional hazards models and Kaplan-Meier curves were calculated correlating disease free survival with TGF-beta expression. Expression of one or more TGF-beta isoforms was found in all the osteosarcomas. Immunoreactivity for TGF-beta1 and TGF-beta3 generally was stronger than for TGF-beta2. The cytoplasm of the tumor cells showed stronger staining than their surrounding extracellular stroma. Most notably, osteoclasts showed strong to intense staining for all three isoforms. In 11 of 25 specimens angiogenic activity was noted with staining of multiple small vessels in the tumor stroma. Expression of TGF-beta3, but not of TGF-beta2 or TGF-beta1, related to disease progression, such that there was a statistically significant decrease in the disease free interval as the immunoreactivity for TGF-beta3 increased. All osteosarcomas expressed TGF-beta in the cytoplasm of the tumor cells as well as in their extracellular stroma. The presence of TGF-beta in the endothelial and perivascular layers of small vessels in the tumor stroma suggests angiogenic activity of this growth factor. The expression of TGF-beta3 was correlated strongly with disease progression (P = 0.027). These data suggest that increased expression of TGF-beta isoforms, especially TGF-beta3, may play a role in osteosarcoma progression.

  20. Disulfide isoforms of recombinant glia maturation factor beta.

    Science.gov (United States)

    Zaheer, A; Lim, R

    1990-09-14

    Recombinant human glia maturation factor beta (r-hGMF-beta) is a single-chain polypeptide (141 amino acid residues) containing three cysteines, at positions 7, 86 and 95. Nascent r-hGMF-beta exists in the reduced state and has no biological activity. The protein can be activated through oxidative refolding by incubation with a mixture of reduced and oxidized glutathione. Reverse-phase HPLC analysis of the refolded r-hGMF-beta shows the presence of four peaks, corresponding to the reduced form plus three newly generated intrachain disulfide-containing isoforms predicted from the number of cysteine residues. Only one isoform shows biological activity when tested for growth suppression on C6 glioma cells. We infer from the HPLC elution pattern that the active form contains the disulfide bridge Cys86-Cys95.

  1. Beta-nerve growth factor levels in newborn cord sera.

    Science.gov (United States)

    Haddad, J; Vilge, V; Juif, J G; Maitre, M; Donato, L; Messer, J; Mark, J

    1994-06-01

    This study was designed to examine beta-nerve growth factor (NGF) levels in human cord blood by a two-site enzyme immunoassay using MAb 27/21 to mouse NGF and to determine whether beta-NGF levels show developmental changes. Blood was collected at delivery from 61 newborns, 55 neonates appropriate for gestational age (46 term infants and 9 premature infants), 5 neonates small for gestational age, and 1 neonate with congenital hydrocephalus. In addition, samples were collected from 2 microcephalic children (microcephaly vera) aged 15 and 18 mo, 2 control children, and 4 healthy adults. Mean levels of NGF in preterm infants (n = 9; 13.7 +/- 8 pg/mL) were significantly lower than levels in term infants (n = 47; 21.2 +/- 8.8 pg/mL; p = 0.034 by Mann-Whitney U test). There was no correlation between birth weight, length, head circumference, and beta-NGF levels. In microcephalic children, NGF levels were low (8 pg/mL) compared with control infants' values (22 pg/mL). In adults, beta-NGF levels were higher and ranged between 238 and 292 pg/mL. Our study demonstrates that beta-NGF levels can be assessed in human newborn sera using a two-site enzyme immunoassay with MAb 27/21 to mouse beta-NGF, that beta-NGF levels are extremely low in newborns compared with adults, that beta-NGF levels seems to show developmental changes, and that beta-NGF levels may be used to assess NGF utilization under normal and pathologic conditions such as cerebral malformations.

  2. Gap junction reduction in cardiomyocytes following transforming growth factor-beta treatment and Trypanosoma cruzi infection.

    Science.gov (United States)

    Waghabi, Mariana C; Coutinho-Silva, Robson; Feige, Jean-Jacques; Higuchi, Maria de Lourdes; Becker, David; Burnstock, Geoffrey; Araújo-Jorge, Tânia C de

    2009-12-01

    Gap junction connexin-43 (Cx43) molecules are responsible for electrical impulse conduction in the heart and are affected by transforming growth factor-beta (TGF-beta). This cytokine increases during Trypanosoma cruzi infection, modulating fibrosis and the parasite cell cycle. We studied Cx43 expression in cardiomyocytes exposed or not to TGF-beta T. cruzi, or SB-431542, an inhibitor of TGF-beta receptor type I (ALK-5). Cx43 expression was also examined in hearts with dilated cardiopathy from chronic Chagas disease patients, in which TGF-beta signalling had been shown previously to be highly activated. We demonstrated that TGF-beta treatment induced disorganised gap junctions in non-infected cardiomyocytes, leading to a punctate, diffuse and non-uniform Cx43 staining. A similar pattern was detected in T. cruzi-infected cardiomyocytes concomitant with high TGF-beta secretion. Both results were reversed if the cells were incubated with SB-431542. Similar tests were performed using human chronic chagasic patients and we confirmed a down-regulation of Cx43 expression, an altered distribution of plaques in the heart and a significant reduction in the number and length of Cx43 plaques, which correlated negatively with cardiomegaly. We conclude that elevated TGF-beta levels during T. cruzi infection promote heart fibrosis and disorganise gap junctions, possibly contributing to abnormal impulse conduction and arrhythmia that characterise severe cardiopathy in Chagas disease.

  3. Expression of transforming growth factor-beta 1, -beta 2, and -beta 3 in human developing teeth: immunolocalization according to the odontogenesis phases.

    Science.gov (United States)

    Sassá Benedete, Ana Paula; Sobral, Ana Paula Veras; Lima, Dirce Mary Correia; Kamibeppu, Leonardo; Soares, Fernando Augusto; Lourenço, Silvia Vanessa

    2008-01-01

    Transforming growth factor-beta (TGF-beta) is a multifunctional growth factor that has several biological effects in vivo, including control of cell growth and differentiation, cell migration, lineage determination, motility, adhesion, apoptosis, and synthesis and degradation of extracellular matrix, and TGF-beta plays an important role in regulating tissue repair and regeneration. Our study analyzed the participation of TGF-beta 1, -beta 2, and -beta 3 in the different stages of morphogenesis and differentiation of human developing dental organ using immunohistochemistry. The maxillae and mandibles of 10 human embryos ranging from 8 to 23 weeks of gestation were employed, according to the approval of the ethical committee. Our study revealed that the TGF-beta subunits-beta 1, beta 2, and beta 3-were present in the various stages of tooth development, but the expression varied according to the differentiation stage, tissue, and TGF-beta subunit. Our results indicated that TGF-beta 1 is closely related to differentiation of enamel organ and initiation of matrix secretion, TGF-beta 2 to cellular differentiation, and TGF-beta 3 to mineral maturation matrix.

  4. Rheumatoid factors from patients with rheumatoid arthritis react with Des-Lys58-beta 2m, modified beta 2-microglobulin

    DEFF Research Database (Denmark)

    Williams, R C; Nissen, Mogens Holst; Malone, C C

    1993-01-01

    Ten polyclonal IgM rheumatoid factor (RF) preparations, affinity-purified from IgG columns, from patients with rheumatoid arthritis were studied for their ELISA reactivity with native beta 2m in parallel with Lys58-cleaved beta 2m and Des-Lys58-beta 2m, the latter representing cleavage products...

  5. Anti-inflammatory action of type I interferons deduced from mice expressing interferon beta.

    Science.gov (United States)

    Boscá, L; Bodelón, O G; Hortelano, S; Casellas, A; Bosch, F

    2000-05-01

    Type I interferons (IFN) are widely used for the therapeutic treatment of viral infections, tumor growth and various chronic diseases such as multiple sclerosis. Antagonism between type I IFNs and IFN-gamma has been described in cells of the immune system, in particular in the activation of macrophages. To study the systemic effects of type I IFNs we used transgenic mice carrying a human IFN-beta (hIFN-beta) gene under the control of the rat insulin I promoter. These animals expressed high levels of hIFN-beta in beta-pancreatic cells, and the ability of the macrophages to respond to pro-inflammatory stimuli was analyzed. Transgenic mice exhibited an increased extravasation of cells to the peritoneal cavity after eliciting with thioglycollate broth. The expression of the inducible form of nitric oxide synthase and cyclooxygenase-2, two enzymes involved in inflammation, was impaired in transgenic animals challenged with lipopolysaccharide and IFN-gamma. Analysis of the mechanisms leading to this attenuated inflammatory response showed a decrease in the serum levels of TNF-alpha and an inhibition of the activation of the transcription factor NF-KB in various tissues. These results indicate that systemic administration of IFN-beta might influence the response to pro-inflammatory stimuli, in particular through the antagonism of IFN-gamma signaling.

  6. Age-related changes in the expression of 11beta-hydroxysteroid dehydrogenase type 2 in rat Leydig cells.

    Directory of Open Access Journals (Sweden)

    Katerina Georgieva

    2009-12-01

    Full Text Available Previous studies in rats have shown that the ability of Leydig cells (LCs to produce testosterone significantly declines with age. To address the possible mechanisms by which aging LCs lose their steroidogenic function, we determined the effect of aging on the expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD type 2. The enzyme plays a protective role in blunting the suppressive effects of glucocorticoids on LCs steroidogenesis. Our immunohistochemical analysis revealed progressive decline in 11beta-HDS type 2 expression in LCs of the 18 months of age rats and the most significant reduction in 11beta-HSD2 immunoreactivity was evident in the testicular interstitium of 24- month-old rats. The decrease in the 11beta-HDS type 2 immunostaining in LCs during aging coincided with decline in insulin-like 3/relaxin-like factor (INSL3/RLF expression, an independent marker for LCs differentiation status. Concomitant with the age-related decrease of 11beta-HDS type 2 immunoreactivity in the LCs population, the immunoexpression of 3beta-hydroxysteroid dehydrogenase (3beta-HSD, marker for LCs steroidogenic activity, was greatly reduced at 24 months compared to 3-month-old control. Similar pattern of expression exhibited also androgen receptor (AR which is localized in the nuclei of Sertoli cells (SCs, LCs, and peritubular cells. During ages we observed progressive decrease in the immunoreactivity for AR in the testicular types and there was a loss of stage specificity in SCs at age of 24 months. It now seems evident that a variety of factors are likely to be involved in age-related decreases in LCs steroidogenesis, including 11beta-HSD type 2. The observed reduction in 11beta-HSD type 2 expression in aging LCs reflects the decline in their protection ability, opposing the suppressive effect of glucocorticoids on testosterone production.

  7. The Neuroprotective Functions of Transforming Growth Factor Beta Proteins

    Directory of Open Access Journals (Sweden)

    Gábor Lovas

    2012-07-01

    Full Text Available Transforming growth factor beta (TGF-β proteins are multifunctional cytokines whose neural functions are increasingly recognized. The machinery of TGF-β signaling, including the serine kinase type transmembrane receptors, is present in the central nervous system. However, the 3 mammalian TGF-β subtypes have distinct distributions in the brain suggesting different neural functions. Evidence of their involvement in the development and plasticity of the nervous system as well as their functions in peripheral organs suggested that they also exhibit neuroprotective functions. Indeed, TGF-β expression is induced following a variety of types of brain tissue injury. The neuroprotective function of TGF-βs is most established following brain ischemia. Damage in experimental animal models of global and focal ischemia was shown to be attenuated by TGF-βs. In addition, support for their neuroprotective actions following trauma, sclerosis multiplex, neurodegenerative diseases, infections, and brain tumors is also accumulating. The review will also describe the potential mechanisms of neuroprotection exerted by TGF-βs including anti-inflammatory, -apoptotic, -excitotoxic actions as well as the promotion of scar formation, angiogenesis, and neuroregeneration. The participation of these mechanisms in the neuroprotective effects of TGF-βs during different brain lesions will also be discussed.

  8. Transforming growth factor: beta signaling is essential for limb regeneration in axolotls.

    Directory of Open Access Journals (Sweden)

    Mathieu Lévesque

    Full Text Available Axolotls (urodele amphibians have the unique ability, among vertebrates, to perfectly regenerate many parts of their body including limbs, tail, jaw and spinal cord following injury or amputation. The axolotl limb is the most widely used structure as an experimental model to study tissue regeneration. The process is well characterized, requiring multiple cellular and molecular mechanisms. The preparation phase represents the first part of the regeneration process which includes wound healing, cellular migration, dedifferentiation and proliferation. The redevelopment phase represents the second part when dedifferentiated cells stop proliferating and redifferentiate to give rise to all missing structures. In the axolotl, when a limb is amputated, the missing or wounded part is regenerated perfectly without scar formation between the stump and the regenerated structure. Multiple authors have recently highlighted the similarities between the early phases of mammalian wound healing and urodele limb regeneration. In mammals, one very important family of growth factors implicated in the control of almost all aspects of wound healing is the transforming growth factor-beta family (TGF-beta. In the present study, the full length sequence of the axolotl TGF-beta1 cDNA was isolated. The spatio-temporal expression pattern of TGF-beta1 in regenerating limbs shows that this gene is up-regulated during the preparation phase of regeneration. Our results also demonstrate the presence of multiple components of the TGF-beta signaling machinery in axolotl cells. By using a specific pharmacological inhibitor of TGF-beta type I receptor, SB-431542, we show that TGF-beta signaling is required for axolotl limb regeneration. Treatment of regenerating limbs with SB-431542 reveals that cellular proliferation during limb regeneration as well as the expression of genes directly dependent on TGF-beta signaling are down-regulated. These data directly implicate TGF-beta

  9. Cardiac fibroblasts are predisposed to convert into myocyte phenotype: Specific effect of transforming growth factor. beta

    Energy Technology Data Exchange (ETDEWEB)

    Eghbali, M.; Tomek, R.; Woods, C.; Bhambi, B. (Univ. of Chicago, IL (United States))

    1991-02-01

    Cardiac fibroblasts are mainly responsible for the synthesis of major extracellular matrix proteins in the heart, including fibrillar collagen types I and III and fibronectin. In this report we show that these cells, when stimulated by transforming growth factor {beta}{sub 1} (TGF-{beta}{sub 1}), acquire certain myocyte-specific properties. Cultured cardiac fibroblasts from adult rabbit heart were treated with TGF-{beta}{sub 1}, (10-15 ng/ml) for different periods of time. Northern hybridization analysis of total RNA showed that cells treated with TGF-{beta}{sub 1} became stained with a monoclonal antibody to muscle-specific actin. After treatment of quiescent cells with TGF-{beta}{sub 1}, cell proliferation (as measured by ({sup 3}H)thymidine incorporation) was moderately increased. Cultured cardiac fibroblasts at the subconfluent stage, when exposed to TGF-{beta}{sub 1} in the presence of 10% fetal bovine serum, gave rise to a second generation of slowly growing cells that expressed muscle-specific actin filaments. The findings demonstrate that cardiac fibroblasts can be made to differentiate into cells that display many characteristics of cardiac myocytes. TGF-{beta}{sub 1} seems to be a specific inducer of such conversion.

  10. Recombinant soluble betaglycan is a potent and isoform-selective transforming growth factor-beta neutralizing agent.

    Science.gov (United States)

    Vilchis-Landeros, M M; Montiel, J L; Mendoza, V; Mendoza-Hernández, G; López-Casillas, F

    2001-01-01

    Betaglycan is an accessory receptor of members of the transforming growth factor-beta (TGF-beta) superfamily, which regulates their actions through ligand-dependent interactions with type II receptors. A natural soluble form of betaglycan is found in serum and extracellular matrices. Soluble betaglycan, prepared as a recombinant protein using the baculoviral expression system, inhibits the actions of TGF-beta. Because of its potential use as an anti-TGF-beta therapeutic agent, we have purified and characterized baculoviral recombinant soluble betaglycan. Baculoviral soluble betaglycan is a homodimer formed by two 110 kDa monomers associated by non-covalent interactions. This protein is devoid of glycosaminoglycan chains, although it contains the serine residues, which, in vertebrate cells, are modified by these carbohydrates. On the other hand, mannose-rich carbohydrates account for approximately 20 kDa of the mass of the monomer. End-terminal sequence analysis of the soluble betaglycan showed that Gly(24) is the first residue of the mature protein. Similarly to the natural soluble betaglycan, baculoviral soluble betaglycan has an equilibrium dissociation constant (K(d)) of 3.5 nM for TGF-beta1. Ligand competition assays indicate that the relative affinities of recombinant soluble betaglycan for the TGF-beta isoforms are TGF-beta2>TGF-beta3>TGF-beta1. The anti-TGF-beta potency of recombinant soluble betaglycan in vitro is 10-fold higher for TGF-beta2 than for TGF-beta1. Compared with a commercial pan-specific anti-TGF-beta neutralizing antibody, recombinant soluble betaglycan is more potent against TGF-beta2 and similar against TGF-beta1. These results indicate that baculoviral soluble betaglycan has the biochemical and functional properties that would make it a suitable agent for the treatment of the diseases in which excess TGF-beta plays a central physiopathological role. PMID:11256966

  11. Autoantibodies to REG, a beta-cell regeneration factor, in diabetic patients.

    Science.gov (United States)

    Shervani, N J; Takasawa, S; Uchigata, Y; Akiyama, T; Nakagawa, K; Noguchi, N; Takada, H; Takahashi, I; Yamauchi, A; Ikeda, T; Iwamoto, Y; Nata, K; Okamoto, H

    2004-11-01

    Regenerating gene (Reg) product, Reg, acts as an autocrine/paracrine growth factor for beta-cell regeneration. The presence of autoimmunity against REG may affect the operative of the regenerative mechanisms in beta cells of Type 1 and Type 2 diabetes patients. We screened sera from Type 1 and Type 2 diabetes subjects for anti-REG autoantibodies, searched for correlations in the general characteristics of the subjects with the presence of anti-REG autoimmunity, and tested the attenuation of REG-induced beta-cell proliferation by the autoanitibodies. We examined the occurrence of anti-REG autoantibodies in patients' sera (265 Type 1, 368 Type 2 diabetes patients, and 75 unrelated control subjects) by Western blot analysis, and evaluated inhibitory effects of the sera on REG-stimulated beta-cell proliferation by a 5'-Bromo-2'-deoxyuridine (BrdU) incorporation assay in vitro. Anti-REG autoantibodies were found in 24.9% of Type 1, 14.9% of Type 2 and 2.7% of control subjects (P = 0.0004). There were significant differences between the autoantibody positive and negative groups in the duration of disease in the Type 1 subjects (P = 0.0035), and the age of onset in the Type 2 subjects (P = 0.0274). The patient sera containing anti-REG autoantibodies significantly attenuated the BrdU incorporation by REG (35.6 +/- 4.06% of the control), whereas the nondiabetic sera without anti-REG autoantibodies scarcely reduced the incorporation (88.8 +/- 5.10%). Anti-REG autoantibodies, which retard beta-cell proliferation in vitro, are found in some diabetic patients. Thus, autoimmunity to REG may be associated with the development/acceleration of diabetes in at least some patients.

  12. Surface proteome analysis identifies platelet derived growth factor receptor-alpha as a critical mediator of transforming growth factor-beta-induced collagen secretion.

    Science.gov (United States)

    Heinzelmann, Katharina; Noskovičová, Nina; Merl-Pham, Juliane; Preissler, Gerhard; Winter, Hauke; Lindner, Michael; Hatz, Rudolf; Hauck, Stefanie M; Behr, Jürgen; Eickelberg, Oliver

    2016-05-01

    Fibroblasts are extracellular matrix-producing cells in the lung. Fibroblast activation by transforming growth factor-beta leads to myofibroblast-differentiation and increased extracellular matrix deposition, a hallmark of pulmonary fibrosis. While fibroblast function with respect to migration, invasion, and extracellular matrix deposition has been well-explored, little is known about the surface proteome of lung fibroblasts in general and its specific response to fibrogenic growth factors, in particular transforming growth factor-beta. We thus performed a cell-surface proteome analysis of primary human lung fibroblasts in presence/absence of transforming growth factor-beta, followed by characterization of our findings using FACS analysis, Western blot, and siRNA-mediated knockdown experiments. We identified 213 surface proteins significantly regulated by transforming growth factor-beta, platelet derived growth factor receptor-alpha being one of the top down-regulated proteins. Transforming growth factor beta-induced downregulation of platelet derived growth factor receptor-alpha induced upregulation of platelet derived growth factor receptor-beta expression and phosphorylation of Akt, a downstream target of platelet derived growth factor signaling. Importantly, collagen type V expression and secretion was strongly increased after forced knockdown of platelet derived growth factor receptor-alpha, an effect that was potentiated by transforming growth factor-beta. We therefore show previously underappreciated cross-talk of transforming growth factor-beta and platelet derived growth factor signaling in human lung fibroblasts, resulting in increased extracellular matrix deposition in a platelet derived growth factor receptor-alpha dependent manner. These findings are of particular importance for the treatment of lung fibrosis patients with high pulmonary transforming growth factor-beta activity.

  13. Differential Regulation of Human Thymosin Beta 15 Isoforms by Transforming Growth Factor Beta 1

    Science.gov (United States)

    Banyard, Jacqueline; Barrows, Courtney; Zetter, Bruce R.

    2009-01-01

    We recently identified an additional isoform of human thymosin beta 15 (also known as NB-thymosin beta, gene name TMSB15A) transcribed from an independent gene, and designated TMSB15B. The purpose of this study was to investigate whether these isoforms were differentially expressed and functional. Our data show that the TMSB15A and TMSB15B isoforms have distinct expression patterns in different tumor cell lines and tissues. TMSB15A was expressed at higher levels in HCT116, DU145, LNCaP and LNCaP-LN3 cancer cells. In MCF-7, SKOV-3, HT1080 and PC-3MLN4 cells, TMSB15A and TMSB15B showed approximately equivalent levels of expression, while TMSB15B was the predominant isoform expressed in PC-3, MDA-MB-231, NCI-H322 and Caco-2 cancer cells. In normal human prostate and prostate cancer tissues, TMSB15A was the predominant isoform expressed. In contrast, normal colon and colon cancer tissue expressed predominantly TMSB15B. The two gene isoforms are also subject to different transcriptional regulation. Treatment of MCF-7 breast cancer cells with transforming growth factor beta 1 repressed TMSB15A expression but had no effect on TMSB15B. siRNA specific to the TMSB15B isoform suppressed cell migration of prostate cancer cells to epidermal growth factor, suggesting a functional role for this second isoform. In summary, our data reveal different expression patterns and regulation of a new thymosin beta 15 gene paralog. This may have important consequences in both tumor and neuronal cell motility. PMID:19296525

  14. Compound list: transforming growth factor beta 1 [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available transforming growth factor beta 1 TGFB1 00182 ftp://ftp.biosciencedbc.jp/archive/op...en-tggates/LATEST/Human/in_vitro/transforming_growth_factor_beta_1.Human.in_vitro.Liver.zip ...

  15. Effects of transforming growth factor-beta on long-term human cord blood monocyte cultures

    Energy Technology Data Exchange (ETDEWEB)

    Orcel, P.; Bielakoff, J.; De Vernejoul, M.C. (INSERM U18, Hopital Lariboisiere, Paris (France))

    1990-02-01

    Transforming growth factor-beta (TGF-beta) modulates growth and differentiation in many cell types and is abundant in bone matrix. We recently showed that human cord blood monocytes cultured in the presence of 1,25(OH)2D3 acquire some features of osteoclast precursors. Since TGF-beta has been shown to influence bone resorption in organ culture, we have studied the effect of TGF-beta (1-1,000 pg/ml) on cord blood monocyte cultures. These cells were cultured on plastic substrate during 3 weeks in the presence of 20% horse serum and 10(-9) M 1,25(OH)2D3. TGF-beta, from a concentration of 10 pg/ml in the culture medium, decreased in a dose dependent manner the formation of multinucleated cells. At a concentration of TGF-beta of 1 ng/ml, the multinucleated cells were reduced to 2.1% +/- 0.3%, compared to 19.3% +/- 1.5% in control cultures. TGF-beta inhibited in a dose-dependent manner the proliferation of cord blood monocytes as assessed by 3H-thymidine incorporation at 7 and 14 days of culture. The fusion index was also decreased by 3 weeks of treatment with TGF-beta. Indomethacin did not reverse the inhibitory effects of TGF-beta. The expression of the osteoclastic phenotype was assessed using two different antibodies: 23C6, a monoclonal antibody directed against the vitronectin receptor, which is highly expressed by osteoclasts but not by adult monocytes, and an antibody to HLA-DR, which is not present on osteoclast. TGF-beta decreased the expression of HLA-DR and increased in a dose-dependent manner the proportion of 23C6-labeled cells; these results suggest that TGF-beta could modulate a differentiation effect to the osteoclastic phenotype. However, when cord blood monocytes were cultured on devitalized rat calvariae prelabeled with 45Ca, TGF-beta did not induce any 45Ca release from bone cultured with monocytes.

  16. Transforming growth factor beta1 regulates melanocyte proliferation and differentiation in mouse neural crest cells via stem cell factor/KIT signaling.

    Science.gov (United States)

    Kawakami, Tamihiro; Soma, Yoshinao; Kawa, Yoko; Ito, Masaru; Yamasaki, Emiko; Watabe, Hidenori; Hosaka, Eri; Yajima, Kenji; Ohsumi, Kayoko; Mizoguchi, Masako

    2002-03-01

    Stem cell factor is essential to the migration and differentiation of melanocytes during embryogenesis based on the observation that mutations in either the stem cell factor gene, or its ligand, KIT, result in defects in coat pigmentation in mice. Stem cell factor is also required for the survival of melanocyte precursors while they are migrating towards the skin. Transforming growth factor beta1 has been implicated in the regulation of both cellular proliferation and differentiation. NCC-melb4, an immortal cloned cell line, was cloned from a mouse neural crest cell. NCC-melb4 cells provide a model to study the specific stage of differentiation and proliferation of melanocytes. They also express KIT as a melanoblast marker. Using the NCC-melb4 cell line, we investigated the effect of transforming growth factor beta1 on the differentiation and proliferation of immature melanocyte precursors. Immunohistochemically, NCC-melb4 cells showed transforming growth factor beta1 expression. The anti-transforming growth factor beta1 antibody inhibited the cell growth, and downregulated the KIT protein and mRNA expression. To investigate further the activation of autocrine transforming growth factor beta1, NCC-melb4 cells were incubated in nonexogenous transforming growth factor beta1 culture medium. KIT protein decreased with anti-transforming growth factor beta1 antibody concentration in a concentration-dependent manner. We concluded that in NCC-melb4 cells, transforming growth factor beta1 promotes melanocyte precursor proliferation in autocrine and/or paracrine regulation. We further investigated the influence of transforming growth factor beta1 in vitro using a neural crest cell primary culture system from wild-type mice. Anti-transforming growth factor beta1 antibody decreased the number of KIT positive neural crest cell. In addition, the anti-transforming growth factor beta1 antibody supplied within the wild-type neural crest explants abolished the growth of the neural

  17. Transforming growth factor-beta inhibits aromatase gene transcription in human trophoblast cells via the Smad2 signaling pathway

    Directory of Open Access Journals (Sweden)

    Fu Guodong

    2009-12-01

    Full Text Available Abstract Background Transforming growth factor-beta (TGF-beta is known to exert multiple regulatory functions in the human placenta, including inhibition of estrodial production. We have previously reported that TGF-beta1 decreased aromatase mRNA levels in human trophoblast cells. The objective of this study was to investigate the molecular mechanisms underlying the regulatory effect of TGF-beta1 on aromatase expression. Methods To determine if TGF-beta regulates aromatase gene transcription, several reporter constructs containing different lengths of the placental specific promoter of the human aromatase gene were generated. JEG-3 cells were transiently transfected with a promoter construct and treated with or without TGF-beta1. The promoter activity was measured by luciferase assays. To examine the downstream signaling molecule mediating the effect of TGF-beta on aromatase transcription, cells were transiently transfected with dominant negative mutants of TGF-beta type II (TbetaRII and type I receptor (ALK5 receptors before TGF-beta treatment. Smad2 activation was assessed by measuring phophorylated Smad2 protein levels in cytosolic and nuclear fractions. Smad2 expression was silenced using a siRNA expression construct. Finally, aromatase mRNA half-life was determined by treating cells with actinomycin D together with TGF-beta1 and measuring aromatase mRNA levels at various time points after treatment. Results and Discussion TGF-beta1 inhibited the aromatase promoter activity in a time- and dose-dependent manner. Deletion analysis suggests that the TGF-β1 response element resides between -422 and -117 nucleotides upstream from the transcription start site where a Smad binding element was found. The inhibitory effect of TGF-beta1 was blocked by dominant negative mutants of TbetaRII and ALK5. TGF-beta1 treatment induced Smad2 phosphorylation and translocation into the nucleus. On the other hand, knockdown of Smad2 expression reversed the

  18. Efficiency Calibration of a Mini-Orange Type beta-Spectrometer by the $\\beta^{-}$-Spectrum of $^{90}$Sr

    CERN Document Server

    Kalinnikov, V G; Solnyshkin, A A; Sereeter, Z; Lebedev, N A; Chumin, V G; Ibrakhin, Ya S

    2002-01-01

    A specific method for efficiency calibration of a mini-orange type beta-spectrometer by means of the continuous beta^{-}-spectrum of ^{90}Sr and the conversion electron spectrum of ^{207}Bi in the energy range from 500 to 2200 keV has been elaborated. In the experiment typical SmCo_5 magnets (6A and 8A) were used. An accuracy of efficiency determination was 5-10 %.

  19. Oral administration of GW788388, an inhibitor of TGF-beta type I and II receptor kinases, decreases renal fibrosis.

    Science.gov (United States)

    Petersen, M; Thorikay, M; Deckers, M; van Dinther, M; Grygielko, E T; Gellibert, F; de Gouville, A C; Huet, S; ten Dijke, P; Laping, N J

    2008-03-01

    Progressive kidney fibrosis precedes end-stage renal failure in up to a third of patients with diabetes mellitus. Elevated intra-renal transforming growth factor-beta (TGF-beta) is thought to underlie disease progression by promoting deposition of extracellular matrix and epithelial-mesenchymal transition. GW788388 is a new TGF-beta type I receptor inhibitor with a much improved pharmacokinetic profile compared with SB431542. We studied its effect in vitro and found that it inhibited both the TGF-beta type I and type II receptor kinase activities, but not that of the related bone morphogenic protein type II receptor. Further, it blocked TGF-beta-induced Smad activation and target gene expression, while decreasing epithelial-mesenchymal transitions and fibrogenesis. Using db/db mice, which develop diabetic nephropathy, we found that GW788388 given orally for 5 weeks significantly reduced renal fibrosis and decreased the mRNA levels of key mediators of extracellular matrix deposition in kidneys. Our study shows that GW788388 is a potent and selective inhibitor of TGF-beta signalling in vitro and renal fibrosis in vivo.

  20. Suppressor of cytokine signalling-3 inhibits Tumor necrosis factor-alpha induced apoptosis and signalling in beta cells

    DEFF Research Database (Denmark)

    Bruun, Christine; Heding, Peter E; Rønn, Sif G

    2009-01-01

    Tumor necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine involved in the pathogenesis of several diseases including type 1 diabetes mellitus (T1DM). TNFalpha in combination with interleukin-1-beta (IL-1beta) and/or interferon-gamma (IFNgamma) induces specific destruction of the pancr......Tumor necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine involved in the pathogenesis of several diseases including type 1 diabetes mellitus (T1DM). TNFalpha in combination with interleukin-1-beta (IL-1beta) and/or interferon-gamma (IFNgamma) induces specific destruction...... in INSr3#2 cells and in primary rat islets. Furthermore, SOCS-3 repressed TNFalpha-induced degradation of IkappaB, NFkappaB DNA binding and transcription of the NFkappaB-dependent MnSOD promoter. Finally, expression of Socs-3 mRNA was induced by TNFalpha in rat islets in a transient manner with maximum...

  1. Discovery of adamantyl ethanone derivatives as potent 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors.

    Science.gov (United States)

    Su, Xiangdong; Pradaux-Caggiano, Fabienne; Thomas, Mark P; Szeto, Michelle W Y; Halem, Heather A; Culler, Michael D; Vicker, Nigel; Potter, Barry V L

    2010-07-05

    11Beta-hydroxysteroid dehydrogenases (11beta-HSDs) are key enzymes regulating the pre-receptor metabolism of glucocorticoid hormones. The modulation of 11beta-HSD type 1 activity with selective inhibitors has beneficial effects on various conditions including insulin resistance, dyslipidemia and obesity. Inhibition of tissue-specific glucocorticoid action by regulating 11beta-HSD1 constitutes a promising treatment for metabolic and cardiovascular diseases. A series of novel adamantyl ethanone compounds was identified as potent inhibitors of human 11beta-HSD1. The most active compounds identified (52, 62, 72, 92, 103 and 104) display potent inhibition of 11beta-HSD1 with IC(50) values in the 50-70 nM range. Compound 72 also proved to be metabolically stable when incubated with human liver microsomes. Furthermore, compound 72 showed very weak inhibitory activity for human cytochrome P450 enzymes and is therefore a candidate for in vivo studies. Comparison of the publicly available X-ray crystal structures of human 11beta-HSD1 led to docking studies of the potent compounds, revealing how these molecules may interact with the enzyme and cofactor.

  2. Values of the phase space factors for double beta decay

    Energy Technology Data Exchange (ETDEWEB)

    Stoica, Sabin, E-mail: stoica@theory.nipne.ro; Mirea, Mihai [Horia Hulubei Foundation, 407, Atomistilor street, P.O. Box MG12, 077125 Magurele (Romania); Horia Hulubei National Institute of Physics and Nuclear Engineering, 30 Reactorului street, P.O. Box MG6, Magurele (Romania)

    2015-10-28

    We report an up-date list of the experimentally most interesting phase space factors for double beta decay (DBD). The electron/positron wave functions are obtained by solving the Dirac equations with a Coulomb potential derived from a realistic proton density distribution in nucleus and with inclusion of the finite nuclear size (FNS) and electron screening (ES) effects. We build up new numerical routines which allow us a good control of the accuracy of calculations. We found several notable differences as compared with previous results reported in literature and possible sources of these discrepancies are discussed.

  3. Intact proinsulin and beta-cell function in lean and obese subjects with and without type 2 diabetes

    DEFF Research Database (Denmark)

    Røder, M E; Dinesen, B; Hartling, S G;

    1999-01-01

    OBJECTIVE: Type 2 diabetes is a heterogeneous disease in which both beta-cell dysfunction and insulin resistance are pathogenetic factors. Disproportionate hyperproinsulinemia (elevated proinsulin/insulin) is another abnormality in type 2 diabetes whose mechanism is unknown. Increased demand due...... to obesity and/or insulin resistance may result in secretion of immature beta-cell granules with a higher content of intact proinsulin. RESEARCH DESIGN AND METHODS: We investigated the impact of obesity on beta-cell secretion in normal subjects and in type 2 diabetic patients by measuring intact proinsulin......, total proinsulin immunoreactivity (PIM), intact insulin, and C-peptide (by radioimmunoassay) by specific enzyme-linked immunosorbent assays in the fasting state and during a 120-min glucagon (1 mg i.v.) stimulation test. Lean (BMI 23.5 +/- 0.3 kg/m2) (LD) and obese (30.1 +/- 0.4 kg/m2) (OD) type 2...

  4. [Expression of beta-catenin and estrogen receptor in desmoid-type fibromatosis].

    Science.gov (United States)

    Zhang, Hong-Ying; Ke, Qi; Zhang, Zhang; Zhang, Rui; Fu, Jing; Chen, Hui-Jiao; Wei, Bing; Bu, Hong

    2010-01-01

    To detect the expression of beta-catenin and Estrogen Receptor in desmoid-type fibromatosis. Nuclear beta-catenin expression was detected by immunohistochemistry in 77 lesions with desmoid-type fibromatosis and 171 other spindle cell lesions, including superficial fibromatosis (n = 18), nodular fasciitis (n = 36), keloid (n = 16), scar (n = 10), granulation tissue (n = 9), synovial sarcoma (n = 38), neufibroma (n = 13), solitary fibrous tumor (n =12), gastrointestinal stromal tumor (n = 10), low-grade myxofibrosarcoma (n = 3), low-grade fibromyxoid sarcoma (n = 3), and smooth muscle tumor (n = 10). In addition, the immunohistochemical expressions of ER-alpha, ER-beta and Ki-67 were examined in all of the lesions with desmoid-type fibromatosis. The nuclear immunohistochemical staining for nuclear beta-catenin and ER-beta was graded as high level ( > or = 25% of cells), low level (5%-25%) or none. High-level nuclear beta-catenin staining was detected in a very limited subset of tissue types, which included 70.1% of lesions with desmoid-type fibromatosis (54/77) and 6.3% of lesions with keloid (1/16). No high-level nuclear beta-catenin staining was seen in any of the other lesions. None of the lesions with desmoid-type fibromatosis expressed ER-alpha. However, 62 (80.5%) of the lesions with desmoids-type fibromatosis were positive in ER-beta, which included 52 (67.5%) with high-level expression, and 10 (13%) with low-level expression. The Spearman correlation analysis suggested that the expression of beta-catenin was positively correlated (r = 0.867, P fibromatosis had very low Ki-67 positive rate. The recurrence of desmoids-type fibromatosis was not correlated independently with beta-catenin, ER-beta or Ki-67. High-level nuclear beta-catenin staining serves as a useful diagnostic tool for desmoid-type fibromatosis. The high expression of ER-beta in desmoid-type fibromatosis provides a biological mechanism for the antiestrogenic compounds to treat fibromatosis. There

  5. Production of tumor necrosis factors alpha and beta by human mononuclear leukocytes stimulated with mitogens, bacteria, and malarial parasites.

    OpenAIRE

    Ferrante, A; Staugas, R E; Rowan-Kelly, B; Bresatz, S; Kumaratilake, L M; Rzepczyk, C M; Adolf, G R

    1990-01-01

    Tumor necrosis factors alpha and beta (TNF-alpha and TNF-beta) are multifaceted polypeptide cytokines which may mediate some of the significant changes in cellular homeostasis which accompany the invasion of the mammalian host by viruses, bacteria, and parasites. Although it is well established that bacterial lipopolysaccharide is a potent inducer of TNF-alpha, there is still very little known of the types of agents which can trigger the production of TNFs in mononuclear leukocytes. Using an ...

  6. Interleukin-1 beta targeted therapy for type 2 diabetes

    DEFF Research Database (Denmark)

    Maedler, K.; Dharmadhikari, G.; Schumann, D.M.

    2009-01-01

    Since having been cloned in 1984, IL-1beta has been the subject of over 22,000 citations in Pubmed, among them over 800 reviews. This is because of its numerous effects. IL-1beta is a regulator of the body's inflammatory response and is produced after infection, injury, and antigenic challenge. I...

  7. Suramin inhibits growth and transforming growth factor-beta 1 (TGF-beta 1) binding in osteosarcoma cell lines.

    Science.gov (United States)

    Kloen, P; Jennings, C L; Gebhardt, M C; Springfield, D S; Mankin, H J

    1994-01-01

    Autocrine production of growth factors has been shown to be involved in the multistep process of tumorigenesis. The ability of suramin, a polyanionic anti-parasitic drug, to block growth factor-induced cell proliferation makes it a potential antineoplastic drug. We studied the effects of suramin on seven osteosarcoma cell lines. Using clinically achievable concentrations of suramin (50-400 micrograms/ml), we found a time- and dose-dependent inhibition of [3H]thymidine incorporation. We also showed that suramin is able, dose-dependently, to prevent binding of transforming growth factor (TGF)-beta 1 to its receptors. DNA synthesis inhibition by suramin was attenuated by TGF-beta 1 in some cell lines. Two cell lines that were inhibited by TGF-beta 1 were affected similarly by suramin as cell lines that were stimulated by TGF-beta 1. In conclusion, in five out of seven osteosarcoma cell lines, we showed a correlation between inhibition of growth factor-stimulated mitogenesis and binding of TGF-beta 1 to its receptor. Similar effects in TGF-beta 1-inhibited osteosarcoma cell lines suggest involvement of other mechanisms and/or growth factors. However, suramin proves to be a potent inhibitor of osteosarcoma cell proliferation in vitro.

  8. Beta-cell function and mass in type 2 diabetes.

    Science.gov (United States)

    Larsen, Marianne O

    2009-08-01

    The aim of the work described here was to improve our understanding of beta-cell function (BCF) and beta-cell mass (BCM) and their relationship in vivo using the minipig as a model for some of the aspects of human type 2 diabetes (T2DM). More specifically, the aim was to evaluate the following questions: How is BCF, especially high frequency pulsatile insulin secretion, affected by a primary reduction in BCM or by primary obesity or a combination of the two in the minipig? Can evaluation of BCF in vivo be used as a surrogate measure to predict BCM in minipigs over a range of BCM and body weight? We first developed a minipig model of reduced BCM and mild diabetes using administration of a combination of streptozotocin (STZ) and nicotinamide (NIA) as a tool to study effects of a primary reduction of BCM on BCF. The model was characterized using a mixed-meal oral glucose tolerance test and intravenous stimulation with glucose and arginine as well as by histology of the pancreas after euthanasia. It was shown that stable, moderate diabetes can be induced and that the model is characterized by fasting and postprandial hyperglycemia, reduced insulin secretion and reduced BCM. Several defects in insulin secretion are well documented in human T2DM; however, the role in the pathogenesis and the possible clinical relevance of high frequency (rapid) pulsatile insulin secretion is still debated. We therefore investigated this phenomenon in normal minipigs and found easily detectable pulses in peripheral vein plasma samples that were shown to be correlated with pulses found in portal vein plasma. Furthermore, the rapid kinetics of insulin in the minipig strongly facilitates pulse detection. These characteristics make the minipig particularly suitable for studying the occurrence of disturbed pulsatility in relation to T2DM. Disturbances of rapid pulsatile insulin secretion have been reported to be a very early event in the development of T2DM and include disorderliness of pulses

  9. Role of transforming growth factor-beta (TGF) beta in the physiopathology of rheumatoid arthritis.

    Science.gov (United States)

    Gonzalo-Gil, Elena; Galindo-Izquierdo, María

    2014-01-01

    Transforming growth factor-beta (TGF-β) is a cytokine with pleiotropic functions in hematopoiesis, angiogenesis, cell proliferation, differentiation, migration and apoptosis. Although its role in rheumatoid arthritis is not well defined, TGF-β activation leads to functional immunomodulatory effects according to environmental conditions. The function of TGF-β in the development of arthritis in murine models has been extensively studied with controversial results. Recent findings point to a non-relevant role for TGF-β in a mice model of collagen-induced arthritis. The study of TGF-β on T-cell responses has shown controversial results as an inhibitor or promoter of the inflammatory response. This paper presents a review of the role of TGF-β in animal models of arthritis. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  10. The role of transforming growth factor beta in tertiary dentinogenesis

    Directory of Open Access Journals (Sweden)

    Tetiana Haniastuti

    2008-03-01

    Full Text Available The most visible repair response to pulp injury is the deposition of a tertiary dentin matrix over the dentinal tubules of the primary or secondary dentin. Tertiary dentin is distinguished as reactionary and reparative dentin, depending on the severity of the initiating response and the conditions under which the newly deposited dentin matrix was elaborated. Transforming growth factor beta (TGF-b superfamily is a large group of growth factors that serve important roles in regulating cell growth, differentiation, and function. Members of this superfamily have been implicated in the repair process of the dental tissue after injury. Although numerous studies have proved that those bioactive molecules carry out an important role in the formation of tertiary dentin, comprehensive report regarding that phenomenon is not yet available. This review article aimed to summarize the role of TGF-b on tertiary dentinogenesis during the progression of a carious lesion.

  11. Transforming growth factor beta stimulates collagen-matrix contraction by fibroblasts: implications for wound healing.

    OpenAIRE

    Montesano, R; Orci, L.

    1988-01-01

    An important event during wound healing is the contraction of newly formed connective tissue (granulation tissue) by fibroblasts. The role of polypeptide growth factors in the process of wound contraction was investigated by analyzing the influence of transforming growth factor beta (TGF-beta), platelet-derived growth factor on the ability of fibroblasts to contract a collagen matrix in an in vitro system. TGF-beta, but not the other growth factors tested, markedly enhanced the ability of BHK...

  12. Transforming growth factor beta stimulates collagen-matrix contraction by fibroblasts: implications for wound healing.

    OpenAIRE

    Montesano, R; Orci, L

    1988-01-01

    An important event during wound healing is the contraction of newly formed connective tissue (granulation tissue) by fibroblasts. The role of polypeptide growth factors in the process of wound contraction was investigated by analyzing the influence of transforming growth factor beta (TGF-beta), platelet-derived growth factor on the ability of fibroblasts to contract a collagen matrix in an in vitro system. TGF-beta, but not the other growth factors tested, markedly enhanced the ability of BHK...

  13. Importance of Beta Cell Function for the Treatment of Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Yoshifumi Saisho

    2014-08-01

    Full Text Available Type 2 diabetes (T2DM is characterized by insulin resistance and beta cell dysfunction. Recent evidence has emerged that beta cell dysfunction is a common pathogenetic feature of both type 1 and type 2 diabetes, and T2DM never develops without beta cell dysfunction. Therefore, treatment of T2DM should aim to restore beta cell function. Although the treatment of T2DM has greatly improved over the past few decades, remaining issues in the current treatment of T2DM include (1 hypoglycemia; (2 body weight gain; (3 peripheral hyperinsulinemia and (4 postprandial hyperglycemia, which are all associated with inappropriate insulin supplementation, again underpinning the important role of endogenous and physiological insulin secretion in the management of T2DM. This review summarizes the current knowledge on beta cell function in T2DM and discusses the treatment strategy for T2DM in relation to beta cell dysfunction.

  14. [Transforming growth factor beta (TGF-beta): its structure, function, and role in the pathogenesis of systemic lupus erythematosus].

    Science.gov (United States)

    Stepień-Wyrobiec, Olga; Hrycek, Antoni; Wyrobiec, Grzegorz

    2008-12-12

    TGF-beta is a cytokine of great importance in many common diseases because it takes part in many physiological processes such as angiogenesis and stimulation of the synthesis and degradation of extracellular matrix proteins. It also regulates the entrance of cells to the apoptotic pathway and can stimulate the division of mesenchymal cells and inhibit hemopoietic, endothelial, and lymphatic cells. There are five genes which encode TGF-beta in vertebrates, of which only three are present in mammals. The best known member of the family of TGF-beta proteins is TGF-beta 1. TGF-beta is synthetized as a precursor protein which, after enzymatic modification, is present as a small or large complex. Three membrane receptors, serine/threonine kinase, are arranged for signal transduction with TGF-beta. Smad proteins are responsible for sending the signal into the cell nucleus; its influence on different transcriptive factors in the cell nucleus promotes the expressions of different genes. Disturbances in TGF-beta expression have been noted in many diseases. Current results clearly indicate an important role of this cytokine in autoimmunological disorders, especially in systemic lupus erythematosus. Studies on an animal model revealed that endogenic TGF-beta can control the progression of systemic lupus erythematosus.

  15. Transforming growth factor beta stimulation of biglycan gene expression is potentially mediated by sp1 binding factors

    DEFF Research Database (Denmark)

    Heegaard, Anne-Marie; Xie, Zhongjian; Young, Marian Frances;

    2004-01-01

    Biglycan is a small leucine-rich proteoglycan which is localized in the extracellular matrix of bone and other specialized connective tissues. Both biglycan mRNA and protein are up-regulated by transforming growth factor-beta(1) (TGF-beta(1)) and biglycan appears to influence TGF-beta(1) activity...

  16. Endoglin structure and function - Determinants of endoglin phosphorylation by transforming growth factor-beta receptors

    NARCIS (Netherlands)

    Koleva, Rositsa I.; Conley, Barbara A.; Romero, Diana; Riley, Kristin S.; Marto, Jarrod A.; Lux, Andreas; Vary, Calvin P. H.

    2006-01-01

    Determination of the functional relationship between the transforming growth factor-beta(TGF beta) receptor proteins endoglin and ALK1 is essential to the understanding of the human vascular disease, hereditary hemorrhagic telangiectasia. TGF beta 1 caused recruitment of ALK1 into a complex with end

  17. Structural alterations of transforming growth factor-beta receptor genes in human cervical carcinoma

    NARCIS (Netherlands)

    Chen, TP; De Vries, EGE; Hollema, H; Yegen, HA; Vellucci, VF; Strickler, HD; Hildesheim, A; Reiss, M

    1999-01-01

    The development and progression of invasive uterine cervical carcinomas appear to be associated with the progressive loss of sensitivity to transforming growth factor-beta (TGF beta)-mediated cell cycle arrest. In order to identify possible molecular mechanisms responsible for TGF beta resistance, w

  18. Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes

    Energy Technology Data Exchange (ETDEWEB)

    Miklossy, J.; Miller, L.; Qing, H.; Radenovic, A.; Kis, A.; Vileno, B.; Laszlo, F.; Martins, R.N.; Waeber, G.; Mooser, V.; Bosman, F.; Khalili, K.; Darbinian, N.; McGeer, P.L.

    2008-08-25

    Strong epidemiologic evidence suggests an association between Alzheimer disease (AD) and type 2 diabetes. To determine if amyloid beta (A{beta}) and hyperphosphorylated tau occurs in type 2 diabetes, pancreas tissues from 21 autopsy cases (10 type 2 diabetes and 11 controls) were analyzed. APP and tau mRNAs were identified in human pancreas and in cultured insulinoma beta cells (INS-1) by RT-PCR. Prominent APP and tau bands were detected by Western blotting in pancreatic extracts. Aggregated A{beta}, hyperphosphorylated tau, ubiquitin, apolipoprotein E, apolipoprotein(a), IB1/JIP-1 and JNK1 were detected in Langerhans islets in type 2 diabetic patients. A{beta} was co-localized with amylin in islet amyloid deposits. In situ beta sheet formation of islet amyloid deposits was shown by infrared microspectroscopy (SIRMS). LPS increased APP in non-neuronal cells as well. We conclude that A{beta} deposits and hyperphosphorylated tau are also associated with type 2 diabetes, highlighting common pathogenetic features in neurodegenerative disorders, including AD and type 2 diabetes and suggesting that A{beta} deposits and hyperphosphorylated tau may also occur in other organs than the brain.

  19. 11-Beta hydroxysteroid dehydrogenase type 2 expression in white adipose tissue is strongly correlated with adiposity.

    Science.gov (United States)

    Milagro, Fermin I; Campión, Javier; Martínez, J Alfredo

    2007-04-01

    Glucocorticoid action within the cells is regulated by the levels of glucocorticoid receptor (GR) expression and two enzymes, 11-beta hydroxysteroid dehydrogenase type 1 (11betaHSD1), which converts inactive to active glucocorticoids, and 11-beta hydroxysteroid dehydrogenase type 2 (11betaHSD2), which regulates the access of active glucocorticoids to the receptor by converting cortisol/corticosterone to the glucocorticoid-inactive form cortisone/dehydrocorticosterone. Male Wistar rats developed obesity by being fed a high-fat diet for 56 days, and GR, 11betaHSD1 and 11betaHSD2 gene expression were compared with control-diet fed animals. Gene expression analysis of 11betaHSD1, 11betaHSD2 and GR were performed by RT-PCR in subcutaneous and retroperitoneal adipose tissue. High-fat fed animals overexpressed 11betaHSD2 in subcutaneous but not in retroperitoneal fat. Interestingly, mRNA levels strongly correlated in both tissues with different parameters related to obesity, such as body weight, adiposity and insulin resistance, suggesting that this gene is a reliable marker of adiposity in this rat model of obesity. Thus, 11betaHSD2 is expressed in adipose tissue by both adipocytes and stromal-vascular cells, which suggests that this enzyme may play an important role in preventing fat accumulation in adipose tissue.

  20. Factors contributing to decreased protein stability when aspartic acid residues are in {beta}-sheet regions.

    Energy Technology Data Exchange (ETDEWEB)

    Pokkuluri, P. R.; Cai, X.; Raffen, R.; Gu, M.; Stevens, F. J.; Schiffer, M.

    2002-07-01

    Asp residues are significantly under represented in {beta}-sheet regions of proteins, especially in the middle of {beta}-strands, as found by a number of studies using statistical, modeling, or experimental methods. To further understand the reasons for this under representation of Asp, we prepared and analyzed mutants of a {beta}-domain. Two Gln residues of the immunoglobulin light-chain variable domain (V{sub L}) of protein Len were replaced with Asp, and then the effects of these changes on protein stability and protein structure were studied. The replacement of Q38D, located at the end of a {beta}-strand, and that of Q89D, located in the middle of a {beta}-strand, reduced the stability of the parent immunoglobulin VL domain by 2.0 kcal/mol and 5.3 kcal/mol, respectively. Because the Q89D mutant of the wild-type V{sub L}-Len domain was too unstable to be expressed as a soluble protein, we prepared the Q89D mutant in a triple mutant background, V{sub L}-Len M4L/Y27dD/T94H, which was 4.2 kcal/mol more stable than the wild-type V{sub L}-Len domain. The structures of mutants V{sub L}-Len Q38D and V{sub L}-Len Q89D/M4L/Y27dD/T94H were determined by X-ray diffraction at 1.6 A resolution. We found no major perturbances in the structures of these QD mutant proteins relative to structures of the parent proteins. The observed stability changes have to be accounted for by cumulative effects of the following several factors: (1) by changes in main-chain dihedral angles and in side-chain rotomers, (2) by close contacts between some atoms, and, most significantly, (3) by the unfavorable electrostatic interactions between the Asp side chain and the carbonyls of the main chain. We show that the Asn side chain, which is of similar size but neutral, is less destabilizing. The detrimental effect of Asp within a {beta}-sheet of an immunoglobulin-type domain can have very serious consequences. A somatic mutation of a {beta}-strand residue to Asp could prevent the expression of the

  1. Identification of a Wnt/Dvl/beta-Catenin --> Pitx2 pathway mediating cell-type-specific proliferation during development.

    Science.gov (United States)

    Kioussi, Chrissa; Briata, Paola; Baek, Sung Hee; Rose, David W; Hamblet, Natasha S; Herman, Thomas; Ohgi, Kenneth A; Lin, Chijen; Gleiberman, Anatoli; Wang, Jianbo; Brault, Veronique; Ruiz-Lozano, Pilar; Nguyen, H D; Kemler, Rolf; Glass, Christopher K; Wynshaw-Boris, Anthony; Rosenfeld, Michael G

    2002-11-27

    Understanding the cell type-specific molecular mechanisms by which distinct signaling pathways combinatorially control proliferation during organogenesis is a central issue in development and disease. Here, we report that the bicoid-related transcription factor Pitx2 is rapidly induced by the Wnt/Dvl/beta-catenin pathway and is required for effective cell-type-specific proliferation by directly activating specific growth-regulating genes. Regulated exchange of HDAC1/beta-catenin converts Pitx2 from repressor to activator, analogous to control of TCF/LEF1. Pitx2 then serves as a competence factor required for the temporally ordered and growth factor-dependent recruitment of a series of specific coactivator complexes that prove necessary for Cyclin D2 gene induction. The molecular strategy underlying interactions between the Wnt and growth factor-dependent signaling pathways in cardiac outflow tract and pituitary proliferation is likely to be prototypic of cell-specific proliferation strategies in other tissues.

  2. Beta-Delayed Multiparticle Emission Studies at ISOL-type Facilities

    Energy Technology Data Exchange (ETDEWEB)

    Borge, M.J.G. [Instituto de Estructura de la Materia, CSIC, E-28006 Madrid (Spain); Bergmann, U.C. [Institut for fysik og astronomi, Aarhus Universitet, DK-8000 Aarhus C (Denmark); EP Division, CERN, CH-1211 Geneva 23 (Switzerland); Boutami, R. [Instituto de Estructura de la Materia, CSIC, E-28006 Madrid (Spain); Cederkaell, J. [EP Division, CERN, CH-1211 Geneva 23 (Switzerland); Dendooven, P. [Department of Physics, University of Jyvaaeskylae, FIN-40351 Jyvaaeskylae (Finland); Fraile, L.M. [Instituto de Estructura de la Materia, CSIC, E-28006 Madrid (Spain); Fynbo, H.O.U. [Institut for fysik og astronomi, Aarhus Universitet, DK-8000 Aarhus C (Denmark); Huang, W.X. [Department of Physics, University of Jyvaaeskylae, FIN-40351 Jyvaaeskylae (Finland); Huikari, J. [Department of Physics, University of Jyvaaeskylae, FIN-40351 Jyvaaeskylae (Finland); Jading, Y. [EP Division, CERN, CH-1211 Geneva 23 (Switzerland); Jeppesen, H. [Institut for fysik og astronomi, Aarhus Universitet, DK-8000 Aarhus C (Denmark); Jokinen, A. [Department of Physics, University of Jyvaaeskylae, FIN-40351 Jyvaaeskylae (Finland); Jonson, B. [Experimentell Fysik, Chalmers Tekniska Hoegskola, S-41296 Goeteborg (Sweden); Martel, I. [Instituto de Estructura de la Materia, CSIC, E-28006 Madrid (Spain); Meister, M. [Experimentell Fysik, Chalmers Tekniska Hoegskola, S-41296 Goeteborg (Sweden); Nilsson, T. [Experimentell Fysik, Chalmers Tekniska Hoegskola, S-41296 Goeteborg (Sweden); Nyman, G. [Experimentell Fysik, Chalmers Tekniska Hoegskola, S-41296 Goeteborg (Sweden); Prezado, Y. [Instituto de Estructura de la Materia, CSIC, E-28006 Madrid (Spain); Riisager, K. [Institut for fysik og astronomi, Aarhus Universitet, DK-8000 Aarhus C (Denmark)] [and others

    2004-12-27

    We report here on the recent {beta}-decay studies made at ISOL-type Facilities to determine the multiparticle breakup mechanism of excited states in light nuclei by studying them in full kinematics. In particular the results obtained for the A = 9 isobars and the breakup of the 12.7 MeV state in {sup 12}C of unnatural parity are discussed. The breakup of the latter has been debated since more than a decade. Mirror beta transitions in the A=9 chain are compared and a large asymmetry factor is deduced for the transitions to high excitation energy in {sup 9}Be (11.8 MeV) and {sup 9}B (12.2 MeV) fed in the {beta}-decay of {sup 9}Li and {sup 9}C respectively. It is shown that the asymmetry is not due to experimental problems or differences in the mechanisms of breakup or in the spin of the states. As no asymmetry is found in the gs to gs transition it must be due to the particular structure of these excited states. The controversy on the breakup mechanism of the 12.7 MeV state is resolved.

  3. 11beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle.

    LENUS (Irish Health Repository)

    Morgan, Stuart A

    2009-11-01

    Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning glucocorticoid-induced insulin resistance in skeletal muscle and indentify how 11beta-HSD1 inhibitors improve insulin sensitivity.

  4. Sequential mutations in the interleukin-3 (IL3)/granulocyte-macrophage colony-stimulating factor/IL5 receptor beta-subunit genes are necessary for the complete conversion to growth autonomy mediated by a truncated beta C subunit.

    Science.gov (United States)

    Hannemann, J; Hara, T; Kawai, M; Miyajima, A; Ostertag, W; Stocking, C

    1995-05-01

    An amino-terminally truncated beta C receptor (beta C-R) subunit of the interleukin-3 (IL3)/granulocyte-macrophage colony-stimulating factor/IL5 receptor complex mediates factor-independent and tumorigenic growth in two spontaneous mutants of a promyelocytic cell line. The constitutive activation of the JAK2 protein kinase in these mutants confirms that signaling occurs through the truncated receptor protein. Noteworthily, in addition to a 10-kb deletion in the beta C-R subunit gene encoding the truncated receptor, several secondary and independent mutations that result in the deletion or functional inactivation of the allelic beta C-R subunit and the closely related beta IL3-R subunit genes were observed in both mutants, suggesting that such mutations are necessary for the full oncogenic penetrance of the truncated beta C-R subunit. Reversion of these mutations by the expression of the wild-type beta C-R in the two mutants resulted in a fivefold decrease in cloning efficiency of the mutants in the absence of IL3, confirming a functional interaction between the wild-type and truncated proteins. Furthermore, expression of the truncated beta C-R subunit in factor-dependent myeloid cells did not immediately render the cells autonomous but increased the spontaneous frequency to factor-independent growth by 4 orders of magnitude. Implications for both leukemogenic progression and receptor-subunit interaction and signaling are discussed.

  5. Dysregulated transforming growth factor-beta in neonatal and adult autoimmune MRL-lpr mice.

    Science.gov (United States)

    Kreft, B; Yokoyama, H; Naito, T; Kelley, V R

    1996-08-01

    Transforming growth factor- beta (TGF- beta) is a cytokine that promotes inflammatory processes and prevents tissue injury. Autoimmune destruction of the kidney in MRL-lpr mice is spontaneous, rapid, fatal and consists of glomerular damage and an influx of lymphocytes surrounding vessels and in the interstitium. In MRL-lpr mice, cytokine dysregulation is apparent in neonates and continues throughout the life span. Circulating levels of tumour necrosis factor (TNF- alpha) and colony stimulating factor-1 (CSF-1) are detected in neonatal mice and progressively increase in proportion to the loss of renal function. We now report elevated intracellular expression of distinct isoforms of TGF- beta (TGF- beta 3, TGF- beta 2, and TGF- beta 1) detected immunohistochemically in MRL-lpr kidneys and other tissues including the liver and thymus. Enhanced TGF- beta 3 and TGF- beta 2 isoforms are detectable in neonatal mice within the renal tubular epithelial cells (TEC) and vascular smooth muscle cells (VSMC). In MRL-lpr mice 4-6 months of age, TGF- beta 2 and TGF- beta 1 are detected in TEC, VSMC, glomerular epithelial cells (GEC) and in perivascular infiltrating cells. By comparison, TGF- beta is minimally detectable in the normal kidneys of age and sex matched MRL(-)+2 or C3H/Fej mice. Paradoxically, in vitro cultured TEC and VSMC from MRL-lpr mice secrete less TGF- beta than TEC and VSMC isolated from MRL(-)+2 or C3H/FeJ mice. TNF- alpha, but not IL-6, CSF-1, or IFN- gamma stimulated the secretion of TGF- beta in TEC and VSMC. Our data demonstrate the dysregulation of TGF- beta isoforms in neonatal and adult MRL-lpr mice prior to and after the onset of autoimmune renal disease. We suggest that TNF- alpha and/or other molecules increase TGF- beta expression in MRL-lpr mice. We speculate that enhanced expression of TGF- beta promotes autoinmune renal injury in MRL-lpr mice.

  6. Potential targets of transforming growth factor-beta1 during inhibition of oocyte maturation in zebrafish

    Directory of Open Access Journals (Sweden)

    Clelland Eric

    2005-09-01

    Full Text Available Abstract Background TGF-beta is a multifunctional growth factor involved in regulating a variety of cellular activities. Unlike mammals, the function of TGF-beta in the reproduction of lower vertebrates, such as fish, is not clear. Recently, we showed that TGF-beta1 inhibits gonadotropin- and 17alpha, 20beta-dihydroxyprogesterone (DHP-induced maturation in zebrafish. The aim of the present study was to investigate the mechanisms underlying this action. Method To determine if the effect of TGF-beta1 on oocyte maturation involves transcription and/or translation, ovarian follicles were pre-treated with actinomycin D, a blocker of transcription, and cyclohexamide, an inhibitor of translation, and incubated with hCG or DHP, either alone or in combination with TGF-beta1 and oocyte maturation scored. To determine the effect of TGF-beta1 on mRNA levels of several key effectors of oocyte maturation, three sets of experiments were performed. First, follicles were treated with control medium or TGF-beta1 for 2, 6, 12, and 24 h. Second, follicles were treated with different concentrations of TGF-beta1 (0 to 10 ng/ml for 18 h. Third, follicles were incubated with hCG in the absence or presence of TGF-beta1 for 18 h. At the end of each experiment, total RNA was extracted and reverse transcribed. PCR using primers specific for 20beta-hydroxysteroid dehydrogenase (20beta-HSD which is involved in DHP production, follicle stimulating hormone receptor (FSHR, luteinizing hormone receptor (LHR, the two forms of membrane progestin receptor: mPR-alpha and mPR-beta, as well as GAPDH (control, were performed. Results Treatment with actinomycin D, a blocker of transcription, reduced the inhibitory effect of TGF-beta1 on DHP-induced oocyte maturation, indicating that the inhibitory action of TGF-beta1 is in part due to regulation of gene transcription. Treatment with TGF-beta1 caused a dose and time-dependent decrease in mRNA levels of 20beta-HSD, LHR and mPR-beta in

  7. Novel non-steroidal inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1.

    Science.gov (United States)

    Vicker, Nigel; Su, Xiangdong; Ganeshapillai, Dharshini; Smith, Andrew; Purohit, Atul; Reed, Michael J; Potter, Barry V L

    2007-05-01

    11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regulates glucocorticoid action at the pre-receptor stage by converting cortisone to cortisol. 11beta-HSD1 is selectively expressed in many tissues including the liver and adipose tissue where metabolic events are important. Metabolic syndrome relates to a number of metabolic abnormalities and currently has a prevalence of >20% in adult Americans. 11beta-HSD1 inhibitors are being investigated by many major pharmaceutical companies for type 2 diabetes and other abnormalities associated with metabolic syndrome. In this area of intense interest a number of structural types of 11beta-HSD1 inhibitor have been identified. It is important to have an array of structural types as the physicochemical properties of the compounds will determine tissue distribution, HPA effects, and ultimately clinical utility. Here we report the discovery and synthesis of three structurally different series of novel 11beta-HSD1 inhibitors that inhibit human 11beta-HSD1 in the low micromolar range. Docking studies with 1-3 into the crystal structure of human 11beta-HSD1 reveal how the molecules may interact with the enzyme and cofactor and give further scope for structure based drug design in the optimisation of these series.

  8. Apolipoprotein M predicts pre-beta-HDL formation: studies in type 2 diabetic and nondiabetic subjects

    DEFF Research Database (Denmark)

    Plomgaard, P; Dullaart, R P F; de Vries, R;

    2009-01-01

    OBJECTIVE: Studies in mice suggest that plasma apoM is lowered in hyperinsulinaemic diabetes and that apoM stimulates formation of pre-beta-HDL. Pre-beta-HDL is an acceptor of cellular cholesterol and may be critical for reverse cholesterol transport. Herein, we examined whether patients with type...... 2 diabetes have reduced plasma apoM and whether apoM is associated with pre-beta-HDL formation and cellular cholesterol efflux. DESIGN: In 78 patients with type 2 diabetes and 89 control subjects, we measured plasma apoM with ELISA, pre-beta-HDL and pre-beta-HDL formation, phospholipid transfer...... to diabetes-associated obesity. ApoM was positively related to both HDL (r = 0.16; P = 0.04) and LDL cholesterol (r = 0.28; P = 0.0003). Pre-beta-HDL and pre-beta-HDL formation were not different between diabetic and control subjects. ApoM predicted pre-beta-HDL (r = 0.16; P = 0.04) and pre-beta-HDL formation...

  9. El factor de crecimiento transformante beta como blanco terapéutico Transforming growth factor-beta as a therapeutic target

    Directory of Open Access Journals (Sweden)

    Francisco Javier Gálvez-Gastélum

    2004-08-01

    Full Text Available El factor de crecimiento transformante beta (TGF-beta es una familia de proteínas que incluye al TGF-beta, activinas y a la proteína morfogénica de hueso (BMP, por sus siglas en inglés, citocinas que son secretadas y se relacionan estructuralmente en diferentes especies de metazoarios. Los miembros de la familia del TGF-beta regulan diferentes funciones celulares como proliferación, apoptosis, diferenciación, migración, y tienen un papel clave en el desarrollo del organismo. El TGF-beta está implicado en varias patologías humanas, incluyendo desórdenes autoinmunes y vasculares, así como enfermedades fibróticas y cáncer. La activación del receptor del TGF-beta propicia su fosforilación en residuos de serina/treonina y dispara la fosforilación de proteínas efectoras intracelulares (smad, que una vez activas se translocan al núcleo para inducir la transcripción de genes blanco, y así regular procesos y funciones celulares. Se están desarrollando novedosas estrategias terapéuticas encaminadas a corregir las alteraciones presentes en patologías que involucran al TGF-beta como actor principal.Transforming growth factor-beta (TGF-beta family members include TGF-beta, activins, and bone morphogenetic proteins (BMP. These proteins are structurally related cytokines secreted in diverse Metazoans. TGF-beta family members regulate cellular functions such as proliferation, apoptosis, differentiation, and migration, and play an important role in organism development. Deregulated TGF-beta family signaling participates in various human pathologies including auto-immune diseases, vascular disorders, fibrotic disease, and cancer. Ligand-induced activation of TGF-beta family receptors with intrinsic serine/threonine kinase activity, triggers phosphorylation of the intracellular effectors of TGF-beta signaling, the Smads proteins. Once these proteins are activated they translocate into the nucleus, where they induce transcription of target

  10. Implications for the offspring of circulating factors involved in beta cell adaptation in pregnancy

    DEFF Research Database (Denmark)

    Nalla, Amarnadh; Ringholm, Lene; Søstrup, Birgitte

    2014-01-01

    is able to stimulate proliferation of rat beta cells. We have identified several circulating factors that may contribute to beta cell adaptation to pregnancy. Further studies are needed to elucidate their possible role in glucose homeostasis in the mother and her offspring.......OBJECTIVE: Several studies have shown an increase in beta cell mass during pregnancy. Somatolactogenic hormones are known to stimulate the proliferation of existing beta cells in rodents whereas the mechanism in humans is still unclear. We hypothesize that in addition to somatolactogenic hormones...... there are other circulating factors involved in beta cell adaptation to pregnancy. This study aimed at screening for potential pregnancy-associated circulating beta cell growth factors. SAMPLES: Serum samples from nonpregnant and pregnant women. METHODS: The effect of serum from pregnant women...

  11. The transforming growth factor-beta receptor genes and the risk of intracranial aneurysms

    NARCIS (Netherlands)

    Ruigrok, Ynte M.; Baas, Annette F.; Medic, Jelena; Wijmenga, Cisca; Rinkel, Gabriel J. E.

    2012-01-01

    Background Mutations in the receptor genes of the transforming growth factor beta pathway, TGFBR1 and TGFBR2, cause syndromes with thoracic aortic aneurysms, while genetic variants in TGFBR1 and TGFBR2 are associated with abdominal aortic aneurysms. The transforming growth factor-beta pathway may be

  12. Immunohistochemical detection of active transforming growth factor-beta in situ using engineered tissue

    Science.gov (United States)

    Barcellos-Hoff, M. H.; Ehrhart, E. J.; Kalia, M.; Jirtle, R.; Flanders, K.; Tsang, M. L.; Chatterjee, A. (Principal Investigator)

    1995-01-01

    The biological activity of transforming growth factor-beta 1 (TGF-beta) is governed by dissociation from its latent complex. Immunohistochemical discrimination of active and latent TGF-beta could provide insight into TGF-beta activation in physiological and pathological processes. However, evaluation of immunoreactivity specificity in situ has been hindered by the lack of tissue in which TGF-beta status is known. To provide in situ analysis of antibodies to differentiate between these functional forms, we used xenografts of human tumor cells modified by transfection to overexpress latent TGF-beta or constitutively active TGF-beta. This comparison revealed that, whereas most antibodies did not differentiate between TGF-beta activation status, the immunoreactivity of some antibodies was activation dependent. Two widely used peptide antibodies to the amino-terminus of TGF-beta, LC(1-30) and CC(1-30) showed marked preferential immunoreactivity with active TGF-beta versus latent TGF-beta in cryosections. However, in formalin-fixed, paraffin-embedded tissue, discrimination of active TGF-beta by CC(1-30) was lost and immunoreactivity was distinctly extracellular, as previously reported for this antibody. Similar processing-dependent extracellular localization was found with a neutralizing antibody raised to recombinant TGF-beta. Antigen retrieval recovered cell-associated immunoreactivity of both antibodies. Two antibodies to peptides 78-109 showed mild to moderate preferential immunoreactivity with active TGF-beta only in paraffin sections. LC(1-30) was the only antibody tested that discriminated active from latent TGF-beta in both frozen and paraffin-embedded tissue. Thus, in situ discrimination of active versus latent TGF-beta depends on both the antibody and tissue preparation. We propose that tissues engineered to express a specific form of a given protein provide a physiological setting in which to evaluate antibody reactivity with specific functional forms of a

  13. A cDNA cloned from Physarum polycephalum encodes new type of family 3 beta-glucosidase that is a fusion protein containing a calx-beta motif.

    Science.gov (United States)

    Maekawa, Akinori; Hayase, Masato; Yubisui, Toshitsugu; Minami, Yoshiko

    2006-01-01

    The microplasmodia of Physarum polycephalum express three types of beta-glucosidases: secretory enzyme, a soluble cytoplasmic enzyme and a membrane-bound enzyme. We are interested in the physiological role of three enzymes. We report the sequence of cDNA for membrane beta-glucosidase 1, which consists of 3825 nucleotides that includes an open reading frame encoding 1248 amino acids. The molecular weight of membrane beta-glucosidase 1 was calculated to be 131,843 based on the predicted amino acid composition. Glycosyl hydrolase family 3 N-terminal and C-terminal domains were found within the N-terminal half of the membrane beta-glucosidase 1 sequence and were highly homologous with the primary structures of fungal beta-glucosidases. Notably, the C-terminal half of membrane beta-glucosidase 1 contains two calx-beta motifs, which are known to be Ca(2+) binding domains in the Drosophila Na(+)/Ca(2+) exchanger; an RGD sequence, which is known to be a cell attachment sequence; and a transmembrane region. In this way, Physarum membrane beta-glucosidase 1 differs from all previously identified family 3 beta-glucosidases. In addition to cDNA for membrane beta-glucosidase 1, two other distinctly different mRNAs were also isolated. Two sequences were largely identical to cDNA for membrane beta-glucosidase 1, but included a long insert sequence having a stop codon, leading to truncation of their products, which could account for other beta-glucosidase forms occurred in Physarum poycephalum. Thus, the membrane beta-glucosidase is a new type family 3 enzyme fused with the Calx-beta domain. We propose that Calx-beta domain may modulate the beta-glucosidase activity in response to changes in the Ca(2+) concentration.

  14. Amyloid-beta: a crucial factor in Alzheimer's disease.

    Science.gov (United States)

    Sadigh-Eteghad, Saeed; Sabermarouf, Babak; Majdi, Alireza; Talebi, Mahnaz; Farhoudi, Mehdi; Mahmoudi, Javad

    2015-01-01

    Alzheimer's disease (AD) is the most prevalent form of dementia which affects people older than 60 years of age. In AD, the dysregulation of the amyloid-beta (Aβ) level leads to the appearance of senile plaques which contain Aβ depositions. Aβ is a complex biological molecule which interacts with many types of receptors and/or forms insoluble assemblies and, eventually, its nonphysiological depositions alternate with the normal neuronal conditions. In this situation, AD signs appear and the patients experience marked cognitional disabilities. In general, intellect, social skills, personality, and memory are influenced by this disease and, in the long run, it leads to a reduction in quality of life and life expectancy. Due to the pivotal role of Aβ in the pathobiology of AD, a great deal of effort has been made to reveal its exact role in neuronal dysfunctions and to finding efficacious therapeutic strategies against its adverse neuronal outcomes. Hence, the determination of its different molecular assemblies and the mechanisms underlying its pathological effects are of interest. In the present paper, some of the well-established structural forms of Aβ, its interactions with various receptors and possible molecular and cellular mechanisms underlying its neurotoxicity are discussed. In addition, several Aβ-based rodent models of AD are reviewed. © 2014 S. Karger AG, Basel.

  15. Transforming growth factor-beta and the glomerular filtration barrier

    Directory of Open Access Journals (Sweden)

    Ayesha Ghayur

    2013-03-01

    Full Text Available The increasing burden of chronic kidney disease worldwide and recent advancements in the understanding of pathologic events leading to kidney injury have opened up new potential avenues for therapies to further diminish progression of kidney disease by targeting the glomerular filtration barrier and reducing proteinuria. The glomerular filtration barrier is affected by many different metabolic and immune-mediated injuries. Glomerular endothelial cells, the glomerular basement membrane, and podocytes—the three components of the filtration barrier—work together to prevent the loss of protein and at the same time allow passage of water and smaller molecules. Damage to any of the components of the filtration barrier can initiate proteinuria and renal fibrosis. Transforming growth factor-beta (TGF-β is a pleiotropic cytokine strongly associated with the fibrogenic response. It has a known role in tubulointerstitial fibrosis. In this review we will highlight what is known about TGF-β and how it interacts with the components of glomerular filtration barrier and causes loss of function and proteinuria.

  16. The pleiotropic roles of transforming growth factor beta inhomeostasis and carcinogenesis of endocrine organs.

    Energy Technology Data Exchange (ETDEWEB)

    Fleisch, Markus C.; Maxwell, Christopher A.; Barcellos-Hoff,Mary-Helen

    2006-01-13

    Transforming growth factor beta (TGF-beta) is a ubiquitous cytokine that plays a critical role in numerous pathways regulating cellular and tissue homeostasis. TGF-beta is regulated by hormones and is a primary mediator of hormone response in uterus, prostate and mammary gland. This review will address the role of TGF-beta in regulating hormone dependent proliferation and morphogenesis. The subversion of TGF-beta regulation during the processes of carcinogenesis, with particular emphasis on its effects on genetic stability and epithelial to mesenchymal transition (EMT), will also be examined. An understanding of the multiple and complex mechanisms of TGF-beta regulation of epithelial function, and the ultimate loss of TGF-beta function during carcinogenesis, will be critical in the design of novel therapeutic interventions for endocrine-related cancers.

  17. Apolipoprotein M predicts pre-beta-HDL formation: studies in type 2 diabetic and nondiabetic subjects.

    Science.gov (United States)

    Plomgaard, P; Dullaart, R P F; de Vries, R; Groen, A K; Dahlbäck, B; Nielsen, L B

    2009-09-01

    Studies in mice suggest that plasma apoM is lowered in hyperinsulinaemic diabetes and that apoM stimulates formation of pre-beta-HDL. Pre-beta-HDL is an acceptor of cellular cholesterol and may be critical for reverse cholesterol transport. Herein, we examined whether patients with type 2 diabetes have reduced plasma apoM and whether apoM is associated with pre-beta-HDL formation and cellular cholesterol efflux. In 78 patients with type 2 diabetes and 89 control subjects, we measured plasma apoM with ELISA, pre-beta-HDL and pre-beta-HDL formation, phospholipid transfer protein (PLTP) activity and the ability of plasma to promote cholesterol efflux from cultured fibroblasts. ApoM was approximately 9% lower in patients with type 2 diabetes compared to controls (0.025 +/- 0.006 vs. 0.027 +/- 0.007 g L(-1), P = 0.01). The difference in apoM was largely attributable to diabetes-associated obesity. ApoM was positively related to both HDL (r = 0.16; P = 0.04) and LDL cholesterol (r = 0.28; P = 0.0003). Pre-beta-HDL and pre-beta-HDL formation were not different between diabetic and control subjects. ApoM predicted pre-beta-HDL (r = 0.16; P = 0.04) and pre-beta-HDL formation (r = 0.19; P = 0.02), even independently of positive relationships with apoA-I, HDL-cholesterol and PLTP activity. Cellular cholesterol efflux to plasma was positively related to pre-beta-HDL and PLTP activity but not significantly to apoM. Plasma apoM is modestly reduced in type 2 diabetes. Pre-beta-HDL and pre-beta-HDL formation are positively associated with apoM, supporting the hypothesis that apoM plays a role in HDL remodelling in humans. Lower apoM may provide a mechanism to explain why pre-beta-HDL formation is not increased in type 2 diabetes despite elevated PLTP activity.

  18. Ursolic acid, an antagonist for transforming growth factor (TGF)-beta1.

    Science.gov (United States)

    Murakami, Shigeru; Takashima, Hajime; Sato-Watanabe, Mariko; Chonan, Sumi; Yamamoto, Koji; Saitoh, Masako; Saito, Shiuji; Yoshimura, Hiromitsu; Sugawara, Koko; Yang, Junshan; Gao, Nannan; Zhang, Xinggao

    2004-05-21

    Transforming growth factor-beta (TGF-beta), a multifunctional cytokine which is involved in extracellular matrix modulation, has a major role in the pathogenesis and progression of fibrotic diseases. We now report the effects of ursolic acid on TGF-beta1 receptor binding and TGF-beta1-induced cellular functions in vitro. Ursolic acid inhibited [(125)I]-TGF-beta1 receptor binding to Balb/c 3T3 mouse fibroblasts with an IC(50) value of 6.9+/-0.8 microM. Ursolic acid dose-dependently recovered reduced proliferation of Minc Mv1Lu cells in the presence of 5 nM of TGF-beta1 and attenuated TGF-beta1-induced collagen synthesis and production in human fibroblasts. Molecular dynamics simulations suggest that ursolic acid may interact with the hydrophobic region of the dimeric interface and thereby inhibit the binding of TGF-beta1 to its receptor. All these findings taken together show that ursolic acid functions as an antagonist for TGF-beta1. This is the first report to show that a small molecule can inhibit TGF-beta1 receptor binding and influence functions of TGF-beta1.

  19. Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function

    DEFF Research Database (Denmark)

    Neve, Bernadette; Fernandez-Zapico, Martin E; Ashkenazi-Katalan, Vered

    2005-01-01

    a role in free radical clearance that may render beta cells more sensitive to oxidative stress. Thus, both functional and genetic analyses reveal that KLF11 plays a role in the regulation of pancreatic beta cell physiology, and its variants may contribute to the development of diabetes.......KLF11 (TIEG2) is a pancreas-enriched transcription factor that has elicited significant attention because of its role as negative regulator of exocrine cell growth in vitro and in vivo. However, its functional role in the endocrine pancreas remains to be established. Here, we report, for the first...... in beta cells. Genetic analysis of the KLF11 gene revealed two rare variants (Ala347Ser and Thr220Met) that segregate with diabetes in families with early-onset type 2 diabetes, and significantly impair its transcriptional activity. In addition, analysis of 1,696 type 2 diabetes mellitus and 1...

  20. The vicious cycle of apoptotic beta-cell death in type 1 diabetes.

    Science.gov (United States)

    Kaminitz, Ayelet; Stein, Jerry; Yaniv, Isaac; Askenasy, Nadir

    2007-01-01

    Autoimmune insulitis, the cause of type 1 diabetes, evolves through several discrete stages that culminate in beta-cell death. In the first stage, antigenic epitopes of B-cell-specific peptides are processed by antigen presenting cells in local lymph nodes, and auto-reactive lymphocyte clones are propagated. Subsequently, cell-mediated and direct cytokine-mediated reactions are generated against the beta-cells, and the beta-cells are sensitized to apoptosis. Ironically, the beta-cells themselves contribute some of the cytokines and chemokines that provoke the immune reaction within the islets. Once this vicious cycle of autoimmunity is fully developed, the fate of the beta-cells in the islets is sealed, and clinical diabetes inevitably ensues. Differences in various aspects of these concurrent events appear to underlie the significant discrepancies in experimental data observed in experimental models that simulate autoimmune insulitis.

  1. Transforming growth factor-beta: possible roles in carcinogenesis.

    OpenAIRE

    Roberts, A B; Thompson, N L; Heine, U.; Flanders, C.; Sporn, M B

    1988-01-01

    TGF-beta is the prototype of a large family of multifunctional regulatory proteins. The principal sources of the peptide, platelets and bone, suggest that it plays a role in healing and remodeling processes. In vitro, TGF-beta is chemotactic for monocytes and fibroblasts and can greatly enhance accumulation of extracellular matrix components by fibroblasts. Its ability to stimulate the formation of granulation tissue locally and the demonstration of specific time- and tissue-dependent express...

  2. The design of novel 17beta-hydroxysteroid dehydrogenase type 3 inhibitors.

    Science.gov (United States)

    Vicker, Nigel; Sharland, Christopher M; Heaton, Wesley B; Gonzalez, Ana M Ramos; Bailey, Helen V; Smith, Andrew; Springall, Jeremy S; Day, Joanna M; Tutill, Helena J; Reed, Michael J; Purohit, Atul; Potter, Barry V L

    2009-03-25

    17beta-Hydroxysteroid dehydrogenase type 3 (17beta-HSD3) is expressed at high levels in the testes and seminal vesicles but has also been shown to be present in prostate tissue, suggesting its potential involvement in both gonadal and non-gonadal testosterone biosynthesis. The role of 17beta-HSD3 in testosterone biosynthesis makes this enzyme an attractive molecular target for small molecule inhibitors for the treatment of prostate cancer. Here we report the design of selective inhibitors of 17beta-HSD3 as potential anti-cancer agents. Due to 17beta-HSD3 being a membrane-bound protein a crystal structure is not yet available. A homology model of 17beta-HSD3 has been built to aid structure-based drug design. This model has been used with docking studies to identify a series of lead compounds that may give an insight as to how inhibitors interact with the active site. Compound 1 was identified as a potent selective inhibitor of 17beta-HSD3 with an IC(50)=700nM resulting in the discovery of a novel lead series for further optimisation. Using our homology model as a tool for inhibitor design compound 5 was discovered as a novel potent and selective inhibitor of 17beta-HSD3 with an IC(50) approximately 200nM.

  3. Pharmacologic inhibition of the TGF-beta type I receptor kinase has anabolic and anti-catabolic effects on bone.

    Directory of Open Access Journals (Sweden)

    Khalid S Mohammad

    Full Text Available During development, growth factors and hormones cooperate to establish the unique sizes, shapes and material properties of individual bones. Among these, TGF-beta has been shown to developmentally regulate bone mass and bone matrix properties. However, the mechanisms that control postnatal skeletal integrity in a dynamic biological and mechanical environment are distinct from those that regulate bone development. In addition, despite advances in understanding the roles of TGF-beta signaling in osteoblasts and osteoclasts, the net effects of altered postnatal TGF-beta signaling on bone remain unclear. To examine the role of TGF-beta in the maintenance of the postnatal skeleton, we evaluated the effects of pharmacological inhibition of the TGF-beta type I receptor (TbetaRI kinase on bone mass, architecture and material properties. Inhibition of TbetaRI function increased bone mass and multiple aspects of bone quality, including trabecular bone architecture and macro-mechanical behavior of vertebral bone. TbetaRI inhibitors achieved these effects by increasing osteoblast differentiation and bone formation, while reducing osteoclast differentiation and bone resorption. Furthermore, they induced the expression of Runx2 and EphB4, which promote osteoblast differentiation, and ephrinB2, which antagonizes osteoclast differentiation. Through these anabolic and anti-catabolic effects, TbetaRI inhibitors coordinate changes in multiple bone parameters, including bone mass, architecture, matrix mineral concentration and material properties, that collectively increase bone fracture resistance. Therefore, TbetaRI inhibitors may be effective in treating conditions of skeletal fragility.

  4. Hepatocyte Nuclear Factor 1beta-Associated Kidney Disease: More than Renal Cysts and Diabetes

    NARCIS (Netherlands)

    Verhave, J.C.; Bech, A.P.; Wetzels, J.F.; Nijenhuis, T.

    2016-01-01

    Hepatocyte nuclear factor 1beta (HNF1beta)-associated disease is a recently recognized clinical entity with a variable multisystem phenotype. Early reports described an association between HNF1B mutations and maturity-onset diabetes of the young. These patients often presented with renal cysts and

  5. Helicobacter pylori type IV secretion apparatus exploits beta1 integrin in a novel RGD-independent manner.

    Directory of Open Access Journals (Sweden)

    Luisa F Jiménez-Soto

    2009-12-01

    Full Text Available Translocation of the Helicobacter pylori (Hp cytotoxin-associated gene A (CagA effector protein via the cag-Type IV Secretion System (T4SS into host cells is a major risk factor for severe gastric diseases, including gastric cancer. However, the mechanism of translocation and the requirements from the host cell for that event are not well understood. The T4SS consists of inner- and outer membrane-spanning Cag protein complexes and a surface-located pilus. Previously an arginine-glycine-aspartate (RGD-dependent typical integrin/ligand type interaction of CagL with alpha5beta1 integrin was reported to be essential for CagA translocation. Here we report a specific binding of the T4SS-pilus-associated components CagY and the effector protein CagA to the host cell beta1 Integrin receptor. Surface plasmon resonance measurements revealed that CagA binding to alpha5beta1 integrin is rather strong (dissociation constant, K(D of 0.15 nM, in comparison to the reported RGD-dependent integrin/fibronectin interaction (K(D of 15 nM. For CagA translocation the extracellular part of the beta1 integrin subunit is necessary, but not its cytoplasmic domain, nor downstream signalling via integrin-linked kinase. A set of beta1 integrin-specific monoclonal antibodies directed against various defined beta1 integrin epitopes, such as the PSI, the I-like, the EGF or the beta-tail domain, were unable to interfere with CagA translocation. However, a specific antibody (9EG7, which stabilises the open active conformation of beta1 integrin heterodimers, efficiently blocked CagA translocation. Our data support a novel model in which the cag-T4SS exploits the beta1 integrin receptor by an RGD-independent interaction that involves a conformational switch from the open (extended to the closed (bent conformation, to initiate effector protein translocation.

  6. MicroRNA-26a modulates transforming growth factor beta-1-induced proliferation in human fetal lung fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xiaoou [Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan (China); Department of Respiratory Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan (China); Liu, Lian [Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan (China); Shen, Yongchun; Wang, Tao; Chen, Lei; Xu, Dan [Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan (China); Department of Respiratory Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan (China); Wen, Fuqiang, E-mail: wenfuqiang.scu@gmail.com [Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan (China); Department of Respiratory Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan (China)

    2014-11-28

    Highlights: • Endogenous miR-26a inhibits TGF-beta 1 induced proliferation of lung fibroblasts. • miR-26a induces G1 arrest through directly targeting 3′-UTR of CCND2. • TGF indispensable receptor, TGF-beta R I, is regulated by miR-26a. • miR-26a acts through inhibiting TGF-beta 2 feedback loop to reduce TGF-beta 1. • Collagen type I and connective tissue growth factor are suppressed by miR-26a. - Abstract: MicroRNA-26a is a newly discovered microRNA that has a strong anti-tumorigenic capacity and is capable of suppressing cell proliferation and activating tumor-specific apoptosis. However, whether miR-26a can inhibit the over-growth of lung fibroblasts remains unclear. The relationship between miR-26a and lung fibrosis was explored in the current study. We first investigated the effect of miR-26a on the proliferative activity of human lung fibroblasts with or without TGF-beta1 treatment. We found that the inhibition of endogenous miR-26a promoted proliferation and restoration of mature miR-26a inhibited the proliferation of human lung fibroblasts. We also examined that miR-26a can block the G1/S phase transition via directly targeting 3′-UTR of CCND2, degrading mRNA and decreasing protein expression of Cyclin D2. Furthermore, we showed that miR-26a mediated a TGF-beta 2-TGF-beta 1 feedback loop and inhibited TGF-beta R I activation. In addition, the overexpression of miR-26a also significantly suppressed the TGF-beta 1-interacting-CTGF–collagen fibrotic pathway. In summary, our studies indicated an essential role of miR-26a in the anti-fibrotic mechanism in TGF-beta1-induced proliferation in human lung fibroblasts, by directly targeting Cyclin D2, regulating TGF-beta R I as well as TGF-beta 2, and suggested the therapeutic potential of miR-26a in ameliorating lung fibrosis.

  7. Rosiglitazone decreases 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue.

    Science.gov (United States)

    Mai, Knut; Andres, Janin; Bobbert, Thomas; Maser-Gluth, Christiane; Möhlig, Matthias; Bähr, Volker; Pfeiffer, Andreas F H; Spranger, Joachim; Diederich, Sven

    2007-09-01

    The peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist rosiglitazone increases insulin sensitivity, which, in animal models, is comparable to the effect of a reduction in 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity. We therefore investigated whether rosiglitazone-induced insulin sensitivity is associated with changes in 11beta-HSD1 activity in different tissues. An oral glucose tolerance test (OGTT) and a euglycaemic hyperinsulinaemic clamp were performed in seven male volunteers [age 59.3 +/- 3.0 years, body mass index (BMI) 29.3 +/- 4.1 kg/m(2)] with impaired glucose tolerance before and after 8 weeks of rosiglitazone treatment. To assess hepatic 11beta-HSD1 activity, serum cortisol levels were measured after oral administration of cortisone acetate. 11beta-HSD1 activity and mRNA expression were assessed in abdominal subcutaneous fat biopsies. Total-body 11beta-HSD activities were estimated by calculating the urinary ratios of glucocorticoid metabolites. As expected, rosiglitazone improved insulin resistance and postprandial hyperglycaemia. In parallel, 11beta-HSD1 mRNA expression [100 +/- 0% (reference) vs. 68.5 +/- 9.3%, P < 0.01] and activity [0.18 +/- 0.02 vs. 0.13 +/- 0.02 pmol/min/mg, P < 0.05] decreased in abdominal subcutaneous fat, while an increase in hepatic 11beta-HSD1 activity was detected [the area under the curve (AUC) for the cortisol/cortisone ratio was 1319 +/- 76 vs. 955 +/- 59; P < 0.05]. No changes in BMI, waist-to-hip ratio (WHR) and whole-body 11beta-HSD1 activity were found. Part of the beneficial effects of rosiglitazone may be mediated by a reduction in the 11beta-HSD1 mRNA expression and activity in subcutaneous abdominal fat.

  8. Factors contributing to the breakdown of sodium beta-alumina

    Energy Technology Data Exchange (ETDEWEB)

    Buechele, A.C.

    1982-05-01

    Clarification of the breakdown process occurring during charge transfer in sodium beta alumina solid electrolytes was derived from: (1) studying the effects of molten sodium contact at 350/sup 0/C on single crystal sodium beta alumina and polycrystalline sodium beta alumina; (2) determination of critical current density by monitoring acoustic emissions accompanying crack growth in sodium/sodium beta alumina/sodium cells subjected to linear current ramping at 1 mA cm/sup -2/ sec/sup -1/; (3) failure analysis conducted on cycled electrolytes, some from commercial sodium/sulfur cells, which had been subjected to up to 703 Ahr cm/sup -2/ of charge transfer. Gray coloration developing in beta aluminas in contact with molten sodium was found to be a consequence of formation, through reduction by sodium, of oxygen vacancies charge compensated by electrons. Electronic conductivity of the electrolyte increases as a result. No second phase formation was detected. Colored electrolytes from sodium/sulfur cells show evidence of a newly recognized degradation mechanism in which fracture occurs when sodium is reduced and deposited internally under pressure as metal in regions where an electronic conductivity gradient exists. Heating colored beta aluminas in air produces reoxidation and bleaching. Kinetics and other properties of the coloration and bleaching processes were determined. Critical current density was found to bear an inverse relation to average electrolyte grain size. Evidence was found in the cycled electrolytes for a slow crack growth mechanism and a progressive mode of degradation advancing from the sulfur electrode interface. Implications of the findings for the construction and operation of sodium/sulfur battery systems are discussed.

  9. Depressed adrenomedullin in the embryonic transforming growth factor-beta1 null mouse becomes elevated postnatally.

    Science.gov (United States)

    Bodegas, Elena; Martínez, Alfredo; Ozbun, Laurent L; Garayoa, Mercedes; Letterio, John J; Montuenga, Luis M; Jakowlew, Sonia B

    2004-02-01

    Transforming growth factor-beta (TGF-beta) and adrenomedullin are multifunctional regulatory proteins which are expressed in developing embryonic and adult tissues. Because of their colocalization, TGF-beta1 and adrenomedullin may be able to coordinately act to influence development and differentiation. In order to learn more about the biology of adrenomedullin in the absence of the effects of TGF-beta1 in vivo, we examined adrenomedullin in the TGF-beta1 null mouse. A generally lower amount of adrenomedullin was detected by immunohistochemical staining analysis in multiple tissues from embryonic TGF-beta1 null mice compared to wildtype animals, including the heart, lung, brain, liver, and kidney, among others. In contrast, immunohistochemical staining for adrenomedullin was more intense in tissues of the postnatal TGF-beta1 null mouse compared to the wildtype mouse. These observations were confirmed by quantitative real time RT-PCR for adrenomedullin in both embryos and postnatal animals, as well as in cultured mouse embryo fibroblasts from TGF-beta1 null and wildtype mice. In addition, when cultured mouse embryo fibroblasts were treated with a neutralizing monoclonal antibody against TGF-beta1, the levels of adrenomedullin expression were statistically reduced compared to untreated cells. Our data show that expression of adrenomedullin is reduced in tissues of the developing embryonic TGF-beta1 null mouse compared to the wildtype mouse, but increases during postnatal development in TGF-beta1 null mice. The elevated expression of adrenomedullin which occurs postnatally in the TGF-beta1 null mouse may be a cause or a consequence of the multifocal wasting syndrome which is characteristic of postnatal TGF-beta1 null mice.

  10. Polarity of response to transforming growth factor-beta1 in proximal tubular epithelial cells is regulated by beta-catenin.

    Science.gov (United States)

    Zhang, Mei; Lee, Chien-Hung; Luo, Dong Dong; Krupa, Aleksandra; Fraser, Donald; Phillips, Aled

    2007-09-28

    Transforming growth factor-beta1 (TGF-beta1)-mediated loss of proximal tubular epithelial cell-cell interaction is regulated in a polarized fashion. The aim of this study was to further explore the polarity of the TGF-beta1 response and to determine the significance of R-Smad-beta-catenin association previously demonstrated to accompany adherens junction disassembly. Smad3 signaling response to TGF-beta1 was assessed by activity of the Smad3-responsive reporter gene construct (SBE)(4)-Lux and by immunoblotting for phospho-Smad proteins. Similar results were obtained with both methods. Apical application of TGF-beta1 led to increased Smad3 signaling compared with basolateral stimulation. Association of Smad proteins with beta-catenin was greater following basolateral TGFbeta-1 stimulation, as was the expression of cytoplasmic Triton-soluble beta-catenin. Inhibition of beta-catenin expression by small interfering RNA augmented Smad3 signaling. Lithium chloride, a GSK-3 inhibitor, increased expression of beta-catenin and attenuated TGF-beta1-dependent Smad3 signaling. Lithium chloride did not influence degradation of Smad3 but resulted in decreased nuclear translocation. Smad2 activation as assessed by Western blot analysis and activity of the Smad2-responsive reporter constructs ARE/MF1 was also greater following apical as compared with basolateral TGFbeta-1 stimulation, suggesting that this is a generally applicable mechanism for the regulation of TGF-beta1-dependent R-Smads. Caco-2 cells are a colonic carcinoma cell line, with known resistance to the anti-proliferative effects of TGF-beta1 and increased expression of beta-catenin. We used this cell line to address the general applicability of our observations. Inhibition of beta-catenin in this cell line by small interfering RNA resulted in increased TGF-beta1-dependent Smad3 phosphorylation and restoration of TGF-beta1 anti-proliferative effects.

  11. Suppressor of cytokine signalling (SOCS)-3 protects beta cells against IL-1beta-mediated toxicity through inhibition of multiple nuclear factor-kappaB-regulated proapoptotic pathways

    DEFF Research Database (Denmark)

    Karlsen, Allan Ertman; Heding, P E; Frobøse, H;

    2004-01-01

    The proinflammatory cytokine IL-1beta induces apoptosis in pancreatic beta cells via pathways dependent on nuclear factor-kappaB (NF-kappaB), mitogen-activated protein kinase, and protein kinase C. We recently showed suppressor of cytokine signalling (SOCS)-3 to be a natural negative feedback...... regulator of IL-1beta- and IFN-gamma-mediated signalling in rat islets and beta cell lines, preventing their deleterious effects. However, the mechanisms underlying SOCS-3 inhibition of IL-1beta signalling and prevention against apoptosis remain unknown....

  12. Discovery of novel inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1.

    Science.gov (United States)

    Su, Xiangdong; Vicker, Nigel; Trusselle, Melanie; Halem, Heather; Culler, Michael D; Potter, Barry V L

    2009-03-25

    11beta-Hydroxysteroid dehydrogenases (11beta-HSDs) are key enzymes regulating the pre-receptor metabolism of glucocorticoid hormones, which play essential roles in various vital physiological processes. The modulation of 11beta-HSD type 1 activity with selective inhibitors has beneficial effects on various conditions including insulin resistance, dyslipidemia and obesity. Therefore, inhibition of tissue-specific glucocorticoid action by regulating 11beta-HSD1 constitutes a promising treatment for metabolic and cardiovascular diseases. Here we report the discovery of a series of novel adamantyl carboxamides as selective inhibitors of human 11beta-HSD1 in HEK-293 cells transfected with the HSD11B1 gene. Compounds 9 and 14 show inhibitory activity against 11beta-HSD1 with IC(50) values in 100nM range. Docking studies with the potent compound 8 into the crystal structure of human 11beta-HSD1 (1XU9) reveals how the molecule may interact with the enzyme and cofactor.

  13. Inhibition of Transforming Growth Factor-Beta1 SignalingAttenuates Ataxia Telangiectasia Mutated Activity in Response toGenotoxic Stress

    Energy Technology Data Exchange (ETDEWEB)

    Kirshner, Julia; Jobling, Michael F.; Pajares, Maria Jose; Ravani, Shraddha A.; Glick, Adam; Lavin, Martin F.; Koslov, Sergei; Shiloh, Yosef; Barcellos-Hoff, Mary Helen

    2006-01-01

    Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor {beta} (TGF{beta})-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGF{beta} inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf{beta}I null murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGF{beta} type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced H2AX radiation-induced foci; and increased radiosensitivity compared with TGF{beta} competent cells. We determined that loss of TGF{beta} signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGF{beta} restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM, which directs epithelial cell stress responses, cell fate, and tissue integrity. Thus, Tgf{beta}I, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGF{beta} may be used to advantage in cancer therapy.

  14. Alterations of expression and regulation of transforming growth factor beta in human cancer prostate cell lines.

    Science.gov (United States)

    Blanchère, M; Saunier, E; Mestayer, C; Broshuis, M; Mowszowicz, I

    2002-11-01

    TGF beta can promote and/or suppress prostate tumor growth through multiple and opposing actions. Alterations of its expression, secretion, regulation or of the sensitivity of target cells can lead to a favorable environment for tumor development. To gain a better insight in TGF beta function during cancer progression, we have used different cultured human prostate cells: preneoplastic PNT2 cells, the androgen-dependent LNCaP and the androgen-independent PC3 and DU145 prostate cancer cell lines. We have studied by specific ELISA assays in conditioned media (CM), the secretion of TGF beta 1 and TGF beta 2 in basal conditions and after hormonal treatment (DHT or E2) and the expression of TGF beta 1 mRNA by Northern blot. We have also compared the effect of fibroblast CM on TGF beta secretion by the different cell types. Compared to PNT2 cells, cancer cell lines secrete lower levels of active TGF beta which are not increased in the presence of fibroblast CM. LNCaP cells respond to androgen or estrogen treatment by a 10-fold increase of active TGF beta secretion while PC3 and DU145 are unresponsive. In conclusion, prostate cancer cell lines have lost part of their ability to secrete and activate TGF beta, and to regulate this secretion through stromal-epithelial interactions. Androgen-sensitive cancer cells may compensate this loss by hormonal regulation.

  15. Novel inhibitors of 17beta-hydroxysteroid dehydrogenase type 1: templates for design.

    Science.gov (United States)

    Allan, Gillian M; Vicker, Nigel; Lawrence, Harshani R; Tutill, Helena J; Day, Joanna M; Huchet, Marion; Ferrandis, Eric; Reed, Michael J; Purohit, Atul; Potter, Barry V L

    2008-04-15

    The 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyze the interconversion between the oxidized and reduced forms of androgens and estrogens at the 17 position. The 17beta-HSD type 1 enzyme (17beta-HSD1) catalyzes the reduction of estrone (E1) to estradiol and is expressed in malignant breast cells. Inhibitors of this enzyme thus have potential as treatments for hormone dependent breast cancer. Syntheses and biological evaluation of novel non-steroidal inhibitors designed to mimic the E1 template are reported using information from potent steroidal inhibitors. Of the templates investigated biphenyl ethanone was promising and led to inhibitors with IC(50) values in the low micromolar range.

  16. Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations.

    Science.gov (United States)

    Prud'homme, Gérald J

    2007-11-01

    Transforming growth factor beta (TGF-beta) is a highly pleiotropic cytokine that plays an important role in wound healing, angiogenesis, immunoregulation and cancer. The cells of the immune system produce the TGF-beta1 isoform, which exerts powerful anti-inflammatory functions, and is a master regulator of the immune response. However, this is context dependent, because TGF-beta can contribute to the differentiation of both regulatory (suppressive) T cells (Tr cells) and inflammatory Th17 cells. While TGF-beta might be underproduced in some autoimmune diseases, it is overproduced in many pathological conditions. This includes pulmonary fibrosis, glomerulosclerosis, renal interstitial fibrosis, cirrhosis, Crohn's disease, cardiomyopathy, scleroderma and chronic graft-vs-host disease. In neoplastic disease, TGF-beta suppresses the progression of early lesions, but later this effect is lost and cancer cells produce TGF-beta, which then promotes metastasis. This cytokine also contributes to the formation of the tumor stroma, angiogenesis and immunosuppression. In view of this, several approaches are being studied to inhibit TGF-beta activity, including neutralizing antibodies, soluble receptors, receptor kinase antagonist drugs, antisense reagents and a number of less specific drugs such as angiotensin II antagonists and tranilast. It might be assumed that TGF-beta blockade would result in severe inflammatory disease, but this has not been the case, presumably because the neutralization is only partial. In contrast, the systemic administration of TGF-beta for therapeutic purposes is limited by toxicity and safety concerns, but local administration appears feasible, especially to promote wound healing. Immunotherapy or vaccination stimulating TGF-beta production and/or Tr differentiation might be applied to the treatment of autoimmune diseases. The benefits of new therapies targeting TGF-beta are under intense investigation.

  17. Regulation of pancreatic islet beta-cell mass by growth factor and hormone signaling.

    Science.gov (United States)

    Huang, Yao; Chang, Yongchang

    2014-01-01

    Dysfunction and destruction of pancreatic islet beta cells is a hallmark of diabetes. Better understanding of cellular signals in beta cells will allow development of therapeutic strategies for diabetes, such as preservation and expansion of beta-cell mass and improvement of beta-cell function. During the past several decades, the number of studies analyzing the molecular mechanisms, including growth factor/hormone signaling pathways that impact islet beta-cell mass and function, has increased exponentially. Notably, somatolactogenic hormones including growth hormone (GH), prolactin (PRL), and insulin-like growth factor-1 (IGF-1) and their receptors (GHR, PRLR, and IGF-1R) are critically involved in beta-cell growth, survival, differentiation, and insulin secretion. In this chapter, we focus more narrowly on GH, PRL, and IGF-1 signaling, and GH-IGF-1 cross talk. We also discuss how these signaling aspects contribute to the regulation of beta-cell proliferation and apoptosis. In particular, our novel findings of GH-induced formation of GHR-JAK2-IGF-1R protein complex and synergistic effects of GH and IGF-1 on beta-cell signaling, proliferation, and antiapoptosis lead to a new concept that IGF-1R may serve as a proximal component of GH/GHR signaling.

  18. Intragraft platelet-derived growth factor-alpha and transforming growth factor-beta1 during the development of accelerated graft vascular disease after clinical heart transplantation

    NARCIS (Netherlands)

    de Groot-Kruseman, H A; Baan, C C; Mol, W M; Niesters, H G; Maat, A P; Balk, A H; Weimar, W

    1999-01-01

    This study was to determine whether the growth factors platelet-derived growth factor-alpha (PDGF-alpha) and transforming growth factor-beta1 (TGF-beta1) contribute to the development of graft vascular disease (GVD) after clinical heart transplantation. We analysed intragraft PDGF-alpha and TGF-beta

  19. Transforming growth factor-beta 1 does not relate to hypertension in pre-eclampsia.

    Science.gov (United States)

    Hennessy, A; Orange, S; Willis, N; Painter, D M; Child, A; Horvath, J S

    2002-11-01

    1. Pre-eclampsia is a human disease of pregnancy characterized by high blood pressure, proteinuria and end-organ damage, if severe. Pre-eclampsia is thought to be related to changes in early placental development, with the formation of a shallower than normal placental bed. 2. Transforming growth factor (TGF)-beta1 is a multifunctional fibrogenic growth factor involved in immune regulation that is elevated in some populations with a high risk of hypertensive end-organ disease related to increases in endothelin release. Transforming growth factor-beta1 is also an important factor in placental implantation. Alterations in TGF-beta1 may be related to abnormal placental development in early pregnancy and, thus, are a candidate for the development of hypertension in pre-eclampsia. 3. The aim of the present study was to examine the placental distribution and serum concentration of TGF-beta1 in patients with pre-eclampsia compared with normal pregnancy. 4. Patients with pre-eclampsia (n = 12) were compared with patients with normal pregnancy (n = 14). Transforming growth factor-beta1 was determined by TGF-beta1 Max ELISA (Promega, Madsion, WI, USA) after serum dilution (1/150) and acid activation. Placental distribution was determined by immunostaining with TGF-beta1 (Santa Cruz, Santa Cruz, CA, USA; 20 ng/mL) and the villi and decidual trophoblast were scored for intensity and extent of staining. 5. Patients with pre-eclampsia had a mean gestational age of 36 weeks, whereas those with a normal pregnancy had a mean gestational age of 39.0 +/- 0.4 weeks. There was no difference in TGF-beta1 concentration between the two groups (mean (+/-SEM) 27.1 +/- 1.0 vs 26.4 +/- 0.7 pg/mL for normal pregnancy and pre-eclampsia, respectively; P = 0.73, Mann-Whitney U-test). There was no correlation between systolic or diastolic blood pressure and TGF-beta1 concentration (regression analysis P = 0.4 and 0.2). Immunostaining was absent in the villous trophoblast cells and endovascular and

  20. 11Beta-HSD type 1 expression in human adipose tissue: impact of gender, obesity, and fat localization

    DEFF Research Database (Denmark)

    Paulsen, Søren Kildeberg; Pedersen, Steen Bønløkke; Fisker, Sanne

    2007-01-01

    OBJECTIVE: Pre-receptor amplification of glucocorticoids is, in part, determined by the isoenzymes 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 and type 2, interconverting inert cortisone and active cortisol. Increased tissue activity of cortisol may play a part in features of the meta......OBJECTIVE: Pre-receptor amplification of glucocorticoids is, in part, determined by the isoenzymes 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 and type 2, interconverting inert cortisone and active cortisol. Increased tissue activity of cortisol may play a part in features...

  1. Superficial zone protein (lubricin) in the different tissue compartments of the knee joint: modulation by transforming growth factor beta 1 and interleukin-1 beta.

    Science.gov (United States)

    Lee, Sang Yang; Niikura, Takahiro; Reddi, A Hari

    2008-11-01

    Superficial-zone protein (SZP), also known as lubricin, is a key mediator of boundary lubrication and plays an important role in the functional integrity of the diarthrodial joint. The aim of this investigation was to examine the role of transforming growth factor beta (TGF-beta) and interleukin-1 beta (IL-1beta) on the expression of SZP in various compartments of the bovine knee joint: the superficial zone of articular cartilage, synovium, meniscus, and anterior and posterior cruciate ligaments. The effects of TGF-beta1 and IL-1beta on SZP expression were examined in explants and cells from the different tissue compartments. TGF-beta1 up-regulated the expression of SZP in cultured explants, but IL-1beta down-regulated it. Quantitative analysis of secreted proteins in the medium of the cells demonstrated significant stimulation by TGF-beta1 and inhibition by IL1-beta of the accumulation of SZP protein in all four tissues. Real-time polymerase chain reaction analysis revealed that TGF-beta1 significantly up-regulated SZP expression and that IL-1beta down-regulated it. These results revealed the modulation of SZP expression in various compartments of the knee joint by TGF-beta1 and IL-1beta. In addition, SZP was found to be immunolocalized at the surface layer of cells in histological sections of all four tissue compartments. Collectively, results of the current study on regulation of SZP expression by TGF-beta and IL-1 help provide new insights, into tissue engineering strategies to repair and regenerate the different tissue compartments in the articular joint with optimal lubrication.

  2. Transforming growth factor-beta pathway: role in pancreas development and pancreatic disease.

    Science.gov (United States)

    Rane, Sushil G; Lee, Ji-Hyeon; Lin, Huei-Min

    2006-01-01

    The pancreas is a complex exocrine and endocrine gland that controls many homeostatic functions. The exocrine pancreas produces and secretes digestive enzymes, whereas, the endocrine pancreas produces four distinct hormones, chief among them being the glucose regulating hormone-insulin. Diabetes, pancreatitis and pancreatic cancer are some of the main afflictions that result from pancreas dysfunction. Transforming growth factor-beta (TGF-beta) proteins are central regulators of pancreas cell function, and have key roles in pancreas development and pancreatic disease. Since expression levels and kinase activities of components of TGF-beta signaling are aberrantly altered in diseases of the pancreas, modulating the activity of TGF-beta provides a unique and rational opportunity for therapeutic intervention. Although TGF-beta still remains elusive in terms of our understanding of its multifunctional modes of action, research is moving closer to the design of approaches directed toward modulating its activities for therapeutic benefit.

  3. Hexose-6-phosphate dehydrogenase modulates 11beta-hydroxysteroid dehydrogenase type 1-dependent metabolism of 7-keto- and 7beta-hydroxy-neurosteroids.

    Directory of Open Access Journals (Sweden)

    Lyubomir G Nashev

    Full Text Available BACKGROUND: The role of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1 in the regulation of energy metabolism and immune system by locally reactivating glucocorticoids has been extensively studied. Experiments determining initial rates of enzyme activity revealed that 11beta-HSD1 can catalyze both the reductase and the dehydrogenase reaction in cell lysates, whereas it predominantly catalyzes the reduction of cortisone to cortisol in intact cells that also express hexose-6-phosphate dehydrogenase (H6PDH, which provides cofactor NADPH. Besides its role in glucocorticoid metabolism, there is evidence that 11beta-HSD1 is involved in the metabolism of 7-keto- and 7-hydroxy-steroids; however the impact of H6PDH on this alternative function of 11beta-HSD1 has not been assessed. METHODOLOGY: We investigated the 11beta-HSD1-dependent metabolism of the neurosteroids 7-keto-, 7alpha-hydroxy- and 7beta-hydroxy-dehydroepiandrosterone (DHEA and 7-keto- and 7beta-hydroxy-pregnenolone, respectively, in the absence or presence of H6PDH in intact cells. 3D-structural modeling was applied to study the binding of ligands in 11beta-HSD1. PRINCIPAL FINDINGS: We demonstrated that 11beta-HSD1 functions in a reversible way and efficiently catalyzed the interconversion of these 7-keto- and 7-hydroxy-neurosteroids in intact cells. In the presence of H6PDH, 11beta-HSD1 predominantly converted 7-keto-DHEA and 7-ketopregnenolone into their corresponding 7beta-hydroxy metabolites, indicating a role for H6PDH and 11beta-HSD1 in the local generation of 7beta-hydroxy-neurosteroids. 3D-structural modeling offered an explanation for the preferred formation of 7beta-hydroxy-neurosteroids. CONCLUSIONS: Our results from experiments determining the steady state concentrations of glucocorticoids or 7-oxygenated neurosteroids suggested that the equilibrium between cortisone and cortisol and between 7-keto- and 7-hydroxy-neurosteroids is regulated by 11beta-HSD1 and greatly

  4. Anti-transforming growth factor-beta monoclonal antibodies prevent lung injury in hemorrhaged mice.

    Science.gov (United States)

    Shenkar, R; Coulson, W F; Abraham, E

    1994-09-01

    Acute lung injury, characterized as the adult respiratory distress syndrome (ARDS), is a common clinical occurrence following blood loss and injury. We previously found increased levels of transforming growth factor (TGF)-beta 1 mRNA in murine intraparenchymal mononuclear cells and in alveolar macrophages within 1 h after hemorrhage. Because TGF-beta has potent proinflammatory and immunoregulatory properties, we investigated the effect of blocking TGF-beta with mAb on hemorrhage-induced pathology, cytokine mRNA levels in lungs, as well as survival from pneumonia. Mice treated with anti-TGF-beta mAb showed normal pulmonary histology 3 days after hemorrhage and resuscitation in contrast to the mononuclear and neutrophil infiltrates, intraalveolar hemorrhage, and interstitial edema found in hemorrhaged mice either treated with control antibody or not treated with any antibody. Decreased mRNA levels for IL-1 beta, TNF-alpha, IL-6, IL-10, and IFN-gamma as compared with untreated, hemorrhaged controls were present in intraparenchymal pulmonary mononuclear cells following therapy with anti-TGF-beta. In contrast, therapy with anti-TGF-beta increased mRNA levels for IL-1 beta and TNF-alpha in alveolar macrophages and for TGF-beta in peripheral blood mononuclear cells collected 3 days after hemorrhage. Administration of anti-TGF-beta to hemorrhaged mice did not correct the enhanced susceptibility to Pseudomonas aeruginosa pneumonia that exists after hemorrhage. These results suggest that TGF-beta has an important role in hemorrhage-induced acute lung injury, but does not contribute to the post-hemorrhage depression in pulmonary antibacterial response.

  5. Transcription factor Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in rodent models.

    Science.gov (United States)

    Chen, Fang; Sha, Min; Wang, Yanyang; Wu, Tijun; Shan, Wei; Liu, Jia; Zhou, Wenbo; Zhu, Yunxia; Sun, Yujie; Shi, Yuguang; Bleich, David; Han, Xiao

    2016-02-01

    'Glucotoxicity' is a term used to convey the negative effect of hyperglycaemia on beta cell function; however, the underlying molecular mechanisms that impair insulin secretion and gene expression are poorly defined. Our objective was to define the role of transcription factor v-ets avian erythroblastosis virus E26 oncogene homologue 1 (Ets-1) in beta cell glucotoxicity. Primary islets and Min6 cells were exposed to high glucose and Ets-1 expression was measured. Recombinant adenovirus and transgenic mice were used to upregulate Ets-1 expression in beta cells in vitro and in vivo, and insulin secretion was assessed. The binding activity of H3/H4 histone on the Ets-1 promoter, and that of forkhead box (FOX)A2, FOXO1 and Ets-1 on the Pdx-1 promoter was measured by chromatin immunoprecipitation and quantitative real-time PCR assay. High glucose induced upregulation of Ets-1 expression and hyperacetylation of histone H3 and H4 at the Ets-1 gene promoter in beta cells. Ets-1 overexpression dramatically suppressed insulin secretion and biosynthesis both in vivo and in vitro. Besides, Ets-1 overexpression increased the activity of FOXO1 but decreased that of FOXA2 binding to the pancreatic and duodenal homeobox 1 (PDX-1) homology region 2 (PH2), resulting in inhibition of Pdx-1 promoter activity and downregulation of PDX-1 expression and activity. In addition, high glucose promoted the interaction of Ets-1 and FOXO1, and the activity of Ets-1 binding to the Pdx-1 promoter. Importantly, PDX-1 overexpression reversed the defect in pancreatic beta cells induced by Ets-1 excess, while knockdown of Ets-1 prevented hyperglycaemia-induced dysfunction of pancreatic beta cells. Our observations suggest that Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in type 2 diabetes.

  6. Potassium inhibits dietary salt-induced transforming growth factor-beta production.

    Science.gov (United States)

    Ying, Wei-Zhong; Aaron, Kristal; Wang, Pei-Xuan; Sanders, Paul W

    2009-11-01

    Human and animal studies demonstrate an untoward effect of excess dietary NaCl (salt) intake on cardiovascular function and life span. The endothelium in particular augments the production of transforming growth factor (TGF)-beta, a fibrogenic growth factor, in response to excess dietary salt intake. This study explored the initiating mechanism that regulates salt-induced endothelial cell production of TGF-beta. Male Sprague-Dawley rats were given diets containing different amounts of NaCl and potassium for 4 days. A bioassay for TGF-beta demonstrated increased (35.2%) amounts of active TGF-beta in the medium of aortic ring segments from rats on the high-salt diet compared with rats maintained on a 0.3% NaCl diet. Inhibition of the large-conductance, calcium-activated potassium channel inhibited dietary salt-induced vascular production of TGF-beta but did not affect production of TGF-beta by ring segments from rats on the low-salt diet. Immunohistochemical and Western analyses demonstrated the alpha subunit of the calcium-activated potassium channel in endothelial cells. Increasing medium [K+] inhibited production of dietary salt-induced vascular production levels of total and active TGF-beta but did not alter TGF-beta production by aortic rings from rats on the 0.3% NaCl diet. Increasing dietary potassium content decreased urinary active TGF-beta in animals receiving the high-salt diet but did not change urinary active TGF-beta in animals receiving the low-salt diet. The findings demonstrated an interesting interaction between the dietary intake of potassium and excess NaCl and further showed the fundamental role of the endothelial calcium-activated potassium channel in the vascular response to excess salt intake.

  7. Molecular cloning and characterization of mutant and wild-type human. beta. -actin genes

    Energy Technology Data Exchange (ETDEWEB)

    Leavitt, J.; Gunning, P.; Porreca, P.; Ng, S.Y.; Lin, C.H.; Kedes, L.

    1984-10-01

    There are more than 20 ..beta..-actin-specific sequences in the human genome, many of which are pseudogenes. To facilitate the isolation of potentially functional ..beta..-actin genes, they used the new method of B. Seed for selecting genomic clones by homologous recombination. A derivative of the ..pi..VX miniplasmid, ..pi..AN7..beta..1, was constructed by insertion of the 600-base-pair 3' untranslated region of the ..beta..-actin mRNA expressed in human fibroblasts. Five clones containing ..beta..-actin sequences were selected from an amplified human fetal gene library by homologous recombination between library phage and the miniplasmid. One of these clones contained a complete ..beta..-actin gene with a coding sequence identical to that determined for the mRNA of human fibroblasts. A DNA fragment consisting of mostly intervening sequences from this gene was then use to identify 13 independent recombinant copies of the analogous gene from two specially constructed gene libraries, each containing one of the two types of mutant ..beta..-actin genes found in a line of neoplastic human fibroblasts. The amino acid and nucleotide sequences encoded by the unmutated gene predict that a guanine-to-adenine transition is responsible for the glycine-to-aspartic acid mutation at codon 244 and would also result in the loss of a HaeIII site. Detection of this HaeIII polymorphism among the fibroblast-derived closed verified the identity of the ..beta..-actin gene expressed in human fibroblasts.

  8. Trefoil factor 3 stimulates human and rodent pancreatic islet beta-cell replication with retention of function.

    Science.gov (United States)

    Fueger, Patrick T; Schisler, Jonathan C; Lu, Danhong; Babu, Daniella A; Mirmira, Raghavendra G; Newgard, Christopher B; Hohmeier, Hans E

    2008-05-01

    Both major forms of diabetes involve a decline in beta-cell mass, mediated by autoimmune destruction of insulin-producing cells in type 1 diabetes and by increased rates of apoptosis secondary to metabolic stress in type 2 diabetes. Methods for controlled expansion of beta-cell mass are currently not available but would have great potential utility for treatment of these diseases. In the current study, we demonstrate that overexpression of trefoil factor 3 (TFF3) in rat pancreatic islets results in a 4- to 5-fold increase in [(3)H]thymidine incorporation, with full retention of glucose-stimulated insulin secretion. This increase was almost exclusively due to stimulation of beta-cell replication, as demonstrated by studies of bromodeoxyuridine incorporation and co-immunofluorescence analysis with anti-bromodeoxyuridine and antiinsulin or antiglucagon antibodies. The proliferative effect of TFF3 required the presence of serum or 0.5 ng/ml epidermal growth factor. The ability of TFF3 overexpression to stimulate proliferation of rat islets in serum was abolished by the addition of epidermal growth factor receptor antagonist AG1478. Furthermore, TFF3-induced increases in [3H]thymidine incorporation in rat islets cultured in serum was blocked by overexpression of a dominant-negative Akt protein or treatment with triciribine, an Akt inhibitor. Finally, overexpression of TFF3 also caused a doubling of [3H]thymidine incorporation in human islets. In summary, our findings reveal a novel TFF3-mediated pathway for stimulation of beta-cell replication that could ultimately be exploited for expansion or preservation of islet beta-cell mass.

  9. Immunohistochemical localization of transforming growth factor-beta 1 in the lungs of patients with systemic sclerosis, cryptogenic fibrosing alveolitis and other lung disorders.

    Science.gov (United States)

    Corrin, B; Butcher, D; McAnulty, B J; Dubois, R M; Black, C M; Laurent, G J; Harrison, N K

    1994-02-01

    To study the role of transforming growth factor-beta 1 (TGF-beta 1) in the pathogenesis of pulmonary fibrosis we have examined lung biopsies from nine patients with systemic sclerosis and interstitial lung disease, eight with 'lone' cryptogenic fibrosing alveolitis, two with cystic fibrosis, two with extrinsic allergic alveolitis, two with Langerhans' cell histiocytosis, one with lymphangioleiomyomatosis, one with giant cell interstitial pneumonia, and one adenocarcinoma of the lung. In cryptogenic fibrosing alveolitis, both 'lone' and associated with systemic sclerosis alveolar macrophages, bronchial epithelium and hyperplastic type II pneumonocytes expressed intracellular TGF-beta 1. Extracellular TGF-beta 1 was found in the fibrous tissue immediately beneath the bronchial and hyperplastic alveolar epithelium. In normal lung, however, the alveolar epithelium and alveolar interstitium were negative for both forms of TGF-beta 1. There was strong expression of TGF-beta 1 in hyperplastic mesothelium and its underlying connective tissue and in Langerhans' cells in the two cases of histiocytosis. In the organizing pneumonia in cystic fibrosis, the intraalveolar buds of granulation tissue reacted strongly for the extracellular form of TGF-beta 1 and the overlying hyperplastic epithelium expressed the intracellular form. In lymphangioleiomyomatosis, the aberrant smooth muscle cells strongly expressed intracellular TGF-beta 1 and the extracellular form was expressed in the adjacent connective tissue. In giant cell interstitial pneumonia, the numerous alveolar macrophage including the multinucleate forms, expressed intracellular TGF-beta 1, as did the hyperplastic alveolar epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Endoglin negatively regulates transforming growth factor beta1-induced profibrotic responses in intestinal fibroblasts.

    LENUS (Irish Health Repository)

    Burke, J P

    2012-02-01

    BACKGROUND: Fibroblasts isolated from strictures in Crohn\\'s disease (CD) exhibit reduced responsiveness to stimulation with transforming growth factor (TGF) beta1. TGF-beta1, acting through the smad pathway, is critical to fibroblast-mediated intestinal fibrosis. The membrane glycoprotein, endoglin, is a negative regulator of TGF-beta1. METHODS: Intestinal fibroblasts were cultured from seromuscular biopsies of patients undergoing intestinal resection for CD strictures or from control patients. Endoglin expression was assessed using confocal microscopy, flow cytometry and western blot. The effect of small interfering (si) RNA-mediated knockdown and plasmid-mediated overexpression of endoglin on fibroblast responsiveness to TGF-beta1 was assessed by examining smad phosphorylation, smad binding element (SBE) promoter activity, connective tissue growth factor (CTGF) expression and ability to contract collagen. RESULTS: Crohn\\'s stricture fibroblasts expressed increased constitutive cell-surface and whole-cell endoglin relative to control cells. Endoglin co-localized with filamentous actin. Fibroblasts treated with siRNA directed against endoglin exhibited enhanced TGF-beta1-mediated smad-3 phosphorylation, and collagen contraction. Cells transfected with an endoglin plasmid did not respond to TGF-beta1 by exhibiting SBE promoter activity or producing CTGF. CONCLUSION: Fibroblasts from strictures in CD express increased constitutive endoglin. Endoglin is a negative regulator of TGF-beta1 signalling in the intestinal fibroblast, modulating smad-3 phosphorylation, SBE promoter activity, CTGF production and collagen contraction.

  11. Beta cell function and BMI in ethnically diverse children with newly diagnosed autoimmune type 1 diabetes

    Science.gov (United States)

    The objective of our study was to examine the relationship between BMI and beta-cell function at diagnosis of autoimmune type 1 diabetes (T1D) in a large group of ethnically diverse children. Cross-sectional analysis of 524 children (60.8% White, 19.5% Hispanic, 14.5% African-American, 5.2% other n...

  12. New Calculations for Phase Space Factors Involved in Double Beta Decay

    CERN Document Server

    Stoica, Sabin

    2013-01-01

    We present new results for the phase space factors involved in double beta decay for beta-beta- transitions to ground states and excited 0+1 states, for isotopes of experimental interest. The Coulomb distortion of the electron wave functions is treated by solving numerically the Dirac equation with inclusion of the finite nuclear size and electron screening effects, and using a Coulomb potential derived from a realistic proton density distribution in the daughter nucleus. Our results are compared with other results from literature, obtained in different approximations, and possible causes that can give differences are discussed.

  13. A new compound heterozygous frameshift mutation in the type II 3{beta}-hydroxysteroid dehydrogenase 3{beta}-HSD gene causes salt-wasting 3{beta}-HSD deficiency congenital adrenal hyperplasia

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, L.; Sakkal-Alkaddour, S.; Chang, Ying T.; Yang, Xiaojiang; Songya Pang [Univ. of Illinois, Chicago, IL (United States)

    1996-01-01

    We report a new compound heterozygous frameshift mutation in the type II 3{Beta}-hydroxysteroid dehydrogenase (3{beta}-HSD) gene in a Pakistanian female child with the salt-wasting form of 3{Beta}-HSD deficiency congenital adrenal hyperplasia. The etiology for her congenital adrenal hyperplasia was not defined. Although the family history suggested possible 3{beta}-HSd deficiency disorder, suppressed adrenal function caused by excess glucocorticoid therapy in this child at 7 yr of age did not allow hormonal diagnosis. To confirm 3{beta}-HSD deficiency, we sequenced the type II 3{beta}-HSD gene in the patient, her family, and the parents of her deceased paternal cousins. The type II 3{beta}-HSD gene region of a putative promotor, exons I, II, III, and IV, and exon-intron boundaries were amplified by PCR and sequenced in all subjects. The DNA sequence of the child revealed a single nucleotide deletion at codon 318 [ACA(Thr){r_arrow}AA] in exon IV in one allele, and two nucleotide deletions at codon 273 [AAA(Lys){r_arrow}A] in exon IV in the other allele. The remaining gene sequences were normal. The codon 318 mutation was found in one allele from the father, brother, and parents of the deceased paternal cousins. The codon 273 mutation was found in one allele of the mother and a sister. These findings confirmed inherited 3{beta}-HSD deficiency in the child caused by the compound heterozygous type II 3{beta}-HSD gene mutation. Both codons at codons 279 and 367, respectively, are predicted to result in an altered and truncated type II 3{beta}-HSD protein, thereby causing salt-wasting 3{beta}-HSD deficiency in the patient. 21 refs., 2 figs., 1 tab.

  14. Polyclonal antibody localizes glia maturation factor beta-like immunoreactivity in neurons and glia.

    Science.gov (United States)

    Wang, B R; Zaheer, A; Lim, R

    1992-09-18

    A rabbit polyclonal antibody (91-01) was raised against recombinant human glia maturation factor beta (r-hGMF-beta). The antibody did not cross-react with a number of other growth factors on ELISA test. When compared with the monoclonal antibody G2-09 previously obtained, 91-01 immunoblotted the same protein band in rat brain extract. However, unlike G2-09 which immunostained only astrocytes and Bergmann glia, 91-01 stained neurons as well. Many but not all neurons in the central and peripheral nervous system were positive for GMF-beta. The larger cell population stained by the polyclonal antibody was most likely due to its increased sensitivity, although other explanations are possible. The presence of GMF-beta-like immunoreactivity in both neurons and glia raises the possibility of a wider range of cell-cell interaction than was previously considered.

  15. Evaluation of susceptibility patterns and BRO beta-lactamase types among clinical isolates of Moraxella catarrhalis.

    Science.gov (United States)

    Esel, D; Ay-Altintop, Y; Yagmur, G; Gokahmetoglu, S; Sumerkan, B

    2007-10-01

    The aims of this study were to detect BRO beta-lactamase types and to evaluate any correlation with the susceptibility patterns of 90 clinical isolates of Moraxella catarrhalis. The overall prevalences of the bro-1 and bro-2 genes were 78% and 12%, respectively. Penicillin G MICs for BRO-1+ isolates were significantly higher than those for BRO-2+ isolates. All the isolates were susceptible to amoxycillin-clavulanate, levofloxacin and cefixime. Resistance to clarithromycin, tetracycline and trimethoprim-sulphamethoxazole was 1.1%, 2.2% and 1.1%, respectively. One-step, length-based PCR was an efficient method to screen for BRO beta-lactamase genes.

  16. Identification of Tctex2 beta, a novel dynein light chain family member that interacts with different transforming growth factor-beta receptors

    NARCIS (Netherlands)

    Meng, QingJun; Lux, Andreas; Holloschi, Andreas; Li, Jian; Hughes, John M. X.; Foerg, Tassilo; McCarthy, John E. G.; Heagerty, Anthony M.; Kioschis, Petra; Hafner, Mathias; Garland, John M.

    2006-01-01

    Endoglin is a membrane-inserted protein that is preferentially synthesized in angiogenic vascular endothelial and smooth muscle cells. Endoglin associates with members of the transforming growth factor-beta(TGF-beta) receptor family and has been identified as the gene involved in hereditary hemorrha

  17. Factors That Affect the Degree of Twist in beta-Sheet Structures : A Molecular Dynamics Simulation Study of a Cross-beta Filament of the GNNQQNY Peptide

    NARCIS (Netherlands)

    Periole, Xavier; Rampioni, Aldo; Vendruscolo, Michele; Mark, Alan E.

    2009-01-01

    By exploiting the recent availability of the crystal structure of a cross-beta filament of the GNNQQNY peptide fragment of the yeast prion protein Sup35, possible factors affecting the twisting of beta-sheets structures have been analyzed. The advantage of this system is that it is composed entirely

  18. Adeno-Associated Vector mediated gene transfer of Transforming Growth Factor-beta1 to normal and osteoarthritic human chondrocytes stimulates cartilage anabolism

    Directory of Open Access Journals (Sweden)

    Ulrich-Vinther M.

    2005-11-01

    Full Text Available The objective of the present study was to investigate whether cartilage anabolism in human primary osteoarthritic chondrocytes could be improved by adeno-associated virus (AAV vector-mediated gene transduction of transforming growth factor TGF-beta1 (TGF-beta1. A bi-cistronic AAV-TGF-beta1-IRES-eGFP (AAV-TGF-beta1 vector was generated and used for transduction of a normal human articular chondrocyte cell line (tsT/AC62 and primary human osteoarthritic articular chondrocytes harvested from 8 patients receiving total knee joint arthroplasty. Transduction efficiency was detected by fluorescent microscopy for gene expression of enhanced green fluorescent protein (eGFP. TGF-beta1 synthesis was determined by ELISA. To assess the influence of TGF-beta1 gene therapy on chondrocyte cartilage metabolism, mRNA expressions of type II collagen, aggrecan, and matrix metalloproteinase 3 (MMP-3 were determined by quantitative real-time PCR. AAV-TGF-beta1 transduction resulted in increased synthesis of TGF-beta1 in both osteoarthritic chondrocytes and the normal articular chondrocyte cell line. The expression levels of the transduced genes were correlated to "multiplicity of infection" (MOI and post-infectious time. In both osteoarthritic chondrocytes and the normal articular chondrocyte cell line, AAV-TGF-beta1 treatment increased mRNA expression of both type II collagen and aggrecan, but decreased MMP-3 mRNA expression. Osteoarthritic chondrocytes and the normal articular chondrocyte cell line could be transduced with equal efficiencies. In conclusion, it was demonstrated that AAV-TGF-beta1 gene transfer stimulates cartilage anabolism and decreases expression of enzymes responsible for cartilage degradation in human osteoarthritic chondrocytes. The results indicate that the AAV vector is an efficient mediator of growth factors to human articular chondrocytes, and that it might be useful in future chondrocyte gene therapy.

  19. The Trp64Arg amino acid polymorphism of the beta3-adrenergic receptor gene does not contribute to the genetic susceptibility of diabetic microvascular complications in Caucasian type 1 diabetic patients

    DEFF Research Database (Denmark)

    Tarnow, L; Urhammer, S A; Mottlau, B

    1999-01-01

    OBJECTIVE: The beta3-adrenergic receptor is involved in regulation of microvascular blood flow. A missense mutation (Trp64Arg) in the beta3-adrenergic receptor gene has been suggested as a risk factor for proliferative retinopathy in Japanese type 2 diabetic patients. The aim of the present study...

  20. Growth factor expression in degenerated intervertebral disc tissue. An immunohistochemical analysis of transforming growth factor beta, fibroblast growth factor and platelet-derived growth factor.

    Science.gov (United States)

    Tolonen, Jukka; Grönblad, Mats; Vanharanta, Heikki; Virri, Johanna; Guyer, Richard D; Rytömaa, Tapio; Karaharju, Erkki O

    2006-05-01

    Degenerated intervertebral disc has lost its normal architecture, and there are changes both in the nuclear and annular parts of the disc. Changes in cell shape, especially in the annulus fibrosus, have been reported. During degeneration the cells become more rounded, chondrocyte-like, whereas in the normal condition annular cells are more spindle shaped. These chondrocyte-like cells, often forming clusters, affect extracellular matrix turnover. In previous studies transforming growth factor beta (TGFbeta) -1 and -2, basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) have been highlighted in herniated intervertebral disc tissue. In the present study the same growth factors are analysed immunohistochemically in degenerated intervertebral disc tissue. Disc material was obtained from 16 discs operated for painful degenerative disc disease. Discs were classified according to the Dallas Discogram Description. Different disc regions were analysed in parallel. As normal control disc tissue material from eight organ donors was used. Polyclonal antibodies against different growth factors and TGFbeta receptor type II were used, and the immunoreaction was detected by the avidin biotin complex method. All studied degenerated discs showed immunoreactivity for TGFbeta receptor type II and bFGF. Fifteen of 16 discs were immunopositive for TGFbeta-1 and -2, respectively, and none showed immunoreaction for PDGF. Immunopositivity was located in blood vessels and in disc cells. In the nucleus pulposus the immunoreaction was located almost exclusively in chondrocyte-like disc cells, whereas in the annular region this reaction was either in chondrocyte-like disc cells, often forming clusters, or in fibroblast-like disc cells. Chondrocyte-like disc cells were especially prevalent in the posterior disrupted area. In the anterior area of the annulus fibrosus the distribution was more even between these two cell types. bFGF was expressed in the anterior annulus

  1. Pulsational mode-typing in line profile variables. I - Four Beta Cephei stars

    Science.gov (United States)

    Campos, A. J.; Smith, M. A.

    1980-01-01

    The detailed variations of line profiles in the Beta Cephei-type variable stars Gamma Pegasi, Beta Cephei, Delta Ceti and Sigma Scorpii are modeled throughout their pulsation cycles in order to classify the dominant pulsation mode as radial or nonradial. High-dispersion Reticon observations of the variables were obtained for the Si III line at 4567 A, and line profiles broadened by radial or nonradial pulsations, rotation and radial-tangential macroturbulence were calculated based on a model atmosphere. It is found that only a radial pulsation mode can reproduce the radial velocity amplitude, changes in line asymmetry and uniform line width observed in all four stars. Results are in agreement with the color-to-light arguments of Stamford and Watson (1978), and suggest that radial pulsation plays the dominant role in the observed variations in most Beta Cephei stars. Evidence for shocks or moving shells is also found in visual line data for Sigma Scorpii and an ultraviolet line of Beta Cephei, together with evidence of smooth, secular period changes in Beta Cephei and Delta Ceti.

  2. 11Beta-HSD type 1 expression in human adipose tissue: impact of gender, obesity, and fat localization

    DEFF Research Database (Denmark)

    Paulsen, Søren Kildeberg; Pedersen, Steen Bønløkke; Fisker, Sanne

    2007-01-01

    OBJECTIVE: Pre-receptor amplification of glucocorticoids is, in part, determined by the isoenzymes 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 and type 2, interconverting inert cortisone and active cortisol. Increased tissue activity of cortisol may play a part in features of the meta...... relative risk of cardiovascular disease in women suffering from the metabolic syndrome. Udgivelsesdato: 2007-Aug...

  3. Tumor necrosis factor beta and ultraviolet radiation are potent regulators of human keratinocyte ICAM-1 expression

    Energy Technology Data Exchange (ETDEWEB)

    Krutmann, J.; Koeck, A.S.; Schauer, E.; Parlow, F.; Moeller, A.K.; Kapp, A.; Foerster, E.S.; Schoepf, E.L.; Luger, T.A. (Univ. of Freiburg (Germany, F.R.))

    1990-08-01

    Intercellular adhesion molecule-1 (ICAM-1) functions as a ligand of leukocyte function-associated antigen-1 (LFA-1), as well as a receptor for human picorna virus, and its regulation thus affects various immunologic and inflammatory reactions. The weak, constitutive ICAM-1 expression on human keratinocytes (KC) can be up-regulated by cytokines such as interferon-gamma (IFN gamma) and tumor necrosis factor alpha (TNF alpha). In order to further examine the regulation of KC ICAM-1 expression, normal human KC or epidermoid carcinoma cells (KB) were incubated with different cytokines and/or exposed to ultraviolet (UV) radiation. Subsequently, ICAM-1 expression was monitored cytofluorometrically using a monoclonal anti-ICAM-1 antibody. Stimulation of cells with recombinant human (rh) interleukin (IL) 1 alpha, rhIL-4, rhIL-5, rhIL-6, rh granulocyte/macrophage colony-stimulating factor (GM-CSF), rh interferon alpha (rhIFN alpha), and rh transforming growth factor beta (TGF beta) did not increase ICAM-1 surface expression. In contrast, rhTNF beta significantly up-regulated ICAM-1 expression in a time- and dose-dependent manner. Moreover, the combination of rhTNF beta with rhIFN gamma increased the percentage of ICAM-1-positive KC synergistically. This stimulatory effect of rhTNF beta was further confirmed by the demonstration that rhTNF beta was capable of markedly enhancing ICAM-1 mRNA expression in KC. Finally, exposure of KC in vitro to sublethal doses of UV radiation (0-100 J/m2) prior to cytokine (rhIFN tau, rhTNF alpha, rhTNF beta) stimulation inhibited ICAM-1 up-regulation in a dose-dependent fashion. These studies identify TNF beta and UV light as potent regulators of KC ICAM-1 expression, which may influence both attachment and detachment of leukocytes and possibly viruses to KC.

  4. Critical Role of Transforming Growth Factor Beta in Different Phases of Wound Healing

    Science.gov (United States)

    Pakyari, Mohammadreza; Farrokhi, Ali; Maharlooei, Mohsen Khosravi; Ghahary, Aziz

    2013-01-01

    Significance This review highlights the critical role of transforming growth factor beta (TGF-β)1–3 within different phases of wound healing, in particular, late-stage wound healing. It is also very important to identify the TGF-β1–controlling factors involved in slowing down the healing process upon wound epithelialization. Recent Advances TGF-β1, as a growth factor, is a known proponent of dermal fibrosis. Several strategies to modulate or regulate TGF's actions have been thoroughly investigated in an effort to create successful therapies. This study reviews current discourse regarding the many roles of TGF-β1 in wound healing by modulating infiltrated immune cells and the extracellular matrix. Critical Issues It is well established that TGF-β1 functions as a wound-healing promoting factor, and thereby if in excess it may lead to overhealing outcomes, such as hypertrophic scarring and keloid. Thus, the regulation of TGF-β1 in the later stages of the healing process remains as critical issue of which to better understand. Future Directions One hypothesis is that cell communication is the key to regulate later stages of wound healing. To elucidate the role of keratinocyte/fibroblast cross talk in controlling the later stages of wound healing we need to: (1) identify those keratinocyte-released factors which would function as wound-healing stop signals, (2) evaluate the functionality of these factors in controlling the outcome of the healing process, and (3) formulate topical vehicles for these antifibrogenic factors to improve or even prevent the development of hypertrophic scarring and keloids as a result of deep trauma, burn injuries, and any type of surgical incision. PMID:24527344

  5. Critical Role of Transforming Growth Factor Beta in Different Phases of Wound Healing.

    Science.gov (United States)

    Pakyari, Mohammadreza; Farrokhi, Ali; Maharlooei, Mohsen Khosravi; Ghahary, Aziz

    2013-06-01

    This review highlights the critical role of transforming growth factor beta (TGF-β)1-3 within different phases of wound healing, in particular, late-stage wound healing. It is also very important to identify the TGF-β1-controlling factors involved in slowing down the healing process upon wound epithelialization. TGF-β1, as a growth factor, is a known proponent of dermal fibrosis. Several strategies to modulate or regulate TGF's actions have been thoroughly investigated in an effort to create successful therapies. This study reviews current discourse regarding the many roles of TGF-β1 in wound healing by modulating infiltrated immune cells and the extracellular matrix. It is well established that TGF-β1 functions as a wound-healing promoting factor, and thereby if in excess it may lead to overhealing outcomes, such as hypertrophic scarring and keloid. Thus, the regulation of TGF-β1 in the later stages of the healing process remains as critical issue of which to better understand. One hypothesis is that cell communication is the key to regulate later stages of wound healing. To elucidate the role of keratinocyte/fibroblast cross talk in controlling the later stages of wound healing we need to: (1) identify those keratinocyte-released factors which would function as wound-healing stop signals, (2) evaluate the functionality of these factors in controlling the outcome of the healing process, and (3) formulate topical vehicles for these antifibrogenic factors to improve or even prevent the development of hypertrophic scarring and keloids as a result of deep trauma, burn injuries, and any type of surgical incision.

  6. Effects of ultrasound on Transforming Growth Factor-beta genes in bone cells

    Directory of Open Access Journals (Sweden)

    J Harle

    2005-12-01

    Full Text Available Therapeutic ultrasound (US is a widely used form of biophysical stimulation that is increasingly applied to promote fracture healing. Transforming growth factor-beta (TGF-beta, which is encoded by three related but different genes, is known to play a major part in bone growth and repair. However, the effects of US on the expression of the TGF-beta genes and the physical acoustic mechanisms involved in initiating changes in gene expression in vitro, are not yet known. The present study demonstrates that US had a differential effect on these TGF-beta isoforms in a human osteoblast cell line, with the highest dose eliciting the most pronounced up-regulation of both TGF-beta1 and TGF-beta3 at 1 hour after treatment and thereafter declining. In contrast, US had no effect on TGF-beta2 expression. Fluid streaming rather than thermal effects or cavitation was found to be the most likely explanation for the gene responses observed in vitro.

  7. Transforming growth factor-beta is elevated in unpasteurized cow's milk.

    Science.gov (United States)

    Peroni, Diego G; Piacentini, Giorgio L; Bodini, Alessandro; Pigozzi, Roberta; Boner, Attilio L

    2009-02-01

    Unpasteurized milk consumption was associated with less atopy prevalence. Not only microbial load but also fatty acids and cytokines such as transforming growth factor-beta(1) (TGF-beta(1)) may play a role on the effect of unpasteurized milk. Levels of TGF-beta(1) in different cow's milk samples were evaluated: we consider raw unpasteurized milk before and after boiling, commercial pasteurized and micro-filtrated cow's milk and different commercially available cow's milk formulas. TGF-beta(1) concentration in raw unpasteurized cow's milk was 642.0 +/- 52.9 pg/ml before boiling and decreased significantly after boiling (302.7 +/- 50.59 pg/ml) (p < 0.05). TGF-beta(1) concentrations were also significantly lower in commercial pasteurized milk (246.2 +/- 43.15 pg/ml) and in commercial micro-filtrated milk (213.0 +/- 31.6 pg/ml) in comparison to unpasteurized unboiled milk (p = 0.002). The levels of TGF-beta(1) in all formula samples were below the threshold of detectability for the assays. As TGF-beta(1) in the milk may contribute to the development of the immature gastrointestinal tract by influencing IgA production and oral tolerance induction, we suggest to consider not only the microbial compounds but also the cytokine patterns to explain the protective effect of unpasteurized cow's milk on allergic disorders.

  8. Salicylate decreases production of AmpC type beta-lactamases and increases susceptibility to beta-lactams in a Morganella morganii clinical isolate.

    Science.gov (United States)

    Tavío, María M; Perilli, Mariagrazia; Vila, Jordi; Becerro, Pino; Casañas, Lucía; Amicosante, Gianfranco; Jiménez de Anta, María Teresa

    2004-09-01

    The effect of salicylate, a marRAB inducer, on the resistance to beta-lactams was characterized in an AmpC beta-lactamase hyperproducer Morganella morganii clinical isolate (the M1 strain). Results were compared with those of the effect of salicylate in a wild-type M. morganii strain. Salicylate induced a decreased susceptibility to nalidixic acid, norfloxacin and tetracycline and simultaneously increased the susceptibility to beta-lactams apparently due to the repression of AmpC beta-lactamase synthesis in the M1 strain. Likewise, salicylate only repressed 46 kDa outer membrane protein expression in the wild-type strain, since the clinical isolate M1 did not express it.

  9. Homeodomain Protein Transforming Growth Factor Beta-Induced Factor 2 Like, X-Linked Function in Colon Adenocarcinoma Cells

    Science.gov (United States)

    Akbari, Abolfazl; Agah, Shahram; Heidari, Mansour; Mobini, Gholam Reza; Faghihloo, Ebrahim; Sarveazad, Arash; Mirzaei, Alireza

    2017-08-27

    Background: TGIF2LX (transforming growth factor beta-induced factor 2 like, X-linked) is a homeodomain (HD) protein that has been implicated in the negative regulation of cell signaling pathways. The aim of this study was to investigate the possible functions of TGIF2LX in colon adenocarcinoma cells. Methods: The human SW48 cell line was transfected with cDNA for the wild-type TGIF2LX gene and gene/protein over-expression was confirmed by microscopic analysis, real time RT-PCR and Western blotting techniques. In vitro cell proliferation was evaluated by MTT and BrdU assays. After developing a colon tumor model in nude mice, immunohistochemical (IHC) staining of tumor tissue was carried out for Ki-67 (proliferation) and CD34 (angiogenesis) markers. To predict potential protein partners of TGIF2LX, in-silico analysis was also conducted. Results: Obtained results showed over-expression of TGIF2LX as a potential transcription factor could inhibit either proliferation or angiogenesis (P<0.05) in colon tumors. In-silico results predicted interaction of TGIF2LX with other proteins considered important for cellular development. Conclusions: Our findings provided evidence of molecular mechanisms by which TGIF2LX could act as a tumor suppressor in colon adenocarcinoma cells. Thus, this gene may potentially be a promising option for colon cancer gene-based therapeutic strategies. Creative Commons Attribution License

  10. Efficiency calibration of a mini-orange type beta-spectrometer by the beta sup - -spectrum of sup 9 sup 0 Sr

    CERN Document Server

    Kalinnikov, V G; Ibrakhim, Y S; Lebedev, N A; Samatov, Z K; Sehrehehtehr, Z; Solnyshkin, A A

    2002-01-01

    A specific method for efficiency calibration of a mini-orange type beta-spectrometer by means of the continuous beta sup - -spectrum of sup 9 sup 0 Sr and the conversion electron spectrum of sup 2 sup 0 sup 7 Bi in the energy range from 500 to 2200 keV has been elaborated. In the experiment typical SmCo sub 5 magnets (6A and 8A) were used. An accuracy of efficiency determination was 5-10 %.

  11. Interaction of transforming growth factor-beta-1 with alpha-2-macroglobulin from normal and inflamed equine joints.

    OpenAIRE

    Coté, N; Trout, D R; Hayes, M. A.

    1998-01-01

    Binding between equine plasma alpha-2-macroglobulin (alpha 2M) and several cytokines known to participate in inflammatory reactions in other species was initially examined. Plasma was obtained from 5 horses with various abnormalities. Samples, both untreated and after reaction with methylamine, were incubated with exogenous, radiolabeled, porcine-derived transforming growth factor-beta-1 (125I-TGF-beta 1), recombinant human interleukin-1-beta (125I-IL-1 beta), and recombinant human tumor necr...

  12. Is Serum Transforming Growth Factor beta-1 Superior to Serum Creatinine for assessing Renal Failure and Renal Transplant Rejection

    OpenAIRE

    Gyanendra Kumar Sonkar, Usha; R.G. Singh

    2009-01-01

    A sustained overexpression of Transforming Growth Factor beta1 (TGF beta1), a cytokine has beenimplicated in the pathogenesis of fibrosis of kidney leading to end stage . The main aim of present studywas to find the utility of TGF beta1 and serum creatinine in differentiating chronic renal failure (CRF)from acute renal failure (ARF), renal transplant rejection (Tx Rej) and stable renal transplant (Tx Stb)and to study has attempted histopathological correlation of rejection cases with TGF beta...

  13. Beta cell response to a mixed meal in nigerian patients with type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Young Ekenechukwu E

    2012-06-01

    Full Text Available Abstract Background The pathophysiology of type2 diabetes involves both insulin resistance and poor beta cell function. Studies have been done in several populations to assess the relative importance of these mechanisms in individual patients. In our environment studies to assess beta cell function have been done with glucagon stimulation or an oral glucose tolerance test. This study was done to assess the response of the beta cell to a standardized mixed meal and its relationship with glycaemic control in patients with type2 diabetes. Methods Ninety patients with type 2 diabetes were recruited into the study. Weight, height, body mass index and waist circumference were measured. Blood samples were analysed for fasting plasma glucose (FPG and fasting C peptide (FCP and glycated haemoglobin (HbA1c. Patients were given their usual drugs for management of their diabetes and then served with a standard meal calculated to contain 50 g of carbohydrate, made up of 53 % carbohydrate, 17 % of protein and 30 % of lipids, providing 500 kcal. Blood samples 2 hours after the start of the meal were analysed for postprandial glucose (PPG and postprandial C peptide (PCP. Fasting (M0 and postprandial beta cell responsiveness (M1 were calculated. Results The mean FPG and PPG were 7.51+/− 3.39 mmol/l and 11.02+/−4.03 mmol/l respectively while the mean glycated haemoglobin (HbA1c was 9.0+/−2.5 %. The mean fasting C peptide was 1.44+/−1.80ug/ml. Many of the patients (56.7 % had low FCP levels. The mean postprandial C peptide was 4.0+/−2.8 ng/ml. There were significant correlations between M1, HbA1c and PPG (p = 0.015, 0.024, 0.001 respectively and also between M0, HbA1c, PPG and FPG (p = 0.001, 0.002, 0.001. HbA1c decreased across increasing tertiles of M0 (p  Conclusions Many of the patients had low C peptide levels with poor beta cell response to the meal. The patients had poor glycaemic control and poor beta cell function

  14. 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue and prospective changes in body weight and insulin resistance

    DEFF Research Database (Denmark)

    Koska, Juraj; de Courten, Barbora; Wake, Deborah J

    2006-01-01

    Increased mRNA and activity levels of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) in human adipose tissue (AT) are associated with obesity and insulin resistance. The aim of our study was to investigate whether 11betaHSD1 expression or activity in abdominal subcutaneous AT of non......-diabetic subjects are associated with subsequent changes in body weight and insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)]....

  15. Analytical expression for an optimised link bar mechanism for a beta-type Stirling engine

    DEFF Research Database (Denmark)

    Carlsen, Henrik; Bovin, Jonas Kabell

    2007-01-01

    The design of a mechanism for kinematic beta-type Stirling engines, where the displacer piston and the working piston share the same cylinder, is complicated. A well-known solution is the rhombic drive, but this solution depends on oil lubrication because of the gear wheels connecting the two...... mechanism is a further development of the mechanism in a previous 9 kW engine. The crank mechanism for the beta-type Stirling engine is based on two four-link straight line mechanisms pointing up and down, respectively. The mechanism pointing upwards is connected to the working piston, while the mechanism...... counter rotating crank shafts. In a hermetically sealed Stirling engine it is an advantage to avoid oil in the crank case, making the application of the rhombic drive difficult. In this paper, another crank mechanism is presented, which has been developed for a 9 kW single cylinder engine. The new crank...

  16. Phase Space Factors for Double Beta Decay: an up-date

    CERN Document Server

    Mirea, M; Stoica, S

    2014-01-01

    We give a complete, up-date list of the phase space factors (PSF) for beta-beta-, beta+beta+, EC beta+ and ECEC double beta decay (DBD) modes, in all nuclei of interest and possible transitions to final states. In calculation, the Coulomb distortion of the electron wave functions is treated by solving numerically the Dirac equation with inclusion of the finite nuclear size and electron screening effects. In addition to the previous calculations we use a Coulomb potential derived from a realistic proton density distribution in nucleus, improve the precision of the numerical routines used to solve the Dirac equations and to integrate the PSF expressions, and use recently reported Q-values. These ingredients proved to be important, leading in many cases to significant differences as compared to the present available PSF values, which are discussed as well. Accurate values of the PSF are necessary ingredients both for theorists, to improve the DBD lifetime predictions and constraint the neutrino parameters, and f...

  17. Identification of a novel human islet amyloid polypeptide beta-sheet domain and factors influencing fibrillogenesis.

    Science.gov (United States)

    Jaikaran, E T; Higham, C E; Serpell, L C; Zurdo, J; Gross, M; Clark, A; Fraser, P E

    2001-05-04

    Human islet amyloid polypeptide (hIAPP) accumulates as pancreatic amyloid in type 2 diabetes and readily forms fibrils in vitro. Investigations into the mechanism of hIAPP fibril formation have focused largely on residues 20 to 29, which are considered to comprise a primary amyloidogenic domain. In rodents, proline substitutions within this region and the subsequent beta-sheet disruption, prevents fibril formation. An additional amyloidogenic fragment within the C-terminal sequence, residues 30 to 37, has been identified recently. We have extended these observations by examining a series of overlapping peptide fragments from the human and rodent sequences. Using protein spectroscopy (CD/FTIR), electron microscopy and X-ray diffraction, a previously unrecognised amyloidogenic domain was localised within residues 8 to 20. Synthetic peptides corresponding to this region exhibited a transition from random coil to beta-sheet conformation and assembled into fibrils having a typical amyloid-like morphology. The comparable rat 8-20 sequence, which contains a single His18Arg substitution, was also capable of assembling into amyloid-like fibrils. Examination of peptide fragments corresponding to residues 1 to 13 revealed that the immediate N-terminal region is likely to have only a modulating influence on fibril formation or conformational conversion. The contributions of charged residues as they relate to the amyloid-forming 8-20 sequence were also investigated using IAPP fragments and by assessing the effects of pH and counterions. The identification of these principal amyloidogenic sequences and the effects of associated factors provide details on the IAPP aggregation pathway and structure of the peptide in its fibrillar state. Copyright 2001 Academic Press.

  18. Transforming growth factor-beta (TGF-beta) and its role in the pathogenesis of systemic sclerosis: a novel target for therapy?

    Science.gov (United States)

    Derk, Chris T

    2007-06-01

    One of the growth factors that appear to play a crucial role in the pathogenesis of systemic sclerosis is TGF-beta. The three functionally and structurally similar human isoforms of TGF-beta play important roles in embryonic development, in the regulation of tissue repair following injury and in immune responses. Systemic sclerosis fibroblasts express increased levels of TGF-beta receptors on their surface which in turn results in increased signalimg of TGF-beta induced collagen gene expression. Some of the patents and intricate pathways that mediate the stimulation of collagen gene expression by TGF-beta have recently been described and a potential inhibition of these pathways may lead to novel therapeutic targets for systemic sclerosis.

  19. An analysis of beta type Stirling engine with rhombic drive mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Shendage, D.J.; Kedare, S.B. [Department of Energy Science and Engineering, Indian Institute of Technology Bombay, Powai, Mumbai 400 076 (India); Bapat, S.L. [Department of Mechanical Engineering, Indian Institute of Technology Bombay, Powai, Mumbai 400 076 (India)

    2011-01-15

    Stirling engine system is one of the options for electrifying a remote community not serviceable by the grid, which can operate on energy input in the form of heat. Major hurdle for the wide-spread usage of rhombic drive beta type Stirling engine is complexity of the drive and requirement of tight tolerances for its proper functioning. However, if the operating and geometrical constraints of the system are accounted for, different feasible design options can be identified. In the present work, various aspects that need to be considered at different decision making stages of the design and development of a Stirling engine are addressed. The proposed design methodology can generate and evaluate a range of possible design alternatives which can speed up the decision making process and also provide a clear understanding of the system design considerations. The present work is mainly about the design methodology for beta type Stirling engine and the optimization of phase angle, considering the effect of overlapping volume between compression and expansion spaces. It is also noticed that variation of compression space volume with phase angle remains sinusoidal for any phase difference. The aim of the present work is to find a feasible solution which should lead to a design of a single cylinder, beta type Stirling engine of 1.5 kW{sub e} capacity for rural electrification. (author)

  20. Importin-beta is a GDP-to-GTP exchange factor of Ran: implications for the mechanism of nuclear import.

    Science.gov (United States)

    Lonhienne, Thierry G; Forwood, Jade K; Marfori, Mary; Robin, Gautier; Kobe, Bostjan; Carroll, Bernard J

    2009-08-21

    Ran-GTP interacts strongly with importin-beta, and this interaction promotes the release of the importin-alpha-nuclear localization signal cargo from importin-beta. Ran-GDP also interacts with importin-beta, but this interaction is 4 orders of magnitude weaker than the Ran-GTP.importin-beta interaction. Here we use the yeast complement of nuclear import proteins to show that the interaction between Ran-GDP and importin-beta promotes the dissociation of GDP from Ran. The release of GDP from the Ran-GDP-importin-beta complex stabilizes the complex, which cannot be dissociated by importin-alpha. Although Ran has a higher affinity for GDP compared with GTP, Ran in complex with importin-beta has a higher affinity for GTP. This feature is responsible for the generation of Ran-GTP from Ran-GDP by importin-beta. Ran-binding protein-1 (RanBP1) activates this reaction by forming a trimeric complex with Ran-GDP and importin-beta. Importin-alpha inhibits the GDP exchange reaction by sequestering importin-beta, whereas RanBP1 restores the GDP nucleotide exchange by importin-beta by forming a tetrameric complex with importin-beta, Ran, and importin-alpha. The exchange is also inhibited by nuclear-transport factor-2 (NTF2). We suggest a mechanism for nuclear import, additional to the established RCC1 (Ran-guanine exchange factor)-dependent pathway that incorporates these results.

  1. Smad4 and ERK2 stimulated by transforming growth factor beta1 in rhabdomyosarcoma

    Institute of Scientific and Technical Information of China (English)

    GUO Hua; ZHANG Hong-ying; WANG Shou-li; YE Lü; YANG Guang-hua; BU Hong

    2007-01-01

    Background Transforming growth factor beta (TGF-beta) plays an essential role in the regulation of normal physiologic processes of cells. TGF-beta has been shown to regulate several mitogen-a ctivated protein kinases (MAPK) pathways in several epithelial cells. However, the effects of TGF-beta on soft tissue sarcoma are seldom reported. Our previous studies suggested that there should be some other signal transduction pathways besides Smads, which are important to regulate the growth of human embryonal rhabdomyosarcoma (RMS) cells. In the present study, we examined the expression and functional relations of extracellular signal-regulated kinase 2 (ERK2) and Smad4 in human RMS tissue and a RMS cell line, RD.Methods RD cells and normal human primary skeletal myoblasts (Mb) were treated with TGF-beta1 to establish the expression profile of ERK2 at the mRNA and protein levels detected by RT-PCR and immunofluorescence.Immunohistochemistry was used to detect the expression of ERK2 and Smad4 in 50 tissue specimens of human RMS and 23 specimens of normal skeletal muscles. Follow-up of specimens was performed 6 months to 70 months later.Results RD cells and human RMS tissues showed the higher expression of ERK2 and Smad4 than the normal control,either the protein level or the mRNA level. And, exogenous TGF-beta1 stimulation can lead to higher expression of ERK2and its nuclear translocation, so TGF-beta1 can also activated MAPK (ERK2) pathway, resulting in a sustained activation of ERK2 for at least 2 hours. Immunohistochemistry analysis, however, showed that there was no correlation between ERK2 and Smad4 protein. The overexpression of ERK2 and Smad4 had no indicative effects on histological subtypes,histological grading, gender, age, and prognosis.Conclusions In RMS, signaling of TGF-beta1 from cell surface to nucleus can also be directed through the MAPK (ERK2) pathway besides the TGF-beta1/Smads pathway. The activation of ERK2 by TGF-beta1 may be Smad4independent

  2. Progestin treatment induces apoptosis and modulates transforming growth factor-beta in the uterine endometrium.

    Science.gov (United States)

    Rodriguez, Gustavo C; Rimel, B J; Watkin, William; Turbov, Jane M; Barry, Cathy; Du, Hongyan; Maxwell, George L; Cline, J M

    2008-03-01

    Epidemiologic, animal, and human data suggest that progestins are potent endometrial cancer preventive agents. In the ovarian surface epithelium, progestins have been hypothesized to confer a cancer preventive effect via apoptosis and modulation of transforming growth factor-beta (TGF-beta). Given that the ovarian epithelium and endometrium share a common embryologic origin and similar reproductive and hormonal risk factors for malignancy, we tested the hypothesis that progestins confer biological effects in the endometrium similar to those in the ovary. Postmenopausal female macaques (n = 78) were randomized into four groups to receive a diet for 36 months containing no hormone versus conjugated equine estrogen (CEE), medroxyprogesterone acetate (MPA), or CEE + MPA. The endometrium was then examined immunohistochemically for treatment-specific changes using antibodies to activated caspase-3 (for apoptosis), Ki-67 (proliferation), and the TGF-beta1, TGF-beta2, and TGF-beta3 isoforms. Percentages of caspase-positive endometrial glandular cells were 3- to 5-fold higher in CEE + MPA-treated animals compared with all others (P < 0.05). Caspase-expressing cells were six times more numerous in the endometrial stroma of animals treated with MPA alone relative to other groups (P < 0.0001). Induction of endometrial glandular cell apoptosis in the CEE + MPA-treated group was associated with a dramatic increase in expression of TGF-beta2 and TGF-beta3 in the stromal compartment of the endometrium (P < 0.0001). Progestin treatment activates chemopreventive biological effects in the endometrium that are similar to those in the ovarian surface epithelium. These data may facilitate identification of a chemopreventive approach that dramatically lessens the risk of both uterine and ovarian cancer.

  3. Interleukin-1beta induced vascular permeability is dependent on induction of endothelial tissue factor (TF) activity.

    Science.gov (United States)

    Puhlmann, Markus; Weinreich, David M; Farma, Jeffrey M; Carroll, Nancy M; Turner, Ewa M; Alexander, H Richard

    2005-09-30

    IL-1beta is a pleotropic cytokine that may mediate increased procoagulant activity and permeability in endothelial tissue during inflammatory conditions. The procoagulant effects of IL-1beta are mediated through induction of tissue factor (TF) but its alterations on vascular permeability are not well characterized. We found that IL-1beta induced a rapid and dose-dependent increase in TF activity in human umbilical vein endothelial cells (ECs) under routine culture conditions. However, IL-1beta caused a rapid and marked increase in permeability across confluent EC monolayers using a two-compartment in vitro model only in the presence of factor VIII-deficient plasma that was completely abrogated by neutralizing anti-TF antibody pre-treatment. In vitro permeability was associated with loss of EC surface expression of VE-cadherin and contraction of F-actin cytoskeletal elements that resulted in EC intercellular gap formation. These data demonstrate that IL-1beta induces marked changes in permeability across activated endothelium via a TF dependent mechanism and suggest that modulation of TF activity may represent a strategy to treat various acute and chronic inflammatory conditions mediated by this cytokine.

  4. The Influence of Stromal Transforming Growth Factor-(beta) Receptor Signaling on Mouse Mammary Neoplasia

    Science.gov (United States)

    2002-08-01

    responsiveness to TGF-BETA in the stroma effects tumor development transgenic and wild type mice were given pituitary isografts followed by zinc water and...pituitary isograft , zinc and DMBA) while only one tumor has arisen in the control group. To date, only two tumors have arisen in the transgenic mice

  5. Myofibroblasts and Transforming Growth Factor-Beta1 in Reactive Gingival Overgrowths

    Directory of Open Access Journals (Sweden)

    Apostolos Epivatianos

    2013-03-01

    Full Text Available Objectives: The aim of this study was to detect the presence of myofibroblasts and transforming growth factor-beta1 in fibrous and ossifying-fibrous epulis and their possible contribution to the collagenous connective tissue formation. The correlation between the myofibroblasts and the degree of inflammatory infiltration was also examined. Material and Methods: The presence of myofibroblasts as well as transforming growth factor-beta1 was examined in twenty cases of fibrous epulis and 22 ossifying fibrous epulis, using immunohistochemistry. Results: Myofibroblasts positive for alpha smooth muscle actin and vimentin but negative to desmin were found in 20% and 45% in fibrous epulis and ossifying fibrous epulis, respectively. Myofibroblasts were distributed in areas with and without inflammatory infiltration and their presence in inflammatory areas was not related with the degree of inflammatory infiltration. A percentage of 21 - 60% of fibroblasts and chronic inflammatory cells expressed transforming growth factor-beta1 in all cases. Conclusions: These data suggest that transforming growth factor-beta1 and myofibroblasts contribute to the formation of collagenous connective tissue in fibrous epulis and ossifying fibrous epulis. Myofibroblasts are mainly presented in ossifying fibrous epulis than in fibrous epulis. It seems to be no relationship between the presence of myofibroblasts and the degree of inflammatory infiltration of the lesions.

  6. The Disulfide Bond Pattern of Transforming Growth Factor Beta-Induced protein

    DEFF Research Database (Denmark)

    Lukassen, Marie V; Scavenius, Carsten; Thøgersen, Ida B;

    2016-01-01

    Transforming growth factor beta-induced protein (TGFBIp) is an extracellular matrix protein composed of an NH2-terminal cysteine-rich domain (CRD) annotated as an emilin (EMI) domain, and four fasciclin-1 (FAS1-1 to FAS1-4) domains. Mutations in the gene cause corneal dystrophies, a group...

  7. Delayed diagnosis of congenital adrenal hyperplasia with salt wasting due to type II 3beta-hydroxysteroid dehydrogenase deficiency

    DEFF Research Database (Denmark)

    Johannsen, Trine H; Mallet, Delphine; Dige-Petersen, Harriet

    2005-01-01

    Classical 3beta-hydroxysteroid dehydrogenase (3beta-HSD) deficiency is a rare cause of congenital adrenal hyperplasia. We report two sisters presenting with delayed diagnoses of classical 3beta-HSD, despite salt wasting (SW) episodes in infancy. Sibling 1 was referred for premature pubarche, slight....... There is no previous report of the combination of SW and premature pubarche due to mutations in the type II 3beta-HSD gene. Because neonatal diagnosis could have prevented life-threatening crises in these girls, this report further supports the benefits for neonatal screening for congenital adrenal hyperplasia...

  8. Detection and functional characterization of the novel missense mutation Y254D in type II 3{beta}-hydroxysteroid dehydrogenase (3{beta}HSD) gene of a female patient with nonsalt-losing 3{beta}HSD deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Sanchez, R.; Rheaume, E.; Laflamme, N.; Labrie, F.; Simard, J. [Laval Univ., Quebec (Canada); Rosenfield, R.L. [Univ. of Chicago, IL (United States)

    1994-03-01

    Three {beta}-hydroxysteroid dehydrogenase/{Delta}{sup 5}-{Delta}{sup 4}-isomerase (3{beta}HSD) deficiency is a form of congenital adrenal hyperplasia characterized by severe impairment of steroid biosynthesis in the adrenals and gonads. To better understand the molecular basis of the phenotypic heterogeneity found in 3{beta}HSD deficiency, the authors analyzed the structure of type I and II 3{beta}HSD genes in a female patient with nonsalt-losing 3{beta}HSD deficiency diagnosed at puberty. They directly sequenced DNA fragments generated by polymerase chain reaction amplification of the four exons, the exon-intron boundaries, and the 5{prime}-flanking regions of each gene. No mutation was detected in the type I 3{beta}HSD gene, which is the predominant species expressed in the placenta and peripheral tissues. They detected a novel missense mutation, Y254D, in one allele of the patient`s type II 3{beta}HSD gene, which is the almost exclusive type expressed in the adrenals and gonads. The influence of the Y254D mutation on enzymatic activity was assessed by analyzing the recombinant mutant enzyme generated by site-directed mutagenesis after its transient expression in COS-1 monkey kidney cells. Recombinant mutant type II 3{beta}HSD enzyme carrying the Y254D substitution exhibits no detectable activity with C{sub 21} {Delta}{sup 5}-steroid pregnenolone or C{sub 19} {Delta}{sup 5}-steroid hydroepiandrosterone used as substrate. The absence of restriction fragment length polymorphism by Southern blot analysis and the finding that all of the amplified DNA fragments possess the expected length suggest the absence of deletions, duplications, or rearrangements in the other allele. A putative second mutation could be located farther than 1427 basepairs upstream of the initiation codon, thus potentially affecting the normal expression of this gene or within intronic regions, generating an alternative aberrant splicing site. 43 refs., 5 figs., 1 tab.

  9. Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions.

    OpenAIRE

    Sanderson, N.; Factor, V; Nagy, P; Kopp, J; Kondaiah, P; WAKEFIELD, L.; Roberts, A B; Sporn, M B; Thorgeirsson, S S

    1995-01-01

    Aberrant expression of transforming growth factor beta 1 (TGF-beta 1) has been implicated in a number of disease processes, particularly those involving fibrotic and inflammatory lesions. To determine the in vivo effects of overexpression of TGF-beta 1 on the function and structure of hepatic as well as extrahepatic tissues, transgenic mice were generated containing a fusion gene (Alb/TGF-beta 1) consisting of modified porcine TGF-beta 1 cDNA under the control of the regulatory elements of th...

  10. Cytokines interleukin-1beta and tumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells

    DEFF Research Database (Denmark)

    Ortis, Fernanda; Naamane, Najib; Flamez, Daisy

    2010-01-01

    , and global gene expression was analyzed by microarray. Key results were confirmed by RT-PCR, and small-interfering RNAs were used to investigate the mechanistic role of novel and relevant transcription factors identified by pathway analysis. RESULTS Nearly 16,000 transcripts were detected as present in beta...... of genes involved in the maintenance of beta-cell phenotype and growth/regeneration. Cytokines induced hypoxia-inducible factor-alpha, which in this context has a proapoptotic role. Cytokines also modified the expression of >20 genes involved in RNA splicing, and exon array analysis showed cytokine......-induced changes in alternative splicing of >50% of the cytokine-modified genes. CONCLUSIONS: The present study doubles the number of known genes expressed in primary beta-cells, modified or not by cytokines, and indicates the biological role for several novel cytokine-modified pathways in beta-cells. It also...

  11. Early-life origins of type 2 diabetes: fetal programming of the beta-cell mass.

    Science.gov (United States)

    Portha, Bernard; Chavey, Audrey; Movassat, Jamileh

    2011-01-01

    A substantial body of evidence suggests that an abnormal intrauterine milieu elicited by maternal metabolic disturbances as diverse as undernutrition, placental insufficiency, diabetes or obesity, may program susceptibility in the fetus to later develop chronic degenerative diseases, such as obesity, hypertension, cardiovascular diseases and diabetes. This paper examines the developmental programming of glucose intolerance/diabetes by disturbed intrauterine metabolic condition experimentally obtained in various rodent models of maternal protein restriction, caloric restriction, overnutrition or diabetes, with a focus on the alteration of the developing beta-cell mass. In most of the cases, whatever the type of initial maternal metabolic stress, the beta-cell adaptive growth which normally occurs during gestation, does not take place in the pregnant offspring and this results in the development of gestational diabetes. Therefore gestational diabetes turns to be the ultimate insult targeting the offspring beta-cell mass and propagates diabetes risk to the next generation again. The aetiology and the transmission of spontaneous diabetes as encountered in the GK/Par rat model of type 2 diabetes, are discussed in such a perspective. This review also discusses the non-genomic mechanisms involved in the installation of the programmed effect as well as in its intergenerational transmission.

  12. Early-Life Origins of Type 2 Diabetes: Fetal Programming of the Beta-Cell Mass

    Directory of Open Access Journals (Sweden)

    Bernard Portha

    2011-01-01

    Full Text Available A substantial body of evidence suggests that an abnormal intrauterine milieu elicited by maternal metabolic disturbances as diverse as undernutrition, placental insufficiency, diabetes or obesity, may program susceptibility in the fetus to later develop chronic degenerative diseases, such as obesity, hypertension, cardiovascular diseases and diabetes. This paper examines the developmental programming of glucose intolerance/diabetes by disturbed intrauterine metabolic condition experimentally obtained in various rodent models of maternal protein restriction, caloric restriction, overnutrition or diabetes, with a focus on the alteration of the developing beta-cell mass. In most of the cases, whatever the type of initial maternal metabolic stress, the beta-cell adaptive growth which normally occurs during gestation, does not take place in the pregnant offspring and this results in the development of gestational diabetes. Therefore gestational diabetes turns to be the ultimate insult targeting the offspring beta-cell mass and propagates diabetes risk to the next generation again. The aetiology and the transmission of spontaneous diabetes as encountered in the GK/Par rat model of type 2 diabetes, are discussed in such a perspective. This review also discusses the non-genomic mechanisms involved in the installation of the programmed effect as well as in its intergenerational transmission.

  13. Localization and functional roles of corticotropin-releasing factor receptor type 2 in the cerebellum

    NARCIS (Netherlands)

    Gounko, Natalia V.; Gramsbergen, Albert; van der Want, Johannes J. L.

    2008-01-01

    The corticotropin-releasing factor (CRF) type 2 receptor has three splice variants alpha, beta, and gamma. In the rodent brain only CRF-R2 alpha is present. In the cerebellum, CRF-R2 alpha has two different isoforms: a full-length form (fl) and truncated (tr). Both forms CRF-R2 have a unique cellula

  14. A new tool in peptide engineering: a photoswitchable stilbene-type beta-hairpin mimetic.

    Science.gov (United States)

    Erdélyi, Máté; Karlén, Anders; Gogoll, Adolf

    2005-12-23

    Peptide secondary structure mimetics are important tools in medicinal chemistry, as they provide analogues of endogenous peptides with new physicochemical and pharmacological properties. The development, synthesis, photochemical investigation, and conformational analysis of a stilbene-type beta-hairpin mimetic capable of light-triggered conformational changes have been achieved. In addition to standard spectroscopic techniques (nuclear Overhauser effects, amide temperature coefficients, circular dichroism spectroscopy), the applicability of self-diffusion measurements (longitudinal eddy current delay pulsed-field gradient spin echo (LED-PGSE) NMR technique) in conformational studies of oligopeptides is demonstrated. The title compound shows photoisomerization of the stilbene chromophore, resulting in a change in solution conformation between an unfolded structure and a folded beta-hairpin.

  15. DMPD: The interferon signaling network and transcription factor C/EBP-beta. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18163952 The interferon signaling network and transcription factor C/EBP-beta. Li H..., Gade P, Xiao W, Kalvakolanu DV. Cell Mol Immunol. 2007 Dec;4(6):407-18. (.png) (.svg) (.html) (.csml) Show The... interferon signaling network and transcription factor C/EBP-beta. PubmedID 18163952 Title The interfero

  16. Association of coatomer proteins with the beta-receptor for platelet-derived growth factor

    DEFF Research Database (Denmark)

    Hansen, Klaus; Rönnstrand, L; Rorsman, C

    1997-01-01

    of intracellular vesicle transport. In order to explore the functional significance of the interaction between alpha- and beta'-COP and the PDGF receptor, a receptor mutant was made in which the conserved histidine residue 928 was mutated to an alanine residue. The mutant receptor, which was unable to bind alpha......The nonreceptor tyrosine kinase Src binds to and is activated by the beta-receptor for platelet-derived growth factor (PDGF). The interaction leads to Src phosphorylation of Tyr934 in the kinase domain of the receptor. In the course of the functional characterization of this phosphorylation, we...... noticed that components of 136 and 97 kDa bound to a peptide from this region of the receptor in a phosphorylation-independent manner. These components have now been purified and identified as alpha- and beta'-coatomer proteins (COPs), respectively. COPs are a family of proteins involved in the regulation...

  17. Growth hormone is a growth factor for the differentiated pancreatic beta-cell

    DEFF Research Database (Denmark)

    Linde, S; Welinder, B S; Billestrup, N;

    1989-01-01

    The regulation of the growth of the pancreatic beta-cell is poorly understood. There are previous indications of a role of GH in the growth and insulin production of the pancreatic islets. In the present study we present evidence for a direct long-term effect of GH on proliferation and insulin...... biosynthesis of pancreatic beta-cells in monolayer culture. In culture medium RPMI 1640 supplemented with 2% normal human serum islets or dissociated islet cells from newborn rats maintained their insulin-producing capacity. When supplemented with 1-1000 ng/ml pituitary or recombinant human GH the islet cells....... It is concluded that GH is a potent growth factor for the differentiated pancreatic beta-cell....

  18. Systematic comparison of beta spectra calculations using improved analytical screening correction with experimental shape factors.

    Science.gov (United States)

    Mougeot, X

    2016-03-01

    From a review of the available literature, a database of experimental shape factors from measured beta spectra was created in previous work. Classical assumptions applied in beta spectra calculations which avoid the determination of the electron and nuclear wave functions were tested by comparison with each measured spectrum present in the database. From this systematic comparison, it was demonstrated that the typical assumption λk=1 is inappropriate for all forbidden unique transitions. Moreover, the equally common ξ-approximation was also proved to be incorrect for about half of the listed first forbidden non-unique transitions and for all second non-unique ones. In present work, this study has been performed once again using an improved analytical screening correction. General results from previous study still remain the same. Except for allowed transitions, the mean energies in current nuclear databases are expected to be erroneous. Some selected beta spectra are also given to illustrate these results.

  19. The chicken transforming growth factor-beta 3 gene: genomic structure, transcriptional analysis, and chromosomal location.

    Science.gov (United States)

    Burt, D W; Dey, B R; Paton, I R; Morrice, D R; Law, A S

    1995-02-01

    In this paper, we report the isolation, characterization, and mapping of the chicken transforming growth factor-beta 3 (TGF-beta 3) gene. The gene contains seven exons and six introns spanning 16-kb of the chicken genome. A comparison of the 5'-flanking regions of human and chicken TGF-beta 3 genes reveals two regions of sequence conservation. The first contains ATF/CRE and TBP/TATA sequence motifs within an 87-bp region. The second is a 162-bp region with no known sequence motifs. Identification of transcription start sites using chicken RNA isolated from various embryonic and adult tissues reveals two sites of initiation, P1 and P2, which map to these two conserved regions. Comparison of 3'-flanking regions of chicken and mammalian TGF-beta 3 genes also revealed conserved sequences. The most significant homologies were found in the 3'-most end of the transcribed region. DNA sequence analysis of chicken TGF-beta 3 cDNAs isolated by 3'-RACE revealed multiple polyadenylation sites unusually distant from a poly(A) signal motif. A Msc I restriction fragment length polymorphism (RFLP) marker was used to map the TGFB3 locus to linkage group E7 on the East Lansing reference backcross. Linkage to the TH locus showed that the TGFB3 locus was physically located on chicken chromosome 5.

  20. Loss of transforming growth factor-beta 2 leads to impairment of central synapse function

    Directory of Open Access Journals (Sweden)

    Rickmann Michael

    2008-10-01

    Full Text Available Abstract Background The formation of functional synapses is a crucial event in neuronal network formation, and with regard to regulation of breathing it is essential for life. Members of the transforming growth factor-beta (TGF-β superfamily act as intercellular signaling molecules during synaptogenesis of the neuromuscular junction of Drosophila and are involved in synaptic function of sensory neurons of Aplysia. Results Here we show that while TGF-β2 is not crucial for the morphology and function of the neuromuscular junction of the diaphragm muscle of mice, it is essential for proper synaptic function in the pre-Bötzinger complex, a central rhythm organizer located in the brainstem. Genetic deletion of TGF-β2 in mice strongly impaired both GABA/glycinergic and glutamatergic synaptic transmission in the pre-Bötzinger complex area, while numbers and morphology of central synapses of knock-out animals were indistinguishable from their wild-type littermates at embryonic day 18.5. Conclusion The results demonstrate that TGF-β2 influences synaptic function, rather than synaptogenesis, specifically at central synapses. The functional alterations in the respiratory center of the brain are probably the underlying cause of the perinatal death of the TGF-β2 knock-out mice.

  1. FoxO3a mediates transforming growth factor-beta1-induced apoptosis in FaO rat hepatoma cells.

    Science.gov (United States)

    Kim, Byung-Chul

    2008-10-31

    FoxO3a is a member of the forkhead box class O (FoxO) transcription factor family and an important regulator of apoptosis. This work aimed to elucidate the involvement of FoxO3a in transforming growth factor-beta1 (TGF-beta1)-induced apoptosis in FaO rat hepatoma cells. TGF-beta1 caused a time-dependent activation of FoxO3a and a subsequent increase in FoxO response-element-containing luciferase reporter activity, which was Akt-sensitive. The FaO cells stably transfected with a wild type FoxO3a were more susceptible to the formation of apoptotic bodies, populations of sub-G1 apoptotic cells, and collapse of the mitochondrial-membrane potential triggered by TGF-beta1. In contrast, transfection with small-interfering RNA (siRNA) oligonucleotide specific for FoxO3a significantly inhibited caspase activation in FaO cells treated with TGF-beta1. It thus appears that FoxO3a plays a crucial mediatory role in the TGF-beta1 signaling pathway leading to apoptosis.

  2. Overexpression of transforming growth factor-beta 1 in the valvular fibrosis of chronic rheumatic heart disease.

    Science.gov (United States)

    Kim, Lucia; Kim, Do Kyun; Yang, Woo Ick; Shin, Dong Hwan; Jung, Ick Mo; Park, Han Ki; Chang, Byung Chul

    2008-02-01

    For the purpose of determining the pathogenic role of transforming growth factor-beta1 (TGF-beta 1) in the mechanism of chronic rheumatic heart disease, we evaluated the expression of TGF-beta 1, proliferation of myofibroblasts, and changes in extracellular matrix components including collagen and proteoglycan in 30 rheumatic mitral valves and in 15 control valves. High TGF-beta 1 expression was identified in 21 cases (70%) of rheumatic mitral valves, whereas only 3 cases (20%) of the control group showed high TGF-beta 1 expression (pvalves. High TGF-beta1 expression positively correlated with the proliferation of myofibroblasts (p=0.004), valvular fibrosis (pvalves (p=0.040). In conclusion, an ongoing inflammatory process, the expression of TGF-beta 1, and proliferation of myofibroblasts within the valves have a potential role in the valvular fibrosis, calcification, and changes in the extracellular matrix that lead to the scarring sequelae of rheumatic heart disease.

  3. Measurements of beta ray spectra inside nuclear generating stations using a silicon detector coincidence telescope: skin dose beta correction factors for TL elements

    Energy Technology Data Exchange (ETDEWEB)

    Horowitz, Y.S.; Weizmann, Y. [Ben Gurion University of the Negev (Israel); Hirning, C.R. [Ontario Hydro, Whitby (Canada). Health Physics

    1996-10-01

    The measurement of beta ray spectra at various work locations inside nuclear generating stations operated by Ontario Hydro is described. The measurements were carried out using an advanced coincidence telescope spectrometer using silicon detectors only. The spectrometer is capable of measuring electron energies over the range 70-2500 keV with close to 100% efficiency. Over 40 beta ray spectra were measured at various work locations in three nuclear generating stations. Photon rejection is carried out by requiring a coincidence between either two or three detectors. Monte Carlo calculations were then used to estimate beta correction factors for the LiF:Mg,Ti elements used in the Ontario Hydro thermoluminescence dosemeters. Averaging over all the measured beta correction factors for the `skin chip (100 mg. cm{sup -2}) results in a value of 2.73 {+-} 0.77 and for the extremity dosemeter (240 mg.cm{sup -2}) an average value of 4.42 {+-} 1.17 is obtained. These values are 57% and 120% greater, respectively, than the current values used by Ontario Hydro. In addition, beta correction factors for nine representative spectra were calculated for 40 mg.cm{sup -2} and 20 mg.cm{sup -2} chips, and the results demonstrate the benefits of decreased dosemeter thickness. The average value of the beta correction factor, as well as the spread in the beta correction factor, decreases dramatically from 4.80 {+-} 2.1 (240 mg.cm{sup -2}) to 1.29 {+-} 0.1 (20mg.cm{sup -2}). (Author).

  4. Islet autoantibodies and residual beta cell function in type 1 diabetes children followed for 3-6 years

    DEFF Research Database (Denmark)

    Sørensen, Jesper Sand; Vaziri-Sani, Fariba; Maziarz, M

    2012-01-01

    To test if islet autoantibodies at diagnosis of type 1 diabetes (T1DM) and after 3-6 years with T1D predict residual beta-cell function (RBF) after 3-6 years with T1D.......To test if islet autoantibodies at diagnosis of type 1 diabetes (T1DM) and after 3-6 years with T1D predict residual beta-cell function (RBF) after 3-6 years with T1D....

  5. [Analysis of the effect of diabetes type 2 duration on beta cell secretory function and insulin resistance].

    Science.gov (United States)

    Popović, Ljiljana; Zamaklar, Miroslava; Lalić, Katarina; Vasović, Olga

    2006-01-01

    Diabetes type 2 is a chronic metabolic disorder. Pathogenesis of diabetes type 2 results from the impaired insulin secretion, impaired insulin action and increased endogenous glucose production. Diabetes evolves through several phases characterized by qualitative and quantitative changes of beta cell secretory function. The aim of our study was to analyze the impact of diabetes duration on beta cell secretory function and insulin resistance. The results indicated significant negative correlation of diabetes duration and fasting insulinemia, as well as beta cell secretory function assessed by HOMA beta index. Our study also found significant negative correlation of diabetes duration and insulin resistance assessed by HOMA IR index. Significant positive correlation was established between beta cell secretory capacity (fasting insulinemia and HOMA beta) and insulin resistance assessed by HOMA IR index, independently of diabetes duration. These results indicate that: beta cell secretory capacity, assessed by HOMA beta index, significantly decreases with diabetes duration. In parallel with decrease of fasting insulinemia, reduction of insulin resistance assessed by HOMA IR index was found as well.

  6. Protective effect of niacinamide on interleukin-1beta-induced annulus fibrosus type II collagen degeneration in vitro.

    Science.gov (United States)

    Duan, Deyu; Yang, Shuhua; Shao, Zengwu; Wang, Hong; Xiong, Xiaoqian

    2007-02-01

    The protective effect of niacinamide on interleukin-1beta (IL-1beta)-induced annulus fibrosus (AF) type II collagen degeneration in vitro and the mechanism were investigated. Chiba's intervertebral disc (IVD) culture models in rabbits were established and 48 IVDs from 12 adult Japanese white rabbits were randomly divided into 4 groups: normal control group, niacinamide-treated group, type II collagen degneration group (IL-1beta) and treatment group (niacinamide+IL-1beta). After culture for one week, AFs were collected for inducible nitric oxide synthase (iNOS), cysteine containing aspartate specific protease-3 (Caspase-3) and type II collagen immunohistochemical examination, and type II collagen reverse transcription polymerase chain reaction (RT-PCR). The results showed that rate of iNOS positive staining AF cells in the 4 groups was 17.6%, 10.9%, 73.9% and 19.3% respectively. The positive rate in treatment group was significantly lower than in the type II collagen degeneration group (Pniacinamide could effectively inhibit IL-1beta stimulated increase of iNOS and Caspase-3 in AF, and alleviate IL-1beta-caused destruction and synthesis inhibition of type II collagen. Niacinamide is of potential for clinical treatment of IVD degeneration.

  7. Fatigue properties of a metastable beta-type titanium alloy with reversible phase transformation.

    Science.gov (United States)

    Li, S J; Cui, T C; Hao, Y L; Yang, R

    2008-03-01

    Due to recent concern about allergic and toxic effects of Ni ions released from TiNi alloy into human body, much attention has been focused on the development of new Ni-free, metastable beta-type biomedical titanium alloys with a reversible phase transformation between the beta phase and the alpha'' martensite. This study investigates the effect of the stress-induced alpha'' martensite on the mechanical and fatigue properties of Ti-24Nb-4Zr-7.6Sn (wt.%) alloy. The results show that the as-forged alloy has a low dynamic Young's modulus of 55GPa and a recoverable tensile strain of approximately 3%. Compared with Ti-6Al-4V ELI, the studied alloy has quite a high low-cycle fatigue strength because of the effective suppression of microplastic deformation by the reversible martensitic transformation. Due to the low critical stress required to induce the martensitic transformation, it has low fatigue endurance comparable to that of Ti-6Al-4V ELI. Cold rolling produces a beta+alpha'' two-phase microstructure that is characterized by regions of nano-size beta grains interspersed with coarse grains containing alpha'' martensite plates. Cold rolling increases fatigue endurance by approximately 50% while decreasing the Young's modulus to 49GPa along the rolling direction but increasing it to 68GPa along the transverse direction. Due to the effective suppression of the brittle isothermal omega phase, balanced properties of high strength, low Young's modulus and good ductility can be achieved through ageing treatment at intermediate temperature.

  8. Effects of concomitant use of fibroblast growth factor (FGF)-2 with beta-tricalcium phosphate ({beta}-TCP) on the beagle dog 1-wall periodontal defect model

    Energy Technology Data Exchange (ETDEWEB)

    Anzai, Jun, E-mail: anzai_jun@kaken.co.jp [Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., 14, Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607-8042 (Japan); Department of Periodontology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka 565-0871 (Japan); Kitamura, Masahiro, E-mail: kitamura@dent.osaka-u.ac.jp [Department of Periodontology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka 565-0871 (Japan); Nozaki, Takenori, E-mail: tnozaki@dent.osaka-u.ac.jp [Department of Periodontology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka 565-0871 (Japan); Nagayasu, Toshie, E-mail: nagayasu_toshie@kaken.co.jp [Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., 14, Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607-8042 (Japan); Terashima, Akio, E-mail: terashima_akio@kaken.co.jp [Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., 14, Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607-8042 (Japan); Asano, Taiji, E-mail: asano_taiji@kaken.co.jp [Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., 14, Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607-8042 (Japan); Murakami, Shinya, E-mail: ipshinya@dent.osaka-u.ac.jp [Department of Periodontology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka 565-0871 (Japan)

    2010-12-17

    Research highlights: {yields} Concomitant use of FGF-2 and {beta}-TCP (an osteo-conductive scaffold) significantly promotes periodontal regeneration in the severe periodontitis model (1-wall defect model) of beagle dog. {yields} FGF-2 enhanced new bone formation via {beta}-TCP at the defects. {yields} In particular, FGF-2 dramatically regenerated new periodontal ligament and cementum formations at the defects, that is one of the most important healing outcomes during the process of periodontal regeneration. {yields} Epithelial downgrowth (undesirable wound healing) was decreased by administration of FGF-2. {yields} This manuscript indicates for the first time that concomitant use of FGF-2 and {beta}-TCP is efficacious in regenerating periodontal tissue following severe destruction of the tissue by progression of periodontitis. -- Abstract: The effects of concomitant use of fibroblast growth factor-2 (FGF-2) and beta-tricalcium phosphate ({beta}-TCP) on periodontal regeneration were investigated in the beagle dog 1-wall periodontal defect model. One-wall periodontal defects were created in the mesial portion of both sides of the mandibular first molars, and 0.3% FGF-2 plus {beta}-TCP or {beta}-TCP alone was administered. Radiographic evaluation was performed at 0, 3, and 6 weeks. At 6 weeks, the periodontium with the defect site was removed and histologically analyzed. Radiographic findings showed that co-administration of FGF-2 significantly increased bone mineral contents of the defect sites compared with {beta}-TCP alone. Histologic analysis revealed that the length of the regenerated periodontal ligament, the cementum, distance to the junctional epithelium, new bone height, and area of newly formed bone were significantly increased in the FGF-2 group. No abnormal inflammatory response or ankylosis was observed in either group. These findings indicate the efficacy of concomitant use of FGF-2 and {beta}-TCP as an osteoconductive material for periodontal

  9. Arsenic exposure and calpain-10 polymorphisms impair the function of pancreatic beta-cells in humans: a pilot study of risk factors for T2DM.

    Directory of Open Access Journals (Sweden)

    Andrea Díaz-Villaseñor

    Full Text Available The incidence of type 2 diabetes mellitus (T2DM is increasing worldwide and diverse environmental and genetic risk factors are well recognized. Single nucleotide polymorphisms (SNPs in the calpain-10 gene (CAPN-10, which encodes a protein involved in the secretion and action of insulin, and chronic exposure to inorganic arsenic (iAs through drinking water have been independently associated with an increase in the risk for T2DM. In the present work we evaluated if CAPN-10 SNPs and iAs exposure jointly contribute to the outcome of T2DM. Insulin secretion (beta-cell function and insulin sensitivity were evaluated indirectly through validated indexes (HOMA2 in subjects with and without T2DM who have been exposed to a gradient of iAs in their drinking water in northern Mexico. The results were analyzed taking into account the presence of the risk factor SNPs SNP-43 and -44 in CAPN-10. Subjects with T2DM had significantly lower beta-cell function and insulin sensitivity. An inverse association was found between beta-cell function and iAs exposure, the association being more pronounced in subjects with T2DM. Subjects without T2DM who were carriers of the at-risk genotype SNP-43 or -44, also had significantly lower beta-cell function. The association of SNP-43 with beta-cell function was dependent on iAs exposure, age, gender and BMI, whereas the association with SNP-44 was independent of all of these factors. Chronic exposure to iAs seems to be a risk factor for T2DM in humans through the reduction of beta-cell function, with an enhanced effect seen in the presence of the at-risk genotype of SNP-43 in CAPN-10. Carriers of CAPN-10 SNP-44 have also shown reduced beta-cell function.

  10. Arsenic Exposure and Calpain-10 Polymorphisms Impair the Function of Pancreatic Beta-Cells in Humans: A Pilot Study of Risk Factors for T2DM

    Science.gov (United States)

    Díaz-Villaseñor, Andrea; Cruz, Laura; Cebrián, Arturo; Hernández-Ramírez, Raúl U.; Hiriart, Marcia; García-Vargas, Gonzálo; Bassol, Susana; Sordo, Monserrat; Gandolfi, A. Jay; Klimecki, Walter T.; López-Carillo, Lizbeth; Cebrián, Mariano E.; Ostrosky-Wegman, Patricia

    2013-01-01

    The incidence of type 2 diabetes mellitus (T2DM) is increasing worldwide and diverse environmental and genetic risk factors are well recognized. Single nucleotide polymorphisms (SNPs) in the calpain-10 gene (CAPN-10), which encodes a protein involved in the secretion and action of insulin, and chronic exposure to inorganic arsenic (iAs) through drinking water have been independently associated with an increase in the risk for T2DM. In the present work we evaluated if CAPN-10 SNPs and iAs exposure jointly contribute to the outcome of T2DM. Insulin secretion (beta-cell function) and insulin sensitivity were evaluated indirectly through validated indexes (HOMA2) in subjects with and without T2DM who have been exposed to a gradient of iAs in their drinking water in northern Mexico. The results were analyzed taking into account the presence of the risk factor SNPs SNP-43 and -44 in CAPN-10. Subjects with T2DM had significantly lower beta-cell function and insulin sensitivity. An inverse association was found between beta-cell function and iAs exposure, the association being more pronounced in subjects with T2DM. Subjects without T2DM who were carriers of the at-risk genotype SNP-43 or -44, also had significantly lower beta-cell function. The association of SNP-43 with beta-cell function was dependent on iAs exposure, age, gender and BMI, whereas the association with SNP-44 was independent of all of these factors. Chronic exposure to iAs seems to be a risk factor for T2DM in humans through the reduction of beta-cell function, with an enhanced effect seen in the presence of the at-risk genotype of SNP-43 in CAPN-10. Carriers of CAPN-10 SNP-44 have also shown reduced beta-cell function. PMID:23349674

  11. Cereblon inhibits proteasome activity by binding to the 20S core proteasome subunit beta type 4.

    Science.gov (United States)

    Lee, Kwang Min; Lee, Jongwon; Park, Chul-Seung

    2012-10-26

    In humans, mutations in the gene encoding cereblon (CRBN) are associated with mental retardation. Although CRBN has been investigated in several cellular contexts, its function remains unclear. Here, we demonstrate that CRBN plays a role in regulating the ubiquitin-proteasome system (UPS). Heterologous expression of CRBN inhibited proteasome activity in a human neuroblastoma cell line. Furthermore, proteasome subunit beta type 4 (PSMB4), the β7 subunit of the 20S core complex, was identified as a direct binding partner of CRBN. These findings suggest that CRBN may modulate proteasome activity by directly interacting with the β7 subunit.

  12. Analytical expression for an optimised link bar mechanism for a beta-type Stirling engine

    DEFF Research Database (Denmark)

    Carlsen, Henrik; Bovin, Jonas Kabell

    2007-01-01

    The design of a mechanism for kinematic beta-type Stirling engines, where the displacer piston and the working piston share the same cylinder, is complicated. A well-known solution is the rhombic drive, but this solution depends on oil lubrication because of the gear wheels connecting the two...... counter rotating crank shafts. In a hermetically sealed Stirling engine it is an advantage to avoid oil in the crank case, making the application of the rhombic drive difficult. In this paper, another crank mechanism is presented, which has been developed for a 9 kW single cylinder engine. The new crank...

  13. Survival Analysis and its Associated Factors of Beta Thalassemia Major in Hamadan Province

    Directory of Open Access Journals (Sweden)

    Reza Zamani

    2015-05-01

    Full Text Available Background: There currently is a lack of knowledge about the long-term survival of patients with beta thalassemia (BT, particularly in regions with low incidence of the disease. The aim of the present study was to determine the survival rate of the patients with BT major and the factors associated with the survival time. Methods: This retrospective cohort study was performed in Hamadan province, located in the west of Iran. The study included patients that referred to the provincial hospitals during 16 year period from 1997 to 2013. The follow up of each subject was calculated from the date of birth to the date of death. Demographic and clinical data were extracted from patients’ medical records using a checklist. Statistical analysis included the Kaplan-Meier method to analyze survivals, log-rank to compare curves between groups, and Cox regression for multivariate prognostic analysis. Results: A total of 133 patients with BT major were enrolled, 54.9% of whom were male and 66.2% were urban. The 10-, 20- and 30-year survival rate for all patients were 98.3%, 88.4% and 80.5%, respectively. Based on hazard ratio (HR, we found that accompanied diseases (P=0.01, blood type (P=0.03 and residency status (P=0.01 were significant predictors for the survival time of patients. Conclusion: The survival rate of BT patients has improved. Future researches such as prospective designs are required for the estimation of survival rate and to find other prognostic factors, which have reliable sources of data.

  14. Gluten-free diet increases beta-cell volume and improves glucose tolerance in an animal model of type 2 diabetes.

    Science.gov (United States)

    Haupt-Jorgensen, Martin; Buschard, Karsten; Hansen, Axel K; Josefsen, Knud; Antvorskov, Julie Christine

    2016-10-01

    Gluten-free (GF) diet alleviates type 1 diabetes in animal models and possibly in humans. We recently showed that fatty acid-induced insulin secretion is enhanced by enzymatically digested gluten (gliadin) stimulation in INS-1E insulinoma cells. We therefore hypothesized that GF diet would induce beta-cell rest and ameliorate type 2 diabetes. C57BL/6JBomTac (B6) mice were fed a high-fat (HF), gluten-free high-fat (GF-HF), standard (STD) or gluten-free (GF) diet for 42 weeks. Short-term (6-24 weeks) GF-HF versus HF feeding impaired glucose tolerance and increased fasting glucose. Long-term (36-42 weeks) GF-HF versus HF feeding improved glucose tolerance and decreased fasting leptin. Mice fed a GF-HF versus HF diet for 42 weeks showed higher volumes of beta cells, islets and pancreas. The beta-cell volume correlated with the islet- and pancreas volume as well as body weight. GF-HF versus HF diet did not influence toll-like receptor 4 (Tlr4), interleukin 1 (IL-1), interleukin 6 (IL-6) or tumour necrosis factor-alpha (TNF-alpha) mRNA expression in intestine. STD versus GF feeding did not affect any parameter studied. Long-term feeding with GF-HF versus HF increases beta-cell volume and improves glucose tolerance in B6 mice. The mechanism may include beta-cell rest, but is unlikely to include TLR4 and proinflammatory cytokines in the intestine. Beta-cell volume correlates with pancreas volume and body weight, indicating that insulin secretion capacity controls pancreas volume. Thus, long-term GF diets may be beneficial for obese type 2 diabetes patients and trials should be performed. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  15. Testosterone stimulates adipose tissue 11beta-hydroxysteroid dehydrogenase type 1 expression in a depot-specific manner in children.

    Science.gov (United States)

    Zhu, Lijun; Hou, Miao; Sun, Bin; Burén, Jonas; Zhang, Li; Yi, Jun; Hernell, Olle; Li, Xiaonan

    2010-07-01

    Activation of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in adipose tissue results in the production of excess tissue glucocorticoids and the induction of adiposity and visceral obesity in particular. Androgens may affect body fat distribution by regulating the local metabolism of cortisol. Our objective was to study 11beta-HSD1 mRNA expression in abdominal sc and omental (om) adipose tissue in children after in vitro testosterone and cortisol treatment. Paired fat biopsies (sc and om) were obtained from 19 boys (age 6-14 yr, body mass index 14.6-25.3 kg/m(2), BMI sd score SDS -1.6-3.1) undergoing open abdominal surgery. Pieces of adipose tissue were incubated with testosterone, cortisol, or both hormones for 24 h, whereupon mRNA expression of 11beta-HSD1 and hexose-6-phosphate dehydrogenase (H6PDH) were measured by real-time PCR, and 11beta-HSD1 enzyme activity was determined. Testosterone treatment up-regulated 11beta-HSD1 mRNA expression compared with control incubations in the absence of testosterone (P tissue. Testosterone and cortisol both increased 11beta-HSD1 mRNA expression in om but not sc adipose tissue in a depot-specific manner by 2.5- and 2.9-fold, respectively (P effect of the two hormones. 11beta-HSD1 enzyme activity correlated positively to mRNA expression (r = 0.610; P = 0.001). Adipose tissue mRNA expression of H6PDH was affected in a similar fashion to 11beta-HSD1 after hormonal treatment. Testosterone and cortisol stimulated 11beta-HSD1 and H6PDH mRNA expression and 11beta-HSD1 activity in om but not in sc adipose tissue. This suggests that these hormones may contribute to fat distribution and accumulation during childhood.

  16. Tissue-specific increases in 11beta-hydroxysteroid dehydrogenase type 1 in normal weight postmenopausal women.

    Directory of Open Access Journals (Sweden)

    Therése Andersson

    Full Text Available With age and menopause there is a shift in adipose distribution from gluteo-femoral to abdominal depots in women. Associated with this redistribution of fat are increased risks of type 2 diabetes and cardiovascular disease. Glucocorticoids influence body composition, and 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1 which converts inert cortisone to active cortisol is a putative key mediator of metabolic complications in obesity. Increased 11betaHSD1 in adipose tissue may contribute to postmenopausal central obesity. We hypothesized that tissue-specific 11betaHSD1 gene expression and activity are up-regulated in the older, postmenopausal women compared to young, premenopausal women. Twenty-three pre- and 23 postmenopausal, healthy, normal weight women were recruited. The participants underwent a urine collection, a subcutaneous adipose tissue biopsy and the hepatic 11betaHSD1 activity was estimated by the serum cortisol response after an oral dose of cortisone. Urinary (5alpha-tetrahydrocortisol+5beta-tetrahydrocortisol/tetrahydrocortisone ratios were higher in postmenopausal women versus premenopausal women in luteal phase (P<0.05, indicating an increased whole-body 11betaHSD1 activity. Postmenopausal women had higher 11betaHSD1 gene expression in subcutaneous fat (P<0.05. Hepatic first pass conversion of oral cortisone to cortisol was also increased in postmenopausal women versus premenopausal women in follicular phase of the menstrual cycle (P<0.01, at 30 min post cortisone ingestion, suggesting higher hepatic 11betaHSD1 activity. In conclusion, our results indicate that postmenopausal normal weight women have increased 11betaHSD1 activity in adipose tissue and liver. This may contribute to metabolic dysfunctions with menopause and ageing in women.

  17. STAT5 activity in pancreatic beta-cells influences the severity of diabetes in animal models of type 1 and 2 diabetes

    DEFF Research Database (Denmark)

    Jackerott, Malene; Møldrup, Annette; Thams, Peter

    2006-01-01

    Pancreatic beta-cell growth and survival and insulin production are stimulated by growth hormone and prolactin through activation of the transcription factor signal transducer and activator of transcription (STAT)5. To assess the role of STAT5 activity in beta-cells in vivo, we generated transgenic...... of glucose tolerance, whereas RIP-CASTAT5 mice were more glucose tolerant and less hyperleptinemic than wild-type mice. Although the pancreatic insulin content and relative beta-cell area were increased in high-fat diet-fed RIP-DNSTAT5 mice compared with wild-type or RIP-CASTAT5 mice, RIP-DNSTAT5 mice showed...... reduced beta-cell proliferation at 6 months of age. The inhibitory effect of high-fat diet or leptin on insulin secretion was diminished in isolated islets from RIP-DNSTAT5 mice compared with wild-type islets. Upon multiple low-dose streptozotocin treatment, RIP-DNSTAT5 mice exhibited higher plasma...

  18. Reference intervals for glucose, beta-cell polypeptides, and counterregulatory factors during prolonged fasting

    DEFF Research Database (Denmark)

    Højlund, Kurt; Wildner-Christensen, M; Eshøj, O

    2001-01-01

    To establish reference intervals for the pancreatic beta-cell response and the counterregulatory hormone response to prolonged fasting, we studied 33 healthy subjects (16 males, 17 females) during a 72-h fast. Glucose, insulin, C-peptide, and proinsulin levels decreased (P ... of counterregulatory factors increased during the fast [P fasting (P ... decreased from the second to third day of fasting (P = 0.03). Males had higher glucose and glucagon levels and lower FFA levels during the fast (P

  19. Varying occurrence of extended-spectrum beta-lactamase bacteria among three produce types

    KAUST Repository

    Toh, Benjamin E. W.

    2017-07-07

    A monitoring effort that spanned across 1.5 years was conducted to examine three types of produce-associated microbiota. The average amount of antibiotic-resistant bacteria recovered from lettuce, tomato, and cucumber was 1.02 × 1010, 2.05 × 107, and 4.78 × 109 cells per 50 g of each produce, respectively. A total of 480 bacterial isolates were obtained and identified from their 16S rRNA genes, revealing isolates that were ubiquitously recovered from all three types of produce. However, sporadic presence of Klebsiella pneumoniae and Acinetobacter baumannii was detected on lettuce and cucumbers but not tomatoes. End-point PCR revealed that the K. pneumoniae and A. baumannii isolates were positive for genes encoding extended spectrum beta-lactamase. Whole genome sequencing of two of the K. pneumoniae isolates further suggested the presence of the blaCTX-M-15 gene in a conjugative plasmid, as well as other antibiotic resistance genes and virulence-associated traits in either conjugative plasmids or the chromosomal genome. Quantitative microbial risk assessment indicated varying levels of ingestion risk associated with different types of produce. In particular, the risk arising from ESBL-positive K. pneumoniae in lettuce, but not in cucumbers or tomatoes, was higher than the acceptable annual risk of 10−4. Practical applications Three types of vegetables were sampled and evaluated over 1.5 years to determine differences in their associated bacterial isolates. Particular emphasis was placed on identifying pathogenic strains that were positive for extended spectrum beta-lactamase (ESBL). Quantitative estimates of the microbial risk associated with the ESBL-positive pathogens showed that different produce types may incur varying levels of ingestion risk. Most of the currently reported ESBL-positive bacterial isolates have been identified in nosocomial environments. However, the carriage of such drug-resistant bacteria in vegetables suggests a possible connection

  20. Expression of transforming growth factor beta type Ⅱ receptor gene in tissue microarray of non-small cell lung cancer%非小细胞肺癌组织芯片中转化生长因子βⅡ型受体的表达

    Institute of Scientific and Technical Information of China (English)

    包阳; 王久存; 徐志云; 刘晓红; 徐激斌

    2011-01-01

    Objective:To evaluate the expression of transforming growth factor beta type II receptor (TGFBR2) in non-small cell lung cancer (NSCLC) and to explore the associations of TGFBR2 expression with NSCLC occurrence and clinical pathological features. Methods; Tissue microarray and immunohistochemistry were used to detect the expression of TGFBR2 in 115 matched-pairs of primary non-small cell lung cancer (NSCLC) samples (50 of adenocarcinoma, 44 of squamous cell carcinoma, 6 of adenosquamous carcinoma, 2 of giant cell carcinoma and 13 of large cell carcinoma) and normal lung tissues. Results.- Significant difference in TCFBR2 expression was noted between NSCLC samples and normal controls ( P 0.05). Conclusion; The altered expression of TGFBR2 may be related with tumor pathology. Down-regulated expression of TGFBR2 is probably linked to development and progression of NSCLC, large cell carcinoma in particular.%目的:检测非小细胞肺癌( NSCLC)中转化生长因子βⅡ型受体(TGFBR2)的表达,并探讨其表达的变化与NSCLC的发生的相关性及与临床病理因素的关系.方法:采用组织芯片技术和免疫组化方法,检测115对原发性NSCLC(腺癌50例,鳞癌44例,腺鳞癌6例,巨细胞癌2例,大细胞癌13例)及其相应正常对照肺组织中TGFBR2蛋白的表达情况.结果:TGFBR2在NSCLC与正常对照组织中的表达差异有统计学意义(P<0.01),大细胞癌与腺癌、鳞癌等病理类型的表达水平差异有统计学意义(P<0.05),但TGFBR2的表达变化与患者年龄、性别、肿瘤大小和局部侵袭、淋巴结侵袭、转移、临床分期差异无统计学意义(P>0.05).结论:TGFBR2的表达异常与病理类型有关,TGFBR2的表达下调可能与NSCLC尤其是大细胞癌的发生或发展相关.

  1. Reduced skeletal muscle inhibitor of kappaB beta content is associated with insulin resistance in subjects with type 2 diabetes: reversal by exercise training.

    Science.gov (United States)

    Sriwijitkamol, Apiradee; Christ-Roberts, Christine; Berria, Rachele; Eagan, Phyllis; Pratipanawatr, Thongchai; DeFronzo, Ralph A; Mandarino, Lawrence J; Musi, Nicolas

    2006-03-01

    Skeletal muscle insulin resistance plays a key role in the pathogenesis of type 2 diabetes. It recently has been hypothesized that excessive activity of the inhibitor of kappaB (IkappaB)/nuclear factor kappaB (NFkappaB) inflammatory pathway is a mechanism underlying skeletal muscle insulin resistance. However, it is not known whether IkappaB/NFkappaB signaling in muscle from subjects with type 2 diabetes is abnormal. We studied IkappaB/NFkappaB signaling in vastus lateralis muscle from six subjects with type 2 diabetes and eight matched control subjects. Muscle from type 2 diabetic subjects was characterized by a 60% decrease in IkappaB beta protein abundance, an indicator of increased activation of the IkappaB/NFkappaB pathway. IkappaB beta abundance directly correlated with insulin-mediated glucose disposal (Rd) during a hyperinsulinemic (40 mU x m(-2) x min(-1))-euglycemic clamp (r = 0.63, P = 0.01), indicating that increased IkappaB/NFkappaB pathway activity is associated with muscle insulin resistance. We also investigated whether reversal of this abnormality could be a mechanism by which training improves insulin sensitivity. In control subjects, 8 weeks of aerobic exercise training caused a 50% increase in both IkappaB alpha and IkappaB beta protein. In subjects with type 2 diabetes, training increased IkappaB alpha and IkappaB beta protein to levels comparable with that of control subjects, and these increments were accompanied by a 40% decrease in tumor necrosis factor alpha muscle content and a 37% increase in insulin-stimulated glucose disposal. In summary, subjects with type 2 diabetes have reduced IkappaB protein abundance in muscle, suggesting excessive activity of the IkappaB/NFkappaB pathway. Moreover, this abnormality is reversed by exercise training.

  2. Rapidly spreading CTX-M-type beta-lactamase-producing Proteus mirabilis in Japan.

    Science.gov (United States)

    Kanayama, Akiko; Iyoda, Takako; Matsuzaki, Kaoru; Saika, Takeshi; Ikeda, Fumiaki; Ishii, Yoshikazu; Yamaguchi, Keizo; Kobayashi, Intetsu

    2010-10-01

    In recent years, increased isolation of extended-spectrum beta-lactamase (ESBL)-producing Proteus mirabilis has been reported in Japan. We undertook an investigation to determine the prevalence of ESBL-producing P. mirabilis isolated in Japan and to characterise the genotype. Seventy-four P. mirabilis isolates recovered from specimens at 54 hospitals in Japan between March and October 2006 were included in the study. Of the 74 P. mirabilis isolates examined, 28 (37.8%) were ESBL-producers. The bla(CTX-M-2) gene was found in 27 isolates, whilst 1 isolate possessed bla(CTX-M-3). Amongst the 28 ESBL-producers, 25 (89.3%) were non-susceptible to ciprofloxacin, whilst 11 (23.9%) of 46 ESBL-non-producing isolates were non-susceptible to ciprofloxacin. Pulsed-field gel electrophoresis (PFGE) analysis of the 28 ESBL-producing isolates from 19 hospitals revealed 17 clusters. The same PFGE type was observed in two or more hospitals especially in the greater Tokyo area, suggesting possible clonal spread and the need for monitoring to determine whether emergence of a dominant clone occurs. Our results show that in Japan there is a high prevalence of CTX-M-type beta-lactamase-producing P. mirabilis. Moreover, these isolates are characterised by reduced susceptibility to fluoroquinolones.

  3. P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors in mice.

    Science.gov (United States)

    Meredith, Jere E; Thompson, Lorin A; Toyn, Jeremy H; Marcin, Lawrence; Barten, Donna M; Marcinkeviciene, Jovita; Kopcho, Lisa; Kim, Young; Lin, Alan; Guss, Valerie; Burton, Catherine; Iben, Lawrence; Polson, Craig; Cantone, Joe; Ford, Michael; Drexler, Dieter; Fiedler, Tracey; Lentz, Kimberley A; Grace, James E; Kolb, Janet; Corsa, Jason; Pierdomenico, Maria; Jones, Kelli; Olson, Richard E; Macor, John E; Albright, Charles F

    2008-08-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease. Amyloid beta (Abeta) peptides are hypothesized to cause the initiation and progression of AD based on pathologic data from AD patients, genetic analysis of mutations that cause early onset forms of AD, and preclinical studies. Based on this hypothesis, beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) inhibitors are an attractive therapeutic approach for AD because cleavage of the APP by BACE1 is required to form Abeta. In this study, three potent BACE1 inhibitors are characterized. All three inhibitors decrease Abeta formation in cultured cells with IC(50) values less than 10 nM. Analysis of APP C-terminal fragments by immunoblotting and Abeta peptides by mass spectrometry showed that these inhibitors decreased Abeta by inhibiting BACE1. An assay for Abeta1-40 in mice was developed and used to show that these BACE1 inhibitors decreased plasma Abeta1-40, but not brain Abeta1-40, in wild-type mice. Because these BACE1 inhibitors were substrates for P-glycoprotein (P-gp), a member of the ATP-binding cassette superfamily of efflux transporters, these inhibitors were administered to P-gp knockout (KO) mice. These studies showed that all three BACE1 inhibitors decreased brain Abeta1-40 in P-gp KO mice, demonstrating that P-gp is a major limitation for development of BACE1 inhibitors to test the amyloid hypothesis. A comparison of plasma Abeta1-40 and brain Abeta1-40 dose responses for these three compounds revealed differences in relative ED(50) values, indicating that factors other than P-gp can also contribute to poor brain activity by BACE1 inhibitors.

  4. Transforming growth factor-beta inhibits human antigen-specific CD4(+) T cell proliferation without modulating the cytokine response

    NARCIS (Netherlands)

    Tiemessen, MM; Kunzmann, S; Schmidt-Weber, CB; Garssen, J; Bruijnzeel-Koomen, CAFM; Knol, EF; Van Hoffen, E

    2003-01-01

    Transforming growth factor (TGF)-beta has been demonstrated to play a key role in the regulation of the immune response, mainly by its suppressive function towards cells of the immune system. In humans, the effect of TGF-beta on antigen-specific established memory T cells has not been investigated y

  5. Age-related alterations in TGF beta signaling as a causal factor of cartilage degeneration in osteoarthritis

    NARCIS (Netherlands)

    Kraan, P.M. van der

    2014-01-01

    BACKGROUND: Age is the most important risk factor for primary osteoarthritis (OA). Members of the TGF-beta superfamily play a crucial role in chondrocyte differentiation and maintenance of healthy articular cartilage. OBJECTIVE: We have investigated whether age-related changes in TGF-beta superfamil

  6. Transforming growth factor-beta plasma dynamics and post-irradiation lung injury in lung cancer patients

    NARCIS (Netherlands)

    Novakova-Jiresova, A; van Gameren, MM; Coppes, RP; Kampinga, HH; Groen, HJM

    2004-01-01

    Purpose: To investigate the relevance of transforming growth factor-beta (TGF-beta) dynamics in plasma for identification of patients at low risk for developing pneumonitis as a complication of thoracic radiotherapy (RT). Patients and methods: Non-small cell lung cancer patients undergoing conventio

  7. Expression and autoregulation of transforming growth factor beta receptor mRNA in small-cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Nørgaard, P; Spang-Thomsen, M; Poulsen, H S

    1996-01-01

    In small-cell lung cancer cell lines resistance to growth inhibition by transforming growth factor (TGF)-beta 1, was previously shown to correlate with lack of TGF-beta receptor I (RI) and II (RII) proteins. To further investigate the role of these receptors, the expression of mRNA for RI, RII...

  8. Prostaglandin E-2 inhibits transforming growth factor beta 1-mediated induction of collagen alpha(1)(I) in hepatic stellate cells

    NARCIS (Netherlands)

    Hui, AY; Dannenberg, AJ; Sung, JJY; Subbaramaiah, K; Du, BH; Olinga, P; Friedman, SL

    Background/Aims: Cyclooxygenase-2 (COX-2) has been implicated in a number of hepatic stellate cell (HSC) functions but its relationship to transforming growth factor-beta1 (TGF-beta1)-mediated fibrogenesis is unknown. We assessed the impact of COX-2 inhibition and PGE(2) on the regulation of

  9. Isolation of novel human cDNA (hGMF-gamma) homologous to Glia Maturation Factor-beta gene.

    Science.gov (United States)

    Asai, K; Fujita, K; Yamamoto, M; Hotta, T; Morikawa, M; Kokubo, M; Moriyama, A; Kato, T

    1998-03-13

    A novel full-length human cDNA homologous to Glia Maturation Factor-beta (GMF-beta) gene was isolated. Sequence analysis of the entire cDNA revealed an open reading frame of 426 nucleotides with a deduced protein sequence of 142 amino acid residues. The deduced amino acid sequences of its putative product is highly homologous to human GMF-beta (82% identity) and named for GMF-gamma. Northern blot analysis indicated that a message of 0.9 kb long, but not 4.1 kb of GMF-beta, is predominantly expressed in human lung, heart, and placenta.

  10. Neutrinoless Double Beta Decay in LRSM with Natural Type-II seesaw Dominance

    CERN Document Server

    Pritimita, Prativa; Patra, Sudhanwa

    2016-01-01

    We present a detailed discussion on neutrinoless double beta decay within a class of left-right symmetric models where neutrino mass originates by natural type II seesaw dominance. The spontaneous symmetry breaking is implemented with doublets, triplets and bidoublet scalars. The fermion sector is extended with an extra sterile neutrino per generation that helps in implementing the seesaw mechanism. The presence of extra particles in the model exactly cancels type-I seesaw and allows large value for Dirac neutrino mass matrix $M_D$. The key feature of this work is that all the physical masses and mixing are expressed in terms of neutrino oscillation parameters and lightest neutrino mass thereby facilitating to constrain light neutrino masses from $0\

  11. Cytokines interleukin-1beta and tumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells

    DEFF Research Database (Denmark)

    Ortis, Fernanda; Naamane, Najib; Flamez, Daisy

    2010-01-01

    OBJECTIVE: Cytokines contribute to pancreatic beta-cell death in type 1 diabetes. This effect is mediated by complex gene networks that remain to be characterized. We presently utilized array analysis to define the global expression pattern of genes, including spliced variants, modified by the cy...

  12. Correlation of plasminogen activator inhibitor-1 and transforming growth factor-beta with diabetic nephropathy in type 2 diabetes mellitus%血浆纤溶酶原激活物抑制物1及血清转化生长因子β与2型糖尿病肾病的相关性研究

    Institute of Scientific and Technical Information of China (English)

    徐丰博; 刘惠兰; 孙懿

    2012-01-01

    目的 研究2型糖尿病肾病(DN)及单纯2型糖尿病(T2DM)患者血浆纤溶酶原激活物抑制物1(PAI-1)及血清转化生长因子β(TGF-β)水平的变化.并进一步探讨在T2DM患者中血浆PAI-1和血清TGF-β的关系.方法 T2DM患者93例,其中T2DM无蛋白尿患者(DM组)37例;微量蛋白尿患者(DN 1组)27例,尿白蛋白/肌酐(A/C)20~200 mg/g;显著蛋白尿患者(DN 2组)29例,A/C>200 mg/g.选取正常对照组32例,均为健康体检者.所有检测对象过夜禁食10~12小时后,于清晨空腹抽取肘静脉血4 ml,其中2 ml不抗凝血用于生化指标检测.酶联免疫吸附试验(ELISA)测定血浆PAI-1、TGF-β水平.结果 ①血浆PAI-1水平DN1、DN2组显著高于正常对照组,(69.28±18.61) ng/L、(69.43±17.86) ng/L vs (51.97±30.11) ng/L(P<0.05).②血清TGF-β水平DM、DN1、DN2组显著高于正常对照组,分别为(137.99±21.47) ng/L、(180.36±40.45) ng/L、(298.92±77.37) ng/L vs(100.65±24.21) ng/L(均P<0.01).③血清TGF-β和血浆PAI-1水平无明显相关性.④血浆PAI-1水平及血清TGF-β水平升高是T2DM并发肾病的危险因素.结论 T2DM合并肾病患者血浆PAI-1水平、血清TGF-β水平升高,两项指标可以预测T2DM合并肾病的危险.%Objective Plasma plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor-beta (TGF-fj) level of type 2 diabetes patients were studied for exploring the pathophysiological mechanism. Methods According to the standards of diabetic diagnosis and typing put forward by ADA in 1997,a total of 93 unrelated patients with type 2 diabetes were randomly recruited in the study. These patients were further divided into type 2 diabetes with nephropathy (DN1,DN2) and without nephropathy (DN) according to their urinary albumin to creatinine ratio (A/C). At the same time,32 healthy controls were selected from population for regular physical examination in the hospital. The levels of PAI-1 and TGF-β were measured by enzyme

  13. Post-transcriptional regulation of Transforming Growth Factor Beta-1 by microRNA-744.

    Directory of Open Access Journals (Sweden)

    John Martin

    Full Text Available Transforming Growth Factor Beta-1 (TGF-β1 is a pleiotropic cytokine that is of central importance in wound healing, inflammation, and in key pathological processes including cancer and progressive tissue fibrosis. TGF-β1 is post-transcriptionally regulated, but the underlying mechanisms remain incompletely defined. Previously, we have extensively delineated post-transcriptional regulation of TGF-β1 synthesis in the kidney, with evidence for relief of translational repression in proximal tubular cells in the context of diabetic nephropathy. In this study, we have investigated the role of the TGF-β1 3'Untranslated Region (3'UTR. Two different 3'UTR lengths have been reported for TGF-β1, of 543 and 137 nucleotides. Absolute quantification showed that, while both UTR lengths were detectable in various human cell types and in a broad range of tissues, the short form predominated in the kidney and elsewhere. Expression of both forms was up-regulated following auto-induction by TGF-β1, but the short:long UTR ratio remained constant. Incorporation of the short UTR into a luciferase reporter vector significantly reduced reporter protein synthesis without major effect on RNA amount, suggesting post-transcriptional inhibition. In silico approaches identified multiple binding sites for miR-744 located in the proximal TGF-β1 3'UTR. A screen in RNA from human tissues showed widespread miR-744 expression. miR-744 transfection inhibited endogenous TGF-β1 synthesis, while direct targeting of TGF-β1 was shown in separate experiments, in which miR-744 decreased TGF-β1 3'UTR reporter activity. This work identifies miR-744-directed post-transcriptional regulation of TGF-β1 which, given the pleiotropic nature of cellular responses to TGF-β1, is potentially widely significant.

  14. Roles for transforming growth factor beta superfamily proteins in early folliculogenesis.

    Science.gov (United States)

    Trombly, Daniel J; Woodruff, Teresa K; Mayo, Kelly E

    2009-01-01

    Primordial follicle formation and the subsequent transition of follicles to the primary and secondary stages encompass the early events during folliculogenesis in mammals. These processes establish the ovarian follicle pool and prime follicles for entry into subsequent growth phases during the reproductive cycle. Perturbations during follicle formation can affect the size of the primordial follicle pool significantly, and alterations in follicle transition can cause follicles to arrest at immature stages or result in premature depletion of the follicle reserve. Determining the molecular events that regulate primordial follicle formation and early follicle growth may lead to the development of new fertility treatments. Over the last decade, many of the growth factors and signaling proteins that mediate the early stages of folliculogenesis have been identified using mouse genetic models, in vivo injection studies, and ex vivo organ culture approaches. These studies reveal important roles for the transforming growth factor beta (TGF-beta) superfamily of proteins in the ovary. This article reviews these roles for TGF-beta family proteins and focuses in particular on work from our laboratories on the functions of activin in early folliculogenesis.

  15. Regulation of duodenal bicarbonate secretion during stress by corticotropin-releasing factor and beta-endorphin.

    Science.gov (United States)

    Lenz, H J

    1989-02-01

    Proximal duodenal mucosal bicarbonate secretion is an important factor in the pathogenesis of duodenal ulcer disease. To examine the central nervous system regulation of duodenal bicarbonate secretion, an animal model was developed that allowed cerebroventricular and intravenous injections as well as collection of duodenal perfusates in awake, freely moving rats. The hypothalamic peptide corticotropin-releasing factor (CRF) and stress (physical restraint) significantly stimulated duodenal bicarbonate secretion. These responses were abolished by pretreatment of the animals with the CRF receptor antagonist alpha-helical CRF-(9-41), hypophysectomy, and naloxone. In contrast, blockade of autonomic efferents by surgical and pharmacological means did not prevent the stimulatory effects of stress and CRF. Intravenous, but not cerebroventricular, administration of beta-endorphin that produced plasma concentrations of beta-endorphin that were similar to those produced by exogenous CRF and stress significantly stimulated duodenal bicarbonate secretion. These results indicate that endogenous CRF released during stress and exogenously administered CRF stimulate duodenal bicarbonate secretion by release of beta-endorphin from the pituitary, thus, demonstrating a functional hypothalamus-pituitary-gut axis.

  16. Beta Cell Formation in vivo Through Cellular Networking, Integration and Processing (CNIP) in Wild Type Adult Mice.

    Science.gov (United States)

    Doiron, Bruno; Hu, Wenchao; DeFronzo, Ralph A

    2016-01-01

    Insulin replacement therapy is essential in type 1 diabetic individuals and is required in ~40- 50% of type 2 diabetics during their lifetime. Prior attempts at beta cell regeneration have relied upon pancreatic injury to induce beta cell proliferation, dedifferentiation and activation of the embryonic pathway, or stem cell replacement. We report an alternative method to transform adult non-stem (somatic) cells into pancreatic beta cells. The Cellular Networking, Integration and Processing (CNIP) approach targets cellular mechanisms involved in pancreatic function in the organ's adult state and utilizes a synergistic mechanism that integrates three important levels of cellular regulation to induce beta cell formation: (i) glucose metabolism, (ii) membrane receptor function, and (iii) gene transcription. The aim of the present study was to induce pancreatic beta cell formation in vivo in adult animals without stem cells and without dedifferentiating cells to recapitulate the embryonic pathway as previously published (1-3). Our results employing CNIP demonstrate that: (i) insulin secreting cells can be generated in adult pancreatic tissue in vivo and circumvent the problem of generating endocrine (glucagon and somatostatin) cells that exert deleterious effects on glucose homeostasis, and (ii) longterm normalization of glucose tolerance and insulin secretion can be achieved in a wild type diabetic mouse model. The CNIP cocktail has the potential to be used as a preventative or therapeutic treatment or cure for both type 1 and type 2 diabetes.

  17. Selective destruction of mouse islet beta cells by human T lymphocytes in a newly-established humanized type 1 diabetic model

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Yong, E-mail: yongzhao@uic.edu [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Guo, Chengshan; Hwang, David; Lin, Brian; Dingeldein, Michael; Mihailescu, Dan; Sam, Susan; Sidhwani, Seema [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Zhang, Yongkang [Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Jain, Sumit [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Skidgel, Randal A. [Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Prabhakar, Bellur S. [Department of Immunology and Microbiology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Mazzone, Theodore [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Holterman, Mark J. [Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612 (United States)

    2010-09-03

    Research highlights: {yields} Establish a human immune-mediated type 1 diabetic model in NOD-scid IL2r{gamma}{sup null} mice. {yields} Using the irradiated diabetic NOD mouse spleen mononuclear cells as trigger. {yields} The islet {beta} cells were selectively destroyed by infiltrated human T cells. {yields} The model can facilitate translational research to find a cure for type 1 diabetes. -- Abstract: Type 1 diabetes (T1D) is caused by a T cell-mediated autoimmune response that leads to the loss of insulin-producing {beta} cells. The optimal preclinical testing of promising therapies would be aided by a humanized immune-mediated T1D model. We develop this model in NOD-scid IL2r{gamma}{sup null} mice. The selective destruction of pancreatic islet {beta} cells was mediated by human T lymphocytes after an initial trigger was supplied by the injection of irradiated spleen mononuclear cells (SMC) from diabetic nonobese diabetic (NOD) mice. This resulted in severe insulitis, a marked loss of total {beta}-cell mass, and other related phenotypes of T1D. The migration of human T cells to pancreatic islets was controlled by the {beta} cell-produced highly conserved chemokine stromal cell-derived factor 1 (SDF-1) and its receptor C-X-C chemokine receptor (CXCR) 4, as demonstrated by in vivo blocking experiments using antibody to CXCR4. The specificity of humanized T cell-mediated immune responses against islet {beta} cells was generated by the local inflammatory microenvironment in pancreatic islets including human CD4{sup +} T cell infiltration and clonal expansion, and the mouse islet {beta}-cell-derived CD1d-mediated human iNKT activation. The selective destruction of mouse islet {beta} cells by a human T cell-mediated immune response in this humanized T1D model can mimic those observed in T1D patients. This model can provide a valuable tool for translational research into T1D.

  18. Species used for drug testing reveal different inhibition susceptibility for 17beta-hydroxysteroid dehydrogenase type 1.

    Directory of Open Access Journals (Sweden)

    Gabriele Möller

    Full Text Available Steroid-related cancers can be treated by inhibitors of steroid metabolism. In searching for new inhibitors of human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD 1 for the treatment of breast cancer or endometriosis, novel substances based on 15-substituted estrone were validated. We checked the specificity for different 17beta-HSD types and species. Compounds were tested for specificity in vitro not only towards recombinant human 17beta-HSD types 1, 2, 4, 5 and 7 but also against 17beta-HSD 1 of several other species including marmoset, pig, mouse, and rat. The latter are used in the processes of pharmacophore screening. We present the quantification of inhibitor preferences between human and animal models. Profound differences in the susceptibility to inhibition of steroid conversion among all 17beta-HSDs analyzed were observed. Especially, the rodent 17beta-HSDs 1 were significantly less sensitive to inhibition compared to the human ortholog, while the most similar inhibition pattern to the human 17beta-HSD 1 was obtained with the marmoset enzyme. Molecular docking experiments predicted estrone as the most potent inhibitor. The best performing compound in enzymatic assays was also highly ranked by docking scoring for the human enzyme. However, species-specific prediction of inhibitor performance by molecular docking was not possible. We show that experiments with good candidate compounds would out-select them in the rodent model during preclinical optimization steps. Potentially active human-relevant drugs, therefore, would no longer be further developed. Activity and efficacy screens in heterologous species systems must be evaluated with caution.

  19. Ketosis-prone type 2 diabetes in patients of sub-Saharan African origin: clinical pathophysiology and natural history of beta-cell dysfunction and insulin resistance.

    Science.gov (United States)

    Mauvais-Jarvis, Franck; Sobngwi, Eugène; Porcher, Raphaël; Riveline, Jean-Pierre; Kevorkian, Jean-Philippe; Vaisse, Christian; Charpentier, Guillaume; Guillausseau, Pierre-Jean; Vexiau, Patrick; Gautier, Jean-François

    2004-03-01

    Nonautoimmune ketosis-prone diabetic syndromes are increasingly frequent in nonwhite populations. We have characterized a cohort of patients of sub-Saharan African origin who had ketosis-prone type 2 diabetes (n = 111), type 1 diabetes (n = 21), and type 2 diabetes (n = 88) and were admitted to a hospital for management of uncontrolled diabetes. We compared epidemiological, clinical, and metabolic features at diabetes onset and measured insulin secretion (glucagon-stimulated C-peptide) and insulin action (short intravenous insulin tolerance test) during a 10-year follow-up. Ketosis-prone type 2 diabetes shows a strong male predominance, stronger family history, higher age and BMI, and more severe metabolic decompensation than type 1 diabetes. In ketosis-prone type 2 diabetes, discontinuation of insulin therapy with development of remission of insulin dependence is achieved in 76% of patients (non-insulin dependent), whereas only 24% of patients remain insulin dependent. During evolution, ketosis-prone type 2 diabetes exhibit specific beta-cell dysfunction features that distinguish it from type 1 and type 2 diabetes. The clinical course of non-insulin-dependent ketosis-prone type 2 diabetes is characterized by ketotic relapses followed or not by a new remission. Progressive hyperglycemia precedes and is a strong risk factor for ketotic relapses (hazard ratio 38). The probability for non-insulin-dependent ketosis-prone type 2 diabetes to relapse is 90% within 10 years, of whom approximately 50% will become definitively insulin dependent. Insulin sensitivity is decreased in equal proportion in both ketosis-prone type 2 diabetes and type 2 diabetes, but improves significantly in non-insulin-dependent ketosis-prone type 2 diabetes, only after correction of hyperglycemia. In conclusion, ketosis-prone type 2 diabetes can be distinguished from type 1 diabetes and classical type 2 diabetes by specific features of clinical pathophysiology and also by the natural history of

  20. Molecular mechanisms associated with increased fetal hemoglobin G gamma-type in part-aboriginal family with beta thalassemia.

    Science.gov (United States)

    Motum, P I; Lammi, A; Trent, R J

    1989-07-01

    A part-Aboriginal family with beta thalassemia and raised hemoglobin F (HbF) was studied at the molecular level to determine if there were identifiable gene changes associated with increased production of HbF. Two beta thalassemia heterozygotes aged eight years and 18 months had raised HbF levels of 2.9% and 22% respectively. HbF was predominantly G gamma in composition. Five family members were typed for restriction fragment length polymorphisms (RFLPs) using nine restriction enzymes and five DNA probes specific for the beta globin cluster on chromosome 11. RFLPs were combined to construct haplotypes for the beta thalassemia and the high HbF defects. A beta globin subhaplotype comprising only 5' RFLP markers (-(+)-(+) +) co-segregated with the high HbF determinant. This has previously been associated with increased G gamma expression in beta thalassemia and sickle cell anemia. An additional Xmnl RFLP 5' to the G gamma gene, which has been described in individuals with elevated G gamma expression, was also demonstrated in those family members with increased G gamma levels. In this study both the 5' beta globin subhaplotype (-(+)-(+) +) and the Xmnl/gamma RFLP are present in the one family but the relative contributions of each cannot be determined.

  1. 17beta-hydroxysteroid dehydrogenase Type 1, and not Type 12, is a target for endocrine therapy of hormone-dependent breast cancer.

    Science.gov (United States)

    Day, Joanna M; Foster, Paul A; Tutill, Helena J; Parsons, Michael F C; Newman, Simon P; Chander, Surinder K; Allan, Gillian M; Lawrence, Harshani R; Vicker, Nigel; Potter, Barry V L; Reed, Michael J; Purohit, Atul

    2008-05-01

    Oestradiol (E2) stimulates the growth of hormone-dependent breast cancer. 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyse the pre-receptor activation/inactivation of hormones and other substrates. 17beta-HSD1 converts oestrone (E1) to active E2, but it has recently been suggested that another 17beta-HSD, 17beta-HSD12, may be the major enzyme that catalyses this reaction in women. Here we demonstrate that it is 17beta-HSD1 which is important for E2 production and report the inhibition of E1-stimulated breast tumor growth by STX1040, a non-oestrogenic selective inhibitor of 17beta-HSD1, using a novel murine model. 17beta-HSD1 and 17beta-HSD12 mRNA and protein expression, and E2 production, were assayed in wild type breast cancer cell lines and in cells after siRNA and cDNA transfection. Although 17beta-HSD12 was highly expressed in breast cancer cell lines, only 17beta-HSD1 efficiently catalysed E2 formation. The effect of STX1040 on the proliferation of E1-stimulated T47D breast cancer cells was determined in vitro and in vivo. Cells inoculated into ovariectomised nude mice were stimulated using 0.05 or 0.1 microg E1 (s.c.) daily, and on day 35 the mice were dosed additionally with 20 mg/kg STX1040 s.c. daily for 28 days. STX1040 inhibited E1-stimulated proliferation of T47D cells in vitro and significantly decreased tumor volumes and plasma E2 levels in vivo. In conclusion, a model was developed to study the inhibition of the major oestrogenic 17beta-HSD, 17beta-HSD1, in breast cancer. Both E2 production and tumor growth were inhibited by STX1040, suggesting that 17beta-HSD1 inhibitors such as STX1040 may provide a novel treatment for hormone-dependent breast cancer.

  2. A functional connection between pRB and transforming growth factor beta in growth inhibition and mammary gland development.

    Science.gov (United States)

    Francis, Sarah M; Bergsied, Jacqueline; Isaac, Christian E; Coschi, Courtney H; Martens, Alison L; Hojilla, Carlo V; Chakrabarti, Subrata; Dimattia, Gabriel E; Khoka, Rama; Wang, Jean Y J; Dick, Frederick A

    2009-08-01

    Transforming growth factor beta (TGF-beta) is a crucial mediator of breast development, and loss of TGF-beta-induced growth arrest is a hallmark of breast cancer. TGF-beta has been shown to inhibit cyclin-dependent kinase (CDK) activity, which leads to the accumulation of hypophosphorylated pRB. However, unlike other components of TGF-beta cytostatic signaling, pRB is thought to be dispensable for mammary development. Using gene-targeted mice carrying subtle missense changes in pRB (Rb1(DeltaL) and Rb1(NF)), we have discovered that pRB plays a critical role in mammary gland development. In particular, Rb1 mutant female mice have hyperplastic mammary epithelium and defects in nursing due to insensitivity to TGF-beta growth inhibition. In contrast with previous studies that highlighted the inhibition of cyclin/CDK activity by TGF-beta signaling, our experiments revealed that active transcriptional repression of E2F target genes by pRB downstream of CDKs is also a key component of TGF-beta cytostatic signaling. Taken together, our work demonstrates a unique functional connection between pRB and TGF-beta in growth control and mammary gland development.

  3. The change of transforming growth factor {beta} 1 (TGF- {beta} 1) expression by melatonin in irradiated lung

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Seong Soon; Choi, Ihl Bohng [College of Medicine, The Catholic University of Korea, Seoul (Korea, Republic of)

    2005-09-15

    The changed expressions of TGF- {beta} 1, as a key cytokine in the fibrotic process, due to melatonin with potent antioxidative effects, were investigated in the irradiated lung using fibrosis-sensitive C57BL/6 mice. Female C57BL/6 mice were divided into control irradiation-only, and melatonin (300 mg/kg i.p. 1 hr before irradiation) pretreatment groups. The thoraces of the mice were irradiated with a single dose of 12 Gy. The mRNA expressions of TGF-{beta} 1 in the lung tissue 2 and 4 weeks after irradiation were quantified using semiquantitive RT-PCR, and the cellular origin and expression levels of TGF- {beta} 1 protein were identified using immunohistochemical staining. The relative mRNA expression levels in the irradiation-only and melatonin pretreatment group 2 and 4 weeks after irradiation were 1.92- and 1.80-fold ({rho} = 0.064) and 2.38- and 1.94-fold ({rho} = 0.004) increased, respectively compared to those in the control group. Increased expressions of TGF- {beta} 1 protein were prominently detected in regions of histopathological radiation injury, with alveolar macrophages and septal epithelial cells serving as important sources of TGF- {beta} 1 expression. At 2 and 4 weeks after irradiation, the expression levels of protein were 15.8% vs. 16.9% ({rho} = 0.565) and 36.1% vs. 25.7% ({rho} = 0.009), respectively. The mRNA and protein expressions of TGF- {beta} 1 in the lung tissue following thoracic irradiation with 12 Gy were significantly decreased by melatonin pretreatment at 4 weeks. These results indicate that melatonin may have a possible application as an antifibrotic agent in radiation-induced lung injury.

  4. Inflammatory cytokine signaling in insulin producing beta-cells enhances the colocalization correlation coefficient between L-type voltage-dependent calcium channel and calcium-sensing receptor.

    Science.gov (United States)

    Parkash, Jai

    2008-08-01

    The immunological processes in type 1 diabetes and metabolic/inflammatory disorder in type 2 diabetes converge on common signaling pathway(s) leading to beta-cell death in these two diseases. The cytokine-mediated beta-cell death seems to be dependent on voltage-dependent calcium channel (VDCC)-mediated Ca2+ entry. The Ca2+ handling molecular networks control the homeostasis of [Ca2+]i in the beta-cell. The activity and membrane density of VDCC are regulated by several mechanisms including G protein-coupled receptors (GPCRs). CaR is a 123-kDa seven transmembrane extracellular Ca2+ sensing protein that belongs to GPCR family C. Tumor necrosis factor-alpha (TNF-alpha), is a cytokine widely known to activate nuclear factor-kappaB (NF-kappaB) transcription in beta-cells. To obtain a better understanding of TNF-alpha-induced molecular interactions between CaR and VDCC, confocal fluorescence measurements were performed on insulin-producing beta-cells exposed to varying concentrations of TNF-alpha and the results are discussed in the light of increased colocalization correlation coefficient. The insulin producing beta-cells were exposed to 5, 10, 20, 30, and 50 ng/ml TNF-alpha for 24 h at 37 degrees . The cells were then immunolabelled with antibodies directed against CaR, VDCC, and NF-kappaB. The confocal fluorescence imaging data showed enhancement in the colocalization correlation coefficient between CaR and VDCC in beta-cells exposed to TNF-alpha thereby indicating increased membrane delimited spatial interactions between these two membrane proteins. TNF-alpha-induced colocalization of VDCC with CaR was inhibited by nimodipine, an inhibitor of L-type VDCC thereby suggesting that VDCC activity is required for spatial interactions with CaR. The 3-D confocal fluorescence imaging data also demonstrated that addition of TNF-alpha to RIN cells led to the translocation of NF-kappaB from the cytoplasm to the nucleus. Such molecular interactions between CaR and VDCC in tissues

  5. Type III factors with unique Cartan decomposition

    CERN Document Server

    Houdayer, Cyril

    2012-01-01

    We prove that for any free ergodic nonsingular nonamenable action \\Gamma\\ \\actson (X,\\mu) of all \\Gamma\\ in a large class of groups including all hyperbolic groups, the associated group measure space factor $L^\\infty(X) \\rtimes \\Gamma$ has L^\\infty(X) as its unique Cartan subalgebra, up to unitary conjugacy. This generalizes the probability measure preserving case that was established in [PV12]. We also prove primeness and indecomposability results for such crossed products, for the corresponding orbit equivalence relations and for arbitrary amalgamated free products $M_1 *_B M_2$ over a subalgebra B of type I.

  6. Translation initiation factor (iso) 4E interacts with BTF3, the beta subunit of the nascent polypeptide-associated complex.

    Science.gov (United States)

    Freire, Miguel Angel

    2005-01-31

    A two-hybrid screen with the translation initiation factor, eIF(iso)4E from Arabidopsis, identified a clone encoding a lipoxygenase type 2 [Freire, M.A., et al., 2000. Plant lipoxygenase 2 is a translation initiation factor-4E-binding protein. Plant Molecular Biology 44, 129-140], and three cDNA clones encoding the homologue of the mammalian BTF3 factor, the beta subunit of the nascent polypeptide-associated complex (NAC). Here we report on the interaction between the translation initiation factor eIF(iso)4E and AtBTF3. AtBTF3 protein is able to interact with the wheat initiation factors eIF4E and eIF(iso)4E. AtBTF3 contains a sequence related to the prototypic motif found on most of the 4E-binding proteins, and competes with the translation initiation factor eIF(iso)4G for eIF4(iso)4E binding, in a two hybrid interference assay. These findings provide a molecular link between the translation initiation mechanism and the emergence of the nascent polypeptide chains.

  7. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.

    Science.gov (United States)

    Jourdan, Tony; Godlewski, Grzegorz; Cinar, Resat; Bertola, Adeline; Szanda, Gergő; Liu, Jie; Tam, Joseph; Han, Tiffany; Mukhopadhyay, Bani; Skarulis, Monica C; Ju, Cynthia; Aouadi, Myriam; Czech, Michael P; Kunos, George

    2013-09-01

    Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB₁Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB₁R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB₁R-deficient (Cnr1(-/-)) or Nlrp3(-/-) mice, with the endocannabinoid anandamide. Peripheral CB₁R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB₁R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB₁R as a therapeutic target in T2DM.

  8. Interaction of Plasminogen Activator Inhibitor-2 and Proteasome Subunit, Beta Type 1

    Institute of Scientific and Technical Information of China (English)

    JingFAN; Yu-QingZHANG; PingLI; MinHOU; LiTAN; XiaWANG; Yun-SongZHU

    2004-01-01

    The apoptosis protection by plasminogen activator inhibitor-2(PAI-2) is dependent on a 33 amino acid fragment between helix C and D of PAI-2 which is probably due to the interaction of PAI-2 with unknown intracellular proteins. In this study, we used the fragment between helix C and D of PAI-2 as bait to screen a HeLa cell cDNA library constructed during apoptosis in a yeast two-hybrid system and retrieved a clone encoding 241 amino acids of proteasome (prosome, macropain) subunit, beta type 1(PSMβ1) which plays important roles in NF-κB activation. GST-pulldown experiments confirmed the interaction between PAI-2 and PSMβ1 in vitro. These data suggest that the antiapoptosis activity of PAI-2 is probably related to its interation with PSMβ1.

  9. Interactions between PPAR Gamma and the Canonical Wnt/Beta-Catenin Pathway in Type 2 Diabetes and Colon Cancer

    Science.gov (United States)

    Claes, Victor

    2017-01-01

    In both colon cancer and type 2 diabetes, metabolic changes induced by upregulation of the Wnt/beta-catenin signaling and downregulation of peroxisome proliferator-activated receptor gamma (PPAR gamma) may help account for the frequent association of these two diseases. In both diseases, PPAR gamma is downregulated while the canonical Wnt/beta-catenin pathway is upregulated. In colon cancer, upregulation of the canonical Wnt system induces activation of pyruvate dehydrogenase kinase and deactivation of the pyruvate dehydrogenase complex. As a result, a large part of cytosolic pyruvate is converted into lactate through activation of lactate dehydrogenase. Lactate is extruded out of the cell by means of activation of monocarboxylate lactate transporter-1. This phenomenon is called Warburg effect. PPAR gamma agonists induce beta-catenin inhibition, while inhibition of the canonical Wnt/beta-catenin pathway activates PPAR gamma.

  10. 11Beta-hydroxysteroid dehydrogenase type 2 in human pregnancy and reduced expression in intrauterine growth restriction.

    Science.gov (United States)

    Shams, M; Kilby, M D; Somerset, D A; Howie, A J; Gupta, A; Wood, P J; Afnan, M; Stewart, P M

    1998-04-01

    The type 2 isoform of 11beta-hydroxysteroid dehydrogenase (11beta-HSD2), which inactivates cortisol (F) to cortisone (E), has been suggested to play a role in the ontogeny of the fetal pituitary-adrenal axis and also protect the developing fetus from the deleterious effects of circulating maternal glucocorticoids. The abundance of 11beta-HSD2 in the placenta and other fetal tissues was inferred from the F/E ratio in 17 term deliveries in both umbilical arterial (1.73 +/- 0.24, mean +/- SE) and umbilical venous blood (1.16 +/- 0.14) compared with adult peripheral venous blood (7.76 +/- 0.57, n = 70). Using sensitive assays for 11beta-HSD2 and an in-house human 11beta-HSD2 antibody, the expression and activity of this enzyme in fresh frozen human placenta increased progressively from first (8-12 weeks, n = 16) and second (13-20 weeks, n = 9) to third trimester (term) pregnancies (39-40 weeks, n = 50). Placental 11beta-HSD2 activity was significantly reduced in deliveries complicated by intrauterine growth restriction (IUGR) [25-36 weeks, n = 12, activity 380 pmol/mg/h median (225-671; 95% confidence interval)], compared with the term deliveries [888 (725-1362)] and with appropriately grown pre-term deliveries [27-36 weeks, n = 14, activity 810 (585-1269)], P < 0.05. In human pregnancy placental 11beta-HSD2 activity increases markedly in the third trimester of pregnancy at a time when maternal circulating levels of glucocorticoid are rising. The finding of attenuated placental 11beta-HSD2 activity in IUGR suggests that glucocorticoids may, in part, contribute to impaired fetal growth and that this is closely controlled in normal gestation through placental 11beta-HSD2 expression.

  11. In vivo activity of 11beta-hydroxysteroid dehydrogenase type 1 and free fatty acid-induced insulin resistance.

    Science.gov (United States)

    Mai, K; Kullmann, V; Bobbert, T; Maser-Gluth, C; Möhlig, M; Bähr, V; Pfeiffer, A F H; Spranger, J; Diederich, S

    2005-10-01

    Free fatty acids (FFAs) induce hepatic insulin resistance and enhance hepatic gluconeogenesis. Glucocorticoids (GCs) also stimulate hepatic gluconeogenesis. The aim of this study was to investigate whether the FFA-induced hepatic insulin resistance is mediated by increased activity of hepatic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), accompanied by elevated hepatic cortisol levels. Following a 10-h overnight fast, six healthy male volunteers were investigated. A euglycaemic hyperinsulinaemic clamp was performed during lipid or saline infusion. To assess hepatic 11beta-HSD1 activity, plasma cortisol levels were measured after oral administration of cortisone acetate during lipid or saline infusion. In addition, 11beta-HSD activities were determined in vivo by calculating the urinary ratios of GC metabolites. Lipid infusion increased FFAs (5.41 +/- 1.00 vs. 0.48 +/- 0.20 mmol/l; P < 0.005) and significantly increased insulin resistance [glucose infusion rate (GIR) 6.02 +/- 2.60 vs. 4.08 +/- 2.15 mg/kg/min; P < 0.005]. After lipid and saline infusions no changes in 11beta-HSD1 activity were found, neither by changes in cortisone acetate to cortisol conversion nor by differences in urinary free cortisol (UFF) or cortisone (UFE), 5beta-tetrahydrocortisol (THF), 5alpha-THF, cortisone (THE), UFF/UFE and (5alpha-THF + THF)/THE ratios. We found no change in hepatic and whole-body 11beta-HSD1 activity during acute FFA-induced insulin resistance. Further studies are necessary to clarify whether 11beta-HSD1 in muscle and adipose tissue is influenced by FFAs and whether 11beta-HSD1 is involved in other conditions of insulin resistance.

  12. Troglitazone stimulates {beta}-arrestin-dependent cardiomyocyte contractility via the angiotensin II type 1{sub A} receptor

    Energy Technology Data Exchange (ETDEWEB)

    Tilley, Douglas G., E-mail: douglas.tilley@jefferson.edu [Department of Pharmaceutical Sciences, Jefferson School of Pharmacy, Thomas Jefferson University (United States); Center for Translational Medicine, Thomas Jefferson University (United States); Nguyen, Anny D. [Department of Pharmaceutical Sciences, Jefferson School of Pharmacy, Thomas Jefferson University (United States); Rockman, Howard A. [Department of Medicine, Duke University Medical Center (United States); Department of Cell Biology, Duke University Medical Center (United States); Department of Molecular Genetics and Microbiology, Duke University Medical Center (United States)

    2010-06-11

    Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonists are commonly used to treat cardiovascular diseases, and are reported to have several effects on cardiovascular function that may be due to PPAR{gamma}-independent signaling events. Select angiotensin receptor blockers (ARBs) interact with and modulate PPAR{gamma} activity, thus we hypothesized that a PPAR{gamma} agonist may exert physiologic effects via the angiotensin II type 1{sub A} receptor (AT1{sub A}R). In AT1{sub A}R-overexpressing HEK 293 cells, both angiotensin II (Ang II) and the PPAR{gamma} agonist troglitazone (Trog) enhanced AT1{sub A}R internalization and recruitment of endogenous {beta}-arrestin1/2 ({beta}arr1/2) to the AT1{sub A}R. A fluorescence assay to measure diacylglycerol (DAG) accumulation showed that although Ang II induced AT1{sub A}R-G{sub q} protein-mediated DAG accumulation, Trog had no impact on DAG generation. Trog-mediated recruitment of {beta}arr1/2 was selective to AT1{sub A}R as the response was prevented by an ARB- and Trog-mediated {beta}arr1/2 recruitment to {beta}1-adrenergic receptor ({beta}1AR) was not observed. In isolated mouse cardiomyocytes, Trog increased both % and rate of cell shortening to a similar extent as Ang II, effects which were blocked with an ARB. Additionally, these effects were found to be {beta}arr2-dependent, as cardiomyocytes isolated from {beta}arr2-KO mice showed blunted contractile responses to Trog. These findings show for the first time that the PPAR{gamma} agonist Trog acts at the AT1{sub A}R to simultaneously block G{sub q} protein activation and induce the recruitment of {beta}arr1/2, which leads to an increase in cardiomyocyte contractility.

  13. Menin expression is regulated by transforming growth factor beta signaling in leukemia cells

    Institute of Scientific and Technical Information of China (English)

    ZHANG Hui; LIU Zu-guo; HUA Xian-xin

    2011-01-01

    Background Menin is a ubiquitously expressed protein encoded by the multiple endocrine neoplasia type 1 (MEN1)gene. Besides its importance in endocrine organs, menin has been shown to interact with the mixed lineage leukemia (MLL) protein, a histone H3 lysine 4 methyltransferase, and plays a critical role in hematopoiesis and leukemogenesis.Previous studies have shown that menin promotes transforming growth factor beta (TGF-β) signaling in endocrine cells.However, little is known regarding the impact of TGF-β pathway on menin in hematopoietic system. Here, with leukemia cell lines generated from conditional MEN1 or TGF-p receptor (TβRII) knockout mouse models, we investigated the possible cross-talk of these two pathways in leukemia cells.Methods MEN1 or TβRII conditional knockout mice were bred and the bone marrow cells were transduced with retroviruses expressing oncogeneic MLL-AF9 (a mixed lineage leukemia fusion protein) to generate two leukemia cell lines. Cell proliferation assays were performed to investigate the effect of TGF-β treatment on MLL-AF9 transformed leukemia cells with/without MEN1 or TβRII excision. Menin protein was detected with Western blotting and mRNA levels of cell proliferation-related genes Cyclin A2 and Cyclin E2 were examined with real-time RT-PCR for each treated sample.In vivo effect of TGF-p signal on menin expression was also investigated in mouse liver tissue after TβRII excision.Results TGF-β not only inhibited the proliferation of wild type MLL-AF9 transformed mouse bone marrow cells, but also up-regulated menin expression in these cells. Moreover, TGF-P failed to further inhibit the proliferation of Men1-null cells as compared to Men1-expressing control cells. Furthermore, excision of TβRII, a vital component in TGF-β signaling pathway, down-regulated menin expression in MLL-AF9 transformed mouse bone marrow cells. In vivo data also confirmed that menin expression was decreased in liver samples of conditional T

  14. Therapeutic and epidemiologic recommendations to reduce the spread of type-I beta-lactamase resistance.

    Science.gov (United States)

    Neu, H C; Duma, R J; Jones, R N; McGowan, J E; O'Brien, T F; Sabath, L D; Sanders, C C; Schaffner, W; Tenover, F C; Young, L S

    1992-02-01

    The objectives of this United States Consensus Panel meeting were to evaluate the effectiveness of current surveillance systems for the detection of bacterial resistance as well as to formulate recommendations that can assist hospitals in determining actions that should be taken when a resistance problem is detected. These recommendations may be particularly helpful in controlling the emergence and spread of type-I beta-lactamase resistance. Numerous case reports of antimicrobial resistance among Enterobacter species, Pseudomonas aeruginosa, and other Gram-negative nosocomial pathogens known to produce type-I beta-lactamases have appeared in the literature since the introduction of the newer "third-generation" cephalosporins. The widespread use of these newer antimicrobial agents, often selected as standard therapy for serious hospital-acquired infections, has been associated with a corresponding increase in resistance to them. The failure of hospitalwide surveillance methods to describe the scope of this problem, especially among the most critically ill patients, may have resulted in a false sense of security among some infectious disease specialists and clinicians prescribing these antimicrobials as empiric therapy. High-level resistance in individual hospital units may be masked in hospitalwide antibiograms. A variety of conclusions and recommendations were formulated based on the collective experiences of the Consensus Panel members. Microbiology laboratories must make it a high priority to identify markers that will assist in rapidly identifying resistant organisms. Cooperative efforts are needed among users of commercial and automated microbiology test instruments to standardize results and to improve quality control, thereby making the data more directly comparable between laboratories.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Plasma pre beta-HDL formation is decreased by atorvastatin treatment in type 2 diabetes mellitus : Role of phospholipid transfer protein

    NARCIS (Netherlands)

    Dallinga-Thie, G. M.; van Tol, A.; Dullaart, R. P. F.

    2009-01-01

    Atorvastatin lowers plasma phospholipid transfer protein (PLTP) activity, which stimulates pre-beta-HDL, generation in vitro. We determined the effect of atorvastatin on pre-beta-HDL formation and its relation with PLTP activity in type 2 diabetes. Methods: Plasma pre-beta-HDL formation as well as p

  16. Amyloid beta-induced nerve growth factor dysmetabolism in Alzheimer disease.

    Science.gov (United States)

    Bruno, Martin A; Leon, Wanda C; Fragoso, Gabriela; Mushynski, Walter E; Almazan, Guillermina; Cuello, A Claudio

    2009-08-01

    We previously reported that the precursor form of nerve growth factor (pro-NGF) and not mature NGF is liberated in the CNS in an activity-dependent manner, and that its maturation and degradation occur in the extracellular space by the coordinated action of proteases.Here, we present evidence of diminished conversion of pro-NGF to its mature form and of greater NGF degradation in Alzheimer disease (AD) brain samples compared with controls. These alterations of the NGF metabolic pathway likely resulted in the increased pro-NGF levels. The pro-NGF was largely in a peroxynitrited form in the AD samples. Intrahippocampal injection of amyloid-beta oligomers provoked similar upregulation of pro-NGF in naive rats that was accompanied by evidence of microglial activation (CD40), increased levels of inducible nitric oxide synthase, and increased activity of the NGF-degrading enzyme matrix metalloproteinase 9. The elevated inducible nitric oxide synthase provoked the generation of biologically inactive, peroxynitrite-modified pro-NGF in amyloid-beta oligomer-injected rats. These parameters were corrected by minocycline treatment. Minocycline also diminished altered matrix metalloproteinase 9, inducible nitric oxide synthase, and microglial activation (CD40); improved cognitive behavior; and normalized pro-NGF levels in a transgenic mouse AD model. The effects of amyloid-beta amyloid CNS burden on NGF metabolism may explain the paradoxical upregulation of pro-NGF in AD accompanied by atrophy of forebrain cholinergic neurons.

  17. Estrogen receptors (alpha and beta) and 17beta-hydroxysteroid dehydrogenase type 1 and 2 in thyroid disorders: possible in situ estrogen synthesis and actions.

    Science.gov (United States)

    Kawabata, Wakako; Suzuki, Takashi; Moriya, Takuya; Fujimori, Keisei; Naganuma, Hiroshi; Inoue, Satoshi; Kinouchi, Yositaka; Kameyama, Kaori; Takami, Hiroshi; Shimosegawa, Tooru; Sasano, Hironobu

    2003-05-01

    Both epidemiological and experimental findings suggest the possible roles of sex steroids in the pathogenesis and/or development of various human thyroid disorders. In this study, we evaluated the expression of estrogen receptors (ER) alpha and beta in normal thyroid glands (N = 25; female: n = 13, male: n = 10, unknown: n = 2) ranging in age from fetus to adult. Furthermore, using immunohistochemistry, we investigated the expression of ERalpha and beta in 206 cases of thyroid disorders, including 24 adenomatous goiters, 23 follicular adenomas, and 159 thyroid carcinomas. In addition, we also studied the mRNA expression of ERalpha and beta and 17beta-hydroxysteroid dehydrogenase Type 1 and 2, enzymes involved in the interconversion between estrone and estradiol, using reverse transcription polymerase chain reaction (RT-PCR), in 48 of these 206 cases (10 adenomatous goiters, 10 follicular adenomas, and 28 papillary thyroid carcinomas) in which fresh frozen tissues were available for examination to further elucidate the possible involvement of intracrine estrogen metabolism and/or actions in thyroid disorders. ERalpha labeling index, or percentage of cells immunopositive for ERalpha, was significantly higher in adenomatous goiter (14.2 +/- 6.4), follicular adenoma (13.4 +/- 5.1), and thyroid carcinoma (16.4 +/- 2.1) than in normal thyroid gland (0; P thyroid glands. In papillary carcinoma, ERalpha labeling index was significantly higher in premenopausal women (28.1 +/- 4.5) than in postmenopausal women (14.2 +/- 2.9) and in men of various ages (7.6 +/- 2.7; P thyroid carcinoma, no significant correlations were detected. ERbeta immunoreactivity was detected in both follicular and C-cells of normal thyroid glands, including those in developing fetal thyroid glands. In addition, ERbeta immunoreactivity was detected in the nuclei of various thyroid lesions. But no significant correlations were detected between ERbeta labeling index and clinicopathological findings

  18. Neddylation is required for herpes simplex virus type I (HSV-1)-induced early phase interferon-beta production.

    Science.gov (United States)

    Zhang, Xueying; Ye, Zhenjie; Pei, Yujun; Qiu, Guihua; Wang, Qingyang; Xu, Yunlu; Shen, Beifen; Zhang, Jiyan

    2016-09-01

    Type I interferons such as interferon-beta (IFN-β) play essential roles in the host innate immune response to herpes simplex virus type I (HSV-1) infection. The transcription of type I interferon genes is controlled by nuclear factor-κB (NF-κB) and interferon regulatory factor (IRF) family members including IRF3. NF-κB activation depends on the phosphorylation of inhibitor of κB (IκB), which triggers its ubiqitination and degradation. It has been reported that neddylation inhibition by a pharmacological agent MLN4924 potently suppresses lipopolysaccharide (LPS)-induced proinflammatory cytokine production with the accumulation of phosphorylated IκBα. However, the role of neddylation in type I interferon expression remains unknown. Here, we report that neddylation inhibition with MLN4924 or upon UBA3 deficiency led to accumulation of phosphorylated IκBα, impaired IκBα degradation, and impaired NF-κB nuclear translocation in the early phase of HSV-1 infection even though phosphorylation and nuclear translocation of IRF3 were not affected. The blockade of NF-κB nuclear translocation by neddylation inhibition becomes less efficient at the later time points of HSV-1 infection. Consequently, HSV-1-induced early phase IFN-β production significantly decreased upon MLN4924 treatment and UBA3 deficiency. NF-κB inhibitor JSH-23 mimicked the effects of neddylation inhibition in the early phase of HSV-1 infection. Moreover, the effects of neddylation inhibition on HSV-1-induced early phase IFN-β production diminished in the presence of NF-κB inhibitor JSH-23. Thus, neddylation contributes to HSV-1-induced early phase IFN-β production through, at least partially, promoting NF-κB activation.

  19. Associations between intestinal lesions and detection of Clostridium perfringens type A or beta-2 toxin in neonatal piglets with diarrhoea

    DEFF Research Database (Denmark)

    Kongsted, Hanne; Jonach, Beata Renata; Kokotovic, Branko

    Objective: To evaluate associations between gross and histopathological lesions and the presence of Clostridium perfringens type A (CpA) and beta-2 toxin in piglets from 4 herds with outbreaks of diarrhoea. Methods: Pathological examinations on 51 diarrhoeic piglets aged 3-7 days were carried out....... CpA was cultured and typed by PCR. A Clostridium perfringens spp targeted probe was used for flourescent in situ hybridization (FISH) and detection of beta-2 toxin in intestinal contents was performed by enzyme-linked immunosorbent assay (ELISA). Results: Piglets without intestinal lesions had...

  20. Glucose Driven Changes in Beta Cell Identity Are Important for Function and Possibly Autoimmune Vulnerability during the Progression of Type 1 Diabetes

    Science.gov (United States)

    Weir, Gordon C.; Bonner-Weir, Susan

    2017-01-01

    This commentary explores the hypothesis that when autoimmunity leads to a fall of beta cell mass during the progression of type 1 diabetes (T1D), rising glucose levels cause major changes in beta cell identity. This then leads to profound changes in secretory function and less well-understood changes in beta cell susceptibility to autoimmune destruction, which may influence of rate of progression of beta cell killing. PMID:28174593

  1. Latent Transforming Growth Factor-beta1 Functionalised Electrospun Scaffolds Promote Human Cartilage Differentiation: Towards an Engineered Cartilage Construct

    Directory of Open Access Journals (Sweden)

    Erh-Hsuin Lim

    2013-11-01

    Full Text Available BackgroundTo overcome the potential drawbacks of a short half-life and dose-related adverse effects of using active transforming growth factor-beta 1 for cartilage engineering, a cell-mediated latent growth factor activation strategy was developed incorporating latent transforming growth factor-β1 (LTGF into an electrospun poly(L-lactide scaffold.MethodsThe electrospun scaffold was surface modified with NH3 plasma and biofunctionalised with LTGF to produce both random and orientated biofunctionalised electrospun scaffolds. Scaffold surface chemical analysis and growth factor bioavailability assays were performed. In vitro biocompatibility and human nasal chondrocyte gene expression with these biofunctionalised electrospun scaffold templates were assessed. In vivo chondrogenic activity and chondrocyte gene expression were evaluated in athymic rats.ResultsChemical analysis demonstrated that LTGF anchored to the scaffolds was available for enzymatic, chemical and cell activation. The biofunctionalised scaffolds were non-toxic. Gene expression suggested chondrocyte re-differentiation after 14 days in culture. By 6 weeks, the implanted biofunctionalised scaffolds had induced highly passaged chondrocytes to re-express Col2A1 and produce type II collagen.ConclusionsWe have demonstrated a proof of concept for cell-mediated activation of anchored growth factors using a novel biofunctionalised scaffold in cartilage engineering. This presents a platform for development of protein delivery systems and for tissue engineering.

  2. Migraine Types and Triggering Factors in Children

    Directory of Open Access Journals (Sweden)

    Habibe NEJAD BIGLARI

    2012-06-01

    Full Text Available How to Cite this Article: Nejad Biglari H, Karimzadeh P, Mohammadi Kord-kheyli M, Hashemi SM. Migraine Types and Triggering Factors in Children. Iran J  Child Neurol 2012;6(2:33-38.Objective Migraine is a common problem in children and the mean prevalence of migraine in Europe among 170,000 adults was 14.7% (8% in men and 17.6% in women and in children and youth (36,000 participants, the prevalences were (9.2% for all, 5.2% in boys and 9.1% in girls and the lifetime prevalences were (16, 11 and 20%, respectively. To determine the epidemiology of migraine and evaluate migraine triggering factors in children. Materials & Methods Two-hundred twenty-eight children with a maximum age of 12 years who fulfilled the ICHD-II criteria for pediatric migraine were enrolled into the study. Results This study shows that migraine is slightly more common in boys and its peak incidence is between ages 8 and 12 and most patients have three to five headache attacks per month. The pain has a tightening, stabbing or vague quality in about 70% of children with migraine and bilateral headache is slightly more common. The common triggering factors in children migraine were stress, noise, sleeplessness, hunger and light and the common relieving factors were sleep, analgesics, silence, darkness and eating. Conclusion Migraine is a common problem in children with an equal incidence in boys and girls before adolescence and more common in girls after adolescence. ReferencesPowers SW, Andrasik F. Biobehavioral treatment, disability, and psychological effects of pediatric headache. Pediatr Ann 2005;34(6:461-5. Rosenblum RK, Fisher PG. A guide to children with acute and chronic headaches. J Pediatr Health Care 2001;15(5:229-35. Fallahzadeh H, Alihaydari M. Prevalence of migraine and tension-type headache among school children in Yazd, Iran. J Pediatr Neurosci 2011;6(2:106-9. Ayatollahi SM, Khosravi A. Prevalence of migraine and tension-type headache in primaryschool

  3. Do amyloid beta-associated factors co-deposit with Abeta in mouse models for Alzheimer's disease?

    NARCIS (Netherlands)

    Timmer, N.M.; Kuiperij, H.B.; Waal, R.M.W. de; Verbeek, M.M.

    2010-01-01

    Senile plaques and cerebral amyloid angiopathy in Alzheimer's disease (AD) patients not only consist of the amyloid-beta protein (Abeta), but also contain many different Abeta-associated factors, such as heparan sulfate proteoglycans, apolipoproteins, and complement factors. These factors may all

  4. Critical role of transcription factor cyclic AMP response element modulator in beta1-adrenoceptor-mediated cardiac dysfunction.

    Science.gov (United States)

    Lewin, Geertje; Matus, Marek; Basu, Abhijit; Frebel, Karin; Rohsbach, Sebastian Pius; Safronenko, Andrej; Seidl, Matthias Dodo; Stümpel, Frank; Buchwalow, Igor; König, Simone; Engelhardt, Stefan; Lohse, Martin J; Schmitz, Wilhelm; Müller, Frank Ulrich

    2009-01-06

    Chronic stimulation of the beta(1)-adrenoceptor (beta(1)AR) plays a crucial role in the pathogenesis of heart failure; however, underlying mechanisms remain to be elucidated. The regulation by transcription factors cAMP response element-binding protein (CREB) and cyclic AMP response element modulator (CREM) represents a fundamental mechanism of cyclic AMP-dependent gene control possibly implicated in beta(1)AR-mediated cardiac deterioration. We studied the role of CREM in beta(1)AR-mediated cardiac effects, comparing transgenic mice with heart-directed expression of beta(1)AR in the absence and presence of functional CREM. CREM inactivation protected from cardiomyocyte hypertrophy, fibrosis, and left ventricular dysfunction in beta(1)AR-overexpressing mice. Transcriptome and proteome analysis revealed a set of predicted CREB/CREM target genes including the cardiac ryanodine receptor, tropomyosin 1alpha, and cardiac alpha-actin as altered on the mRNA or protein level along with the improved phenotype in CREM-deficient beta(1)AR-transgenic hearts. The results imply the regulation of genes by CREM as an important mechanism of beta(1)AR-induced cardiac damage in mice.

  5. Ultraviolet irradiation of DNA complexed with. alpha. /. beta. -type small, acid-soluble proteins from spores of Bacillus or Clostridium species makes spore photoproduct but not thymine dimers

    Energy Technology Data Exchange (ETDEWEB)

    Nicholson, W.L.; Setlow, B.; Setlow, P. (Univ. of Connecticut Health Center, Farmington (United States))

    1991-10-01

    UV irradiation of complexes of DNA and an {alpha}/{beta}-type small, acid-soluble protein (SASP) from Bacillus subtilis spores gave decreasing amounts of pyrimidine dimers and increasing amounts of spore photoproduct as the SASP/DNA ratio was increased. The yields of pyrimidine dimers and spore photoproduct were < 0.2% and 8% of total thymine, respectively, when DNA saturated with SASP was irradiated at 254 nm with 30 kJ/m{sup 2}; in the absence of SASP the yields were reversed - 4.5% and 0.3%, respectively. Complexes of DNA with {alpha}/{beta}-type SASP from Bacillus cereus, Bacillus megaterium, or Clostridium bifermentans spores also gave spore photoproduct upon UV irradiation. However, incubation of these SASPs with DNA under conditions preventing complex formation or use of mutant SASPs that do not form complexes did not affect the photoproducts formed in vitro. These results suggest that the UV photochemistry of bacterial spore DNA in vivo is due to the binding of {alpha}/{beta}-type SASP, a binding that is known to cause a change in DNA conformation in vitro from the B form to the A form. The yields of spore photoproduct in vitro were significantly lower than in vivo, perhaps because of the presence of substances other than SASP in spores. It is suggested that as these factors diffuse out in the first minutes of spore germination, spore photoproduct yields become similar to those observed for irradiation of SASP/DNA complexes in vitro.

  6. Neurotrophic factors in tension-type headache

    Directory of Open Access Journals (Sweden)

    Renan B. Domingues

    2015-05-01

    Full Text Available Neurotrophic factors (NF are involved in pain regulation and a few studies have suggested that they may play a pathophysiological role in primary headaches. The aim of this study was to investigate NF levels in patients with tension type headache (TTH. We carried out a cross sectional study including 48 TTH patients and 48 age and gender matched controls. Beck Depression and Anxiety Inventories, and Headache Impact Test were recorded. Serum levels of NF were determined by ELISA. There were not significant differences between NF levels between TTH patients and controls. Patients with chronic and episodic TTH had not significant differences in NF levels. The presence of headache at the time of evaluation did not significantly alter the levels of NF. Depression and anxiety scores as well as headache impact did not correlate with NF levels. Our study suggest that the serum levels of NF are not altered in TTH.

  7. Transnasal delivery of human A-beta peptides elicits impaired learning and memory performance in wild type mice.

    Science.gov (United States)

    Endres, Kristina; Reinhardt, Sven; Geladaris, Anastasia; Knies, Julia; Grimm, Marcus; Hartmann, Tobias; Schmitt, Ulrich

    2016-07-04

    Murine models of Alzheimer's disease (AD) are mainly based on overexpression of pathologic amyloid precursor protein and/or presenilins. Those genes resemble underlying cause of early onset type of AD while about 99 % of all human cases are to be characterized as sporadic, late onset. Appropriate animal models for this type of AD are still missing. We here investigated, if transnasal delivery of A-beta 42 peptides might serve to mimic pathological effects in mice. A-beta 42 peptides, used for the behavioral study, showed the expected dose-dependent toxicity in neur oblastoma cell line SH-SY5Y and were able to form higher molecular weight species in vitro. Upon delivery into nostrils of wild type mice, protein bands that might represent aggregation products of the exogenously applied human A-beta 42 were only observed in total brain homogenates from mice pre-treated with mannitol. By using TAMRA-labeled A-beta 42 peptides we demonstrated, that transport throughout the brain was achieved already 1 h after administration. FVB/N mice treated with A-beta 42 for 3 days were significantly impaired in the cue-retention condition of the fear conditioning task as compared to controls whereas A-beta-treated C57B6/J mice were impaired in the context condition. In the Morris water maze test, these mice also displayed a delayed learning performance, indicated by significantly longer time to find the platform. Those deficits were also seen for memory performance in the probe trial as measured by number of crossings of the former platform position and time spent in the goal quadrant. Existing AD mouse models are of genetic origin and need prolonged housing time before onset of pathology. Our short-term treatment induced learning and memory deficits via exogenous application of A-beta peptides comparable to those observed for the transgenic animals. With the transnasal A-beta 42 treatment we present an approach to investigate purely A-beta related changes suitable as a model for

  8. Oxidative Stress Type Influences the Properties of Antioxidants Containing Polyphenols in RINm5F Beta Cells

    Science.gov (United States)

    Auberval, Nathalie; Dal, Stéphanie; Bietiger, William; Seyfritz, Elodie; Peluso, Jean; Muller, Christian; Zhao, Minjie; Marchioni, Eric; Pinget, Michel; Jeandidier, Nathalie; Maillard, Elisa; Schini-Kerth, Valérie; Sigrist, Séverine

    2015-01-01

    The in vitro methods currently used to screen bioactive compounds focus on the use of a single model of oxidative stress. However, this simplistic view may lead to conflicting results. The aim of this study was to evaluate the antioxidant properties of two natural extracts (a mix of red wine polyphenols (RWPs) and epigallocatechin gallate (EGCG)) with three models of oxidative stress induced with hydrogen peroxide (H2O2), a mixture of hypoxanthine and xanthine oxidase (HX/XO), or streptozotocin (STZ) in RINm5F beta cells. We employed multiple approaches to validate their potential as therapeutic treatment options, including cell viability, reactive oxygen species production, and antioxidant enzymes expression. All three oxidative stresses induced a decrease in cell viability and an increase in apoptosis, whereas the level of ROS production was variable depending on the type of stress. The highest level of ROS was found for the HX/XO-induced stress, an increase that was reflected by higher expression antioxidant enzymes. Further, both antioxidant compounds presented beneficial effects during oxidative stress, but EGCG appeared to be a more efficient antioxidant. These data indicate that the efficiency of natural antioxidants is dependent on both the nature of the compound and the type of oxidative stress generated. PMID:26508986

  9. Oxidative Stress Type Influences the Properties of Antioxidants Containing Polyphenols in RINm5F Beta Cells

    Directory of Open Access Journals (Sweden)

    Nathalie Auberval

    2015-01-01

    Full Text Available The in vitro methods currently used to screen bioactive compounds focus on the use of a single model of oxidative stress. However, this simplistic view may lead to conflicting results. The aim of this study was to evaluate the antioxidant properties of two natural extracts (a mix of red wine polyphenols (RWPs and epigallocatechin gallate (EGCG with three models of oxidative stress induced with hydrogen peroxide (H2O2, a mixture of hypoxanthine and xanthine oxidase (HX/XO, or streptozotocin (STZ in RINm5F beta cells. We employed multiple approaches to validate their potential as therapeutic treatment options, including cell viability, reactive oxygen species production, and antioxidant enzymes expression. All three oxidative stresses induced a decrease in cell viability and an increase in apoptosis, whereas the level of ROS production was variable depending on the type of stress. The highest level of ROS was found for the HX/XO-induced stress, an increase that was reflected by higher expression antioxidant enzymes. Further, both antioxidant compounds presented beneficial effects during oxidative stress, but EGCG appeared to be a more efficient antioxidant. These data indicate that the efficiency of natural antioxidants is dependent on both the nature of the compound and the type of oxidative stress generated.

  10. Neutrinoless double beta decay in LRSM with natural type-II seesaw dominance

    Science.gov (United States)

    Pritimita, Prativa; Dash, Nitali; Patra, Sudhanwa

    2016-10-01

    We present a detailed discussion on neutrinoless double beta decay within a class of left-right symmetric models where neutrino mass originates by natural type-II seesaw dominance. The spontaneous symmetry breaking is implemented with doublets, triplets and bidoublet scalars. The fermion sector is extended with an extra sterile neutrino per generation that helps in implementing the seesaw mechanism. The presence of extra particles in the model exactly cancels type-I seesaw and allows large value for Dirac neutrino mass matrix M D . The key feature of this work is that all the physical masses and mixing are expressed in terms of neutrino oscillation parameters and lightest neutrino mass thereby facilitating to constrain light neutrino masses from 0ν ββ decay. With this large value of M D new contributions arise due to; i) purely left-handed current via exchange of heavy right- handed neutrinos as well as sterile neutrinos, ii) the so called λ and η diagrams. New physics contributions also arise from right-handed currents with right-handed gauge boson W R mass around 3 TeV. From the numerical study, we find that the new contributions to 0 νββ decay not only saturate the current experimental bound but also give lower limit on absolute scale of lightest neutrino mass and favor NH pattern of light neutrino mass hierarchy.

  11. Transforming growth factor-beta-induced regulatory T cells referee inflammatory and autoimmune diseases.

    Science.gov (United States)

    Wahl, Sharon M; Chen, Wanjun

    2005-01-01

    Naturally occurring CD4+CD25+ regulatory T cells mediate immune suppression to limit immunopathogenesis associated with chronic inflammation, persistent infections and autoimmune diseases. Their mode of suppression is contact-dependent, antigen-nonspecific and involves a nonredundant contribution from the cytokine transforming growth factor (TGF)-beta. Not only can TGF-beta mediate cell-cell suppression between the regulatory T cells and CD4+CD25- or CD8+ T cells, but new evidence also reveals its role in the conversion of CD4+CD25- T cells, together with TCR antigen stimulation, into the regulatory phenotype. Elemental to this conversion process is induction of expression of the forkhead transcription factor, Foxp3. This context-dependent coercion of naive CD4+ T cells into a powerful subset of regulatory cells provides a window into potential manipulation of these cells to orchestrate therapeutic intervention in diseases characterized by inadequate suppression, as well as a promising means of controlling pathologic situations in which excessive suppression dominates.

  12. Analysis of the effect of diabetes type 2 duration on beta cell secretory function and insulin resistance

    Directory of Open Access Journals (Sweden)

    Popović Ljiljana

    2006-01-01

    Full Text Available Diabetes type 2 is a chronic metabolic disorder. Pathogenesis of diabetes type 2 results from the impaired insulin secretion, impaired insulin action and increased endogenous glucose production. Diabetes evolves through several phases characterized by qualitative and quantitative changes of beta cell secretory function. The aim of our study was to analyze the impact of diabetes duration on beta cell secretory function and insulin resistance. The results indicated significant negative correlation of diabetes duration and fasting insulinemia, as well as beta cell secretory function assessed by HOMA β index. Our study also found significant negative correlation of diabetes duration and insulin resistance assessed by HOMA IR index. Significant positive correlation was established between beta cell secretory capacity (fasting insulinemia and HOMA β and insulin resistance assessed by HOMA IR index, independently of diabetes duration. These results indicate that: beta cell secretory capacity, assessed by HOMA β index, significantly decreases with diabetes duration. In parallel with decrease of fasting insulinemia, reduction of insulin resistance assessed by HOMA IR index was found as well.

  13. Prevalence of metabolic syndrome in patients with minor beta thalassemia and its related factors: a cross-sectional study

    OpenAIRE

    Gozashti, Mohammad Hossein; Hasanzadeh, Ali; Mashrouteh, Mahdieh

    2014-01-01

    Background Atherosclerotic disorders, hypertension and lipid profile alterations are of a lower prevalence in patients with minor beta thalassemia. On the other hand, nowadays, metabolic syndrome is considered as one of the major risk factors of developing cardiovascular diseases. Therefore, the present study was performed to determine the prevalence of metabolic syndrome in patients with minor beta thalassemia. Methods In this case-control study, body length, weight and waist circumference, ...

  14. beta-Arrestin 1 and 2 stabilize the angiotensin II type I receptor in distinct high-affinity conformations

    DEFF Research Database (Denmark)

    Sanni, S J; Hansen, J T; Bonde, M M;

    2010-01-01

    The angiotensin II type 1 (AT(1)) receptor belongs to family A of 7 transmembrane (7TM) receptors. The receptor has important roles in the cardiovascular system and is commonly used as a drug target in cardiovascular diseases. Interaction of 7TM receptors with G proteins or beta-arrestins often...

  15. Failing beta-cell adaptation in South Asian families with a high risk of type 2 diabetes

    NARCIS (Netherlands)

    S. Jainandunsing (Sjaam); B. Özcan (Behiye); T. Rietveld (Trinet); J.N.I. van Miert (Joram); A.J. Isaacs (Aaron); J.G. Langendonk (Janneke); F.W.M. de Rooij (Felix); E.J.G. Sijbrands (Eric)

    2014-01-01

    textabstractWe performed an extended oral glucose tolerance test (OGTT) to investigate the relationship between early and late beta-cell response and type 2 diabetes (T2D) in families of South Asian origin and indigenous Dutch, burdened by T2D. Based on the OGTT, 22 individuals were normoglycemic, 1

  16. Signalling by Transforming Growth Factor Beta Isoforms in Wound Healing and Tissue Regeneration

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    Richard W.D. Gilbert

    2016-06-01

    Full Text Available Transforming growth factor beta (TGFβ signalling is essential for wound healing, including both non-specific scar formation and tissue-specific regeneration. Specific TGFβ isoforms and downstream mediators of canonical and non-canonical signalling play different roles in each of these processes. Here we review the role of TGFβ signalling during tissue repair, with a particular focus on the prototypic isoforms TGFβ1, TGFβ2, and TGFβ3. We begin by introducing TGFβ signalling and then discuss the role of these growth factors and their key downstream signalling mediators in determining the balance between scar formation and tissue regeneration. Next we discuss examples of the pleiotropic roles of TGFβ ligands during cutaneous wound healing and blastema-mediated regeneration, and how inhibition of the canonical signalling pathway (using small molecule inhibitors blocks regeneration. Finally, we review various TGFβ-targeting therapeutic strategies that hold promise for enhancing tissue repair.

  17. The time has come to test the beta cell preserving effects of exercise in patients with new onset type 1 diabetes

    DEFF Research Database (Denmark)

    Narendran, Parth; Solomon, Thomas; Kennedy, Amy

    2015-01-01

    Type 1 diabetes is characterised by immune-mediated destruction of insulin-producing beta cells. Significant beta cell function is usually present at the time of diagnosis with type 1 diabetes, and preservation of this function has important clinical benefits. The last 30 years have seen a number...... for physical exercise as a therapy for the preservation of beta cell function in patients with newly diagnosed type 1 diabetes. We highlight possible mechanisms by which exercise could preserve beta cell function and then present evidence from other models of diabetes that demonstrate that exercise preserves...... beta cell function. We conclude by proposing that there is now a need for studies to explore whether exercise can preserve beta cell in patients newly diagnosed with type 1 diabetes....

  18. Beta-catenin regulates myogenesis by relieving I-mfa-mediated suppression of myogenic regulatory factors in P19 cells.

    Science.gov (United States)

    Pan, Weijun; Jia, Yingying; Wang, Jiyong; Tao, Donglei; Gan, Xiaoqing; Tsiokas, Leonidas; Jing, Naihe; Wu, Dianqing; Li, Lin

    2005-11-29

    Wnt/beta-catenin signaling plays a critical role in embryonic myogenesis. Here we show that, in P19 embryonic carcinoma stem cells, Wnt/beta-catenin signaling initiates the myogenic process depends on beta-catenin-mediated relief of I-mfa (inhibitor of MyoD Family a) suppression of myogenic regulatory factors (MRFs). We found that beta-catenin interacted with I-mfa and that the interaction was enhanced by Wnt3a. In addition, we found that the interaction between beta-catenin and I-mfa was able to attenuate the interaction of I-mfa with MRFs, relieve I-mfa-mediated suppression of the transcriptional activity and cytosolic sequestration of MRFs, and initiate myogenesis in a P19 myogenic model system that expresses exogenous myogenin. This work reveals a mechanism for the regulation of MRFs during myogenesis by elucidating a beta-catenin-mediated, but lymphoid enhancing factor-1/T cell factor independent, mechanism in regulation of myogenic fate specification and differentiation of P19 mouse stem cells.

  19. Etiopathogenesis of type 1 diabetes mellitus: prognostic factors for the evolution of residual β cell function

    Directory of Open Access Journals (Sweden)

    Dib Sergio A

    2009-12-01

    Full Text Available Abstract Type 1A diabetes mellitus (T1ADM is a progressive autoimmune disease mediated by T lymphocytes with destruction of beta cells. Up to now, we do not have precise methods to assess the beta cell mass, "in vivo" or "ex-vivo". The studies about its genetic susceptibility show strong association with class II antigens of the HLA system (particularly DQ. Others genetics associations are weaker and depend on the population studied. A combination of precipitating events may occur at the beginning of the disease. There is a silent loss of immune-mediated beta cells mass which velocity has an inverse relation with the age, but it is influenced by genetic and metabolic factors. We can predict the development of the disease primarily through the determination of four biochemically islet auto antibodies against antigens like insulin, GAD65, IA2 and Znt8. Beta cell destruction is chronically progressive but at clinical diagnosis of the disease a reserve of these cells still functioning. The goal of secondary disease prevention is halt the autoimmune attack on beta cells by redirecting or dampening the immune system. It is remains one of the foremost therapeutic goals in the T1ADM. Glycemic intensive control and immunotherapeutic agents may preserve beta-cell function in newly diagnosed patients with T1ADM. It may be assessed through C-peptide values, which are important for glycemic stability and for the prevention of chronic complications of this disease. This article will summarize the etiopathogenesis mechanisms of this disease and the factors can influence on residual C-peptide and the strategies to it preservation.

  20. Transforming growth factor-beta1 stimulates the production of insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in human bone marrow stromal osteoblast progenitors

    DEFF Research Database (Denmark)

    Kveiborg, Marie; Flyvbjerg, Allan; Eriksen, E F

    2001-01-01

    While transforming growth factor-beta1 (TGF-beta1) regulates proliferation and differentiation of human osteoblast precursor cells, the mechanisms underlying these effects are not known. Several hormones and locally acting growth factors regulate osteoblast functions through changes in the insulin......-like growth factors (IGFs) and IGF-binding proteins (IGFBPs). Thus, we studied the effects of TGF-beta1 on IGFs and IGFBPs in human marrow stromal (hMS) osteoblast precursor cells. TGF-beta1 increased the steady-state mRNA level of IGF-I up to 8.5+/-0.6-fold (P...

  1. 11beta-Hydroxysteroid dehydrogenase type 1-driven cortisone reactivation regulates plasminogen activator inhibitor type 1 in adipose tissue of obese women.

    Science.gov (United States)

    Ayachi, S Ei; Paulmyer-Lacroix, O; Verdier, M; Alessi, M-C; Dutour, A; Grino, M

    2006-03-01

    Plasminogen activator inhibitor type 1 (PAI-1) is the main inhibitor of the fibrinolytic system and contributes to an increased risk of atherothrombosis in insulin-resistant obese patients. In adipose tissue, we have shown that PAI-1 is synthesized mainly in the visceral stromal compartment and is positively regulated by glucocorticoids. We have demonstrated that adipose tissue expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1), an enzyme that catalyzes the conversion of inactive cortisone to active cortisol, is exaggerated in obese patients. We hypothesized that increased action of 11beta-HSD-1 in adipose tissue of obese subjects may contribute to PAI-1 overproduction. Using in situ hybridization, we studied the expression of the mRNAs coding for PAI-1 and 11beta-HSD-1 in the stromal compartment of visceral adipose tissue obtained from obese women. The regulation of PAI-1 secretion from in vitro incubated tissue explants was also investigated. Regression analysis showed a significant positive linear relationship between PAI-1 and 11beta-HSD-1 mRNAs expression. In vitro incubation of adipose tissue explants demonstrated that cortisone stimulated PAI-1 gene expression and secretion, and that these effects were inhibited by co-incubation with the 11beta-HSD inhibitor, glycyrrhetinic acid. Our data demonstrate that 11beta-HSD-1-driven cortisone reactivation regulates adipose PAI-1 synthesis and secretion. They suggest that the increased PAI-1 synthesis and secretion observed in obese patients can be also related, at least in part, to an increased local conversion of cortisone to cortisol. Therefore, local cortisol metabolism in adipose tissue may be involved in increasing the risk of cardiovascular disease in obese subjects.

  2. Types and prevalence of extended-spectrum beta-lactamase producing Enterobacteriaceae in poultry.

    Science.gov (United States)

    Saliu, Eva-Maria; Vahjen, Wilfried; Zentek, Jürgen

    2017-06-01

    For several billion years, bacteria have developed mechanisms to resist antibacterial substances. In modern time, antibiotics are frequently used in veterinary and human medicine for prevention and treatment of diseases, globally still also for their growth promoting effects as feed additives. This complex situation has evolved in accelerating development and prevalence of multi-drug resistant bacteria in livestock and people. Extended-spectrum beta-lactamase (ESBL) producing bacteria are resistant to a wide range of ß-lactam antibiotics. They are currently considered as one of the main threats for the treatment of infections in humans and animals. In livestock and animal products, poultry and poultry products show the highest prevalence of ESBL-producers with CTX-M-1, TEM-52 and SHV-12 being the most common ESBL-types in poultry. Escherichia coli and Salmonella spp. are the bacteria in poultry, which carry ESBL-genes most frequently. ESBL-producing bacteria are present at every level of the poultry production pyramid and can be detected even in the meconium of newly hatched chicks. The environment close to poultry barns shows high prevalence rates of these bacteria and contributes to an ongoing infection pressure with further ESBL-types. Probiotics have been shown to successfully reduce ESBL-producers in chicken, as well as ESBL-gene transfer. Other feed additives, such as zinc and copper, increase the prevalence of ESBL-producing bacteria when fed to animals. To our best knowledge, this is the first publication presenting a comparative overview of the prevalence of ESBL-types using data from different countries. To reduce the hazard for public health from poultry carrying high numbers of ESBL-producers, preventive measurements must include the surrounding environment and avoidance of antibiotic usage at all levels of the production pyramid. The first results, of the research on the impact of feed additives on the spread of ESBL-genes, indicate the diet as a

  3. Do post-translational beta cell protein modifications trigger type 1 diabetes?

    DEFF Research Database (Denmark)

    Størling, Joachim; Overgaard, Anne Julie; Brorsson, Caroline Anna;

    2013-01-01

    forms capable of specifically triggering beta cell destruction. In other immune-mediated diseases, autoantigens targeted by the immune system have undergone post-translational modification (PTM), thereby creating tissue-specific neo-epitopes. In a similar manner, PTM of beta cell proteins might create...

  4. Tumor necrosis factor-alpha inhibits pre-osteoblast differentiation through its type-1 receptor.

    Science.gov (United States)

    Abbas, Sabiha; Zhang, Yan-Hong; Clohisy, John C; Abu-Amer, Yousef

    2003-04-01

    Tumor necrosis factor-alpha (TNF) is a pro-inflammatory cytokine with a profound role in many skeletal diseases. The cytokine has been described as a mediator of bone loss in osteolysis and other inflammatory bone diseases. In addition to its known bone resorptive action, TNF reduces bone formation by inhibiting osteoblast differentiation. Using primary and transformed osteoblastic cells, we first document that TNF inhibits expression of alkaline phosphatase and matrix deposition, both considered markers of osteoblast differentiation. The effects are dose- and time-dependent. Core-binding factor A1 (cbfa1) is a transcription factor critical for osteoblast differentiation, and we show here that it is activated by the osteoblast differentiation agent, beta-glycerophosphate. Therefore, we investigated whether the inhibitory effects of TNF were associated with altered activity of this transcription factor. Using retardation assays, we show that TNF significantly inhibits cbfal activation by beta-glycerophosphate, manifested by reduced DNA-binding activity. Next, we turned to determine the signaling pathway by which TNF inhibits osteoblast differentiation. Utilizing animals lacking individual TNF receptors, we document that TNFr1 is required for transmitting the cytokine's inhibitory effect. In the absence of this receptor, TNF failed to impact all osteoblast differentiation markers tested. In summary, TNF blocks expression of osteoblast differentiation markers and inhibits beta-glycerophosphate-induced activation of the osteoblast differentiation factor cbfa1. Importantly, these effects are mediated via a mechanism requiring the TNF type-1 receptor.

  5. Endothelial binding of beta toxin to small intestinal mucosal endothelial cells in early stages of experimentally induced Clostridium perfringens type C enteritis in pigs.

    Science.gov (United States)

    Schumacher, V L; Martel, A; Pasmans, F; Van Immerseel, F; Posthaus, H

    2013-07-01

    Beta toxin (CPB) is known to be an essential virulence factor in the development of lesions of Clostridium perfringens type C enteritis in different animal species. Its target cells and exact mechanism of toxicity have not yet been clearly defined. Here, we evaluate the suitability of a neonatal piglet jejunal loop model to investigate early lesions of C. perfringens type C enteritis. Immunohistochemically, CPB was detected at microvascular endothelial cells in intestinal villi during early and advanced stages of lesions induced by C. perfringens type C. This was first associated with capillary dilatation and subsequently with widespread hemorrhage in affected intestinal segments. CPB was, however, not demonstrated on intestinal epithelial cells. This indicates a tropism of CPB toward endothelial cells and suggests that CPB-induced endothelial damage plays an important role in the early stages of C. perfringens type C enteritis in pigs.

  6. Glucocorticoids, feto-placental 11 beta-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease.

    Science.gov (United States)

    Seckl, J R

    1997-01-01

    Increasing human epidemiological data suggest that events that subtly retard intrauterine growth may determine common disorders, such as hypertension and non-insulin-dependent diabetes, in adult life. The underlying mechanisms are unknown. However, excessive fetal exposure to glucocorticoids retards growth and "programs" adult hypertension in rats. 11 beta-Hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) catalyzes the rapid inactivation of cortisol and corticosterone to inert 11 keto-products. Normally, 11 beta-HSD2 in the placenta and some fetal tissues is thought to protect the fetus from excess maternal glucocorticoids. In both rats and humans there is considerable natural variation in placental 11 beta-HSD2, and enzyme activity correlates with birth weight. Moreover, inhibition of feto-placental 11 beta-HSD2 in the rat reduces birth weight and produces hypertensive and hyperglycaemic adult offspring, many months after prenatal treatment; effects are dependent upon intact maternal adrenals, suggesting a direct action on the fetus or placenta. Maternal protein restriction during pregnancy also produces hypertensive offspring and selectively attenuates placental 11 beta-HSD2 activity. These data suggest that feto-placental 11 beta-HSD2, by regulating fetal exposure to maternal glucocorticoids, crucially determines fetal growth and the programming of later disorders. Deficiency of the barrier to maternal glucocorticoids may represent a common pathway between the maternal environment and feto-placental programming of later disease. These data may, at least in part, explain the human observations linking early life events to the risk of subsequent disease.

  7. Monte Carlo calculations of monoenergetic electron depth dose distributions in LiF chips: Skin dose correction factors for beta rays

    Energy Technology Data Exchange (ETDEWEB)

    Horowitz, Y.S. [Ben Gurion Univ. of the Negev, Beersheva (Israel); Hirning, C.R. [Ontario Hydro, Whitby (Canada); Yuen, P.; Wong, P. [Chalk River Labs., Ontario (Canada)

    1994-10-01

    Monte Carlo calculations have been carried out for monoenergetic electrons from 0.1 to 4 MeV irradiating LiF chips in both perpendicular and isotropic geometry. This enabled the calculation of skin dose correction factors (beta factors) for typical beta energy spectra as measured with a beta-ray spectrometer at CANDU nuclear generating stations. The correction factors were estimated by averaging the depth dose distributions for the monoenergetic electrons over the experimentally measured beta-ray spectra. The calculations illustrate the large uncertainty in beta factors arising from the unknown angular distribution of the beta-ray radiation field and uncertainties in the shape of the beta-ray spectra below 500 keV. 28 refs., 8 figs., 2 tabs.

  8. PKCalpha-induced drug resistance in pancreatic cancer cells is associated with transforming growth factor-beta1.

    Science.gov (United States)

    Chen, Ying; Yu, Guanzhen; Yu, Danghui; Zhu, Minghua

    2010-08-05

    Drug resistance remains a great challenge in the treatment of pancreatic cancer. The goal of this study was to determine whether TGF-beta1 is associated with drug resistance in pancreatic cancer. Pancreatic cancer BxPC3 cells were stably transfected with TGF-beta1 cDNA. Cellular morphology and cell cycle were determined and the suppressive subtracted hybridization (SSH) assay was performed to identify differentially expressed genes induced by TGF-beta1. Western blotting and immunohistochemistry were used to detect expression of TGF-beta1-related genes in the cells and tissue samples. After that, the cells were further treated with an anti-cancer drug (e.g., cisplatin) after pre-incubated with the recombinant TGF-beta1 plus PKCalpha inhibitor Gö6976. TGF-beta1 type II receptor, TbetaRII was also knocked down using TbetaRII siRNA to assess the effects of these drugs in the cells. Cell viability was assessed by MTT assay. Overexpression of TGF-beta1 leads to a markedly increased invasion potential but a reduced growth rate in BxPC3 cells. Recombinant TGF-beta1 protein increases expression of PKCalpha in BxPC3 cells, a result that we confirmed by SSH. Moreover, TGF-beta1 reduced the sensitivity of BxPC3 cells to cisplatin treatment, and this was mediated by upregulation of PKCalpha. However, blockage of PKCalpha with Gö6976 and TbetaRII with siRNA reversed the resistance of BxPC3 cells to gemcitabine, even in the presence of TGF-beta1. Immunohistochemical data show that pancreatic cancers overexpress TGF-beta1 and P-gp relative to normal tissues. In addition, TGF-beta1 expression is associated with P-gp and membranous PKCalpha expression in pancreatic cancer. TGF-beta1-induced drug resistance in pancreatic cancer cells was associated with PKCalpha expression. The PKCalpha inhibitor Gö6976 could be a promising agent to sensitize pancreatic cancer cells to chemotherapy.

  9. Beta-lactam type molecular scaffolds for antiproliferative activity: synthesis and cytotoxic effects in breast cancer cells.

    Science.gov (United States)

    Meegan, Mary J; Carr, Miriam; Knox, Andrew J S; Zisterer, Daniela M; Lloyd, David G

    2008-10-01

    A series of novel beta-lactam containing compounds are described as antiproliferative agents and potential selective modulators of the oestrogen receptor. The purpose of the study is to evaluate the antiproliferative effects of these compounds on human MCF-7 and MDA MB-231 breast cancer cells. The compounds are designed to contain three aryl ring substituents arranged on the heterocyclic azetidin-2-one (beta-lactam), thus providing conformationally restrained analogues of the triarylethylene arrangement exemplified in the tamoxifen type structure. The compounds demonstrated potency in antiproliferative assays against MCF-7 human breast cancer cell line at low micromolar to nanomolar concentrations with low cytotoxicity and moderate binding affinity to the oestrogen receptor. The effect of a number of aryl and amine functional group substitutions on the antiproliferative activity of the beta-lactam products was explored and a brief computational structure-activity relationship investigation with molecular simulation was investigated.

  10. Prognostic factors in bone marrow transplantation for beta thalassemia major: experiences from Iran.

    Science.gov (United States)

    Ghavamzadeh, A; Nasseri, P; Eshraghian, M R; Jahani, M; Baybordi, I; Nateghi, J; Khodabandeh, A; Sadjadi, A R; Mohyeddin, M; Khademi, Y

    1998-12-01

    This study concerns the effects of several pre-transplant features on outcome for patients with beta thalassemia major who underwent bone marrow transplantation (BMT). Seventy patients with beta thalassemia major underwent bone marrow transplantation during the period 1991-1997 in Shariati Hospital in Tehran, Iran. The survival and rejection curves levelled off at 8 and 18 months after transplantation at 82.6% and 11.4%, respectively. Pre-transplant clinical features (age, serum ferritin, portal fibrosis, hepatomegaly and quality of chelation therapy) were examined for their effects on survival and recurrence of thalassemia in this group of patients who were less than 16 years old. Increasing age, presence of portal fibrosis and increasing serum ferritin were significantly associated with reduced probability of survival (P = 0.0047, P = 0.016 and P = 0.024, respectively). Hepatomegaly and inadequate pre-transplant chelation therapy which were documented as poor prognostic factors in previous studies, were not evaluable in this study. We also showed the benefits of transplanting more than 5.5 x 10(8)/kg cells in this group of patients with no increase in complications.

  11. Bayesian Nonparametric Measurement of Factor Betas and Clustering with Application to Hedge Fund Returns

    Directory of Open Access Journals (Sweden)

    Urbi Garay

    2016-03-01

    Full Text Available We define a dynamic and self-adjusting mixture of Gaussian Graphical Models to cluster financial returns, and provide a new method for extraction of nonparametric estimates of dynamic alphas (excess return and betas (to a choice set of explanatory factors in a multivariate setting. This approach, as well as the outputs, has a dynamic, nonstationary and nonparametric form, which circumvents the problem of model risk and parametric assumptions that the Kalman filter and other widely used approaches rely on. The by-product of clusters, used for shrinkage and information borrowing, can be of use to determine relationships around specific events. This approach exhibits a smaller Root Mean Squared Error than traditionally used benchmarks in financial settings, which we illustrate through simulation. As an illustration, we use hedge fund index data, and find that our estimated alphas are, on average, 0.13% per month higher (1.6% per year than alphas estimated through Ordinary Least Squares. The approach exhibits fast adaptation to abrupt changes in the parameters, as seen in our estimated alphas and betas, which exhibit high volatility, especially in periods which can be identified as times of stressful market events, a reflection of the dynamic positioning of hedge fund portfolio managers.

  12. Gene Expression Analysis of Murine and Human Osteoarthritis Synovium Reveals Elevation of Transforming Growth Factor beta-Responsive Genes in Osteoarthritis-Related Fibrosis

    NARCIS (Netherlands)

    Remst, D. F. G.; Blom, A. B.; Vitters, E. L.; Bank, R. A.; van den Berg, W. B.; Davidson, E. N. Blaney; van der Kraan, P. M.

    Objective. Synovial fibrosis is a major contributor to joint stiffness in osteoarthritis (OA). Transforming growth factor beta (TGF beta), which is elevated in OA, plays a key role in the onset and persistence of synovial fibrosis. However, blocking of TGF beta in OA as a therapeutic intervention

  13. Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice

    DEFF Research Database (Denmark)

    Clausen, Bettina Hjelm; Lambertsen, Kate Lykke; Babcock, Alicia

    2008-01-01

    BACKGROUND: Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are expressed by microglia and infiltrating macrophages following ischemic stroke. Whereas IL-1beta is primarily neurotoxic in ischemic stroke, TNF-alpha may have neurotoxic and/or neuroprotective effects. We inv...

  14. Production and action of transforming growth factor-beta in human osteoblast cultures: dependence on cell differentiation and modulation by calcitriol

    DEFF Research Database (Denmark)

    Kassem, M; Kveiborg, Marie; Eriksen, E F

    2000-01-01

    Transforming growth factor beta (TGF-beta) plays an important role in skeletal remodelling. However, few studies have examined its effects on cultured human osteoblasts. Our aim is to characterise the biological effects of TGF-beta1 on human osteoblasts and to examine the interaction between TGF-...

  15. Production and action of transforming growth factor-beta in human osteoblast cultures: dependence on cell differentiation and modulation by calcitriol

    DEFF Research Database (Denmark)

    Kassem, M; Kveiborg, Marie; Eriksen, E F

    2000-01-01

    Transforming growth factor beta (TGF-beta) plays an important role in skeletal remodelling. However, few studies have examined its effects on cultured human osteoblasts. Our aim is to characterise the biological effects of TGF-beta1 on human osteoblasts and to examine the interaction between TGF-...

  16. Estrogen reduces 11beta-hydroxysteroid dehydrogenase type 1 in liver and visceral, but not subcutaneous, adipose tissue in rats.

    Science.gov (United States)

    Andersson, Therése; Söderström, Ingegerd; Simonyté, Kotryna; Olsson, Tommy

    2010-03-01

    Following menopause, body fat is redistributed from peripheral to central depots. This may be linked to the age related decrease in estrogen levels. We hypothesized that estrogen supplementation could counteract this fat redistribution through tissue-specific modulation of glucocorticoid exposure. We measured fat depot masses and the expression and activity of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) in fat and liver of ovariectomized female rats treated with or without 17beta-estradiol. 11betaHSD1 converts inert cortisone, or 11-dehydrocorticosterone in rats into active cortisol and corticosterone. Estradiol-treated rats gained less weight and had significantly lower visceral adipose tissue weight than nontreated rats (P adipose weight was unaltered. In addition, 11betaHSD1 activity/expression was downregulated in liver and visceral, but not subcutaneous, fat of estradiol-treated rats (P adipose tissue depots, with higher levels in subcutaneous than visceral adipose tissue of estradiol-treated animals (P effects on tissue-specific glucocorticoid metabolism, suggesting that estrogen replacement therapy could influence obesity related morbidity in postmenopausal women.

  17. Transforming Growth Factor-Beta and Matrix Metalloproteinases: Functional Interactions in Tumor Stroma-Infiltrating Myeloid Cells

    Science.gov (United States)

    Santibanez, Juan F.

    2014-01-01

    Transforming growth factor-beta (TGF-β) is a pleiotropic factor with several different roles in health and disease. In tumorigenesis, it may act as a protumorigenic factor and have a profound impact on the regulation of the immune system response. Matrix metalloproteinases (MMPs) are a family that comprises more than 25 members, which have recently been proposed as important regulators acting in tumor stroma by regulating the response of noncellular and cellular microenvironment. Tumor stroma consists of several types of resident cells and infiltrating cells derived from bone marrow, which together play crucial roles in the promotion of tumor growth and metastasis. In cancer cells, TGF-β regulates MMPs expression, while MMPs, produced by either cancer cells or residents' stroma cells, activate latent TGF-β in the extracellular matrix, together facilitating the enhancement of tumor progression. In this review we will focus on the compartment of myeloid stroma cells, such as tumor-associated macrophages, neutrophils, and dendritic and mast cells, which are potently regulated by TGF-β and produce large amounts of MMPs. Their interplay and mutual implications in the generation of pro-tumorigenic cancer microenvironment will be analyzed. PMID:24578639

  18. Transforming Growth Factor-Beta and Matrix Metalloproteinases: Functional Interactions in Tumor Stroma-Infiltrating Myeloid Cells

    Directory of Open Access Journals (Sweden)

    Jelena Krstic

    2014-01-01

    Full Text Available Transforming growth factor-beta (TGF-β is a pleiotropic factor with several different roles in health and disease. In tumorigenesis, it may act as a protumorigenic factor and have a profound impact on the regulation of the immune system response. Matrix metalloproteinases (MMPs are a family that comprises more than 25 members, which have recently been proposed as important regulators acting in tumor stroma by regulating the response of noncellular and cellular microenvironment. Tumor stroma consists of several types of resident cells and infiltrating cells derived from bone marrow, which together play crucial roles in the promotion of tumor growth and metastasis. In cancer cells, TGF-β regulates MMPs expression, while MMPs, produced by either cancer cells or residents’ stroma cells, activate latent TGF-β in the extracellular matrix, together facilitating the enhancement of tumor progression. In this review we will focus on the compartment of myeloid stroma cells, such as tumor-associated macrophages, neutrophils, and dendritic and mast cells, which are potently regulated by TGF-β and produce large amounts of MMPs. Their interplay and mutual implications in the generation of pro-tumorigenic cancer microenvironment will be analyzed.

  19. Transforming growth factor-beta1 stimulates the production of insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in human bone marrow stromal osteoblast progenitors

    DEFF Research Database (Denmark)

    Kveiborg, Marie; Flyvbjerg, Allan; Eriksen, E F;

    2001-01-01

    While transforming growth factor-beta1 (TGF-beta1) regulates proliferation and differentiation of human osteoblast precursor cells, the mechanisms underlying these effects are not known. Several hormones and locally acting growth factors regulate osteoblast functions through changes in the insuli...

  20. Intense physical exercise increases systemic 11beta-hydroxysteroid dehydrogenase type 1 activity in healthy adult subjects.

    Science.gov (United States)

    Dovio, Andrea; Roveda, Eliana; Sciolla, Chiara; Montaruli, Angela; Raffaelli, Andrea; Saba, Alessandro; Calogiuri, Giovanna; De Francia, Silvia; Borrione, Paolo; Salvadori, Piero; Carandente, Franca; Angeli, Alberto

    2010-03-01

    Intense physical exercise activates the hypothalamic-pituitary-adrenocortical axis but little is known about changes in glucocorticoid sensitivity at the target cell level. No data are available on the acute effects of exercise on 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 activity, which generates biologically active cortisol from inactive cortisone and is expressed also in skeletal muscle. Fifteen healthy, trained males (age mean +/- SE 28 +/- 1) were assessed on three non-consecutive days: at rest, during an endurance and strength sessions. During each session, between 1000 and 1600 hours, 6-h urine and four salivary samples were collected. Urinary total tetrahydrocortisol (THF) + alloTHF, tetrahydrocortisone (THE), cortisol (F) and cortisone (E) were measured with HPLC-tandem mass spectrometry; urinary-unconjugated F and E were measured by HPLC-UV. Salivary cortisol and interleukin (IL)-6 were measured by RIA and ELISA, respectively. Both endurance and strength exercises caused an increase in (THF + alloTHF)/THE ratio (mean +/- SE 1.90 +/- 0.07 and 1.82 +/- 0.05 vs. 1.63 +/- 0.06, P < 0.01 and P = 0.03, respectively), consistent with increased systemic 11beta-HSD type 1 activity. No relationship was found with age, BMI, VO(2max) maximal power load or perceived exertion. No significant change was apparent in F/E ratio, an index of 11beta-HSD type 2 activity. No effect of exercise on salivary cortisol and IL-6 was observed, whereas a significant effect of sampling time was found. Intense physical exercise acutely increases systemic 11beta-HSD type 1 activity in humans. Such an increase may lead to higher cortisol concentration in target tissues, notably in skeletal muscle where it could contribute to limit exercise-induced muscle inflammatory response.

  1. [Influence of ASODN to the human tenon's fibroblasts in expressing CTGF induced by transforming growth factor beta2].

    Science.gov (United States)

    Hu, Yi-Zhen; Wang, Yu-Hong; Cao, Yang; Zhang, Ming-Chang

    2008-02-01

    To investigate the effect of connective tissue growth factor's antisense oligonucleotides (ASODN) on the growth of human tenon' s capsule fibroblasts (HTF) induced by transforming growth factor beta2 (TGF-beta2) in vitro. It was a experimental study. HTF was collected from glaucoma patients and cultured. The 5-6 passage was used for experiments. The HTF induced by TGF-beta2 was divided into the following groups: N group: normal HTF; T group: HTF induced by TGF-beta2; A group: CTGF ASODN antisense:5'-TACTGGCGGCGGTCAT-3' encapsulated with liposome; S group: sense 5'-ATGACCGCCGCCAGTA-3' encapsulated with liposome; D group: HTF encapsulated with liposome only. The activity of HTF treated by different concentrations of liposome was detected using methylthianolyldiphenyl tetrazolium bromide (MT) colorimetry. The expression of CTGF was detected by reverse transcription-polymerase chain reaction (RT-PCR) and immunocytochemistry assays. The expression of fibronectin (Fn) was examined by Western blot and immunocytochemistry assays. Liposome-ASODN (A group) significantly (F=15.25, 204.88, 19.73, 90.00; P HTF induced by TGF-beta2 compared with S and D group. However, Liposome alone (T group) has no significant impact in HTF growth compared with T group (t = 0.90, 2.32, 0.75, 2.11; P > 0.05). CTGF-ASODN inhibits the CTGF and Fn expression of HTF induced by TGF-beta2, which may delay the formation of scar in glaucoma filtering surgery.

  2. Apolipoproteins A1, B, and other prognostic biochemical cardiovascular risk factors in patients with beta-thalassemia major.

    Science.gov (United States)

    Ghorban, Khodayar; Shanaki, Mehrnoosh; Mobarra, Naser; Azad, Mehdi; Asadi, Jahanbakhsh; Pakzad, Reza; Ehteram, Hassan

    2016-03-01

    The occurrence of cardiac iron deposition is one of the late effect of iron over load which causes cardiovascular disease (CVD) in patients who are affected by beta-thalassemia major. Evaluation of some cardiovascular risk factors plays a crucial role in prediction and prevention of CVD. This study consisted of 70 young adult subjects with beta-thalassemia major (beta-TM) (aged  0.05) were different. Some elements included ferritin (P  0.05) was not significantly different in study groups. Exception of high-density lipoprotein (P > 0.05), other lipid profiles, and apoB had a negative meaningful correlation with PAB (P beta-thalassemia major. Even so, they contribute toward the gradual development of CVD.

  3. Transforming growth factor-beta. En potent multifunktionel voekstfaktor for normale og maligne celler

    DEFF Research Database (Denmark)

    Nørgaard, P; Damstrup, L; Spang-Thomsen, M;

    1992-01-01

    incomplete, together with other substances such as steroid hormones, oncogene products and integrins. Five isoforms for TGF-beta and five different TGF-beta receptors have been described. TGF-beta exhibits an antiproliferative effect in vitro and in vivo on many cells of epthelial, myeloid, lymphoid...

  4. [Influence of Smad4-independent pathway of transforming growth factor beta1 on the biological activity of pancreatic cancer cells].

    Science.gov (United States)

    Chen, Ying; Zhu, Ming-hua; Yu, Guan-zhen; Li, Fang-mei; Liu, Xiao-hong

    2005-07-01

    To study effects of the expression of transforming growth factor (TGF)-beta1 on the growth of Smad4-null pancreatic cancer cells. TGF-beta1 eukaryotic expression vector was transfected into pancreatic cancer cell line BxPC3. Effects of the expressison of TGF-beta1 was studied by growth curve analysis and flow cytometry. Cell motility was monitored by wound-healing assay. Western blot was used to estimate the expression level of p21(WAF/CLIP1), a cyclin-dependent kinase inhibitor. Transfection of TGF-beta1 changed the morphology of BxPC3 into spindle shaped cells. The growth rate of BxPC3 began to decrease after the fourth day of TGF-beta1 transfection, compared with the control groups. Flow cytometry showed that the percentages of cells in the S phase were (27.53 +/- 0.02)%, (26.32 +/- 0.01)% and (17.01 +/- 0.03)% in naïve BxPC3, vector-control group and TGF-beta1 transfection group respectively. Lesser cells entered the S phase after TGF-beta1 transfection (P BxPC3 and vector groups (P > 0.05). The expression of p21(WAF/CLIP1) increased upon the expression of TGF-beta1. The Smad4-independent pathway of TGF-beta1 not only induces epithelial-mesenchymal transition in pancreatic cancer BxPC3, but also inhibits its growth through the up-regulation of p21(WAF/CLIP1).

  5. Tumors initiated by constitutive Cdk2 activation exhibit transforming growth factor beta resistance and acquire paracrine mitogenic stimulation during progression

    DEFF Research Database (Denmark)

    Corsino, P.; Davis, B.; Law, M.;

    2007-01-01

    mediate some of the transforming effects that result from cyclin D1 overexpression in human breast cancers. MMTV-DIK2 cancer cells express the hepatocyte growth factor (HGF) receptor, c-Met. MMTV-D1K2 cancer cells also secrete transforming growth factor beta (TGF beta), but are relatively resistant to TGF......Cyclin D1/cyclin-dependent kinase 2 (Cdk2) complexes are present at high frequency in human breast cancer cell lines, but the significance of this observation is unknown. This report shows that expression of a cyclin D1-Cdk2 fusion protein under the control of the mouse mammary tumor virus (MMITV...... beta antiproliferative effects. Fibroblasts derived from MMTV-DIK2 tumors secrete factors that stimulate the proliferation of MMTV-D1K2 cancer cells, stimulate c-Met tyrosine phosphorylation, and stimulate the phosphorylation of the downstream signaling intermediates p70(s6k) and Akt on activating...

  6. Enzyme immunoassay of serum beta-2-microglobulin levels in various histological forms of leprosy with special reference to its elevation in type I and type II lepra reactions.

    Science.gov (United States)

    Saha, K; Bhatnagar, A; Sharma, V K; Chakrabarty, A K

    1985-04-01

    The mean beta-2-microglobulin level in serum (3,362 +/- 2,494 micrograms/liter) for 76 leprosy patients, including 9 borderline-tuberculoid, 8 borderline-borderline, 9 borderline-lepromatous, and 16 lepromatous-lepromatous patients and 34 patients with type I or type II lepra reactions, was significantly higher (P less than 0.001) than that (2,122 +/- 1,844 micrograms/liter) for 35 normal subjects. It decreased significantly (P less than 0.001) as the disease glided down from borderline tuberculoid (3,173 +/- 899 micrograms/liter) to the lepromatous end (1,813 +/- 1,391 micrograms/liter). At the onset of type I or type II reaction, the mean beta-2-microglobulin level in serum increased (4,447 +/- 2,863 micrograms/liter), and it remained unchanged (4,433 +/- 2,623 micrograms/liter) after clinical remission. The beta-2-microglobulin level in serum decreased in 55.5% of the patients tested after subsidence of reaction. The level was significantly higher in patients with type II reactions (5,433 +/- 3,299 micrograms/liter) than in patients with type I reactions (3,558 +/- 2,171 micrograms/liter).

  7. Transforming growth factor-beta messenger RNA and protein in murine colitis

    DEFF Research Database (Denmark)

    Whiting, C V; Williams, A M; Claesson, Mogens Helweg

    2001-01-01

    Using a CD4+ T-cell-transplanted SCID mouse model of colitis, we have analyzed TGF-beta transcription and translation in advanced disease. By in situ hybridization, the epithelium of both control and inflamed tissues transcribed TGF-beta1 and TGF-beta3 mRNAs, but both were expressed significantly...... TGF-beta. By ELISA, very low levels (0-69 pg/mg) of soluble total or active TGF-beta were detected in hypotonic tissue lysates. TGF-beta1 and TGF-beta3 are produced by SCID mouse colon and transcription is increased in the colitis caused by transplantation of CD4+ T-cells, but this does not result...

  8. A Robust Skin Colour Segmentation Using Bivariate Pearson Type IIαα (Bivariate Beta) Mixture Model

    OpenAIRE

    B.N.Jagadesh; Srinivasa Rao, K.; Ch.Satyanarayana

    2012-01-01

    Probability distributions formulate the basic framework for developing several segmentation algorithms. Among the various segmentation algorithms, skin colour segmentation is one of the most important algorithms for human computer interaction. Due to various random factors influencing the colour space, there does not exist a unique algorithm which serve the purpose of all images. In this paper a novel and new skin colour segmentation algorithms is proposed based on bivariate Pearson type I...

  9. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses.

    Science.gov (United States)

    Volpe, Elisabetta; Servant, Nicolas; Zollinger, Raphaël; Bogiatzi, Sofia I; Hupé, Philippe; Barillot, Emmanuel; Soumelis, Vassili

    2008-06-01

    Interleukin 17 (IL-17)-producing T helper 17 cells (T(H)-17 cells) have been described as a T helper cell subset distinct from T helper type 1 (T(H)1) and T(H)2 cells, with specific functions in antimicrobial defense and autoimmunity. The factors driving human T(H)-17 differentiation remain controversial. Using a systematic approach combining experimental and computational methods, we show here that transforming growth factor-beta, interleukin 23 (IL-23) and proinflammatory cytokines (IL-1beta and IL-6) were all essential for human T(H)-17 differentiation. However, individual T(H)-17 cell-derived cytokines, such as IL-17, IL-21, IL-22 and IL-6, as well as the global T(H)-17 cytokine profile, were differentially modulated by T(H)-17-promoting cytokines. Transforming growth factor-beta was critical, and its absence induced a shift from a T(H)-17 profile to a T(H)1-like profile. Our results shed new light on the regulation of human T(H)-17 differentiation and provide a framework for the global analysis of T helper responses.

  10. Factor de crecimiento transformante beta-1: estructura, función y mecanismos de regulación en cáncer Transforming growth factor beta-1: structure, function and regulation mechanisms in cancer

    Directory of Open Access Journals (Sweden)

    Oscar Peralta-Zaragoza

    2001-08-01

    Full Text Available El factor de crecimiento transformante beta-1 (TGF-beta1 es sintetizado por muchas estirpes celulares como linfocitos, macrófagos y células dendríticas, y su expresión regula de manera autócrina o parácrina la diferenciación, proliferación y el estado de activación de éstas y muchas otras células. En general, el TGF-beta1 tiene propiedades pleiotrópicas en el contexto de la respuesta inmune durante el desarrollo de infecciones y procesos neoplásicos; sin embargo, los mecanismos de acción y regulación de la expresión de esta citocina aún no se comprenden del todo. En la presente revisión se describen las propiedades biológicas y los procesos moleculares que regulan la expresión del TGF-beta1, para entender los efectos de esta citocina durante la proliferación y la diferenciación celular. El conocimiento de los mecanismos moleculares de la regulación del TGF-beta1 puede representar una importante estrategia de tratamiento del cáncer. El texto completo en inglés de este artículo está disponible en: http://www.insp.mx/salud/index.htmlTransforming growth factor beta-1 (TGF-beta1 is produced by several cell lineages such as lymphocytes, macrophages, and dendritic cells, and its expression serves in both autocrine and paracrine modes to control the differentiation, proliferation, and state of activation of these and other cells. In general, TGF-beta1 has pleiotropic properties on the immune response during the development of infection diseases and cancer; however, the mechanisms of action and regulation of gene expression of this cytokine are poorly understood, In this review, the biological properties and the molecular mechanisms that regulate TGF-beta1 gene expression are described, to understand the role of this cytokine in growth and cell differentiation. The knowledge of molecular mechanisms of gene expression of TGF-beta1 may serve to develop new cancer therapies. The English version of this paper is available at: http://www.insp.mx/salud/index.html

  11. Reorganization of endothelial cord-like structures on basement membrane complex (Matrigel): involvement of transforming growth factor beta 1.

    Science.gov (United States)

    Kuzuya, M; Kinsella, J L

    1994-11-01

    The formation of capillary-like network structures by cultured vascular endothelial cells on reconstituted basement membrane matrix, Matrigel, models endothelial cell differentiation, the final step of angiogenesis (Kubota et al., 1988; Grant et al., 1989). When endothelial cells derived from bovine aorta and brain capillaries were plated on Matrigel, DNA synthesis was suppressed and a network of capillary-like structures rapidly formed in 8-12 h. With time, the network broke down, resulting in dense cellular cords radiating from multiple cellular clusters in 16-24 h. Finally, multicellular aggregates of cells were formed as the network underwent further retraction. Network regression was prevented when either dithiothreitol (DTT) or anti-TGF-beta 1 antibodies were added during the assay. The addition of exogenous TGF-beta 1 promoted the regression of endothelial cells into the clusters. This response to TGF-beta 1 was blocked by potent serine threonine protein kinase inhibitors, H-7 and HA100. TGF-beta 1 was released from polymerized Matrigel by incubation with Dulbecco's modified eagle's medium (DMEM) in the absence of cells. The Matrigel-conditioned DMEM inhibited endothelial DNA synthesis even in the presence of anti-TGF-beta 1 antibodies. These results suggest that TGF-beta 1 and possibly other soluble factors from Matrigel may be important for differentiation and remodeling of endothelial cells in a capillary network with possible implications for wound healing and development.

  12. Ionizing Radiation Promotes Migration and Invasion of Cancer Cells Through Transforming Growth Factor-Beta-Mediated Epithelial-Mesenchymal Transition

    Energy Technology Data Exchange (ETDEWEB)

    Zhou Yongchun [Department of Radiation Oncology, Xijing Hospital Fourth Military Medical University, Xi' an (China); Department of Radiation Medicine, College of Preventive Medicine, Xijing Hospital Fourth Military Medical University, Xi' an (China); Liu Junye; Li Jing; Zhang Jie [Department of Radiation Medicine, College of Preventive Medicine, Xijing Hospital Fourth Military Medical University, Xi' an (China); Xu Yuqiao [Department of Pathology, Xijing Hospital Fourth Military Medical University, Xi' an (China); Zhang Huawei; Qiu Lianbo; Ding Guirong [Department of Radiation Medicine, College of Preventive Medicine, Xijing Hospital Fourth Military Medical University, Xi' an (China); Su Xiaoming [Department of Radiation Oncology, 306th Hospital of PLA, Beijing (China); Mei Shi [Department of Radiation Oncology, Xijing Hospital Fourth Military Medical University, Xi' an (China); Guo Guozhen, E-mail: guozhenguo@hotmail.com [Department of Radiation Medicine, College of Preventive Medicine, Xijing Hospital Fourth Military Medical University, Xi' an (China)

    2011-12-01

    Purpose: To examine whether ionizing radiation enhances the migratory and invasive abilities of cancer cells through transforming growth factor (TGF-{beta})-mediated epithelial-mesenchymal transition (EMT). Methods and Materials: Six cancer cell lines originating from different human organs were irradiated by {sup 60}Co {gamma}-ray at a total dose of 2 Gy, and the changes associated with EMT, including morphology, EMT markers, migration and invasion, were observed by microscope, Western blot, immunofluorescence, scratch assay, and transwell chamber assay, respectively. Then the protein levels of TGF-{beta} in these cancer cells were detected by enzyme-linked immunosorbent assay, and the role of TGF-{beta} signaling pathway in the effect of ionizing radiation on EMT was investigate by using the specific inhibitor SB431542. Results: After irradiation with {gamma}-ray at a total dose of 2 Gy, cancer cells presented the mesenchymal phenotype, and compared with the sham-irradiation group the expression of epithelial markers was decreased and of mesenchymal markers was increased, the migratory and invasive capabilities were strengthened, and the protein levels of TGF-{beta} were enhanced. Furthermore, events associated with EMT induced by IR in A549 could be reversed through inhibition of TGF-{beta} signaling. Conclusions: These results suggest that EMT mediated by TGF-{beta} plays a critical role in IR-induced enhancing of migratory and invasive capabilities in cancer cells.

  13. Serum interleukin-1beta and tumor necrosis factor-alpha in febrile seizures: is there a link?

    Science.gov (United States)

    Mahyar, Abolfazl; Ayazi, Parviz; Orangpour, Reza; Daneshi-Kohan, Mohammad Mahdi; Sarokhani, Mohammad Reza; Javadi, Amir; Habibi, Morteza; Talebi-Bakhshayesh, Mousa

    2014-10-01

    Febrile seizures are induced by fever and are the most common type of seizures in children. Although numerous studies have been performed on febrile seizures, their pathophysiology remains unclear. Recent studies have shown that cytokines may play a role in the pathogenesis of febrile seizures. The present study was conducted to identify potential links between serum interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and febrile seizures. Ninety-two patients with simple or complex febrile seizures (46 patients per seizure type), and 46 controls with comparable age, sex, and severity of temperature were enrolled. The median concentrations of serum IL-1β in the simple, complex febrile seizure, and control groups were 0.05, 0.1, and 0.67 pg/mL, respectively (P=0.001). Moreover, the median concentrations of TNF-α in the simple, complex febrile seizure, and control groups were 2.5, 1, and 61.5 pg/mL, respectively (P=0.001). Furthermore, there were significant differences between the case groups in serum IL-1β and TNF-α levels (Pfebrile seizures.

  14. Effects of transforming growth factor beta, tumor necrosis factor alpha, interferon gamma and LIF-HILDA on the proliferation of acute myeloid leukemia cells.

    Science.gov (United States)

    Kerangueven, F; Sempere, C; Tabilio, A; Mannoni, P

    1990-01-01

    A group of polypeptide factors that regulate cell growth and differentiation has been tested for their biological activities on the growth and differentiation of leukemic cells isolated from patients with Acute Myeloid Leukemias (AML). The effects of Transforming Growth Factor beta 1 (TGF beta), Tumor Necrosis Factor alpha (TNF alpha), Interferon gamma (IFN gamma) and LIF-HILDA were compared on leukemic cells cultured in vitro for seven days. Spontaneously growing leukemic cells were selected in order to study either inhibition or enhancement of proliferation induced by these factors. Only TGF beta 1 was found to induce a clear inhibition of leukemic proliferation in all cases tested. Recombinant TNF alpha and IFN gamma were found to induce either inhibition or enhancement of the proliferation on separate specimens. Under the conditions of culture, it was not possible to document any effect of LIF-HILDA. Cell differentiation and cell maturation were documented studying the modulation of cell surface antigens. TGF beta did not modify antigen expression on the cells surviving after 3 days in culture. Both TNF alpha and IFN gamma were found to enhance the expression of adhesion molecules and to a lesser extent, the expression of some lineage associated antigens. No effect of LIF-HILDA on antigen modulation was documented in the cases tested. These data confirm that TGF beta is by itself a potent inhibitor of the myeloid leukemia cells proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. ICAT Inhibits beta-Catenin Binding to Tcf/Lef-Family Transcription Factors and in the General Coactivator p300 Using Independent Structural Modules

    Energy Technology Data Exchange (ETDEWEB)

    Daniels, D. L.

    2002-01-01

    In the canonical Wnt signaling pathway, {beta}-catenin activates target genes through its interactions with Tcf/Lef-family transcription factors and additional transcriptional coactivators. The crystal structure of ICAT, an inhibitor of {beta}-catenin-mediated transcription, bound to the armadillo repeat domain of {beta}-catenin, has been determined. ICAT contains an N-terminal helilical domain that binds to repeats 11 and 12 of {beta}-catenin, and an extended C-terminal region that binds to repeats 5-10 in a manner similar that of Tcfs and other {beta}-catenin ligands. Full-length ICAT dissociates complexes of {beta}-catenin, Lef-1, and the transcriptional coactivator p300, whereas the helical domain alone selectively blocks binding to p300. The C-terminal armadillo repeats of {beta}-catenin may be an attractive target for compounds designed to disrupt aberrant {beta}-catenin-mediated transcription associated with various cancers.

  16. Impact of inhibitors and L2 antibodies upon the infectivity of diverse alpha and beta human papillomavirus types.

    Directory of Open Access Journals (Sweden)

    Kihyuck Kwak

    Full Text Available The licensed human papillomavirus (HPV vaccines elicit type-restricted immunity but do not target cutaneous HPV types of the beta genus that are associated with non-melanoma skin cancer in immune-compromised patients, and it is unclear if these diverse types share a common mechanism of infection. Residues 11-88 of minor capsid protein L2 contain cross-protective epitopes, and vaccination with concatamers of this region derived from as many as eight alpha HPV (L2 α11-88x8 is being developed as an alternative prophylactic vaccine with potentially broader efficacy. There is also interest in developing broadly protective topical microbicides, such as carrageenan or heparin that block HPV receptor interactions, or small molecule inhibitors of infection. Here we have examined several inhibitors of HPV infection and antisera to L2 α11-88x8 for their breadth of activity against infection by 34 HPV types from within both the alpha and beta families using pseudovirions (PsV carrying a luciferase reporter as surrogates for native virus. We observed that both heparin and carrageenan prevented infection by mucosatropic HPV types, but surprisingly PsV of several epidermotropic alpha4 and beta HPV types exhibited increased infectivity especially at low inhibitor concentrations. Furin and γ-secretase inhibitors and L2 α11-88x8 antiserum blocked infection by all HPV PsV types tested. These findings suggest that the distinct tropism of mucosal and cutaneous HPV may reflect distinct cell surface receptor interactions, but a common uptake mechanism dependent upon furin and γ-secretase proteolytic activities. Carrageenan, which is being tested as a vaginal microbicide, broadly inhibited infection by the high-risk mucosatropic HPV PsV, but not most skin tropic alpha and beta HPV. Vaccination with an L2 multimer derived exclusively from alpha papillomavirus sequences induced antibodies that broadly neutralized PsV of all 34 HPVs from within both the alpha and

  17. Statin, Calcium Channel Blocker and Beta Blocker Therapy May Decrease the Incidence of Tuberculosis Infection in Elderly Taiwanese Patients with Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Mei-Yueh Lee

    2015-05-01

    Full Text Available Background: It is well known that diabetes mellitus impairs immunity and therefore is an independent risk factor for tuberculosis. However, the influence of associated metabolic factors, such as hypertension, dyslipidemia and gout has yet to be confirmed. This study aimed to investigate whether the strong association between tuberculosis and diabetes mellitus is independent from the influence of hypertension and dyslipidemia, and its treatment in elderly Taiwanese patients. Methods: A total of 27,958 patients aged more than 65 years were identified from the National Health Insurance Research Database (NIHRD in 1997 and were followed from 1998 to 2009. The demographic characteristics between the patients with and without diabetes were analyzed using the χ2 test. A total of 13,981 patients with type 2 diabetes were included in this study. Cox proportional hazard regression models were used to determine the independent effects of diabetes on the risk of tuberculosis. Results: After adjusting for age, sex, other co-morbidities and medications, calcium channel blocker, beta blocker and statin users had a lower independent association, with risk ratios of 0.76 (95% CI, 0.58–0.98, 0.72 (95% CI, 0.58–0.91 and 0.76 (95% CI, 0.60–0.97, respectively. Conclusion: Calcium channel blocker, beta blocker and statin therapy may decrease the incidence of tuberculosis infection in elderly Taiwanese patients with type 2 diabetes.

  18. Classification of Gait Types Based on the Duty-factor

    DEFF Research Database (Denmark)

    Fihl, Preben; Moeslund, Thomas B.

    2007-01-01

    This paper deals with classification of human gait types based on the notion that different gait types are in fact different types of locomotion, i.e., running is not simply walking done faster. We present the duty-factor, which is a descriptor based on this notion. The duty-factor is independent...

  19. Transforming growth factor beta 1 prevents cytokine-mediated inhibitory effects and induction of nitric oxide synthase in the RINm5F insulin-containing beta-cell line.

    Science.gov (United States)

    Mabley, J G; Cunningham, J M; John, N; Di Matteo, M A; Green, I C

    1997-12-01

    The aim of this study was to examine if the growth factor, transforming growth factor beta 1 (TGF beta 1), could prevent induction of nitric oxide synthase and cytokine-mediated inhibitory effects in the insulin-containing, clonal beta cell line RINm5F. Treatment of RINm5F cells for 24 h with interleukin-1 beta (IL-1 beta) (100 pM) induced expression of nitric oxide synthase and inhibited glyceraldehyde-stimulated insulin secretion. Combinations of IL-1 beta (100 pM), tumour necrosis factor-alpha (100 pM) and interferon-gamma (100 pM) reduced RINm5F cell viability (determined by the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium (MTT) reduction assay) and de novo protein synthesis, as measured by incorporation of radiolabelled amino acids into perchloric acid-precipitable protein. Pretreatment of RINm5F cells with TGF beta 1 (10 pM) for 18 or 24 h, prior to the addition of either IL-1 beta or combined cytokines, prevented cytokine-induced inhibition of insulin secretion, protein synthesis and the loss of cell viability. TGF beta 1 pretreatment inhibited cytokine-induced expression and activity of nitric oxide synthase in RINm5F cells as determined by Western blotting and by cytosolic conversion of radiolabelled arginine into labelled citrulline and nitric oxide. Chemically generated superoxide also induced expression of nitric oxide synthase possibly due to direct activation of the nuclear transcription factor NF kappa B, an effect prevented by both an antioxidant and TGF beta 1 pretreatment. In conclusion, the mechanism of action of TGF beta 1 in blocking cytokine inhibitory effects was by preventing induction of nitric oxide synthase.

  20. Prevalence, types and factors associated with echocardiographic ...

    African Journals Online (AJOL)

    gram in this study was defined as the presence of LVH, diastolic and/or ... In bivariate logistic regression analysis, the factors associated with an abnormal echocardiogram were age (OR ... African Health Sciences Vol 16 Issue 1, March 2016.

  1. Vertebral Artery Aneurysm Mimicking as Left Subclavian Artery Aneurysm in a Patient with Transforming Growth Factor Beta Receptor II Mutation.

    Science.gov (United States)

    Afifi, Rana O; Dhillon, Baltej Singh; Sandhu, Harleen K; Charlton-Ouw, Kristofer M; Estrera, Anthony L; Azizzadeh, Ali

    2015-10-01

    We report successful endovascular repair of a left vertebral artery aneurysm in a patient with transforming growth factor beta receptor II mutation. The patient was initially diagnosed with a left subclavian artery aneurysm on computed tomography angiography. The patient consented to publication of this report.

  2. Crucial role of synovial lining macrophages in the promotion of transforming growth factor beta-mediated osteophyte formation.

    NARCIS (Netherlands)

    Lent, P.L.E.M. van; Blom, A.B.; Kraan, P.M. van der; Holthuysen, A.E.M.; Vitters, E.L.; Rooijen, N. van; Smeets, R.L.L.; Nabbe, K.C.A.M.; Berg, W.B. van den

    2004-01-01

    OBJECTIVE: To investigate in vivo and in vitro whether macrophages have an intermediate role in transforming growth factor beta (TGFbeta)-induced osteophyte formation. METHODS: In vivo, synovial lining macrophages were selectively depleted by injection of clodronate-laden liposomes 7 days prior to i

  3. TUMOR-NECROSIS-FACTOR-ALPHA, INTERLEUKIN-1-BETA, AND INTERLEUKIN-6 PLASMA-LEVELS IN NEONATAL SEPSIS

    NARCIS (Netherlands)

    DEBONT, ESJM; MARTENS, A; VANRAAN, J; SAMSON, G; FETTER, WPF; OKKEN, A; DELEIJ, LHFM

    Tumor necrosis factor-alpha, IL-1beta, and IL-6 are thought to be involved in the pathogenesis of sepsis with gram-negative bacteria. We studied these cytokines during neonatal sepsis with mainly gram-positive bacteria. Ten newborns with clinical sepsis and 22 healthy controls were enrolled in the

  4. Recombinant expression of human nerve growth factor beta in rabbit bone marrow mesenchymal stem cells.

    Science.gov (United States)

    Fan, Bo-Sheng; Lou, Ji-Yu

    2010-12-01

    Nerve growth factor (NGF) is required for the differentiation and maintenance of sympathetic and sensory neurons. In the present study, the recombinant expression of human nerve growth factor beta (hNGF-β) gene in rabbit bone marrow mesenchymal stem cells (rMSCs) was undertaken. Recombinant vector containing hNGF-β was constructed and transferred into rMSCs, the expressions of the exogenous in rMSCs were determined by reverse transcriptase PCR (RT-PCR), ELISA and Western blot, whereas the biological activity of recombinant hNGF-β was confirmed using PC12 cells and cultures of dorsal root ganglion neurons from chicken embryos. The results showed that the hNGF-β gene expressed successfully in the rMSCs, a polypeptide with a molecular weight of 13.2 kDa was detected. The maximal expression level of recombinant hNGF-β in rMSCs reached 126.8012 pg/10(6) cells, the mean concentration was 96.4473 pg/10(6) cells. The recombinant hNGF-β in the rMSCs showed full biological activity when compared to commercial recombinant hNGF-β.

  5. Association of cardiovascular factors and Alzheimer's disease plasma amyloid-beta protein in subjective memory complainers.

    Science.gov (United States)

    Bates, Kristyn A; Sohrabi, Hamid R; Rodrigues, Mark; Beilby, John; Dhaliwal, Satvinder S; Taddei, Kevin; Criddle, Arthur; Wraith, Megan; Howard, Matthew; Martins, Georgia; Paton, Athena; Mehta, Pankaj; Foster, Jonathan K; Martins, Ian J; Lautenschlager, Nicola T; Mastaglia, Frank L; Laws, Simon M; Gandy, Samuel E; Martins, Ralph N

    2009-01-01

    A strong link is indicated between cardiovascular disease (CVD) and risk for developing Alzheimer's disease (AD), which may be exacerbated by the major AD genetic risk factor apolipoprotein Eepsilon4 (APOEepsilon4). Since subjective memory complaint (SMC) may potentially be an early indicator for cognitive decline, we examined CVD risk factors in a cohort of SMC. As amyloid-beta (Abeta) is considered to play a central role in AD, we hypothesized that the CVD risk profile (increased LDL, reduced HDL, and increased body fat) would be associated with plasma Abeta levels. We explored this in 198 individuals with and without SMC (average age = 63 years). Correlations between Abeta40 and HDL were observed, which were stronger in non-APOEepsilon4 carriers (rho = -0.315, p association between HDL and Abeta, which if demonstrated to be causal has implications for the development of lifestyle interventions and/or novel therapeutics. The relationship between HDL and Abeta and the potential significance of such an association needs to be validated in a larger longitudinal study.

  6. Adenylyl cyclase type 6 overexpression selectively enhances beta-adrenergic and prostacyclin receptor-mediated inhibition of cardiac fibroblast function because of colocalization in lipid rafts.

    Science.gov (United States)

    Liu, Xiaoqiu; Thangavel, Muthusamy; Sun, Shu Qiang; Kaminsky, Joseph; Mahautmr, Penden; Stitham, Jeremiah; Hwa, John; Ostrom, Rennolds S

    2008-06-01

    Cardiac fibroblasts produce and degrade extracellular matrix and are critical in regulating cardiac remodeling and hypertrophy. Fibroblasts are activated by factors such as transforming growth factor beta and inhibited by agents that elevate 3',5'-cyclic adenosine monophosphate (cAMP) levels. cAMP signal generation and response is known to be compartmentalized in many cell types in part through the colocalization of receptors and specific adenylyl cyclase isoforms in lipid rafts and caveolae. The present study sought to define the localization of key G protein-coupled receptors with adenylyl cyclase type 6 (AC6) in lipid rafts of rat cardiac fibroblasts and to determine if this colocalization was functionally relevant. We found that cardiac fibroblasts produce cAMP in response to agonists for beta-adrenergic (isoproterenol), prostaglandin EP2 (butaprost), adenosine (adenosine-5'-N-ethylcarboxamide, NECA), and prostacyclin (beraprost) receptors. Overexpression of AC6 increased cAMP production stimulated by isoproterenol and beraprost but not by butaprost or NECA. A key function of fibroblasts is the production of collagen. Isoproterenol- and beraprostmediated inhibition of collagen synthesis was also enhanced by AC6 overexpression, while inhibition by butaprost and NECA were unaltered. Lipid raft fractions from cardiac fibroblasts contain the preponderance of beta-adrenergic receptors and AC6 but exclude EP2 receptors. While we could not determine the localization of native prostacyclin receptors, we were able to determine that epitope-tagged prostanoid IP receptors (IPR) expressed in COS7 cells did localize, in part, in lipid raft fractions. These findings indicate that IP receptors are expressed in lipid rafts and can activate raft-localized AC isoforms. AC6 is completely compartmentized in lipid raft domains where it is activated solely by coresident G protein-coupled receptors to regulate cardiac fibroblast function.

  7. Beta-Amyloid Deposition and Alzheimer's Type Changes Induced by Borrelia Spirochetes

    Energy Technology Data Exchange (ETDEWEB)

    Miklossy,J.; Kis, A.; Radenovic, A.; Miller, L.; Forro, L.; Martins, R.; Reiss, K.; Darbinian, N.; Darekar, P.; et al.

    2006-01-01

    The pathological hallmarks of Alzheimer's disease (AD) consist of {beta}-amyloid plaques and neurofibrillary tangles in affected brain areas. The processes, which drive this host reaction are unknown. To determine whether an analogous host reaction to that occurring in AD could be induced by infectious agents, we exposed mammalian glial and neuronal cells in vitro to Borrelia burgdorferi spirochetes and to the inflammatory bacterial lipopolysaccharide (LPS). Morphological changes analogous to the amyloid deposits of AD brain were observed following 2-8 weeks of exposure to the spirochetes. Increased levels of {beta}-amyloid presursor protein (A{beta}PP) and hyperphosphorylated tau were also detected by Western blots of extracts of cultured cells that had been treated with spirochetes or LPS. These observations indicate that, by exposure to bacteria or to their toxic products, host responses similar in nature to those observed in AD may be induced.

  8. Association between Plasma Levels of Transforming Growth Factor-beta1, IL-23 and IL-17 and the Severity of Autism in Egyptian Children

    Science.gov (United States)

    Hashim, Haitham; Abdelrahman, Hadeel; Mohammed, Doaa; Karam, Rehab

    2013-01-01

    It has been recently shown that dysregulation of transforming growth factor-beta1 (TGF-beta1), IL-23 and IL-17 has been identified as a major factor involved in autoimmune disorders. Based on the increasing evidence of immune dysfunction in autism the aim of this study was to measure serum levels of TGF-beta1, IL-23 and IL-17 in relation to the…

  9. Factor de crecimiento transformante beta-1: estructura, función y mecanismos de regulación en cáncer Transforming growth factor beta-1: structure, function and regulation mechanisms in cancer

    OpenAIRE

    Oscar Peralta-Zaragoza; A. Lagunas-Martínez; Vicente Madrid-Marina

    2001-01-01

    El factor de crecimiento transformante beta-1 (TGF-beta1) es sintetizado por muchas estirpes celulares como linfocitos, macrófagos y células dendríticas, y su expresión regula de manera autócrina o parácrina la diferenciación, proliferación y el estado de activación de éstas y muchas otras células. En general, el TGF-beta1 tiene propiedades pleiotrópicas en el contexto de la respuesta inmune durante el desarrollo de infecciones y procesos neoplásicos; sin embargo, los mecanismos de acción y r...

  10. 17-Beta-estradiol inhibits transforming growth factor-beta signaling and function in breast cancer cells via activation of extracellular signal-regulated kinase through the G protein-coupled receptor 30.

    Science.gov (United States)

    Kleuser, Burkhard; Malek, Daniela; Gust, Ronald; Pertz, Heinz H; Potteck, Henrik

    2008-12-01

    Breast cancer development and breast cancer progression involves the deregulation of growth factors leading to uncontrolled cellular proliferation, invasion and metastasis. Transforming growth factor (TGF)-beta plays a crucial role in breast cancer because it has the potential to act as either a tumor suppressor or a pro-oncogenic chemokine. A cross-communication between the TGF-beta signaling network and estrogens has been postulated, which is important for breast tumorigenesis. Here, we provide evidence that inhibition of TGF-beta signaling is associated with a rapid estrogen-dependent nongenomic action. Moreover, we were able to demonstrate that estrogens disrupt the TGF-beta signaling network as well as TGF-beta functions in breast cancer cells via the G protein-coupled receptor 30 (GPR30). Silencing of GPR30 in MCF-7 cells completely reduced the ability of 17-beta-estradiol (E2) to inhibit the TGF-beta pathway. Likewise, in GPR30-deficient MDA-MB-231 breast cancer cells, E2 achieved the ability to suppress TGF-beta signaling only after transfection with GPR30-encoding plasmids. It is most interesting that the antiestrogen fulvestrant (ICI 182,780), which possesses agonistic activity at the GPR30, also diminished TGF-beta signaling. Further experiments attempted to characterize the molecular mechanism by which activated GPR30 inhibits the TGF-beta pathway. Our results indicate that GPR30 induces the stimulation of the mitogen-activated protein kinases (MAPKs), which interferes with the activation of Smad proteins. Inhibition of MAPK activity prevented the ability of E2 from suppressing TGF-beta signaling. These findings are of great clinical relevance, because down-regulation of TGF-beta signaling is associated with the development of breast cancer resistance in response to antiestrogens.

  11. Dab2 attenuates brain injur y in APP/PS1 mice via targeting transforming growth factor-beta/SMAD signaling

    Institute of Scientific and Technical Information of China (English)

    Lei Song; Yue Gu; Jing Jie; Xiaoxue Bai; Ying Yang; Chaoying Liu; Qun Liu

    2014-01-01

    Transforming growth factor-beta (TGF-β) type II receptor (TβRII) levels are extremely low in the brain tissue of patients with Alzheimer’s disease. This receptor inhibits TGF-β1/SMAD signaling and thereby aggravates amyolid-beta deposition and neuronal injury. Dab2, a speciifc adapter protein, protects TβRII from degradation and ensures the effective conduction of TGF-β1/SMAD signaling. In this study, we used an adenoviral vector to overexpress the Dab2 gene in the mouse hippocampus and investigated the regulatory effect of Dab2 protein on TGF-β1/SMAD signaling in a mouse model of Alzheimer’s disease, and the potential neuroprotective effect. The results showed that the TβRII level was lower in APP/PS1 mouse hippocampus than in normal mouse hippocampus. After Dab2 expression, hippocampal TβRII and p-SMAD2/3 levels were signiif-cantly increased, while amyloid-beta deposition, microglia activation, tumor necrosis factor-βand interleulin-6 levels and neuronal loss were signiifcantly attenuated in APP/PS1 mouse brain tissue. These results suggest that Dab2 can exhibit neuroprotective effects in Alzheimer’s disease by regulating TGF-β1/SMAD signaling.

  12. Environmental Risk Factors and Type 1 Diabetes: Past, Present, and Future.

    Science.gov (United States)

    Butalia, Sonia; Kaplan, Gilaad G; Khokhar, Bushra; Rabi, Doreen M

    2016-12-01

    Type 1 diabetes is an autoimmune condition that results from the destruction of the insulin-producing beta cells of the pancreas. The excess morbidity and mortality resulting from its complications, coupled with its increasing incidence, emphasize the importance of better understanding the causes of this condition. Over the past several decades, a substantive amount of work has been done and, although many advances have occurred in identifying disease-susceptibility genes, there has been a lag in understanding the environmental triggers. Several putative environmental risk factors have been proposed, including infections, dietary factors, air pollution, vaccines, location of residence, family environment and stress. However, most of these factors have been inconclusive, thus supporting the need for further study into the causes of type 1 diabetes. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  13. Genetic risk factors for type 1 diabetes

    DEFF Research Database (Denmark)

    Pociot, Flemming; Lernmark, Åke

    2016-01-01

    Type 1 diabetes is diagnosed at the end of a prodrome of β-cell autoimmunity. The disease is most likely triggered at an early age by autoantibodies primarily directed against insulin or glutamic acid decarboxylase, or both, but rarely against islet antigen-2. After the initial appearance of one...... of the three stages can differ. Type 1 diabetes could serve as a disease model for organ-specific autoimmune disorders such as coeliac disease, thyroiditis, and Addison's disease, which show similar early markers of a prolonged disease process before clinical diagnosis....... of these autoantibody biomarkers, a second, third, or fourth autoantibody against either islet antigen-2 or the ZnT8 transporter might also appear. The larger the number of β-cell autoantibody types, the greater the risk of rapid progression to clinical onset of diabetes. This association does not necessarily mean...

  14. Health-Related Quality of Life and Health Utility Values in Beta Thalassemia Major Patients Receiving Different Types of Iron Chelators in Iran.

    Science.gov (United States)

    Seyedifar, Meysam; Dorkoosh, Farid Abedin; Hamidieh, Amir Ali; Naderi, Majid; Karami, Hossein; Karimi, Mehran; Fadaiyrayeny, Masoomeh; Musavi, Masoumeh; Safaei, Sanaz; Ahmadian-Attari, Mohammad Mahdi; Hadjibabaie, Molouk; Cheraghali, Abdol Majid; Akbari Sari, Ali

    2016-10-01

    Background: Thalassemia is a chronic, inherited blood disorder, which in its most severe form, causes life-threatening anemia. Thalassemia patients not only engage with difficulties of blood transfusion and iron chelating therapy but also have some social challenges and health threatening factors. There are some reports on quality of life in thalassemia patients around the world from southeast of Asia to Italy in Europe and United States. In this study, we tried to evaluate and compare Health Related Quality of life (HRQoL) and the health utility in beta thalassemia major patients receiving different types of iron chelators and living in different socio-economical situations. Subjects and Methods: EQ-5D-3L accompanied by a Visual Analogue Scale (VAS) questionnaire was used. The respondents were patients with beta thalassemia major that were at least 12 years old selected from 3 provinces of Sistan-Blouchestan, Fars and Mazandaran. Comorbidities including heart complication, Diabetes Mellitus and Hepatitis and also types of iron chelators (oral, injection, combination of both) were also asked. Cross tab and ANOVA analysis conducted to evaluate each dimension score and health utility differences between provinces, iron chelation methods, comorbidities, age group and gender. Results: 528 patients answered the questionnaires. The health utility of patients that received oral iron chelator were 0.87 ± .01 for oral iron chelators versus 0.81 ± .01 for injection dosage form (p<0.05). Increase in age was accompanied by decrease in health utility. Females faced more usual activity problems, anxiety and depression. Heart problems were more prevalent in males. Conclusion: This study suggests that the quality of life of beta thalassemia major patients is dependent on type of iron chelation treatment which they received, the gender they have, the comorbidities they suffer and socio-economical situations they live in.

  15. Effects of low intensity laser acupoint irradiation on inhibiting islet beta-cell apoptosis in rats with type 2 diabetes

    Science.gov (United States)

    Xiong, Guoxin; Xiong, Leilei; Li, Xinzhong

    2016-09-01

    To investigate the effects of low intensity semiconductor laser acupoint irradiation on inhibiting islet beta-cell apoptosis in rats with type 2 diabetes, a method using a high-fat diet and low-dose intraperitoneal injections of streptozotocin established a type 2 diabetes mellitus rat model. Model rats were randomly divided into a laser acupoint irradiation group, rosiglitazone control group, and placebo group; each group had 10 rats. In addition, 10 normal male rats were selected for the normal control group. The Housanli, Neiting and Yishu acupoints of the rats in the laser acupoint irradiation group were irradiated with a 10 mW semiconductor laser; each point was irradiated for 15 min, once every 2 d over 28 d, for a total of 14 episodes of irradiation. The rosiglitazone group rats were given rosiglitazone (0.2 mg kg-1) intragastrically; the placebo group rats were given 0.9% brine (0.2 mg kg-1) intragastrically, once daily, for four consecutive weeks. The change of fasting blood glucose was determined before and after each treatment. The islet beta-cell apoptosis was determined. The islet beta-cell apoptosis rates of the laser acupoint irradiation group and the rosiglitazone group were significantly lower than the rate of the placebo group. Even though the rate was lower in the laser acupoint irradiation group than in the rosiglitazone group, there was no significant difference between them. It is shown that acupoint irradiation with a semiconductor laser can effectively inhibit islet beta-cell apoptosis in rats with type 2 diabetes.

  16. Alpha- and beta-cell abnormalities in haemoglobin A1c-defined prediabetes and type 2 diabetes

    DEFF Research Database (Denmark)

    Calanna, Salvatore; Scicali, Roberto; Di Pino, Antonino;

    2014-01-01

    New recommendations for the use of glycated haemoglobin A1c (HbA1c) to diagnose prediabetes and type 2 diabetes have changed the constitution of the two populations. We aimed to investigate the pathophysiological characteristics of individuals with HbA1c-defined prediabetes and type 2 diabetes...... compared to subjects with HbA1c-defined prediabetes and controls. Plasma levels of incretin hormones were similar across the three groups. HbA1c associated negatively with insulinogenic index, disposition index, and incretin effect. Our findings show clear alpha- and beta-cell dysfunction in HbA1c...

  17. Quantitative analysis of transforming growth factor beta 1 mRNA in patients with alcoholic liver disease

    Institute of Scientific and Technical Information of China (English)

    Wei-Xing Chen; You-Ming Li; Chao-Hui Yu; Wei-Min Cai; Min Zheng; Feng Chen

    2002-01-01

    AIM: To investigate the expression of the transforminggrowth factor beta 1 (TGF- beta 1 ) mRNA in different stagesof alcoholic liver disease (ALD) and its clinical value.METHODS: One hundred and seven male alcoholics weregrouped by clinical findings into four groups: alcoholabusers without liver impairment (n=22 ), alcoholicsteatosis ( n = 30 ); alcoholic hepatitis ( n = 31 ); andalcoholic cirrhosis ( n = 24 ) Using peripheral bloodmononuclear cells(PBMC) as samples the gene expressionof TGF-beta 1 was examined quantitatively by reversetranscription polymerase chain reaction (RT-PCR) and dotblot. There are 34 healthy subjects served as control.RESULTS: The expression of TGF-beta 1 from all ALDpatients was significantly greater than that in controls ( 1. 320± 1.162 vs 0.808±0.276, P<0.001). The differences of theexpressions were significant between the patients from eachgroups ( alcoholic steatosis, alcoholic hepatitis andalcoholic cirrhosis) and the controls ( 1. 168 ± 0.852, 1.462 ±1.657, 1.329± 0.610 vs 0.808 ± 0.276, P< 0.050). Nosignificant differences of TGF -beta 1 mRNA expression wereobserved between alcohol abusers without liver impairmentand controls. The expressions in patients with alcoholichepatitis and alcoholic cirrhosis were significantly greaterthan that in alcohol abusers respectively (1.462 ± 1. 657, 1.329 ± 0. 610 vs 0. 841 ± 0. 706, P < 0. 050). No significantdifferences of TGF -beta 1 mRNA expression were observedbetween alcoholic fatty liver men and alcohol abusers.CONCLUSION: TGF-beta 1 expression level can be a riskfactor for alcoholic liver disease and might be related to theinflammatory activity and fibrosis of the liver in patients .

  18. Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1{alpha}, suppress amyloid {beta}-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Raman, Dayanidhi; Milatovic, Snjezana-Zaja [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Milatovic, Dejan [Department of Pediatrics/Pediatric Toxicology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Splittgerber, Ryan [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Fan, Guo-Huang [Department of Neurobiology and Neurotoxicology, Meharry Medical College, Nashville, TN 37221 (United States); Richmond, Ann, E-mail: ann.richmond@vanderbilt.edu [VA Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States)

    2011-11-15

    Alzheimer's disease (AD) is characterized by a progressive cognitive decline and accumulation of neurotoxic oligomeric peptides amyloid-{beta} (A{beta}). Although the molecular events are not entirely known, it has become evident that inflammation, environmental and other risk factors may play a causal, disruptive and/or protective role in the development of AD. The present study investigated the ability of the chemokines, macrophage inflammatory protein-2 (MIP-2) and stromal cell-derived factor-1{alpha} (SDF-1{alpha}), the respective ligands for chemokine receptors CXCR2 and CXCR4, to suppress A{beta}-induced neurotoxicity in vitro and in vivo. Pretreatment with MIP-2 or SDF-1{alpha} significantly protected neurons from A{beta}-induced dendritic regression and apoptosis in vitro through activation of Akt, ERK1/2 and maintenance of metalloproteinase ADAM17 especially with SDF-1{alpha}. Intra-cerebroventricular (ICV) injection of A{beta} led to reduction in dendritic length and spine density of pyramidal neurons in the CA1 area of the hippocampus and increased oxidative damage 24 h following the exposure. The A{beta}-induced morphometric changes of neurons and increase in biomarkers of oxidative damage, F{sub 2}-isoprostanes, were significantly inhibited by pretreatment with the chemokines MIP-2 or SDF-1{alpha}. Additionally, MIP-2 or SDF-1{alpha} was able to suppress the aberrant mislocalization of p21-activated kinase (PAK), one of the proteins involved in the maintenance of dendritic spines. Furthermore, MIP-2 also protected neurons against A{beta} neurotoxicity in CXCR2-/- mice, potentially through observed up regulation of CXCR1 mRNA. Understanding the neuroprotective potential of chemokines is crucial in defining the role for their employment during the early stages of neurodegeneration. -- Research highlights: Black-Right-Pointing-Pointer Neuroprotective ability of the chemokines MIP2 and CXCL12 against A{beta} toxicity. Black-Right-Pointing-Pointer MIP

  19. Polarity of stimulation and secretion of transforming growth factor-beta 1 by cultured proximal tubular cells.

    OpenAIRE

    Phillips, A.O.; Steadman, R.; Morrisey, K.; Williams, J. D.

    1997-01-01

    Proximal tubular epithelial cells are the most abundant cells in the renal cortex, and recent studies suggest that they may play an important role in initiating pathological changes in renal disease. Transforming growth factor (TGF)-beta 1 has been implicated as a major factor controlling the development and progression of renal fibrosis in numerous diseases, including diabetic nephropathy. We have recently demonstrated that human proximal tubular epithelial cells synthesize and secrete TGF-b...

  20. [Effect of basic fibroblast growth factor and parathyroid hormone-related protein on early and late chondrogenic differentiation of rabbit bone marrow mesenchymal stem cells induced by transforming growth factor beta 1].

    Science.gov (United States)

    Liu, Yin; He, Liping; Tian, Jing

    2013-02-01

    To explore the impact of basic fibroblast growth factor (bFGF) and parathyroid hormone-related protein (PTHrP) on early and late chondrogenic differentiation of rabbit bone marrow mesenchymal stem cells (BMSCs) induced by transforming growth factor beta 1 (TGF-beta1). BMSCs were isolated from 3 healthy Japanese rabbits (2-month-old, weighing 1.6-2.1 kg, male or female), and were clutured to passage 3. The cells were put into pellet culture system and were divided into 5 groups according to different induce conditions: TGF-beta1 group (group A), TGF-beta1/bFGF group (group B), TGF-beta1/21 days bFGF group (group C), TGF-beta1/PTHrP group (group D), and TGF-beta1/21 days PTHrP group (group E). At the beginning, TGF-beta1 (10 ng/mL) was added to all groups, then bFGF and PTHrP (10 ng/mL) were added to groups B and D respectively; bFGF and PTHrP (10 ng/mL) were added to groups C and E at 21 days respectively. The gene expressions of collagen type I (Col I), Col II, Col X, matrix metalloproteinases (MMP)-13, and alkaline phosphatase (ALP) activity were detected once every week for 6 weeks. The 1, 9-dimethylmethylene blue (DMMB) staining was used to observe the extracellular matrix secretion at 6 weeks. The expression of Col I in groups C and E showed a significant downward trend after 3 weeks; the expression in group A was significantly higher than that in groups C and E at 4 and 5 weeks (P PTHrP can inhibit early and late chondrogenic differentiation of BMSCs by changing synthesis and decomposition of the cartilage extracellular matrix. The inhibition is not only by suppressing Col X expression, but also possibly by suppressing other chondrogenic protein.

  1. Regeneration of hyaline cartilage by cell-mediated gene therapy using transforming growth factor beta 1-producing fibroblasts.

    Science.gov (United States)

    Lee, K H; Song, S U; Hwang, T S; Yi, Y; Oh, I S; Lee, J Y; Choi, K B; Choi, M S; Kim, S J

    2001-09-20

    Transforming growth factor beta (TGF-beta) has been considered as a candidate for gene therapy of orthopedic diseases. The possible application of cell-mediated TGF-beta gene therapy as a new treatment regimen for degenerative arthritis was investigated. In this study, fibroblasts expressing active TGF-beta 1 were injected into the knee joints of rabbits with artificially made cartilage defects to evaluate the feasibility of this therapy for orthopedic diseases. Two to 3 weeks after the injection there was evidence of cartilage regeneration, and at 4 to 6 weeks the cartilage defect was completely filled with newly grown hyaline cartilage. Histological analyses of the regenerated cartilage suggested that it was well integrated with the adjacent normal cartilage at the sides of the defect and that the newly formed tissue was indeed hyaline cartilage. Our findings suggest that cell-mediated TGF-beta 1 gene therapy may be a novel treatment for orthopedic diseases in which hyaline cartilage damage has occurred.

  2. Transforming growth factor beta receptor 1 is increased following abstinence from cocaine self-administration, but not cocaine sensitization.

    Directory of Open Access Journals (Sweden)

    Amy M Gancarz-Kausch

    Full Text Available The addicted phenotype is characterized as a long-lasting, chronically relapsing disorder that persists following long periods of abstinence, suggesting that the underlying molecular changes are stable and endure for long periods even in the absence of drug. Here, we investigated Transforming Growth Factor-Beta Type I receptor (TGF-β R1 expression in the nucleus accumbens (NAc following periods of withdrawal from cocaine self-administration (SA and a sensitizing regimen of non-contingent cocaine. Rats were exposed to either (i repeated systemic injections (cocaine or saline, or (ii self-administration (cocaine or saline and underwent a period of forced abstinence (either 1 or 7 days of drug cessation. Withdrawal from cocaine self-administration resulted in an increase in TGF-β R1 protein expression in the NAc compared to saline controls. This increase was specific for volitional cocaine intake as no change in expression was observed following a sensitizing regimen of experimenter-administered cocaine. These findings implicate TGF-β signaling as a novel potential therapeutic target for treating drug addiction.

  3. In type 1 diabetes a subset of anti-coxsackievirus B4 antibodies recognize autoantigens and induce apoptosis of pancreatic beta cells.

    Directory of Open Access Journals (Sweden)

    Caterina Bason

    Full Text Available Type 1 diabetes is characterized by autoimmune destruction of pancreatic beta cells. The role played by autoantibodies directed against beta cells antigens in the pathogenesis of the disease is still unclear. Coxsackievirus B infection has been linked to the onset of type 1 diabetes; however its precise role has not been elucidated yet. To clarify these issues, we screened a random peptide library with sera obtained from 58 patients with recent onset type 1 diabetes, before insulin therapy. We identified an immunodominant peptide recognized by the majority of individual patients'sera, that shares homology with Coxsackievirus B4 VP1 protein and with beta-cell specific autoantigens such as phogrin, phosphofructokinase and voltage-gated L-type calcium channels known to regulate beta cell apoptosis. Antibodies against the peptide affinity-purified from patients' sera, recognized the viral protein and autoantigens; moreover, such antibodies induced apoptosis of the beta cells upon binding the L-type calcium channels expressed on the beta cell surface, suggesting a calcium dependent mechanism. Our results provide evidence that in autoimmune diabetes a subset of anti-Coxsackievirus antibodies are able to induce apoptosis of pancreatic beta cells which is considered the most critical and final step in the development of autoimmune diabetes without which clinical manifestations do not occur.

  4. A quantitation of the factors which affect the hydrolase and transgalactosylase activities of beta-galactosidase (E. coli) on lactose.

    Science.gov (United States)

    Huber, R E; Kurz, G; Wallenfels, K

    1976-05-04

    A study was implemented to quantitate the hydrolase and transgalactosylase activities of beta-galactosidase (E. coli) with lactose as the substrate and to investigate various factors which affect these activities. At low lactose concentrations the rate of galactose production was equal to the rate of glucose production. The rate of galactose production relative to glucose, however, dropped dramatically at lactose concentrations higher than 0.05 M and production of trisaccharides and tetrasaccharides began (galactose/glucose ratios of about 2:1 and 3:1, respectively, were found for these two types of oligosaccharides). At least five different trissacharides were formed and their patterns of formation showed that they probably utilized both lactose and allolactose as galactosyl acceptors. Allolactose was produced in amounts proportional to glucose at all lactose concentrations (ratios of allolactose/glucose were about 0.88). Analyses of various data, including a reaction analyzed at very early times, showed that the major means of production of allolactose (and the only means initially) was the direct enzymatic transfer of galactose from the 4 position to the 6 position of the glucose moiety of lactose without prior release of glucose from the enzyme. It was shown, however, that allolactose could also be formed in significant quantities by the transfer of galactose to the 6 position of free glucose, and also by hydrolysis of preformed trisaccharide. A mechanism which fits the initial velocity data was proposed in which the steps involving the formation of an enzyme-gallactose-glucose complex, the formation and breakage of allolactose on the enzyme, and the release of glucose all seem to be of roughly equal magnitude and rate determining. Various factors affected the amounts of transgalactosylase and hydrolase activities occurring. At high pH values (greater than 7.8) the transgalactosylase/hydrolyase activity ratio increased dramatically while it decreased at low p

  5. Platelet-derived growth factor receptor beta is critical for zebrafish intersegmental vessel formation.

    Directory of Open Access Journals (Sweden)

    Katie M Wiens

    Full Text Available BACKGROUND: Platelet-derived growth factor receptor beta (PDGFRbeta is a tyrosine kinase receptor known to affect vascular development. The zebrafish is an excellent model to study specific regulators of vascular development, yet the role of PDGF signaling has not been determined in early zebrafish embryos. Furthermore, vascular mural cells, in which PDGFRbeta functions cell autonomously in other systems, have not been identified in zebrafish embryos younger than 72 hours post fertilization. METHODOLOGY/PRINCIPAL FINDINGS: In order to investigate the role of PDGFRbeta in zebrafish vascular development, we cloned the highly conserved zebrafish homolog of PDGFRbeta. We found that pdgfrbeta is expressed in the hypochord, a developmental structure that is immediately dorsal to the dorsal aorta and potentially regulates blood vessel development in the zebrafish. Using a PDGFR tyrosine kinase inhibitor, a morpholino oligonucleotide specific to PDGFRbeta, and a dominant negative PDGFRbeta transgenic line, we found that PDGFRbeta is necessary for angiogenesis of the intersegmental vessels. SIGNIFICANCE/CONCLUSION: Our data provide the first evidence that PDGFRbeta signaling is required for zebrafish angiogenesis. We propose a novel mechanism for zebrafish PDGFRbeta signaling that regulates vascular angiogenesis in the absence of mural cells.

  6. [Enterobacteriaceae producing extended spectrum beta-lactamase: epidemiology, risk factors, and prevention].

    Science.gov (United States)

    Vodovar, D; Marcadé, G; Raskine, L; Malissin, I; Mégarbane, B

    2013-11-01

    Multidrug-resistant bacteria are a major worldwide health public concern. It results from the growing increase in antibiotic prescriptions, which are responsible for selection pressure on bacteria. In France like in other countries, enterobacteriaceae producing extended spectrum beta-lactamase (EESBL) are the predominant multidrug-resistant bacteria. EESBL may be responsible for severe infections and require prescription of broad-spectrum antibacterial agents. The current EESBL outbreak is different from methicillin-resistant Staphylococcus aureus outbreak that occurred in the early 1980. Consistently, EESBL are isolated both in hospital and community. Moreover, standard hygiene measures appear ineffective since EESBL prevalence is still increasing. The current inability to contain EESBL outbreak is due to several factors, including the existence of a wide community- and hospital-acquired tank of EESBL, failure to follow strict rules for hygiene, and the current irrational prescription of antibiotics. Copyright © 2012 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  7. Induction of gastric cancer cell adhesion through transforming growth factor-beta1-mediated peritoneal fibrosis

    Directory of Open Access Journals (Sweden)

    Ma Xiao-Yang

    2010-10-01

    Full Text Available Abstract Background Peritoneal dissemination is one of the main causes of death in gastric cancer patients. Transforming growth factor-beta1 (TGF-β1, one of the most potent fibrotic stimuli for mesothelial cells, may play a key role in this processing. The purpose of this study is to elucidate the effects of TGF-β1 on regulation of gastric cancer adhesion to mesothelial cells. Methods Peritoneal tissues and peritoneal wash fluid were obtained for hematoxylin and eosin staining or ELISA to measure fibrosis and TGF-β1 levels, respectively. The peritoneal mesothelial cell line, HMrSV5, was used to determine the role of TGF-β1 in regulation of gastric cancer cell adhesion to mesothelial cells and expression of collagen, fibronectin, and Smad 2/3 by using adhesion assay, western blot, and RT-PCR. Results The data showed that TGF-β1 treatment was able to induce collagen III and fibronectin expression in the mesothelial cells, which was associated with an increased adhesion ability of gastric cancer cells, but knockdown of minimal sites of cell binding domain of extracellular matrix can partially inhibit these effects. Conclusion Peritoneal fibrosis induced by TGF-β1 may provide a favorable environment for the dissemination of gastric cancer.

  8. Peptide-based targeting of the platelet-derived growth factor receptor beta.

    Science.gov (United States)

    Askoxylakis, Vasileios; Marr, Annabell; Altmann, Annette; Markert, Annette; Mier, Walter; Debus, Jürgen; Huber, Peter E; Haberkorn, Uwe

    2013-04-01

    The aim of this work is to identify new ligands targeting the platelet-derived growth factor receptor beta (PDGFRβ). Biopanning was carried out with a 12-amino-acid phage display library against the recombinant extracellular domain of PDGFRβ. The identified peptide PDGFR-P1 was chemically synthesized and labeled with (125)I or (131)I. In vitro studies were performed on the PDGFRβ-expressing cell lines BxPC3 and MCF7 and on PDGFRβ-transfected HEK cells in comparison to negative control wtHEK293 and CaIX-transfected HEK cells. Biodistribution experiments were performed in Balb/c nude mice, carrying subcutaneously BxPC3 tumors. In vitro studies demonstrated a higher binding to BxPC3, MCF7, and PDGFRβ-tr-HEK cells in comparison to negative control cell lines. Binding was inhibited up to 90% by the unlabeled PDGFR-P1 peptide. Organ distribution studies revealed a higher accumulation in BxPC3 tumors than in most organs. PDGFR-P1 is a promising candidate for targeting human PDGFRβ.

  9. [Associations of insulin resistance and pancreatic beta-cell function with plasma glucose level in type 2 diabetes].

    Science.gov (United States)

    Nian, Xiaoping; Sun, Gaisheng; Dou, Chunmei; Hou, Hongbo; Fan, Xiuping; Yu, Hongmei; Ma, Ling; He, Bingxian

    2002-06-10

    To investigate the influence of insulin resistance and pancreatic beta-cell function on plasma glucose level in type 2 diabetes so as to provide theoretical basis for reasonable selection of hypoglycemic agents. The plasma non-specific insulin (NSINS), true insulin (TI) and glucose in eight-one type 2 diabetics, 38 males and 43 females, with a mean age of 53 years, were examined 0, 30, 60 and 120 minutes after they had 75 grams of instant noodles. The patients were divided into two groups according to their fasting plasma glucose (FPG): group A (FPG = 8.89 mmol/L). The insulin resistance was evaluated by HOMA-IR, the beta-cell function was evaluated by HOMA-beta formula and the formula deltaI(30)/deltaG(30) = (deltaI(30)-deltaI(0))/(deltaG(30)-deltaG(0)). The insulin area under curve (INSAUC) was evaluated by the formula INSAUC=FINS/2+INS(30)+INS(60)+INS(120)/2. The mean FPG was 6.23 mmol/L in group A and 12.6 mmol/L in group B. PG2H was 11.7 mmol/L in group A and 19.2 mmol/L in group B. The TI levels in group B at 0, 30, 60, 120 min during standard meal test were significantly higher than those in group A: 6.15 +/- 1.06 vs 4.77 +/- 1.06, 9.76 +/- 1.1 vs 5.88 +/- 1.1,14.68 +/- 1.11 vs 6.87 +/- 1.1 and 17.13 +/- 1.12 vs 8.0 +/- 1.1 microU/dl (all P< 0.01). The NSINS showed the same trend. The insulin resistance in group B was 1.5 times that in group A. With the insulin resistance adjusted, the beta cell function in group A was 5 to 6 times that in group B. The INSAUC in group A was 1.66 times larger than that in group B, especially the INSAUC for true insulin (2 times larger). The contribution of insulin resistance and beta cell function to PG2H was half by half in group A and 1:8 in group B. beta cell function calculated by insulin (Homa-beta) explained 41% of the plasma glucose changes in group A and 54% of the plasma glucose changes in group B. The contribution of insulin deficiency to plasma glocose was 3.3.times that of insulin resistance in group A and was 9

  10. Tenascin C promiscuously binds growth factors via its fifth fibronectin type III-like domain.

    Directory of Open Access Journals (Sweden)

    Laura De Laporte

    Full Text Available Tenascin C (TNC is an extracellular matrix protein that is upregulated during development as well as tissue remodeling. TNC is comprised of multiple independent folding domains, including 15 fibronectin type III-like (TNCIII domains. The fifth TNCIII domain (TNCIII5 has previously been shown to bind heparin. Our group has shown that the heparin-binding fibronectin type III domains of fibronectin (FNIII, specifically FNIII12-14, possess affinity towards a large number of growth factors. Here, we show that TNCIII5 binds growth factors promiscuously and with high affinity. We produced recombinant fragments of TNC representing the first five TNCIII repeats (TNCIII1-5, as well as subdomains, including TNCIII5, to study interactions with various growth factors. Multiple growth factors of the platelet-derived growth factor (PDGF family, the fibroblast growth factor (FGF family, the transforming growth factor beta (TGF-β superfamily, the insulin-like growth factor binding proteins (IGF-BPs, and neurotrophins were found to bind with high affinity to this region of TNC, specifically to TNCIII5. Surface plasmon resonance was performed to analyze the kinetics of binding of TNCIII1-5 with TGF-β1, PDGF-BB, NT-3, and FGF-2. The promiscuous yet high affinity of TNC for a wide array of growth factors, mediated mainly by TNCIII5, may play a role in multiple physiological and pathological processes involving TNC.

  11. Archaeal translation initiation revisited: the initiation factor 2 and eukaryotic initiation factor 2B alpha-beta-delta subunit families

    Science.gov (United States)

    Kyrpides, N. C.; Woese, C. R.

    1998-01-01

    As the amount of available sequence data increases, it becomes apparent that our understanding of translation initiation is far from comprehensive and that prior conclusions concerning the origin of the process are wrong. Contrary to earlier conclusions, key elements of translation initiation originated at the Universal Ancestor stage, for homologous counterparts exist in all three primary taxa. Herein, we explore the evolutionary relationships among the components of bacterial initiation factor 2 (IF-2) and eukaryotic IF-2 (eIF-2)/eIF-2B, i.e., the initiation factors involved in introducing the initiator tRNA into the translation mechanism and performing the first step in the peptide chain elongation cycle. All Archaea appear to posses a fully functional eIF-2 molecule, but they lack the associated GTP recycling function, eIF-2B (a five-subunit molecule). Yet, the Archaea do posses members of the gene family defined by the (related) eIF-2B subunits alpha, beta, and delta, although these are not specifically related to any of the three eukaryotic subunits. Additional members of this family also occur in some (but by no means all) Bacteria and even in some eukaryotes. The functional significance of the other members of this family is unclear and requires experimental resolution. Similarly, the occurrence of bacterial IF-2-like molecules in all Archaea and in some eukaryotes further complicates the picture of translation initiation. Overall, these data lend further support to the suggestion that the rudiments of translation initiation were present at the Universal Ancestor stage.

  12. Antibacterial effects of Quercus Brantii fruits and Stachys lavandulifolia methanol extracts on imipenemase-type metallo-beta lactamase-producing Pseudomonas aeruginosa

    National Research Council Canada - National Science Library

    F. Shahi; A. Hashemi; Kh. Abdolmaleki; Z. Shahi; Sh. Amraei; H. Goudarzi; F. Fallah; S. Khoshnood

    2017-01-01

    .... The aim of the present study was to evaluate the antibacterial activity of Stachys lavandulifolia and Quercus brantii on the IMP-type metallo-beta-lactamase-producing Pseudomonas aeruginosa. Methods...

  13. SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of {beta}-catenin

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Il-Rae [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of); Koh, Sang Seok [Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333 (Korea, Republic of); Department of Functional Genomics, University of Science and Technology, Daejeon 305-333 (Korea, Republic of); Malilas, Waraporn; Srisuttee, Ratakorn; Moon, Jeong [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of); Choi, Young-Whan [Department of Horticultural Bioscience, Pusan National University, Miryang 627-706 (Korea, Republic of); Horio, Yoshiyuki [Department of Pharmacology, Sapporo Medical University, Sapporo 060-8556 (Japan); Oh, Sangtaek [Department of Advanced Fermentation Fusion Science and Technology, Kookmin University, Seoul 136-702 (Korea, Republic of); Chung, Young-Hwa, E-mail: younghc@pusan.ac.kr [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of)

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer SIRT1 inhibits protein levels of {beta}-catenin and its transcriptional activity. Black-Right-Pointing-Pointer Nuclear localization of SIRT1 is not required for the decrease of {beta}-catenin expression. Black-Right-Pointing-Pointer SIRT1-mediated degradation of {beta}-catenin is not required for GSK-3{beta} and Siah-1 but for proteosome. Black-Right-Pointing-Pointer SIRT1 activation inhibits proliferation of pancreatic cancer cells expressing PAUF. -- Abstract: Because we found in a recent study that pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, induces a rapid proliferation of pancreatic cells by up-regulation of {beta}-catenin, we postulated that {beta}-catenin might be a target molecule for pancreatic cancer treatment. We thus speculated whether SIRT1, known to target {beta}-catenin in a colon cancer model, suppresses {beta}-catenin in those pancreatic cancer cells that express PAUF (Panc-PAUF). We further evaluated whether such suppression would lead to inhibition of the proliferation of these cells. The ectopic expression of either SIRT1 or resveratrol (an activator of SIRT1) suppressed levels of {beta}-catenin protein and its transcriptional activity in Panc-PAUF cells. Conversely, suppression of SIRT1 expression by siRNA enhanced {beta}-catenin expression and transcriptional activity. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for reduction of {beta}-catenin. Treatment with MG132, a proteasomal inhibitor, restored {beta}-catenin protein levels, suggesting that SIRT1-mediated degradation of {beta}-catenin requires proteasomal activity. It was reported that inhibition of GSK-3{beta} or Siah-1 stabilizes {beta}-catenin in colon cancer cells, but suppression of GSK-3{beta} or Siah-1 using siRNA in the presence of resveratrol instead diminished {beta}-catenin protein levels in Panc-PAUF cells. This suggests that GSK-3{beta} and Siah-1 are not involved in SIRT1

  14. Activation of the human beta interferon gene by the adenovirus type 12 E1B gene

    Energy Technology Data Exchange (ETDEWEB)

    Shiroki, K.; Toth, M.

    1988-01-01

    The transcription of endogenous beta interferon mRNA was activated in human embryo kidney (HEK) cells infected with adenovirus 12 (Ad12) but was activated only inefficiently or not at all in HEK cells infected with Ad5 and rc-1 (Ad5 dl312 containing the Ad12 E1A region). The analysis with Ad12 mutants showed that Ad12 E1B products, especially the 19K protein, were important for the expression of the endogenous beta interferon gene and Ad12 E1A products were not involved in the expression. The expression of exogeneously transfected pIFN-CAT (a hybrid plasmid having the human beta interferon promoter fused with the CAT gene) was activated in HEK and chicken embryo fibroblast (CEF) cells infected with either Ad12 or Ad5. The analysis of cotransfection of CEF cells with pIFN-CAT and plasmids containing fragments of Ad12 or Ad5 DNA showed that Ad12 or Ad5 E1B (possibly the 19K protein) was and E1A was not involved in the expression of the exogenous pIFN-CAT.

  15. Upregulation of adipose 11-beta-hydroxysteroid dehydrogenase type 1 expression in ovariectomized rats is due to obesity rather than lack of estrogen.

    Science.gov (United States)

    Paulsen, Søren K; Nielsen, Maria P; Richelsen, Bjørn; Bruun, Jens M; Flyvbjerg, Allan; Pedersen, Steen B

    2008-04-01

    Increased tissue activity of cortisol induced by the activation of inert cortisone to active cortisol through 11-beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) may play a role in the metabolic syndrome. We recently found that 11beta-HSD1 in subcutaneous adipose tissue (AT) was lower in lean women compared with lean men. Estrogen suppresses hepatic and renal 11beta-HSD1 in rats; hence we investigated the in vitro effect of estrogen on human and rat AT, and the in vivo effects on rat AT 11beta-HSD1 expression. Wistar rats were divided into four groups of eight animals. One group was sham-operated (controls) and others were ovariectomized (OVX). One OVX group was left untreated (OVX-E), another (OVX+E) received estrogen treatment, and one received a hypo-caloric diet (OVX-E+D), matching the weight gain of the control group. AT from women undergoing liposuction or surgery and from killed male and female rats were incubated with estrogen alone or in the presence of IL-1beta. Gene expressions were determined by real-time reverse transcriptase PCR. Ovariectomy resulted in a 280% increase in adipose 11beta-HSD1 expression P effect of estrogen on adipose 11beta-HSD1 was found. The upregulation of 11beta-HSD1 in ovariectomized rats was most likely due to changes in body composition rather than lack of estrogen.

  16. Spatial Factors Play a Major Role as Determinants of Endemic Ground Beetle Beta Diversity of Madeira Island Laurisilva

    Science.gov (United States)

    Boieiro, Mário; Carvalho, José C.; Cardoso, Pedro; Aguiar, Carlos A. S.; Rego, Carla; de Faria e Silva, Israel; Amorim, Isabel R.; Pereira, Fernando; Azevedo, Eduardo B.; Borges, Paulo A. V.; Serrano, Artur R. M.

    2013-01-01

    The development in recent years of new beta diversity analytical approaches highlighted valuable information on the different processes structuring ecological communities. A crucial development for the understanding of beta diversity patterns was also its differentiation in two components: species turnover and richness differences. In this study, we evaluate beta diversity patterns of ground beetles from 26 sites in Madeira Island distributed throughout Laurisilva – a relict forest restricted to the Macaronesian archipelagos. We assess how the two components of ground beetle beta diversity (βrepl – species turnover and βrich - species richness differences) relate with differences in climate, geography, landscape composition matrix, woody plant species richness and soil characteristics and the relative importance of the effects of these variables at different spatial scales. We sampled 1025 specimens from 31 species, most of which are endemic to Madeira Island. A spatially explicit analysis was used to evaluate the contribution of pure environmental, pure spatial and environmental spatially structured effects on variation in ground beetle species richness and composition. Variation partitioning showed that 31.9% of species turnover (βrepl) and 40.7% of species richness variation (βrich) could be explained by the environmental and spatial variables. However, different environmental variables controlled the two types of beta diversity: βrepl was influenced by climate, disturbance and soil organic matter content whilst βrich was controlled by altitude and slope. Furthermore, spatial variables, represented through Moran’s eigenvector maps, played a significant role in explaining both βrepl and βrich, suggesting that both dispersal ability and Madeira Island complex orography are crucial for the understanding of beta diversity patterns in this group of beetles. PMID:23724065

  17. Factors affecting quality for beta dose rate measurements using ISO 6980 series I reference sources

    Energy Technology Data Exchange (ETDEWEB)

    Burns, R.E. Jr.; O`Brien, J.M. Jr. [Atlan-Tech, Rosewll, GA (United States)

    1993-12-31

    Atlan-Tech, Inc. has performed several calibrations of ISO 6980 Series 1 reference beta sources over the past two to three years. There were many problems encountered in attempting to compare the results of these calibrations with those from other laboratories, indicating the need for more standardization in the methodology employed for the measurement of the absorbed dose rate from ISO 6980 Series 1 reference beta sources. This document describes some of the problems encountered in attempting to intercompare results of beta dose-rate measurements. It proposes some solutions in an attempt to open a dialogue among facilities using reference beta standards for the purpose of promoting better measurement quality assurance through data intercomparison.

  18. Formation of L1{sub 0}-type ordered {beta} Prime phase in as-solutionized dental Ag-Pd-Au-Cu alloys and hardening behavior

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yonghwan [Department of Materials Science, Graduate School of Engineering, Tohoku University, 6-6 Aoba, Aramaki Aza, Aoba-ku, Sendai 980-8579 (Japan); Niinomi, Mitsuo, E-mail: niinomi@imr.tohoku.ac.jp [Department of Biomaterials Science, Institute for Materials Research, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577 (Japan); Hieda, Junko; Nakai, Masaaki [Department of Biomaterials Science, Institute for Materials Research, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577 (Japan); Fukui, Hisao [Department of Dental Materials Science, School of Dentistry, Aichi-Gakuin University, Nagoya 464-0045 (Japan)

    2012-04-01

    The relationship between the microstrucutural changes of L1{sub 0}-type ordered {beta} Prime phase and hardening behavior in as-solutionized dental Ag-Pd-Au-Cu alloys was investigated by changing the cooling rate and the solution treatment temperature. Additionally, the formation process of the {beta} Prime phase in as-solutionized Ag-Pd-Au-Cu alloy was attempted to clarify. The microstructural changes were observed by X-ray diffraction (XRD) method and transmission electron microscopy (TEM). The hardness was evaluated using a Vickers microhardness tester. The {beta} Prime phase is precipitated regardless of the cooling rate, after solution treatment at 1123 K. TEM dark field images show that the size of the {beta} Prime phase decreases and the number of {beta} Prime phase increases with an increase in the cooling rate. The Vickers hardness value increases with an increase in cooling rate. TEM dark field images show that the microstructure of {beta} Prime phase is similar when the solution treatment temperature increases from 1123 K to 1173 K. However, the Vickers hardness increases with an increase of solution treatment temperature. It is of great significance to reveal that the {beta} Prime phase precipitated in as-solutionized Ag-Pd-Au-Cu alloy is formed during cooling after high-temperature solution treatment and that the growth of the {beta} Prime phase is diffusion controlled. - Highlights: Black-Right-Pointing-Pointer The microstructure of {beta} Prime phase of Ag-Pd-Au-Cu alloy is changed by cooling rates. Black-Right-Pointing-Pointer The {beta} Prime phase is formed during the cooling process. Black-Right-Pointing-Pointer Growth of the {beta} Prime phase is dominated by diffusion. Black-Right-Pointing-Pointer Hardness of Ag-Pd-Au-Cu alloy increases remarkably with precipitation of the {beta} Prime phase.

  19. Interleukin-4, interleukin-10, and interleukin-1-receptor antagonist but not transforming growth factor-beta induce ramification and reduce adhesion molecule expression of rat microglial cells.

    Science.gov (United States)

    Wirjatijasa, Florentina; Dehghani, Faramarz; Blaheta, Roman A; Korf, Horst-Werner; Hailer, Nils P

    2002-06-01

    The activity of microglial cells is strictly controlled in order to maintain central nervous system (CNS) immune privilege. We hypothesized that several immunomodulatory factors present in the CNS parenchyma, i.e., the Th2-derived cytokines interleukin (IL)-4 and IL-10, interleukin-1-receptor-antagonist (IL-1-ra), or transforming growth factor (TGF)-beta can modulate microglial morphology and functions. Microglial cells were incubated with IL-4, IL-10, IL-1-ra, TGF-beta, or with astrocyte conditioned media (ACM) and were analyzed for morphological changes, expression of intercellular adhesion molecule (ICAM)-1, and secretion of IL-1beta or tumor necrosis factor (TNF)-alpha. Whereas untreated controls showed an amoeboid morphology both Th2-derived cytokines, IL-1-ra, and ACM induced a morphological transformation to the ramified phenotype. In contrast, TGF-beta-treated microglial cells showed an amoeboid morphology. Even combined with the neutralizing antibodies against IL-4, IL-10, or TGF-beta ACM induced microglial ramification. Furthermore, ACM did not contain relevant amounts of IL-4 and IL-10, as measured by enzyme-linked immunosorbent assay (ELISA). Flow cytometry showed that lipopolysaccharide (LPS)-induced ICAM-1-expression on microglial cells was strongly suppressed by ACM, significantly modulated by IL-4, IL-10, or IL-1-ra, but not influenced by TGF-beta. The LPS-induced secretion of IL-1beta and TNF-alpha was only reduced after application of ACM, whereas IL-4 or IL-10 did not inhibit IL-1beta- or TNF-alpha secretion. TGF-beta enhanced IL-1beta- but not TNF-alpha secretion. In summary, we demonstrate that IL-4, IL-10, and IL-1-ra induce microglial ramification and reduce ICAM-1-expression, whereas the secretion of proinflammatory cytokines is not prevented. TGF-beta has no modulating effects. Importantly, unidentified astrocytic factors that are not identical with IL-4, IL-10, or TGF-beta possess strong immunomodulatory properties.

  20. Beta-type calcium phosphates with and without magnesium: From hydrolysis of brushite powder to robocasting of periodic scaffolds.

    Science.gov (United States)

    Richard, Raquel C; Sader, Márcia S; Dai, Jisen; Thiré, Rossana M S M; Soares, Gloria D A

    2014-10-01

    Several approaches have attempted to replace extensive bone loss, but each of them has their limitation. Nowadays, additive manufacture techniques have shown great potential for bone engineering. The objective of this study was to synthesize beta tricalcium phosphate (β-TCP), beta tricalcium phosphate substituted by magnesium (β-TCMP), and biphasic calcium phosphate substituted by magnesium (BCMP) via hydrolysis and produce scaffolds for bone regeneration using robocasting technology. Calcium deficient apatites, with and without magnesium were obtained by hydrolysis, calcined and physico-chemically characterized. Colorimetric cell viability assay, calcium nodule formation, and the expression of alkaline phosphatase, osteocalcin, transforming growth factor beta-1 and collagen were assessed using a mouse osteoblastic cell line (MC3T3-E1). Direct-write assembly of cylindrical periodic scaffolds was done via robotic deposition using β-TCP, β-TCMP, and BCMP colloidal inks. The sintered scaffolds were characterized by X-ray diffraction, Fourier-transform infrared spectroscopy, scanning electron microscopy, Archimede's method, and uniaxial compression test. According to the cell viability assay, the powders induced cell proliferation. Calcium nodule formation and bone markers activity suggested that the materials present potential value in bone tissue engineering. The scaffolds built by robocasting presented interconnected porous and exhibited mean compressive strength between 7.63 and 18.67 MPa, compatible with trabecular bone.

  1. Anodic oxides on a beta type Nb-Ti alloy and their characterization by electrochemical impedance spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Woldemedhin, Michael Teka; Hassel, Achim Walter [Max Planck Institut fuer Eisenforschung GmbH, Duesseldorf (Germany); Institute for Chemical Technology of Inorganic Materials, Johannes Kepler University, Linz (Austria); Raabe, Dierk [Max Planck Institut fuer Eisenforschung GmbH, Duesseldorf (Germany)

    2010-04-15

    Anodic oxides were grown on the surface of an electropolished (Ti-30 at% Nb) beta-titanium ({beta}-Ti) alloy by cyclic voltammetry. The scan rate was 100 mV s{sup -1} between 0 and 8 V in increments of l V in an acetate buffer of pH 6.0. Electrochemical impedance spectroscopy was carried out right after each anodic oxide growth increment to study the electronic properties of the oxide/electrolyte interface in a wide frequency range from 100 kHz to 10 MHz with an AC perturbation voltage of 10 mV. A film formation factor of 2.4 nm V{sup -1} was found and a relative permittivity number (dielectric constant) of 42.4 was determined for the oxide film formed. Mott-Schottky analysis on a potentiostatically formed 7 nm thick oxide film was performed to assess the semiconducting properties of the mixed anodic oxide grown on the alloy. A flat band potential of -0.47 V (standard hydrogen electrode, SHE) was determined, connected to a donor density of 8.2 x 10{sup 17} cm{sup -3}. {beta}-Ti being highly isotropic in terms of mechanical properties should be superior to the stiffer {alpha}-Ti compound. Its application, however, requires a passivation behaviour comparable or better than {alpha}-Ti which in fact is found. (Abstract Copyright [2010], Wiley Periodicals, Inc.)

  2. Interleukin-1 beta impairs brain derived neurotrophic factor-induced signal transduction.

    Science.gov (United States)

    Tong, Liqi; Balazs, Robert; Soiampornkul, Rungtip; Thangnipon, Wipawan; Cotman, Carl W

    2008-09-01

    The expression of IL-1 is elevated in the CNS in diverse neurodegenerative disorders, including Alzheimer's disease. The hypothesis was tested that IL-1 beta renders neurons vulnerable to degeneration by interfering with BDNF-induced neuroprotection. In trophic support-deprived neurons, IL-1 beta compromised the PI3-K/Akt pathway-mediated protection by BDNF and suppressed Akt activation. The effect was specific as in addition to Akt, the activation of MAPK/ERK, but not PLC gamma, was decreased. Activation of CREB, a target of these signaling pathways, was severely depressed by IL-1 beta. As the cytokine did not influence TrkB receptor and PLC gamma activation, IL-1 beta might have interfered with BDNF signaling at the docking step conveying activation to the PI3-K/Akt and Ras/MAPK pathways. Indeed, IL-1 beta suppressed the activation of the respective scaffolding proteins IRS-1 and Shc; this effect might involve ceramide generation. IL-1-induced interference with BDNF neuroprotection and signal transduction was corrected, in part, by ceramide production inhibitors and mimicked by the cell-permeable C2-ceramide. These results suggest that IL-1 beta places neurons at risk by interfering with BDNF signaling involving a ceramide-associated mechanism.

  3. SME-type carbapenem-hydrolyzing class A beta-lactamases from geographically diverse Serratia marcescens strains.

    Science.gov (United States)

    Queenan, A M; Torres-Viera, C; Gold, H S; Carmeli, Y; Eliopoulos, G M; Moellering, R C; Quinn, J P; Hindler, J; Medeiros, A A; Bush, K

    2000-11-01

    Three sets of carbapenem-resistant Serratia marcescens isolates have been identified in the United States: 1 isolate in Minnesota in 1985 (before approval of carbapenems for clinical use), 5 isolates in Los Angeles (University of California at Los Angeles [UCLA]) in 1992, and 19 isolates in Boston from 1994 to 1999. All isolates tested produced two beta-lactamases, an AmpC-type enzyme with pI values of 8.6 to 9.0 and one with a pI value of approximately 9.5. The enzyme with the higher pI in each strain hydrolyzed carbapenems and was not inhibited by EDTA, similar to the chromosomal class A SME-1 beta-lactamase isolated from the 1982 London strain S. marcescens S6. The genes encoding the carbapenem-hydrolyzing enzymes were cloned in Escherichia coli and sequenced. The enzyme from the Minnesota isolate had an amino acid sequence identical to that of SME-1. The isolates from Boston and UCLA produced SME-2, an enzyme with a single amino acid change relative to SME-1, a substitution from valine to glutamine at position 207. Purified SME enzymes from the U. S. isolates had beta-lactam hydrolysis profiles similar to that of the London SME-1 enzyme. Pulsed-field gel electrophoresis analysis revealed that the isolates showed some similarity but differed by at least three genetic events. In conclusion, a family of rare class A carbapenem-hydrolyzing beta-lactamases first described in London has now been identified in S. marcescens isolates across the United States.

  4. Mice deficient in 11beta-hydroxysteroid dehydrogenase type 1 lack bone marrow adipocytes, but maintain normal bone formation

    DEFF Research Database (Denmark)

    Justesen, Jeannette; Mosekilde, Lis; Holmes, Megan

    2004-01-01

    and regenerates active cortisol (corticosterone) from circulating inert 11-keto forms. The aim of the present study was to investigate the role of this intracrine activation of GCs on normal bone physiology in vivo using mice deficient in 11betaHSD1 (HSD1(-/-)). The HSD1(-/-) mice exhibited no significant changes...... in cortical or trabecular bone mass compared with wild-type (Wt) mice. Aged HSD1(-/-) mice showed age-related bone loss similar to that observed in Wt mice. Histomorphometric analysis showed similar bone formation and bone resorption parameters in HSD1(-/-) and Wt mice. However, examination of bone marrow...

  5. Clusters of conserved beta cell marker genes for assessment of beta cell phenotype.

    Directory of Open Access Journals (Sweden)

    Geert A Martens

    Full Text Available BACKGROUND AND METHODOLOGY: The aim of this study was to establish a gene expression blueprint of pancreatic beta cells conserved from rodents to humans and to evaluate its applicability to assess shifts in the beta cell differentiated state. Genome-wide mRNA expression profiles of isolated beta cells were compared to those of a large panel of other tissue and cell types, and transcripts with beta cell-abundant and -selective expression were identified. Iteration of this analysis in mouse, rat and human tissues generated a panel of conserved beta cell biomarkers. This panel was then used to compare isolated versus laser capture microdissected beta cells, monitor adaptations of the beta cell phenotype to fasting, and retrieve possible conserved transcriptional regulators. PRINCIPAL FINDINGS: A panel of 332 conserved beta cell biomarker genes was found to discriminate both isolated and laser capture microdissected beta cells from all other examined cell types. Of all conserved beta cell-markers, 15% were strongly beta cell-selective and functionally associated to hormone processing, 15% were shared with neuronal cells and associated to regulated synaptic vesicle transport and 30% with immune plus gut mucosal tissues reflecting active protein synthesis. Fasting specifically down-regulated the latter cluster, but preserved the neuronal and strongly beta cell-selective traits, indicating preserved differentiated state. Analysis of consensus binding site enrichment indicated major roles of CREB/ATF and various nutrient- or redox-regulated transcription factors in maintenance of differentiated beta cell phenotype. CONCLUSIONS: Conserved beta cell marker genes contain major gene clusters defined by their beta cell selectivity or by their additional abundance in either neural cells or in immune plus gut mucosal cells. This panel can be used as a template to identify changes in the differentiated state of beta cells.

  6. Beta-2 GPI induced tissue factor and placental apoptosis for the pathophysiology of pregnancy loss in antiphospholipid syndrome

    Directory of Open Access Journals (Sweden)

    Shanmugam Velayuthaprabhu

    2016-08-01

    Full Text Available Based on large concurrent studies on human and in vivo results from experimental animals, it is evident that antiphospholipid syndrome (APS plays a vital role in pregnancy failure in human being. Many underlying pathophysiology including venous thrombosis, thrombocytopenia and placental apoptosis have been demonstrated for the APS-mediated pregnancy loss. On the other hand, Tissue factor (TF remains considered as a crucial factor for pregnancy morbidity in women with APS globally. Hence, we hypothesize that TF and/or beta-2 glycoprotein and ndash; I (beta2GPI-induced TF might play an important role for the increased index of apoptosis in placenta, especially during early stages of fetal development. Further, this could represent as potentially preventable etiology of APS-mediated pregnancy loss in women. [Int J Res Med Sci 2016; 4(8.000: 3109-3113

  7. DNase I-hypersensitive sites and transcription factor-binding motifs within the mouse E beta meiotic recombination hot spot.

    Science.gov (United States)

    Shenkar, R; Shen, M H; Arnheim, N

    1991-04-01

    The second intron of the E beta gene in the mouse major histocompatibility complex is the site of a meiotic recombination hot spot. We detected two DNase I-hypersensitive sites in this intron in meiotic cells isolated from mouse testes. One site appears to be constitutive and is found in other tissues regardless of whether or not they express the E beta gene. Near this hypersensitive site are potential binding motifs for H2TF1/KBF1, NF kappa B, and octamer transcription factors. Gel retardation studies with mouse lymphoma cell nuclear extracts confirmed that each of these motifs is capable of binding protein. The binding of transcription factors may contribute to the enhancement of recombination potential by altering chromatin structure and increasing the accessibility of the DNA to the recombination machinery.

  8. Transforming growth factor beta receptor II polymorphisms are associated with Kawasaki disease

    Directory of Open Access Journals (Sweden)

    Yu Mi Choi

    2012-01-01

    Full Text Available Purpose : Transforming growth factor beta receptor 2 (TGFBR2 is a tumor suppressor gene that plays a role in the differentiation of striated cells and remodeling of coronary arteries. Single nucleotide polymorphisms (SNPs of this gene are associated with Marfan syndrome and sudden death in patients with coronary artery disease. Cardiovascular remodeling and T cell activation of TGFBR2 gene suggest that the TGFBR2 gene SNPs are related to the pathogenesis of Kawasaki disease (KD and coronary artery lesion (CAL. Methods : The subjects were 105 patients with KD and 500 healthy adults as controls. Mean age of KD group was 32 months age and 26.6% of those had CAL. We selected TGFBR2 gene SNPs from serum and performed direct sequencing. Results : The sequences of the eleven SNPs in the TGFBR2 gene were compared between the KD group and controls. Three SNPs (rs1495592, rs6550004, rs795430 were associated with development of KD (P=0.019, P=0.026, P=0.016, respectively. One SNP (rs1495592 was associated with CAL in KD group (P=0.022. Conclusion : Eleven SNPs in TGFBR2 gene were identified at that time the genome wide association. But, with the change of the data base, only six SNPs remained associated with the TGFBR2 gene. One of the six SNPs (rs6550004 was associated with development of KD. One SNP associated with CAL (rs1495592 was disassociated from the TGFBR2 gene. The other five SNPs were not functionally identified, but these SNPs are notable because the data base is changing. Further studies involving larger group of patients with KD are needed.

  9. Gene polymorphisms of interleukin-10 and transforming growth factor beta in allergic rhinitis.

    Science.gov (United States)

    Nasiri, R; Hirbod-Mobarakeh, A; Movahedi, M; Farhadi, E; Ansaripour, B; Amirzargar, A A; Rezaei, N

    2016-01-01

    Allergic rhinitis (AR) is a polygenic inflammatory disorder of the upper respiratory airway with an increasing prevalence worldwide. Interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), as two cytokines with pleiotropic effects on both innate and adaptive immunity, play important roles in allergic responses. Therefore, this study was performed to evaluate the associations of five polymorphisms of IL-10 and TGF-β genes with AR. Ninety-eight patients with AR along with 140 healthy volunteers with no history of AR and with the same ethnicity of the patients were recruited in this study. Genotyping was done for three polymorphisms in promoter region of IL-10 gene (rs1800896, rs1800871, rs1800872), and two polymorphisms in the exonic region of TGF-β1 gene (rs1982037, rs1800471) using PCR sequence-specific-primers method. A allele and AA genotype in rs1800896 of IL-10 and TT genotype in rs1982037 in TGF-β were significantly less frequent in the patients than in controls. While the C allele and the CG genotype in rs1800471 in TGF-β1 were associated with a higher susceptibility to AR. C/C and T/C haplotypes (rs1982037, rs1800471) in TGF-β1 gene and A/C/A, A/T/C and G/C/A haplotypes (rs1800896, rs1800871, rs1800872) in IL-10 gene were found with higher frequencies in patients than controls. Patients with CC genotype in rs1800871 in Il-10 had significantly lower levels of IgE. We found that certain genetic variants in IL-10 and TGF-β polymorphisms were associated with susceptibility to AR as well as some clinical parameters in the patients with AR. Copyright © 2015 SEICAP. Published by Elsevier Espana. All rights reserved.

  10. Effect of transforming growth factor-beta1 on decorin expression and muscle morphology during chicken embryonic and posthatch growth and development.

    Science.gov (United States)

    Li, X; Velleman, S G

    2009-02-01

    During skeletal muscle development, transforming growth factor-beta1 (TGF-beta1) is a potent inhibitor of muscle cell proliferation and differentiation, as well as a regulator of extracellular matrix (ECM) production. Decorin, a member of the small leucine-rich ECM proteoglycans, binds to TGF-beta1 and modulates TGF-beta1-dependent cell growth stimulation or inhibition. The expression of decorin can be regulated by TGF-beta1 during muscle proliferation and differentiation. How TGF-beta1 affects decorin and muscle growth, however, has not been well documented in vivo. The present study investigated the effect of TGF-beta1 on decorin expression and intracellular connective tissue development during skeletal muscle growth. Exogenous TGF-beta1 significantly decreased the number of myofibers in a given area at both 1 d and 6 wk posthatch. The TGF-beta1-treated muscle had a significant decrease in decorin mRNA expression at embryonic day (ED) 10, whereas protein amounts decreased at 17 ED and 1 d posthatch compared to the control muscle. Decorin was localized in both the endomysium and perimysium in the control pectoralis major muscle. Transforming growth factor-beta1 reduced decorin in both the endomysium and perimysium from 17 ED to 6 wk posthatch. Compared to the control muscle, the perimysium space in the pectoralis major muscle was dramatically decreased by TGF-beta1 during embryonic development through posthatch growth. Because decorin regulates collagen fibrillogenesis, a major component of the ECM, the reduction of decorin by TGF-beta1 treatment may cause the irregular formation of collagen fibrils, leading to the decrease in endomysium and perimysium space. The results from the current study suggest that the effect of TGF-beta1 on decorin expression and localization was likely associated with altered development of the perimysium and the regulation of muscle fiber development.

  11. Tumors initiated by constitutive Cdk2 activation exhibit transforming growth factor beta resistance and acquire paracrine mitogenic stimulation during progression

    DEFF Research Database (Denmark)

    Corsino, P.; Davis, B.; Law, M.;

    2007-01-01

    sites. Together, these results suggest that deregulation of the Cdk/Rb/E2F axis reprograms mammary epithelial cells to initiate a paracrine loop with tumor-associated fibroblasts involving TGF beta and HGF, resulting in desmoplasia. The MMTV-DIK2 mice should provide a useful model system...... for the development of therapeutic approaches to block the stromal desmoplastic reaction that likely plays an important role in the progression of multiple types of human tumors...

  12. Coefficient of failure: a methodology for examining longitudinal beta-cell function in Type 2 diabetes.

    Science.gov (United States)

    Wallace, T M; Matthews, D R

    2002-06-01

    We describe a new method, the determination of the coefficient of failure, which allows the assessment of beta-cell failure from any index of glycaemia. Previous methods using glycaemic thresholds and calculating time-to-failure have systematic deficiencies relating to bias, reproducibility and statistical power. Analyses using threshold methodologies and conventional survival analysis have an intrinsic disadvantage in that they use categorical data and thus make no allowance for near-failure, or progression towards failure. In contrast, the coefficient of failure includes all data in the analysis and takes into account improvement of glycaemia as well as deterioration of glycaemia. We describe the use of a 'coefficient of failure' defined as the slope of the least-squares regression line of a glycaemic index vs. time calculated for each individual patient on constant monotherapy. We exemplify the method using HbA1c levels from data from patients on chlorpropamide (n = 64) or glibenclamide (n = 65) monotherapy in the Oxford cohort of the UKPDS. Chlorpropamide-treated patients showed a mean coefficient of failure of 0.34 HbA(1c)%/year (0.44%/year sd) and glibenclamide-treated patients 0.50 HbA(1c)%/year (0.50%/year sd) (P = 0.046; unpaired two-tailed t-test). Kolmogorov-Smirnov testing demonstrated that the coefficients did not differ significantly from a normal distribution (chlorpropamide P = 0.12; glibenclamide P = 0.13). The coefficient of failure gives an estimate of beta-cell failure using any index of glycaemia. The coefficient is not constrained by predetermined glycaemic thresholds for failure and it allows the rate of decline in beta-cell function to be determined on any therapy or combination of therapies.

  13. Exposure profiles and human papillomavirus infection in skin cancer: an analysis of 25 genus beta-types in a population-based study.

    Science.gov (United States)

    Patel, Anita S; Karagas, Margaret R; Perry, Ann E; Nelson, Heather H

    2008-12-01

    An increasing number of studies report that genus beta human papillomaviruses (HPVs) are associated with skin cancer, with suggestions of specificity for squamous cell carcinoma (SCC) of the skin. We have conducted a systematic examination of HPV DNA in tumors from immunocompetent hosts, including SCC and basal cell carcinoma (BCC), using a highly sensitive methodology and population-based samples to test the hypothesis that a differential prevalence of beta-HPVs exists between SCC (n=101) and BCC (n=101) tumors. When testing for all known beta-HPV types, we found no significant difference in HPV prevalence between the two histologies. However, SCC lesions were significantly more likely to be infected with HPV genus beta-species 1 (includes types 5 and 8), than BCC samples (P=0.01); this difference was not observed for any other species. A histologic difference was also observed for those HPV types previously reported to be important in skin cancer (P=0.003). SCC samples showed a higher rate of infectivity (that is, were positive for multiple types) than BCC tumors (P=0.02). These data highlight the potential importance of various genus beta-HPV types, in particular genus beta-species 1 in SCC, and support the hypothesis of a behavioral difference of the virus within the two major histological skin cancers.

  14. Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3beta phosphorylation.

    Science.gov (United States)

    Kumar, Anil; Hou, Xu; Lee, Chunsik; Li, Yang; Maminishkis, Arvydas; Tang, Zhongshu; Zhang, Fan; Langer, Harald F; Arjunan, Pachiappan; Dong, Lijin; Wu, Zhijian; Zhu, Linda Y; Wang, Lianchun; Min, Wang; Colosi, Peter; Chavakis, Triantafyllos; Li, Xuri

    2010-05-14

    Platelet-derived growth factor-DD (PDGF-DD) is a recently discovered member of the PDGF family. The role of PDGF-DD in pathological angiogenesis and the underlying cellular and molecular mechanisms remain largely unexplored. In this study, using different animal models, we showed that PDGF-DD expression was up-regulated during pathological angiogenesis, and inhibition of PDGF-DD suppressed both choroidal and retinal neovascularization. We also demonstrated a novel mechanism mediating the function of PDGF-DD. PDGF-DD induced glycogen synthase kinase-3beta (GSK3beta) Ser(9) phosphorylation and Tyr(216) dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3beta activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3beta and many other genes important for angiogenesis and apoptosis. Thus, we identified PDGF-DD as an important target gene for antiangiogenic therapy due to its pleiotropic effects on vascular and non-vascular cells. PDGF-DD inhibition may offer new therapeutic options to treat neovascular diseases.

  15. Genetic effects analysis of myeloid leukemia factor 2 and T cell receptor-beta on resistance to coccidiosis in chickens.

    Science.gov (United States)

    Kim, E-S; Hong, Y H; Lillehoj, H S

    2010-01-01

    Associations between the parameters of resistance to coccidiosis and SNP in 3 candidate genes located on chromosome 1 [T cell receptor-beta (TCR-beta), myeloid leukemia factor 2 (MLF2), and lymphotactin] were determined. Single nucleotide polymorphisms were genotyped in 24 F1 generation and 290 F2 generation birds. Four SNP were identified in the lymphotactin gene, 12 were located in the TCR-beta gene, and 4 in the MLF2 gene. At various times after experimental infection of the F2 generation with Eimeria maxima, BW, fecal oocyst shedding, and biochemical parameters were measured as parameters of coccidiosis resistance. Single marker association test was applied to determine the associations between the 20 SNP and the parameters of coccidiosis resistance. The maximum additive genetic effect on disease resistance of an SNP in MLF2 was explained by BW (P = 0.0002). The SNP in MLF2 significantly associated with BW was also associated with fecal oocyst shedding (P = 0.001). Four SNP associated with oocyst shedding were found within the coding region of TCR-beta (P coccidiosis resistance in chickens.

  16. [Expression of elongation factor-1 alpha-A and beta-actin promoters in embryos of transgenic Medaka (Oryzias latipes)].

    Science.gov (United States)

    Long, Hua

    2003-06-01

    Two expression vectors with the promoter of either Medaka (Oryzias latipes) elongation factor gene or beta-actin gene were constructed based on pBluescript SK+. Both of them are linked with green-fluorescent protein (GFP) gene. And they are named as pB-EF and pB-BA, respectively. The microinjection experiments were conducted with fertilized Medaka eggs at one-cell stage. The expression of two vectors, pB-EF and pB-BA, was observed under stereo-fluorescence microscope. The detection results showed that both EF-1 alpha-A promoter and beta-actin promoter are strong. In the process of embryo development, the activity of beta-actin promoter became stronger while that of EF-1 alpha-A promoter weaker gradually. beta-actin promoter was but EF-1 alpha-A promoter distributed throughout fish body uniformly. The expression rate of two vectors, pB-EF and pB-BA, are 8.23% and 6.10%, respectively.

  17. Evaluación de los niveles del factor de crecimiento transformante beta 1 y beta 3 en plasma y líquido peritoneal de caballos con enfermedad abdominal aguda Evaluation of the transforming growth factor beta 1 and beta 3 levels in plasma and peritoneal fluid from horses with acute abdominal disease

    Directory of Open Access Journals (Sweden)

    D Argüelles

    2009-01-01

    Full Text Available Existe información escasa sobre moléculas presentes en el líquido peritoneal de caballos con cólico relacionadas con el desarrollo potencial de adherencias abdominales. Estudios en especies diferentes correlacionan niveles incrementados de las series del factor de crecimiento transformante beta (TGF-ß con la presencia de adherencias abdominales. Los objetivos de este estudio fueron: 1 documentar y comparar los niveles plasmáticos y del líquido peritoneal del TGF-ß1 y TGF-ß3 en caballos con enfermedad abdominal aguda y en caballos normales. 2 correlacionar los niveles de estos péptidos con los hallazgos del hemograma y los resultados citológicos y bioquímicos del líquido peritoneal. Se tomaron muestras de plasma y líquido peritoneal de 104 caballos con cólico (29 cólicos médicos (15 obstructivos simples y 14 inflamatorios y 65 cólicos quirúrgicos, de los cuales 30 padecían problemas isquémicos y 35 de problemas obstructivos simples y de 10 caballos sanos. En cada paciente se realizó un hemograma, análisis citológico de líquido peritoneal y determinación de los niveles plasmáticos y peritoneales de TGF-ß1 y TGF-ß3 mediante ELISA. Los niveles peritoneales de TGF-ß1 fueron estadísticamente más altos en los cólicos quirúrgicos isquémicos y en los cólicos médicos inflamatorios en comparación con los otros tipos de cólicos y con el grupo control. En conclusión, los niveles peritoneales de TGF-ß1 en caballos con crisis abdominal aguda están incrementados como respuesta a la inflamación. Los caballos con lesiones estrangulantes o peritonitis muestran alteración severa en niveles peritoneales de TGF-ß1.There is few information about the molecules present in the peritoneal fluid of horses with colic that are related to the potential development of abdominal adhesions. Studies carried out in different species correlate high levels of transforming growth factor beta (TGF-ß series with the presence of abdominal

  18. Contribution of Alpha and Beta Diversity Across Land-Use Type to the Regional Diversity of Dung Beetles in Central Sulawesi

    Directory of Open Access Journals (Sweden)

    SHAHABUDDIN

    2013-06-01

    Full Text Available The importance of spatial scale has been acknowledged as one of determining factors of species diversity in local and regional diversity. The aim of this study was to evaluate contribution of alpha ( and beta ( diversity across land-use type to gamma ( diversity at the margins of tropical forest in Central Sulawesi using dung beetles (Coleoptera: Scarabaeidae as a focal group. Baited pitfall traps set in four land-use types ranging from natural forest through cacao agroforestry systems to open areas during two years of sampling (2009 and 2012. A total of 28 dung beetle species belonging to four genera were captured during the study period. The results showed that contribution of  diversity was higher than that of  diversity of dung beetles. Each land-use type contributed about 56.5 to 62.5% of the total species richness ( diversity. The similar pattern of biodiversity between each spatial scale and during the two sampling years emphasized the large contribution of each land-use type to maintaining a high portion of the regional species richness. It suggests the importance of managing other land-use types, such as secondary forest and agroforestry as well as protecting the remaining natural forests.

  19. EFEK SUPLEMENTASI EKSTRAK PROTEIN KECAMBAH KEDELAI TERHADAP KADAR IL-1BETA PENDERITA DIABETES TIPE-2 [The Effect of Soy Germ Protein Extract Supplementation on the Level of IL-1 Beta of Type-2 Diabetic Woman

    Directory of Open Access Journals (Sweden)

    Hery Winarsi1*

    2010-06-01

    Full Text Available The research was conducted to determine the effect of soy germ protein extract supplementation on the IL-1beta level of type-2 diabetic women. Research subjects were 32 type-2 diabetic women, outpatients of Diabetic Clinics of Margono Soekarjo General Hospital-Purwokerto. These women had blood glucose level above normal, BMI > 23 kg/m2, over 40 years old, lived in Purwokerto, and signed the informed consent. Group A (n=8 was given milk containing soy germ protein extract plus Zinc, Group B (n=8 was given milk containing soy germ protein extract without Zinc, Group C (n=8 was given placebo, and Group D (n=8 was given glibenclamide for 8 weeks. Blood samples ware taken 3 times: 0, 4 and 8 weeks after intervention. The plasma IL-1beta level was analyzed using Elisa. After 8 weeks, the IL-1beta level decreased from 6.01 pg/mL to 2.63 pg/mL (p=0.022 in group A. However, the IL-1beta level in Group A was not different from the Group B (p=0.51. Soy germ protein extract decreased cytokine inflammatory production of type-2 dibetic. Soy germ protein extract with or without Zn had similar effects to glibenclamide in reducing the IL-1beta level (p=0.76.

  20. Beta-adrenergic receptor agonists induce the release of granulocyte chemotactic protein-2, oncostatin M, and vascular endothelial growth factor from macrophages

    NARCIS (Netherlands)

    Verhoeckx, K.C.; Doornbos, R.P.; Witkamp, R.F.; Greef, J. van der; Rodenburg, R.J.T.

    2006-01-01

    Vascular endothelial growth factor (VEGF), oncostatin M (OSM), and granulocyte chemotactic protein-2 (GCP-2/CXCL6) are up-regulated in U937 macrophages and peripheral blood macrophages exposed to LPS, beta-adrenergic receptor (beta2-AR) agonists (e.g. zilpaterol, and clenbuterol) and some other agen

  1. Transforming growth factor-beta 1 downregulates dexamethasone-induced tetranectin gene expression during the in vitro mineralization of the human osteoblastic cell line SV-HFO

    DEFF Research Database (Denmark)

    Iba, K; Sawada, N; Chiba, H

    1995-01-01

    treatment as evidenced by Northern blotting. When transforming growth factor-beta 1 (TGF-beta 1) was added together with dexamethasone to the SV-HFO cell cultures, the mineralization process was markedly suppressed and the expression of tetra nectin and alkaline phosphatase was downregulated in a dose...

  2. Type 1 Diabetes Candidate Genes Linked to Pancreatic Islet Cell Inflammation and Beta-Cell Apoptosis

    Science.gov (United States)

    Størling, Joachim; Pociot, Flemming

    2017-01-01

    Type 1 diabetes (T1D) is a chronic immune-mediated disease resulting from the selective destruction of the insulin-producing pancreatic islet β-cells. Susceptibility to the disease is the result of complex interactions between environmental and genetic risk factors. Genome-wide association studies (GWAS) have identified more than 50 genetic regions that affect the risk of developing T1D. Most of these susceptibility loci, however, harbor several genes, and the causal variant(s) and gene(s) for most of the loci remain to be established. A significant part of the genes located in the T1D susceptibility loci are expressed in human islets and β cells and mounting evidence suggests that some of these genes modulate the β-cell response to the immune system and viral infection and regulate apoptotic β-cell death. Here, we discuss the current status of T1D susceptibility loci and candidate genes with focus on pancreatic islet cell inflammation and β-cell apoptosis. PMID:28212332

  3. Type 1 Diabetes Candidate Genes Linked to Pancreatic Islet Cell Inflammation and Beta-Cell Apoptosis.

    Science.gov (United States)

    Størling, Joachim; Pociot, Flemming

    2017-02-16

    Type 1 diabetes (T1D) is a chronic immune-mediated disease resulting from the selective destruction of the insulin-producing pancreatic islet β-cells. Susceptibility to the disease is the result of complex interactions between environmental and genetic risk factors. Genome-wide association studies (GWAS) have identified more than 50 genetic regions that affect the risk of developing T1D. Most of these susceptibility loci, however, harbor several genes, and the causal variant(s) and gene(s) for most of the loci remain to be established. A significant part of the genes located in the T1D susceptibility loci are expressed in human islets and β cells and mounting evidence suggests that some of these genes modulate the β-cell response to the immune system and viral infection and regulate apoptotic β-cell death. Here, we discuss the current status of T1D susceptibility loci and candidate genes with focus on pancreatic islet cell inflammation and β-cell apoptosis.

  4. Dual actions of enflurane on postsynaptic currents abolished by the gamma-aminobutyric acid type A receptor beta3(N265M) point mutation.

    Science.gov (United States)

    Drexler, Berthold; Jurd, Rachel; Rudolph, Uwe; Antkowiak, Bernd

    2006-08-01

    At concentrations close to 1 minimum alveolar concentration (MAC)-immobility, volatile anesthetics display blocking and prolonging effects on gamma-aminobutyric acid type A receptor-mediated postsynaptic currents. It has been proposed that distinct molecular mechanisms underlie these dual actions. The authors investigated whether the blocking or the prolonging effect of enflurane is altered by a point mutation (N265M) in the beta3 subunit of the gamma-aminobutyric acid type A receptor. Furthermore, the role of the beta3 subunit in producing the depressant actions of enflurane on neocortical neurons was elucidated. Spontaneous inhibitory postsynaptic currents were sampled from neocortical neurons in cultured slices derived from wild-type and beta3(N265M) mutant mice. The effects of 0.3 and 0.6 mm enflurane on decay kinetics, peak amplitude, and charge transfer were quantified. Furthermore, the impact of enflurane-induced changes in spontaneous action potential firing was evaluated by extracellular recordings in slices from wild-type and mutant mice. In slices derived from wild-type mice, enflurane prolonged inhibitory postsynaptic current decays and decreased peak amplitudes. Both effects were almost absent in slices from beta3(N265M) mutant mice. At clinically relevant concentrations between MAC-awake and MAC-immobility, the anesthetic was less effective in depressing spontaneous action potential firing in slices from beta3(N265M) mutant mice compared with wild-type mice. At concentrations between MAC-awake and MAC-immobility, beta3-containing gamma-aminobutyric acid type A receptors contribute to the depressant actions of enflurane in the neocortex. The beta3(N265M) mutation affects both the prolonging and blocking effects of enflurane on gamma-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents in neocortical neurons.

  5. Interferon (IFN)-beta induces apoptotic cell death in DHL-4 diffuse large B cell lymphoma cells through tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).

    Science.gov (United States)

    Oehadian, Amaylia; Koide, Naoki; Mu, Mya Mya; Hassan, Ferdaus; Islam, Shamima; Yoshida, Tomoaki; Yokochi, Takashi

    2005-07-08

    The effect of interferon (IFN)-alpha, beta and gamma on the growth of DHL-4 diffuse large B cell lymphoma cells was studied. IFN-beta significantly inhibited the cell growth, and the effect was stronger than that of IFN-alpha. IFN-gamma did not inhibit the cell growth because of lack of IFN-gamma receptors. IFN-beta caused apoptotic cell death which was accompanied by DNA fragmentation, caspase 3 activation and annexin V binding. IFN-beta lead to the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA. Anti-TRAIL antibody significantly prevented IFN-beta-induced apoptosis. It was suggested that IFN-beta might cause apoptosis in DHL-4 cells through TRAIL.

  6. Reduction of beta-amyloid-induced neurotoxicity on hippocampal cell cultures by moderate acidosis is mediated by transforming growth factor beta.

    Science.gov (United States)

    Uribe-San Martín, R; Herrera-Molina, R; Olavarría, L; Ramírez, G; von Bernhardi, R

    2009-02-18

    Progression of Alzheimer's disease (AD) is associated with chronic inflammation and microvascular alterations, which can induce impairment of brain perfusion because of vascular pathology and local acidosis. Acidosis can promote amyloidogenesis, which could further contribute to neurodegenerative changes. Nevertheless, there is also evidence that acidosis has neuroprotective effects in hypoxia models. Here we studied the effect of moderate acidosis on beta-amyloid (Abeta)-mediated neurotoxicity. We evaluated morphological changes, cell death, nitrite production and reductive metabolism of hippocampal cultures from Sprague-Dawley rats exposed to Abeta under physiological (pH 7.4) or moderate acidosis (pH 7.15-7.05). In addition, because transforming growth factor beta (TGFbeta) 1 is neuroprotective and is induced by several pathophysiological conditions, we assessed its presence at the different pHs. The exposure of hippocampal cells to Abeta induced a conspicuous reduction of neurites' arborization, as well as increased neuronal death and nitric oxide production. However, Abeta neurotoxicity was significantly attenuated when hippocampal cultures were kept at pH 7.15-7.05, showing a 68% reduction on lactate dehydrogenase release compared with cultures exposed to Abeta at pH 7.4 (Pacidosis compared with basal pH media (Pacidosis decreased intracellular TGFbeta1 precursor (latency associated protein-TGFbeta1) and increased up to fourfold TGFbeta1 bioactivity, detecting a 43% increase in the active TGFbeta levels in cultures exposed to Abeta and moderate acidosis. Inhibition of TGFbeta signaling abolished the neuroprotective effect of moderate acidosis. Our results show that moderate acidosis protected hippocampal cells from Abeta-mediated neurotoxicity through the increased activation and signaling potentiation of TGFbeta.

  7. Foot-and-mouth disease virus leader proteinase inhibits dsRNA-induced type I interferon transcription by decreasing interferon regulatory factor 3/7 in protein levels

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Dang; Fang, Liurong; Luo, Rui; Ye, Rui; Fang, Ying; Xie, Lilan; Chen, Huanchun [Division of Animal Infectious Diseases, State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070 (China); Xiao, Shaobo, E-mail: shaoboxiao@yahoo.com [Division of Animal Infectious Diseases, State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070 (China)

    2010-08-13

    Research highlights: {yields} FMDV L{sup pro} inhibits poly(I:C)-induced IFN-{alpha}1/{beta} mRNA expression. {yields} L{sup pro} inhibits MDA5-mediated activation of the IFN-{alpha}1/{beta} promoter. {yields} L{sup pro} significantly reduced the transcription of multiple IRF-responsive genes. {yields} L{sup pro} inhibits IFN-{alpha}1/{beta} promoter activation by decreasing IRF-3/7 in protein levels. {yields} The ability to process eIF-4G of L{sup pro} is not necessary to inhibit IFN-{alpha}1/{beta} activation. -- Abstract: The leader proteinase (L{sup pro}) of foot-and-mouth disease virus (FMDV) has been identified as an interferon-{beta} (IFN-{beta}) antagonist that disrupts the integrity of transcription factor nuclear factor {kappa}B (NF-{kappa}B). In this study, we showed that the reduction of double stranded RNA (dsRNA)-induced IFN-{alpha}1/{beta} expression caused by L{sup pro} was also associated with a decrease of interferon regulatory factor 3/7 (IRF-3/7) in protein levels, two critical transcription factors for activation of IFN-{alpha}/{beta}. Furthermore, overexpression of L{sup pro} significantly reduced the transcription of multiple IRF-responsive genes including 2',5'-OAS, ISG54, IP-10, and RANTES. Screening L{sup pro} mutants indicated that the ability to process eIF-4G of L{sup pro} is not required for suppressing dsRNA-induced activation of the IFN-{alpha}1/{beta} promoter and decreasing IRF-3/7 expression. Taken together, our results demonstrate that, in addition to disrupting NF-{kappa}B, L{sup pro} also decreases IRF-3/7 expression to suppress dsRNA-induced type I IFN production, suggesting multiple strategies used by FMDV to counteract the immune response to viral infection.

  8. Environmental particulate (PM2.5 augments stiffness-induced alveolar epithelial cell mechanoactivation of transforming growth factor beta.

    Directory of Open Access Journals (Sweden)

    Marilyn M Dysart

    Full Text Available Dysfunctional pulmonary homeostasis and repair, including diseases such as pulmonary fibrosis (PF, chronic obstructive pulmonary disease (COPD, and tumorigenesis have been increasing over the past decade, a fact that heavily implicates environmental influences. Several investigations have suggested that in response to increased transforming growth factor--beta (TGFβ signaling, the alveolar type II (ATII epithelial cell undergoes phenotypic changes that may contribute to the complex pathobiology of PF. We have previously demonstrated that increased tissue stiffness associated with PF is a potent extracellular matrix (ECM signal for epithelial cell activation of TGFβ. The work reported here explores the relationship between tissue stiffness and exposure to environmental stimuli in the activation of TGFβ. We hypothesized that exposure of ATII cells to fine particulate matter (PM2.5 will result in enhanced cell contractility, TGFβ activation, and subsequent changes to ATII cell phenotype. ATII cells were cultured on increasingly stiff substrates with or without addition of PM2.5. Exposure to PM2.5 resulted in increased activation of TGFβ, increased cell contractility, and elongation of ATII cells. Most notably, on 8 kPa substrates, a stiffness greater than normal but less than established fibrotic lung, addition of PM2.5 resulted in increased cortical cell stiffness, enhanced actin staining and cell elongation; a result not seen in the absence of PM2.5. Our work suggests that PM2.5 exposure additionally enhances the existing interaction between ECM stiffness and TGFβ that has been previously reported. Furthermore, we show that this additional enhancement is likely a consequence of intracellular reactive oxygen species (ROS leading to increased TGFβ signaling events. These results highlight the importance of both the micromechanical and biochemical environment in lung disease initiation and suggest that individuals in early stages of lung

  9. Adipocyte exosomes induce transforming growth factor beta pathway dysregulation in hepatocytes: a novel paradigm for obesity-related liver disease.

    Science.gov (United States)

    Koeck, Emily S; Iordanskaia, Tatiana; Sevilla, Samantha; Ferrante, Sarah C; Hubal, Monica J; Freishtat, Robert J; Nadler, Evan P

    2014-12-01

    The pathogenesis of nonalcoholic fatty liver disease (NAFLD) has been attributed to increased systemic inflammation and insulin resistance mediated by visceral adipose tissue (VAT), although the exact mechanisms are undefined. Exosomes are membrane-derived vesicles containing messenger RNA, microRNA, and proteins, which have been implicated in cancer, neurodegenerative, and autoimmune diseases, which we postulated may be involved in obesity-related diseases. We isolated exosomes from VAT, characterized their content, and identified their potential targets. Targets included the transforming growth factor beta (TGF-β) pathway, which has been linked to NAFLD. We hypothesized that adipocyte exosomes would integrate into HepG2 and hepatic stellate cell lines and cause dysregulation of the TGF-β pathway. Exosomes from VAT from obese and lean patients were isolated and fluorescently labeled, then applied to cultured hepatic cell lines. After incubation, culture slides were imaged to detect exosome uptake. In separate experiments, exosomes were applied to cultured cells and incubated 48-h. Gene expression of TGF-β pathway mediators was analyzed by polymerase chain reaction, and compared with cells, which were not exposed to exosomes. Fluorescent-labeled exosomes integrated into both cell types and deposited in a perinuclear distribution. Exosome exposure caused increased tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and integrin ανβ-5 expression and decreased matrix metalloproteinase-7 and plasminogen activator inhibitor-1 expression in to HepG2 cells and increased expression of TIMP-1, TIMP-4, Smad-3, integrins ανβ-5 and ανβ-8, and matrix metalloproteinase-9 in hepatic stellate cells. Exosomes from VAT integrate into liver cells and induce dysregulation of TGF-β pathway members in vitro and offers an intriguing possibility for the pathogenesis of NAFLD. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Expression and clinical significance of dendritic cell and transforming growth factor-beta 1 in cervical cancer

    Institute of Scientific and Technical Information of China (English)

    Zhao; Shan; Rong; Fengnian

    2006-01-01

    Objective:To explore the density and mature status of Dendritic cell(DC) in cervical cancer and correlation with the expression of transforming growth factor-beta 1(TGF-β1).Methods:Streptavidin-peroxidase(SP) immunohistochemistry methods were used to detect S-100 DC and the expression of TGF-β1 in 20 normal cervical tissues and 53 cervical cancer tissues without any sort of chemotherapy or radiation therapy prior to resection.Medical records were reviewed,clinicopathological variables were retrieved and used for analysis.Results:Two types of DC were observed under the microscope.The expression of DC in cervical cancer was significantly higher than that in normal tissues(23.34 cells/mm2 vs 29.91 cells/mm2,P<0.05),and significantly higher in early stage than that in advanced stage(P<0.05).The expression of TGF-β1 was significantly higher in cervical cancer than that in normal tissues (P<0.025).However,there was no correaction between TGF-β1 and lymph nodes metastasis.The index of DC in cervical cancer was negatively correlated to the expression of TGF-β1 in tumor cells (r=-0.8875,P=0.0001).Conclusion:Maturation of DC in cervical cancer is inhibited.The decreased number of DC and the higher expression of TGF-β1 are due to the failure of the immunity,these may play an important role in the development of the cervical cancer.

  11. Uncovering the profile of mutations of transforming growth factor beta-induced gene in Chinese corneal dystrophy patients

    Directory of Open Access Journals (Sweden)

    Xiao-Dan Hao

    2016-02-01

    Full Text Available AIM: To uncover the mutations profile of transforming growth factor beta-induced (TGFBI gene in Chinese corneal dystrophy patients and further investigate the characteristics of genotype-phenotype correlations. METHODS: Forty-two subjects (6 unrelated families including 15 patients and 8 unaffected members, and 19 sporadic patients of Chinese origin were subjected to phenotypic and genotypic characterization. The corneal phenotypes of patients were documented by slit lamp photography. Mutation screening of the coding regions of TGFBI was performed by direct sequencing. RESULTS: We detected four corneal dystrophy types. The most frequent phenotypes were granular corneal dystrophy (GCD (including 3 families and 8 sporadic patients and lattice corneal dystrophy (LCD (including 2 families and 9 sporadic patients. The next phenotypes were corneal dystrophy of Bowman layer (CDB (1 family and 1 sporadic patient and epithelial basement membrane dystrophy (EBMD (1 sporadic patient. Six distinct mutations responsible for TGFBI corneal dystrophies were identified in 30 individuals with corneal dystrophies. Those were, p.R124H mutation in 1 family and 2 sporadic patients with GCD, p.R555W mutation in 2 families and 3 sporadic patients with GCD, p.R124C mutation in 2 families and 7 sporadic patients with LCD, p.A620D mutation in 1 sporadic patient with LCD, p.H626R mutation in 1 sporadic patient with LCD, and p.R555Q in 1 family and 1 sporadic patient with CDB. No mutation was detected in the remaining 3 atypical GCD patients and 1 EBMD patient. CONCLUSION: GCD and LCD are the most frequent phenotypes in Chinese population. R555W was the most common mutation for GCD; R124C was the most common mutation for LCD. Our findings extend the mutational spectrum of TFGBI, and this is the extensively delineated TGFBI mutation profile associated with the various corneal dystrophies in the Chinese population.

  12. Structure of the human beta-ketoacyl [ACP] synthase from the mitochondrial type II fatty acid synthase

    DEFF Research Database (Denmark)

    Christensen, Caspar Elo; Kragelund, Birthe Brandt; Von Wettstein-Knowles, Penny

    2007-01-01

    Two distinct ways of organizing fatty acid biosynthesis exist: the multifunctional type I fatty acid synthase (FAS) of mammals, fungi, and lower eukaryotes with activities residing on one or two polypeptides; and the dissociated type II FAS of prokaryotes, plastids, and mitochondria with individual...... activities encoded by discrete genes. The beta-ketoacyl [ACP] synthase (KAS) moiety of the mitochondrial FAS (mtKAS) is targeted by the antibiotic cerulenin and possibly by the other antibiotics inhibiting prokaryotic KASes: thiolactomycin, platensimycin, and the alpha-methylene butyrolactone, C75. The high...... degree of structural similarity between mitochondrial and prokaryotic KASes complicates development of novel antibiotics targeting prokaryotic KAS without affecting KAS domains of cytoplasmic FAS. KASes catalyze the C(2) fatty acid elongation reaction using either a Cys-His-His or Cys-His-Asn catalytic...

  13. Transcription of the human beta enolase gene (ENO-3) is regulated by an intronic muscle-specific enhancer that binds myocyte-specific enhancer factor 2 proteins and ubiquitous G-rich-box binding factors.

    Science.gov (United States)

    Feo, S; Antona, V; Barbieri, G; Passantino, R; Calì, L; Giallongo, A

    1995-01-01

    To provide evidence for the cis-regulatory DNA sequences and trans-acting factors involved in the complex pattern of tissue- and stage-specific expression of the beta enolase gene, constructs containing fragments of the gene fused to the chloramphenicol acetyltransferase gene were used in transient-transfection assays of C2C12 myogenic cells. Deletion analysis revealed the presence of four major regions: two negative regions in the 5'-flanking sequence, a basal promoter region which directs expression at low levels in proliferating and differentiated muscle cells, and a positive region within the first intron that confers cell-type-specific and differentiation-induced expression. This positive regulatory element is located in the 3'-proximal portion of the first intron (nucleotides +504 to +637) and acts as an enhancer irrespective of orientation and position from the homologous beta enolase promoter or the heterologous thymidine kinase promoter, conferring in both cases muscle-specific expression to the linked reporter gene. Deletion of a putative myocyte-specific enhancer factor 1 (MEF-1) binding site, containing a canonical E-box motif, had no effects on muscle-specific transcription, indicating that this site is not required for the activity of the enhancer. Gel mobility shift assays, competition analysis, DNase I footprinting, and mutagenesis studies indicated that this element interacts through an A/T-rich box with a MEF-2 protein(s) and through a G-rich box with a novel ubiquitous factor(s). Mutation of either the G-rich box or the A/T-rich box resulted in a significantly reduced activity of the enhancer in transient-transfection assays. These data indicate that MEF-2 and G-rich-box binding factors are each necessary for tissue-specific expression of the beta enolase gene in skeletal muscle cells. PMID:7565752

  14. The signaling pathway of Campylobacter jejuni-induced Cdc42 activation: Role of fibronectin, integrin beta1, tyrosine kinases and guanine exchange factor Vav2

    LENUS (Irish Health Repository)

    Krause-Gruszczynska, Malgorzata

    2011-12-28

    Abstract Background Host cell invasion by the foodborne pathogen Campylobacter jejuni is considered as one of the primary reasons of gut tissue damage, however, mechanisms and key factors involved in this process are widely unclear. It was reported that small Rho GTPases, including Cdc42, are activated and play a role during invasion, but the involved signaling cascades remained unknown. Here we utilised knockout cell lines derived from fibronectin-\\/-, integrin-beta1-\\/-, focal adhesion kinase (FAK)-\\/- and Src\\/Yes\\/Fyn-\\/- deficient mice, and wild-type control cells, to investigate C. jejuni-induced mechanisms leading to Cdc42 activation and bacterial uptake. Results Using high-resolution scanning electron microscopy, GTPase pulldowns, G-Lisa and gentamicin protection assays we found that each studied host factor is necessary for induction of Cdc42-GTP and efficient invasion. Interestingly, filopodia formation and associated membrane dynamics linked to invasion were only seen during infection of wild-type but not in knockout cells. Infection of cells stably expressing integrin-beta1 variants with well-known defects in fibronectin fibril formation or FAK signaling also exhibited severe deficiencies in Cdc42 activation and bacterial invasion. We further demonstrated that infection of wild-type cells induces increasing amounts of phosphorylated FAK and growth factor receptors (EGFR and PDGFR) during the course of infection, correlating with accumulating Cdc42-GTP levels and C. jejuni invasion over time. In studies using pharmacological inhibitors, silencing RNA (siRNA) and dominant-negative expression constructs, EGFR, PDGFR and PI3-kinase appeared to represent other crucial components upstream of Cdc42 and invasion. siRNA and the use of Vav1\\/2-\\/- knockout cells further showed that the guanine exchange factor Vav2 is required for Cdc42 activation and maximal bacterial invasion. Overexpression of certain mutant constructs indicated that Vav2 is a linker

  15. Tissue inhibitor of metalloproteinase-3 is up-regulated by transforming growth factor-beta1 in vitro and expressed in fibroblastic foci in vivo in idiopathic pulmonary fibrosis.

    Science.gov (United States)

    García-Alvarez, Jorge; Ramirez, Remedios; Checa, Marco; Nuttall, Robert K; Sampieri, Clara L; Edwards, Dylan R; Selman, Moisés; Pardo, Annie

    2006-05-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by fibroblast expansion and extracellular matrix accumulation. However, the mechanisms involved in matrix remodeling have not been elucidated. In this study, the authors aimed to evaluate the expression of the tissue inhibitors of matrix metalloproteinases (TIMPs) in human fibroblasts and whole tissues from IPF and normal lungs. They also determined the role of mitogen-activated protein kinase (MAPK) in TIMP3 expression. TIMP1, TIMP2, and TIMP3 were highly expressed in lung fibroblasts. Transforming growth factor (TGF)-beta1, a profibrotic mediator, induced strong up-regulation of TIMP3 at the mRNA and protein levels. The authors examined whether the MAPK pathway was involved in TGF-beta1-induced TIMP3 expression. TGF-beta1 induced the phosphorylation of p38 and extracellular signal-regulated kinase (ERK)1/2. Biochemical blockade of p38 by SB203580, but not of the ERK MAPK pathway, inhibited the effect of this factor. The effect was also blocked by the tyrosine kinase inhibitor genistein and by antagonizing TGF-beta1 receptor type I (activin-linked kinase [ALK5]). In IPF tissues TIMP3 gene expression was significantly increased and the protein was localized to fibroblastic foci and extracellular matrix. Our findings suggest that TGF-beta1-induced TIMP3 may be an important mediator in lung fibrogenesis.

  16. Role of interleukin-10 and transforming growth factor beta 1 in otitis media with effusion

    Institute of Scientific and Technical Information of China (English)

    ZHAO Shou-qin; LI Jie; LIU Hua; ZHANG Quan-geng; WANG Yang; HAN De-min

    2009-01-01

    Background Otitis media with effusion (OME) is a disease with complicated pathogeneses which are not clearly known. Increasing interest has been focused on immunological cells, cytokines and their roles in chronic inflammatory states. This study was designed to disclose the existence and roles of interleukin-10 (IL-10) and transforming growth factor beta1 (TGF-β1) in the cause of OME in adults, and to investigate the probable role of Foxp3+CD4+CD25+ T cells in OME.Methods The concentrations of IL-10 and TGF-β1 in the middle ear effusions (MEEs) and plasmas of 36 adults (45 ears) with OME were measured by means of enzyme linked immunosorbent assay (ELISA). As contrast, the concentrations of IL-10 and TGF-β1 in the plasma of 30 normal volunteers were measured using the same method. Furthermore, the proportion of Foxp3+CD4+CD25+ T cells in CD4+ T cells of blood was tested by flow cytometry. Results (1) The concentrations of IL-10 in all MEEs and plasmas of the chronic OME patients were higher than those in patients with acute OME (both P 0.05). The concentration of IL-10 in MEEs had a strong correlation with the duration of the illness (r=0.547, P<0.01). The same correlation was also found between the concentration of TGF-β1 in MEEs and the times patients being treated (r=0.579, P <0.01). (3) The proportion of Foxp3+CD4+CD25+T/CD4+ T cells in the blood of chronic OME was not only significantly higher than that in the acute OME (P<0.01), but also higher than that in normal volunteers (P <0.01). In chronic OME, there was a correlation between the proportion of Foxp3+CD4+CD25+ T/CD4+ T cells in the blood and the concentration of IL-10 in the plasmas (r=0.602, P <0.05). Conclusions IL-10 and TGF-β1, as two important immunoregulatory mediators, participate in middle ear inflammatory response, especially in chronic course of OME in adults. Foxp3+CD4+CD25+ T cells may play some immunoregulatory roles in the course of this disease.

  17. Discovery of Novel Drugs to Improve Bone Health in Neurofibromatosis Type 1: The Wnt/Beta-Catenin Pathway in Fracture Repair and Pseudarthrosis

    Science.gov (United States)

    2015-08-01

    neurofibromatosis. 4 To identify agents that inhibit beta-catenin signaling, we undertook a high throughput screen using mesenchymal cells exhibiting...Med 2007, 4:e249. [3] Poon R HH, Wei X, Pan J, and Alman BA: A high throughput screen identifies Nefopam as targeting cell proliferation in β...AWARD NUMBER: W81XWH-13-1-0113 TITLE: Discovery of Novel Drugs To Improve Bone Health in Neurofibromatosis Type 1: The Wnt/Beta-Catenin

  18. Multiple factors contribute to the peripheral induction of cerebral beta-amyloidosis

    NARCIS (Netherlands)

    Eisele, Y.S.; Fritschi, S.K.; Hamaguchi, T.; Obermüller, U.; Füger, P.; Skodras, A.; Schäfer, C.; Odenthal, J.; Heikenwalder, M.; Staufenbiel, M.; Jucker, M.

    2014-01-01

    Deposition of aggregated amyloid-beta (Abeta) peptide in brain is an early event and hallmark pathology of Alzheimer's disease and cerebral Abeta angiopathy. Experimental evidence supports the concept that Abeta multimers can act as seeds and structurally corrupt other Abeta peptides by a

  19. Characterization of beta-R1, a gene that is selectively induced by interferon beta (IFN-beta) compared with IFN-alpha.

    Science.gov (United States)

    Rani, M R; Foster, G R; Leung, S; Leaman, D; Stark, G R; Ransohoff, R M

    1996-09-13

    We report preliminary characterization of a gene designated beta-R1, which is selectively expressed in response to interferon beta (IFN-beta) compared with IFN-alpha. In human astrocytoma cells, beta-R1 was induced to an equivalent extent by 10 IU/mL IFN-beta or 2500 IU/mL IFN-alpha2. To address the mechanism of this differential response, we analyzed induction of the beta-R1 gene in fibrosarcoma cells and derivative mutant cells lacking components required for signaling by type I IFNs. beta-R1 was readily induced by IFN-beta in the parental 2fTGH cell line, but not by recombinant IFN-alpha2, IFN-alpha Con1, or a mixture of IFN-alpha subtypes. IFN-alpha8 induced beta-R1 weakly. beta-R1 was not induced by IFN-beta in mutant cell lines U2A, U3A, U4A, and U6A, which lack, respectively, p48, STAT1, JAK1, and STAT2. U5A cells, which lack the Ifnar 2.2 component of the IFN-alpha and -beta receptor, also failed to express beta-R1. U1A cells are partially responsive to IFN-beta and IFN-alpha8 but lacked beta-R1 expression, indicating that TYK2 protein is essential for induction of this gene. Taken together, these results suggest that the expression of beta-R1 in response to type I IFN requires IFN-stimulated gene factor 3 plus an additional component, which is more efficiently formed on induction by IFN-beta compared with IFN-alpha.

  20. 11beta-hydroxysteroid dehydrogenase type 2 expression in the newly formed Leydig cells after ethane dimethanesulphonate treatment of adult rats.

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    Katerina Georgieva

    2008-01-01

    Full Text Available The enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD catalyzes the reversible conversion of physiologically active corticosterone to the biologically inert 11beta-dehydrocorticosterone in rat testis and protect the Leydig cells (LCs against the suppressive effect of glucocorticoids. The developmental pathway of the adult LCs population is accompanied with an increase in the 11beta-HDS activity. Thus, 11beta-HDS together with its role in controlling the toxicological effect of glucocorticoids on LCs can be used as a marker for their functional maturity. Ethane 1,2-dimethanesulphonate (EDS treatment of adult rats become unique appropriate model, which enable to answer many questions related to the differentiation of adult LCs in the prepubertal rat testis. The aim of the present study was to investigate the specific changes in the 11beta-HDS type 2 immunoreactivity in tandem with the expression of androgen receptor (AR during renewal of LCs population after EDS treatment. In the present study, we observed the first appearance of immunostaining for 11beta-HSD2 in new LCs population on day 14 after EDS administration when the progenitor LCs were detected. Our immunohistochemical analysis revealed progressive increases in the 11beta-HSD2 reaction intensity on 21 days after EDS treatment and reached a maximum on day 35. AR immunoexpression was found in new LCs on day 14 and 21 after EDS injection with an increasing curve of intensity. The most prominent AR immunostaining in new population LCs was evident by 35 days after EDS and that coincided with the increased number of LCs and restoration of adult LCs population. Our results demonstrated similar pattern of immunoreactivity for 11beta-HSD2 and AR in new LCs population after EDS treatment and suggested that the changes in 11beta-HSD2 expression can be used for evaluation of adult LCs differentiation in rat testis.

  1. Evaluation of Mental Health and Related Factors Among Patients with Beta-Thalassemia Major in South East of Iran

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    Morteza Ashrafi

    2012-04-01

    Full Text Available Objective: Beta-thalassemia major (β-TM is a chronic, genetic and hematological disorder. Children and teenagers with chronic physical illnesses exemplified by thalassemia are vulnerable to emotional and behavioral problems. The aim of this study was to evaluate mental health and its related factors among young patients with beta-thalassemia major. Methods: In this cross-sectional observational descriptive-analytic study, we studied 164 patients suffering from Beta-thalassemia major with age range of 15-24 years who referred for treatment to Ali Ebn-e Abitaleb (AS University Hospital in Zahedan, a city in South East of Iran, during 2009- 2010. The demographic data and pattern of mental health were collected by standard general health questionnaire (GHQ-28.Data was analyzed using statistical software SPSS (version 17.0; Student t test and Chi-square (χ2 were used. Results: In this study, 96 (58.5% patients were male; the mean age of all patients was 18.78 ±2.28. Based on data analysis, 83 patients (50.8% suspected to have psychiatric disorders (58.8% of girls, 44.8% of boys. In addition, frequency of somatic symptoms, depression disorder, anxiety disorder and social dysfunction in all patients were 7.3%, 11.6%, 8.5% and 4.3% respectively. In illiterate patients, 70.4% suspected to have psychiatric disorder. Except for somatic disorder, other mental disorders were more frequent in girls. No significant association was found between mental state and gender, marital and literacy status and occupation. Conclusion : In this study, due to high prevalence of psychological disorders in young patients with Beta-thalassemia major, especially in girls, we suggest implementing further educational psychological programs to decrease the frequency of disorders. Moreover, conducting more quantitative and comprehensive researches is suggested to evaluate specific effective factors in psycho-social health.

  2. Transforming growth factor-beta induces nerve growth factor expression in pancreatic stellate cells by activation of the ALK-5 pathway.

    Science.gov (United States)

    Haas, Stephan L; Fitzner, Brit; Jaster, Robert; Wiercinska, Eliza; Gaitantzi, Haristi; Jesnowski, Ralf; Jesenowski, Ralf; Löhr, J-Matthias; Singer, Manfred V; Dooley, Steven; Breitkopf, Katja

    2009-10-01

    Nerve growth factor (NGF), a survival factor for neurons enforces pain by sensitizing nociceptors. Also in the pancreas, NGF was associated with pain and it can stimulate the proliferation of pancreatic cancer cells. Hepatic stellate cells (HSC) respond to NGF with apoptosis. Transforming growth factor (TGF)-beta, one of the strongest pro-fibrogenic activators of pancreatic stellate cells (PSC) induced NGF and its two receptors in an immortalized human cell line (ihPSC) and primary rat PSC (prPSC) as determined by RT-PCR, western blot, and immunofluorescence. In contrast to HSC, PSC expressed both NGF receptors, although p75(NTR) expression was weak in prPSC. In contrast to ihPSC TGF-beta activated both Smad signaling cascades in prPSC. NGF secretion was diminished by the activin-like kinase (ALK)-5 inhibitor SB431542, indicating the predominant role of ALK5 in activating the NGF system in PSC. While NGF did not affect proliferation or survival of PSC it induced expression of Inhibitor of Differentiation-1. We conclude that under conditions of upregulated TGF-beta, like fibrosis, NGF levels will also increase in PSC which might contribute to pancreatic wound healing responses.

  3. Effect of transforming growth factor-beta1 on embryonic and posthatch muscle growth and development in normal and low score normal chicken.

    Science.gov (United States)

    Li, X; Velleman, S G

    2009-02-01

    During skeletal muscle development, transforming growth factor-beta1 (TGF-beta1) is a potent inhibitor of muscle cell proliferation and differentiation. The TGF-beta1 signal is carried by Smad proteins into the cell nucleus, inhibiting the expression of key myogenic regulatory factors including MyoD and myogenin. However, the molecular mechanism by which TGF-beta1 inhibits muscle cell proliferation and differentiation has not been well documented in vivo. The present study investigated the effect of TGF-beta1 on in vivo skeletal muscle growth and development. A chicken line, Low Score Normal (LSN) with reduced muscling and upregulated TGF-beta1 expression, was used and compared to a normal chicken line. The injection of TGF-beta1 at embryonic day (ED) 3 significantly reduced the pectoralis major (p. major) muscle weight in the normal birds at 1 wk posthatch, whereas no significant difference was observed in the LSN birds. The difference between normal and LSN birds in response to TGF-beta1 is likely due to different levels of endogenous TGF-beta1 where the LSN birds have increased TGF-beta1 expression in their p. major muscle at both 17 ED and 6 wk posthatch. Smad3 expression was reduced by TGF-beta1 from 10 ED to 1 wk posthatch in normal p. major muscle. Unlike Smad3, Smad7 expression was not significantly affected by TGF-beta1 until posthatch in both normal and LSN p. major muscle. Expression of MyoD was reduced 35% by TGF-beta1 during embryonic development in normal p. major muscle, whereas LSN p. major muscle showed a delayed decrease at 1 d posthatch in MyoD expression in response to the TGF-beta1 treatment. Myogenin expression was reduced 29% by TGF-beta1 after hatch in normal p. major muscle. In LSN p. major muscle, TGF-beta1 treatment significantly decreased myogenin expression by 43% at 1 d posthatch and 32% at 1 wk posthatch. These data suggested that TGF-beta1 reduced p. major muscle growth by inhibiting MyoD and myogenin expression during both embryonic

  4. Role of 17 beta-estradiol on type IV collagen fibers volumetric density in the basement membrane of bladder wall.

    Science.gov (United States)

    de Fraga, Rogerio; Dambros, Miriam; Miyaoka, Ricardo; Riccetto, Cássio Luís Zanettini; Palma, Paulo César Rodrigues

    2007-10-01

    The authors quantified the type IV collagen fibers volumetric density in the basement membrane of bladder wall of ovariectomized rats with and without estradiol replacement. This study was conducted on 40 Wistar rats (3 months old) randomly divided in 4 groups: group 1, remained intact (control); group 2, submitted to bilateral oophorectomy and daily replacement 4 weeks later of 17 beta-estradiol for 12 weeks; group 3, sham operated and daily replacement 4 weeks later of sesame oil for 12 weeks; and group 4, submitted to bilateral oophorectomy and killed after 12 weeks. It was used in immunohistochemistry evaluation using type IV collagen polyclonal antibody to stain the fibers on paraffin rat bladder sections. The M-42 stereological grid system was used to analyze the fibers. Ovariectomy had an increase effect on the volumetric density of the type IV collagen fibers in the basement membrane of rat bladder wall. Estradiol replacement in castrated animals demonstrated a significative difference in the stereological parameters when compared to the castrated group without hormonal replacement. Surgical castration performed on rats induced an increasing volumetric density of type IV collagen fibers in the basement membrane of rats bladder wall and the estradiol treatment had a significant effect in keeping a low volumetric density of type IV collagen fibers in the basement membrane of rats bladder wall.

  5. Interleukin-1beta can mediate growth arrest and differentiation via the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells.

    Science.gov (United States)

    Park, Jong-In; Strock, Christopher J; Ball, Douglas W; Nelkin, Barry D

    2005-02-01

    Interleukin-1beta (IL-1beta) is a pleiotropic cytokine that can induce several cellular signal transduction pathways. Here, we show that IL-1beta can induce cell cycle arrest and differentiation in the human medullary thyroid carcinoma (MTC) cell line, TT. IL-1beta induces cell cycle arrest accompanied by morphological changes and expression of the neuroendocrine marker calcitonin. These changes are blocked by the MEK1/2 specific inhibitor U0126, indicating that MEK1/2 is essential for IL-1beta signaling in TT cells. IL-1beta induces expression of leukemia inhibitory factor (LIF) and activation of STAT3 via the MEK/ERK pathway. This activation of STAT3 could be abrogated by treatment with anti-LIF neutralizing antibody or anti-gp130 blocking antibody, indicating that induction of LIF expression is sufficient and essential for STAT3 activation by IL-1beta. In addition to activation of the LIF/JAK/STAT pathway, IL-1beta also induced an MEK/ERK-mediated intracellular cell-autonomous signaling pathway that is independently sufficient for growth arrest and differentiation. Thus, IL-1beta activates the MEK/ERK pathway to induce growth arrest and differentiation in MTC cells via dual independent signaling mechanisms, the cell-extrinsic LIF/JAK/STAT pathway, and the cell-intrinsic autonomous signaling pathway.

  6. Beta-catenin accelerates human papilloma virus type-16 mediated cervical carcinogenesis in transgenic mice.

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    Gülay Bulut

    Full Text Available Human papilloma virus (HPV is the principal etiological agent of cervical cancer in women, and its DNA is present in virtually all of these tumors. However, exposure to the high-risk HPV types alone is insufficient for tumor development. Identifying specific collaborating factors that will lead to cervical cancer remains an unanswered question, especially because millions of women are exposed to HPV. Our earlier work using an in vitro model indicated that activation of the canonical Wnt pathway in HPV-positive epithelial cells was sufficient to induce anchorage independent growth. We therefore hypothesized that constitutive activation of this pathway might function as the "second hit." To address this possibility, we developed two double-transgenic (DT mouse models, K14-E7/ΔN87βcat and K14-HPV16/ΔN87βcat that express either the proteins encoded by the E7 oncogene or the HPV16 early region along with constitutively active β-catenin, which was expressed by linking it to the keratin-14 (K14 promoter. We initiated tumor formation by treating all groups with estrogen for six months. Invasive cervical cancer was observed in 11% of the K14-ΔN87βcat mice, expressing activated β-catenin and in 50% of the animals expressing the HPV16 E7 oncogene. In double-transgenic mice, coexpression of β-catenin and HPV16 E7 induced invasive cervical cancer at about 7 months in 94% of the cases. We did not observe cervical cancer in any group unless the mice were treated with estrogen. In the second model, K14-HPV16 mice suffered cervical dysplasias, but this phenotype was not augmented in HPV16/ΔN87βcat mice. In summary, the phenotypes of the K14-E7/ΔN87βcat mice support the hypothesis that activation of the Wnt/β-catenin pathway in HPV-associated premalignant lesions plays a functional role in accelerating cervical carcinogenesis.

  7. Elevated D-glucose concentrations modulate TGF-beta 1 synthesis by human cultured renal proximal tubular cells. The permissive role of platelet-derived growth factor.

    OpenAIRE

    Phillips, A.O.; Steadman, R.; Topley, N; Williams, J. D.

    1995-01-01

    Interstitial fibrosis is a marker of progression of renal impairment in diabetic nephropathy. Transforming growth factor (TGF)-beta 1 is one of a group of pro-fibrotic cytokines and growth factors that have been associated with the development of interstitial fibrosis. We have examined the modulating influence of glucose on the production of TGF-beta 1 by cultured human proximal tubular cells. Incubation of growth-arrested human proximal tubular cells (HPTC) (72 hours in serum free medium) in...

  8. Interleukin 1 (IL-1) type I receptors mediate activation of rat hypothalamus-pituitary-adrenal axis and interleukin 6 production as shown by receptor type selective deletion mutants of IL-1beta.

    Science.gov (United States)

    Van Dam, A M; Malinowsky, D; Lenczowski, M J; Bartfai, T; Tilders, F J

    1998-06-01

    The cytokine interleukin 1 (IL-1) plays an important role in the activation of the hypothalamus-pituary-adrenal (HPA)-axis and interleukin 6 (IL-6) production during infection or inflammation. Which of the interleukin-1 receptor types mediates these effects is not known. To investigate this issue a pharmacological approach was chosen by using recently developed IL-1 receptor type selective ligands. Rats were given one of various doses of recombinant human IL-1beta (rhIL-1beta; 1 and 10 microg/kg) and of several IL-1beta mutants (DeltaSND, DeltaQGE and DeltaI; 1, 10 and 100 microg/kg), that differ in their affinities for the IL-1 type I receptor but have similar affinities for the IL-1 type II receptor. One hour after intravenous administration of rhIL-1beta or IL-1beta mutants, plasma levels of ACTH, corticosterone (cort) and IL-6 were measured. Doses of 1 and 10 microg/kg rhIL-1beta markedly elevated plasma levels of ACTH, cort and IL-6. However, 10-100-fold higher doses of IL-1beta mutants DeltaSND and DeltaQGE and at least 100-fold higher doses of DeltaI have to be administered to increase plasma levels of ACTH, cort and IL-6. The potency differences correlate with their respective affinity for the type I receptor but not with that of the IL-1 type II receptor. It is concluded that IL-1beta induced ACTH, cort and IL-6 production is mediated by interleukin 1 type I receptors.

  9. Relationship of Soluble RAGE with Insulin Resistance and Beta Cell Function during Development of Type 2 Diabetes Mellitus.

    Science.gov (United States)

    Biswas, Subrata Kumar; Mohtarin, Sabreena; Mudi, Sonchita Rani; Anwar, Taznuva; Banu, Laila Anjuman; Alam, Sheikh Md Khorshed; Fariduddin, Md; Arslan, M Iqbal

    2015-01-01

    This study examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE) alter in prediabetes and correlate with insulin resistance (IR) and beta cell function in prediabetes and newly diagnosed type 2 diabetes mellitus (T2DM). Subjects without previous history of diabetes were recruited and grouped as control, prediabetes, and newly diagnosed T2DM. The control subjects (n = 40) and people with prediabetes (n = 52) and diabetes (n = 66) were similar in terms of age, sex, BMI, systolic and diastolic BP, and fasting insulin level. HOMA-IR was found significantly higher in people with diabetes than control subjects (p diabetes (p < 0.001) compared to control subjects and people with prediabetes. However, serum sRAGE levels did not show any significant alteration in people with prediabetes compared to control subjects. Moreover, univariate and multivariate analyses did not identify any significant correlation and statistical association of sRAGE with HOMA-IR and HOMA-%B in people with prediabetes and newly diagnosed T2DM. Our data suggest that serum sRAGE levels do not alter in people with prediabetes compared to control subjects and do not correlate or associate with IR and beta cell function during development of T2DM.

  10. Gene expression profiles of Beta-cell enriched tissue obtained by laser capture microdissection from subjects with type 2 diabetes.

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    Lorella Marselli

    Full Text Available BACKGROUND: Changes in gene expression in pancreatic beta-cells from type 2 diabetes (T2D should provide insights into their abnormal insulin secretion and turnover. METHODOLOGY/PRINCIPAL FINDINGS: Frozen sections were obtained from cadaver pancreases of 10 control and 10 T2D human subjects. Beta-cell enriched samples were obtained by laser capture microdissection (LCM. RNA was extracted, amplified and subjected to microarray analysis. Further analysis was performed with DNA-Chip Analyzer (dChip and Gene Set Enrichment Analysis (GSEA software. There were changes in expression of genes linked to glucotoxicity. Evidence of oxidative stress was provided by upregulation of several metallothionein genes. There were few changes in the major genes associated with cell cycle, apoptosis or endoplasmic reticulum stress. There was differential expression of genes associated with pancreatic regeneration, most notably upregulation of members of the regenerating islet gene (REG family and metalloproteinase 7 (MMP7. Some of the genes found in GWAS studies to be related to T2D were also found to be differentially expressed. IGF2BP2, TSPAN8, and HNF1B (TCF2 were upregulated while JAZF1 and SLC30A8 were downregulated. CONCLUSIONS/SIGNIFICANCE: This study made possible by LCM has identified many novel changes in gene expression that enhance understanding of the pathogenesis of T2D.

  11. Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes

    DEFF Research Database (Denmark)

    Greenbaum, Carla J; Mandrup-Poulsen, Thomas; McGee, Paula Friedenberg

    2008-01-01

    OBJECTIVE: Beta-cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). The Type 1 Diabetes TrialNet Research Group and the European C-peptide Trial (ECPT) Stud...

  12. Occurrence of thymosin beta4 in human breast cancer cells and in other cell types of the tumor microenvironment

    DEFF Research Database (Denmark)

    Larsson, L.-I.; Holck, Susanne

    2007-01-01

    that there is a considerable heterogeneity in the cellular distribution of thymosin beta4 in breast cancer. In most tumors examined, cancer cells showed low or intermediate reactivity for thymosin beta4, whereas leukocytes and macrophages showed intense reactivity. In addition, endothelial cells showed variable reactivity...... the tumor microenvironment produce thymosin beta4 and that such expression varies from tumor to tumor. Such heterogeneity of expression should be taken into account when the role of thymosin beta4 in tumor biology is assessed....

  13. Not All Beta-Blockers Are Equal in the Management of Long QT Syndrome Types 1 and 2

    NARCIS (Netherlands)

    Chockalingam, Priya; Crotti, Lia; Girardengo, Giulia; Johnson, Jonathan N.; Harris, Katy M.; van der Heijden, Jeroen F.; Hauer, Richard N. W.; Beckmann, Britt M.; Spazzolini, Carla; Rordorf, Roberto; Rydberg, Annika; Clur, Sally-Ann B.; Fischer, Markus; van den Heuvel, Freek; Kaeaeb, Stefan; Blom, Nico A.; Ackerman, Michael J.; Schwartz, Peter J.; Wilde, Arthur A. M.

    2012-01-01

    Objectives The purpose of this study was to compare the efficacy of beta-blockers in congenital long QT syndrome (LQTS). Background Beta-blockers are the mainstay in managing LQTS. Studies comparing the efficacy of commonly used beta-blockers are lacking, and clinicians generally assume they are equ

  14. Transforming growth factor-beta 1 specifically induce proteins involved in the myofibroblast contractile apparatus

    DEFF Research Database (Denmark)

    Malmström, Johan; Lindberg, Henrik Have; Lindberg, Claes

    2004-01-01

    ) alters protein expression of cytoskeletal-associated proteins. Metabolic labeling of cell cultures by [(35)S]methionine, followed by protein separation on two-dimensional gel electrophoresis, displayed approximately 2500 proteins in the pI interval of 3-10. Treatment of TGF-beta(1) led to specific spot...... expression of alpha-SMA and may participate in the formation of stress fibers, cell contractility, and cell spreading characterizing the myofibroblasts phenotype....

  15. Serum endothelin-1 and transforming growth factor-beta levels in the newborns with respiratory distress.

    Science.gov (United States)

    Benzer, Derya; Aygun, A Denizmen; Godekmerdan, Ahmet; Kurt, A Nese Citak; Akarsu, Saadet; Yilmaz, Erdal

    2006-01-01

    The purpose of this present study was to evaluate the serum levels of ET-1 and TGF-beta in the newborns with respiratory distress. In this study, newborns with respiratory distress hospitalized into the Newborn Intensive Care Unit were included. The highest values of ET-1 and TGF-beta were obtained from newborns with diagnosis as meconium aspiration syndrome (5.70 +/- 5.87 pg/mL and 3.75 +/- 1.94 pg/mL, resp) in the sample obtained in the first six hours after birth, and these are statistically different from control group (P newborns with respiratory distress syndrome (3.37 +/- 1.59 pg/mL and 2.05 +/- 0.98 pg/mL, resp). After oxygen treatment, ET-1 values obtained in the first six hours of life were decreased regularly in the following days (P respiratory distress of newborns, the investigation of ET-1 and TGF-beta levels is meaningful. The ET-1 levels investigated in the first six hours is more useful in determining the prognosis, and repeating ET-1 levels in the following days is more meaningful to determine clinical response.

  16. Up and Down Expression of Androgen Receptor,Estrogen Receptor beta and Platelet Derived Growth Factor beta by Testosterone in Aortic Vascular Smooth Muscle Tissues

    Institute of Scientific and Technical Information of China (English)

    Wu Saizhu; Lv Hongsong; Zhou Kexiang; Sun Fei; Ma Rui; Zheng Hua; Wei Heming; Rong Zhiyi

    2004-01-01

    Objectives To investigate the effects of testosterone enanthate(TE) on serum lipids and lipoproteins metabolism and the expression of androgen receptor ( AR), estrogen receptor beta ( ER -β) and platelet derived growth factor beta (PDGFR-β ) in aortic vascular smooth muscle tissues(VSMTs). Methods Forty aged male rats were randomly divided into 4 groups, group A (placebo group),group B (2.5 mg/kg intramuscular injection of TE once a week ), group C (5.0 mg/kg intramuscular injection of TE once a week ), group D ( 10.0 mg,/kg intramuscular injection of TE once a week). All animals were fed freely during 16 - week treatment periods. The expression of AR , ER - βand PDGFR - β were studied by Western bolt. Results Average serum LDL - C was lower in group D than that in group A ( p < 0.01 ).Compared with the other groups, average serum TC was also lower in group D ( p < 0.05). AR expression in aortic vascular smooth muscle tissues could be regulated by TE: 99.50 ± 21.74, 125.38 ± 28.68 and 101.98 ±15.42 for TE concentrations at 2.5 mg/kg, 5.0 mg/kgand 10.0 mg/kg, respectively , the expression of ER -β could be regulated by TE: 92.34 ± 18.68, 47.72 ±18.12, 82.13 ±23.50, and the expression of PDGFR -β could be regulated as well by TE: 219.70 ± 45.59,50.16 ± 9.72, 125.36 ± 15.74 ( Data for AR , ER - βand PDGFR - β protein band intensity were expressed with x ± s, with control group taken as 100).Conclusions This study indicates that androgens have significant effects on serum lipids and lipoprotein metabolism. Testosterone enanthate at 5.0 mg/kg can stimulate the expression of AR, but inhibite the expression of PDGFR. Testosterone enanthate at the concentrations of 5.0 mg/kg and 10.0 mg/kg can inhibite the expression of ER - β.

  17. KLF10, transforming growth factor-{beta}-inducible early gene 1, acts as a tumor suppressor

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    Song, Ki-Duk [Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921 (Korea, Republic of); Laboratory of Protein Engineering and Comparative Immunology, School of Agricultural Biotechnology, Seoul National University, Seoul 151-921 (Korea, Republic of); Kim, Duk-Jung [The Institute of Hankook Life Science, 7-9 Myungryun-dong, Jongno-gu, Seoul 110-521 (Korea, Republic of); Lee, Jong Eun [Department of Anatomy, College of Medicine, Yonsei University, Seoul 120-752 (Korea, Republic of); Yun, Cheol-Heui [Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921 (Korea, Republic of); Laboratory of Protein Engineering and Comparative Immunology, School of Agricultural Biotechnology, Seoul National University, Seoul 151-921 (Korea, Republic of); Lee, Woon Kyu, E-mail: wklee@inha.ac.kr [Laboratory of Developmental Genetics, School of Medicine, Inha University, Incheon 400-712 (Korea, Republic of); Brain Korea 21 Center for Advanced Medical Education, School of Medicine, Inha University, Incheon 400-712 (Korea, Republic of)

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer KLF10{sup -/-} mice exhibited accelerated papilloma development after DMBA/TPA treatment. Black-Right-Pointing-Pointer KLF10{sup -/-} keratinocytes showed increased proliferation and apoptosis. Black-Right-Pointing-Pointer KLF10{sup -/-} MEFs yielded more colonies than wild-type one with H-Ras transfection. Black-Right-Pointing-Pointer KLF10 dose-dependently activated p21{sup WAF1/CIP1} transcription. Black-Right-Pointing-Pointer KLF10 is a tumor suppressor and that it targets p21{sup WAF1/CIP1} transcription. -- Abstract: Krueppel-like factor 10 (KLF10) has been suggested to be a putative tumor suppressor. In the present study, we generated KLF10 deficient mice to explore this hypothesis in vivo. KLF10 deficient mice exhibited increased predisposition to skin tumorigenesis and markedly accelerated papilloma development after DMBA/TPA treatment. On the other hand, KLF10 deficient keratinocytes showed increased proliferation and apoptosis. In colony formation assays after oncogenic H-Ras transfection, KLF10 deficient mouse embryonic fibroblasts (MEFs) yielded more colonies than wild-type MEFs. Furthermore, KLF10 dose-dependently activated p21{sup WAF1/CIP1} transcription, which was independent of p53 and Sp1 binding sites in p21{sup WAF1/CIP1} promoter. This study demonstrates that KLF10 is a tumor suppressor and that it targets p21{sup WAF1/CIP1} transcription.

  18. Exercise and Beta-Glucan Consumption (Saccharomyces cerevisiae) Improve the Metabolic Profile and Reduce the Atherogenic Index in Type 2 Diabetic Rats (HFD/STZ).

    Science.gov (United States)

    Andrade, Eric Francelino; Lima, Andressa Ribeiro Veiga; Nunes, Ingrid Edwiges; Orlando, Débora Ribeiro; Gondim, Paula Novato; Zangeronimo, Márcio Gilberto; Alves, Fernando Henrique Ferrari; Pereira, Luciano José

    2016-12-17

    Physical activity and the ingestion of dietary fiber are non-drug alternatives commonly used as adjuvants to glycemic control in diabetic individuals. Among these fibers, we can highlight beta-glucans. However, few studies have compared isolated and synergic effects of physical exercise and beta-glucan ingestion, especially in type 2 diabetic rats. Therefore, we evaluated the effects beta-glucan (Saccharomyces cerevisiae) consumption, associated or not to exercise, on metabolic parameters of diabetic Wistar rats. The diabetes mellitus (DM) was induced by high-fat diet (HFD) associated with a low dose of streptozotocin (STZ-35 mg/kg). Trained groups were submitted to eight weeks of exercise in aquatic environment. In the last 28 days of experiment, animals received 30 mg/kg/day of beta-glucan by gavage. Isolated use of beta-glucan decreased glucose levels in fasting, Glycated hemoglobin (HbA1c), triglycerides (TAG), total cholesterol (TC), low-density lipoprotein (LDL-C), the atherogenic index of plasma. Exercise alone also decreased blood glucose levels, HbA1c, and renal lesions. An additive effect for reducing the atherogenic index of plasma and renal lesions was observed when both treatments were combined. It was concluded that both beta-glucan and exercise improved metabolic parameters in type 2 (HFD/STZ) diabetic rats.

  19. Exercise and Beta-Glucan Consumption (Saccharomyces cerevisiae Improve the Metabolic Profile and Reduce the Atherogenic Index in Type 2 Diabetic Rats (HFD/STZ

    Directory of Open Access Journals (Sweden)

    Eric Francelino Andrade

    2016-12-01

    Full Text Available Physical activity and the ingestion of dietary fiber are non-drug alternatives commonly used as adjuvants to glycemic control in diabetic individuals. Among these fibers, we can highlight beta-glucans. However, few studies have compared isolated and synergic effects of physical exercise and beta-glucan ingestion, especially in type 2 diabetic rats. Therefore, we evaluated the effects beta-glucan (Saccharomyces cerevisiae consumption, associated or not to exercise, on metabolic parameters of diabetic Wistar rats. The diabetes mellitus (DM was induced by high-fat diet (HFD associated with a low dose of streptozotocin (STZ—35 mg/kg. Trained groups were submitted to eight weeks of exercise in aquatic environment. In the last 28 days of experiment, animals received 30 mg/kg/day of beta-glucan by gavage. Isolated use of beta-glucan decreased glucose levels in fasting, Glycated hemoglobin (HbA1c, triglycerides (TAG, total cholesterol (TC, low-density lipoprotein (LDL-C, the atherogenic index of plasma. Exercise alone also decreased blood glucose levels, HbA1c, and renal lesions. An additive effect for reducing the atherogenic index of plasma and renal lesions was observed when both treatments were combined. It was concluded that both beta-glucan and exercise improved metabolic parameters in type 2 (HFD/STZ diabetic rats.

  20. Transforming growth factor Beta 3 is required for excisional wound repair in vivo.

    Directory of Open Access Journals (Sweden)

    Mark Le

    Full Text Available Wound healing is a complex process that relies on proper levels of cytokines and growth factors to successfully repair the tissue. Of particular interest are the members of the transforming growth factor family. There are three TGF-ß isoforms-TGF- ß 1, 2, and 3, each isoform showing a unique expression pattern, suggesting that they each play a distinct function during development and repair. Previous studies reported an exclusive role for TGF-ß 3 in orofacial development and a potent anti-scarring effect. However, the role of TGF- ß 3 in excisional wound healing and keratinocyte migration remains poorly understood. We tested the effect of TGF-ß 3 levels on excisional cutaneous wounds in the adult mouse by directly injecting recombinant TGF-ß 3 or neutralizing antibody against TGF-ß 3 (NAB in the wounds. Our results demonstrate that TGF-ß 3 does not promote epithelialization. However, TGF-ß 3 is necessary for wound closure as wounds injected with neutralizing antibody against TGF-ß 3 showed increased epidermal volume and proliferation in conjunction with a delay in keratinocyte migration. Wild type keratinocytes treated with NAB and Tgfb3-deficient keratinocytes closed an in vitro scratch wound with no delay, suggesting that our in vivo observations likely result from a paracrine effect.

  1. [Investigation of OXA type beta-lactamases and PFGE patterns in Acinetobacter baumannii strains resistant to carbapenems].

    Science.gov (United States)

    Keyik, Serafettin; Arslan, Uğur; Türk Dağı, Hatice; Seyhan, Tuba; Fındık, Duygu

    2014-10-01

    Acinetobacter baumannii is an important opportunistic and multidrug-resistant pathogen leading to nosocomial infections. Over the last 10 years, a significant and threatening increase in resistance to carbapenems, mainly due to the dissemination of class D beta-lactamases, has been reported in A.baumannii worldwide. The most common types of beta-lactamases causing carbapenem resistance in A.baumannii are the OXA-23, OXA-24, OXA-40, OXA-58 and OXA-143 type serine beta-lactamases. The aim of this study was to investigate the presence of OXA type beta-lactamases in carbapenem-resistant A.baumannii strains and the clonal relationship between the strains. A total of 105 non-duplicate carbapenem-resistant A.baumannii strains isolated from various clinical samples (68 blood, 18 bronchoalveolar lavage, 13 drainage, 3 urine, 2 cerebrospinal fluid and 1 catheter samples) in the Microbiology Laboratories of Selcuk University, Meram (2009-2012) and Selcuklu (2007-2008) Medical School Hospitals, were included in the study. The isolates were identified by conventional methods and Phoenix 100 BD (BD Diagnostic, USA) and Vitek II (bioMerieux, France) automated systems. Carbapenem susceptibility test was performed by Kirby-Bauer disk diffusion method according to the CLSI standards. bla(OXA 23-like), bla(OXA 24-like), bla(OXA 58-like) and bla(OXA 51-like) genes were amplified by multiplex PCR assay and clonal relatedness was investigated by pulsed-field gel electrophoresis (PFGE) using ApaI enzyme. The bla(OXA 51-like) gene was determined in all carbapenem-resistant A.baumannii isolates, while the bla(OXA 23-like) and bla(OXA 58-like) genes were detected in 46.6% and 53.3% of isolates, respectively. However bla(OXA 24-like) gene was not demonstrated in any isolates. bla(OXA 23-like) gene was determined in both Meram and Selcuklu Medical School hospitals, but bla(OXA 58-like) gene was detected only in Meram Medical School hospital. PFGE analysis of the isolates revealed 32 different

  2. Radiative Corrections to Light Neutrino Masses in Low Scale Type I Seesaw Scenarios and Neutrinoless Double Beta Decay

    CERN Document Server

    Lopez-Pavon, J; Petcov, S T

    2015-01-01

    We perform a detailed analysis of the one-loop corrections to the light neutrino mass matrix within low scale type I seesaw extensions of the Standard Model and their implications in experimental searches for neutrinoless double beta decay. We show that a sizable contribution to the effective Majorana neutrino mass from the exchange of heavy Majorana neutrinos is always possible, provided one requires a fine-tuned cancellation between the tree-level and one-loop contribution to the light neutrino masses. We quantify the level of fine-tuning as a function of the seesaw parameters and introduce a generalisation of the Casas-Ibarra parametrization of the neutrino Yukawa matrix, which easily allows to include the one-loop corrections to the light neutrino masses.

  3. Origin of archosaurian integumentary appendages: the bristles of the wild turkey beard express feather-type beta keratins.

    Science.gov (United States)

    Sawyer, Roger H; Washington, Lynette D; Salvatore, Brian A; Glenn, Travis C; Knapp, Loren W

    2003-06-15

    The discovery that structurally unique "filamentous integumentary appendages" are associated with several different non-avian dinosaurs continues to stimulate the development of models to explain the evolutionary origin of feathers. Taking the phylogenetic relationships of the non-avian dinosaurs into consideration, some models propose that the "filamentous integumentary appendages" represent intermediate stages in the sequential evolution of feathers. Here we present observations on a unique integumentary structure, the bristle of the wild turkey beard, and suggest that this non-feather appendage provides another explanation for some of the "filamentous integumentary appendages." Unlike feathers, beard bristles grow continuously from finger-like outgrows of the integument lacking follicles. We find that these beard bristles, which show simple branching, are hollow, distally, and express the feather-type beta keratins. The significance of these observations to explanations for the evolution of archosaurian integumentary appendages is discussed.

  4. Transcriptional profiling of type 1 diabetes genes on chromosome 21 in a rat beta-cell line and human pancreatic islets

    DEFF Research Database (Denmark)

    Bergholdt, R.; Karlsen, A.E.; Hagedorn, Peter;

    2007-01-01

    We recently finemapped a type 1 diabetes (T1D)-linked region on chromosome 21, indicating that one or more T1D-linked genes exist in this region with 33 annotated genes. In the current study, we have taken a novel approach using transcriptional profiling in predicting and prioritizing the most...... likely candidate genes influencing beta-cell function in this region. Two array-based approaches were used, a rat insulinoma cell line (INS-1alphabeta) overexpressing pancreatic duodenum homeobox 1 (pdx-1) and treated with interleukin 1beta (IL-1beta) as well as human pancreatic islets stimulated...... with a mixture of cytokines. Several candidate genes with likely functional significance in T1D were identified. Genes showing differential expression in the two approaches were highly similar, supporting the role of these specific gene products in cytokine-induced beta-cell damage. These were genes involved...

  5. Macrophage colony-stimulating factor augments beta-amyloid-induced interleukin-1, interleukin-6, and nitric oxide production by microglial cells.

    Science.gov (United States)

    Murphy, G M; Yang, L; Cordell, B

    1998-08-14

    In Alzheimer's disease (AD), a chronic cerebral inflammatory state is thought to lead to neuronal injury. Microglia, intrinsic cerebral immune effector cells, are likely to be key in the pathophysiology of this inflammatory state. We showed that macrophage colony-stimulating factor, a microglial activator found at increased levels in the central nervous system in AD, dramatically augments beta-amyloid peptide (betaAP)-induced microglial production of interleukin-1, interleukin-6, and nitric oxide. In contrast, granulocyte macrophage colony-stimulating factor, another hematopoietic cytokine found in the AD brain, did not augment betaAP-induced microglial secretory activity. These results indicate that increased macrophage colony-stimulating factor levels in AD could magnify betaAP-induced microglial inflammatory cytokine and nitric oxide production, which in turn could intensify the cerebral inflammatory state by activating astrocytes and additional microglia, as well as directly injuring neurons.

  6. Expression of transforming growth factor beta 1-related signaling proteins in irradiated vessels

    Energy Technology Data Exchange (ETDEWEB)

    Preidl, Raimund H.M.; Moebius, Patrick; Weber, Manuel; Neukam, Friedrich W.; Schlegel, Andreas; Wehrhan, Falk [University of Erlangen- Nuernberg, Department of Oral and Maxillofacial Surgery, Erlangen (Germany); University of Erlangen- Nuernberg, Erlangen (Germany); Amann, Kerstin [University of Erlangen- Nuernberg, Erlangen (Germany)

    2014-12-09

    Microvascular free tissue transfer is a standard method in head and neck reconstructive surgery. However, previous radiotherapy of the operative region is associated with an increased incidence in postoperative flap-related complications and complete flap loss. As transforming growth factor beta (TGF-β) 1 and galectin-3 are well known markers in the context of fibrosis and lectin-like oxidized low-density lipoprotein 1 (LOX-1) supports vascular atherosclerosis, the aim of this study was to evaluate the expression of TGF-β1 and related markers as well as LOX-1 in irradiated vessels. To evaluate the expression of galectin-3, Smad 2/3, TGF-β1, and LOX-1, 20 irradiated and 20 nonirradiated arterial vessels were used for immunohistochemical staining. We semiquantitatively assessed the ratio of stained cells/total number of cells (labeling index). Expression of galectin-3, Smad 2/3, and TGF-β1 was significantly increased in previously irradiated vessels compared with nonirradiated controls. Furthermore, LOX-1 was expressed significantly higher in irradiated compared with nonirradiated vessels. Fibrosis-related proteins like galectin-3, Smad 2/3, and TGF-β1 are upregulated after radiotherapy and support histopathological changes leading to vasculopathy of the irradiated vessels. Furthermore, postoperative complications in irradiated patients can be explained by increased endothelial dysfunction caused by LOX-1 in previously irradiated patients. Consequently, not only TGF-β1 but also galectin-3inhibitors may decrease complications after microsurgical tissue transfer. (orig.) [German] Der freie mikrovaskulaere Gewebetransfer gilt heute als fester Standard in der rekonstruktiven Kopf-Hals-Chirurgie. Es zeigte sich jedoch, dass im Falle einer stattgehabten Bestrahlung im Operationsgebiet mit einer erhoehten Rate an transplantatbezogenen Komplikationen gerechnet werden muss. Sowohl TGF-β1 als auch Galektin-3 sind bekannte Mediatoren in Bezug auf die Fibroseentstehung

  7. Lack of regulation of 11beta-hydroxysteroid dehydrogenase type 1 during short-term manipulation of GH in patients with hypopituitarism.

    Science.gov (United States)

    Sigurjonsdottir, Helga A; Andrew, Ruth; Stimson, Roland H; Johannsson, Gudmundur; Walker, Brian R

    2009-09-01

    Evidence from long-term clinical studies measuring urinary steroid ratios, and from in vitro studies, suggests that GH administered for longer than 2 months down-regulates 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), thereby reducing cortisol regeneration in liver and adipose tissue. We aimed to measure acute effects of GH on 11beta-HSD1 in liver and adipose tissue in vivo, including using a stable isotope tracer. Observational studies of GH withdrawal and reintroduction in patients with hypopituitarism. Twelve men with benign pituitary disease causing GH and ACTH deficiency on stable replacement therapy for >6 months were studied after GH withdrawal for 3 weeks, and after either placebo or GH injections were reintroduced for another 3 weeks. We measured cortisol kinetics during 9,11,12,12-(2)H(4)-cortisol (d4-cortisol) infusion, urinary cortisol/cortisone metabolite ratios, liver 11beta-HSD1 by appearance of plasma cortisol after oral cortisone, and 11beta-HSD1 mRNA levels in subcutaneous adipose biopsies. GH withdrawal and reintroduction had no effect on 9,12,12-[(2)H](3)-cortisol (d3-cortisol) appearance, urinary cortisol/cortisone metabolite ratios, initial appearance of cortisol after oral cortisone, or adipose 11beta-HSD1 mRNA. GH withdrawal increased plasma cortisol 30-180 min after oral cortisone, increased d4-cortisol clearance, and decreased relative excretion of 5alpha-reduced cortisol metabolites. In this setting, GH did not regulate 11beta-HSD1 rapidly in vivo in humans. Altered cortisol metabolism with longer term changes in GH may reflect indirect effects on 11beta-HSD1. These data do not suggest that glucocorticoid replacement doses need to be increased immediately after introducing GH therapy to compensate for reduced 11beta-HSD1 activity, although dose adjustment may be required in the longer term.

  8. Residual beta cell function in newly diagnosed type 1 diabetes after treatment with atorvastatin: the Randomized DIATOR Trial.

    Directory of Open Access Journals (Sweden)

    Stephan Martin

    Full Text Available BACKGROUND: Recent evidence suggests that the lipid-lowering agent atorvastatin is also a potent immunomodulator. The aim of this study was to investigate the possible effect of atorvastatin on the decline of residual beta cell function in recent-onset type 1 diabetes. METHODS AND FINDINGS: The randomised placebo-controlled Diabetes and Atorvastatin (DIATOR Trial included 89 patients with newly diagnosed type 1 diabetes and islet autoantibodies (mean age 30 years, 40% females, in 12 centres in Germany. Patients received placebo or 80 mg/d atorvastatin for 18 months. As primary outcome stimulated serum C-peptide levels were determined 90 min after a standardized liquid mixed meal. An intent-to-treat analysis was performed. Fasting and stimulated C-peptide levels were not significantly different between groups at 18 months. However, median fasting serum C-peptide levels dropped from baseline to 12 and 18 months in the placebo group (from 0. 34 to 0.23 and 0.20 nmol/l, p<0.001 versus a nonsignificant decline in the atorvastatin group (from 0.34 to 0.27 and 0.30 nmol/l, ns. Median stimulated C-peptide concentrations declined between baseline and 12 months (placebo from 0.89 to 0.71 nmol/l, atorvastatin from 0.88 to 0.73 nmol/l, p<0.01 each followed by a major loss by month 18 in the placebo group (to 0.48 nmol/l, p = 0.047 but not in the atorvastatin group (to 0.71 nmol/l, ns. Median levels of total cholesterol and C-reactive protein decreased in the atorvastatin group only (p<0.001 and p = 0.04. Metabolic control was similar between groups. CONCLUSIONS: Atorvastatin treatment did not significantly preserve beta cell function although there may have been a slower decline of beta-cell function which merits further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00974740.

  9. Job strain as a risk factor for type 2 diabetes

    DEFF Research Database (Denmark)

    Nyberg, Solja T; Fransson, Eleonor I; Heikkilä, Katriina;

    2014-01-01

    OBJECTIVE: The status of psychosocial stress at work as a risk factor for type 2 diabetes is unclear because existing evidence is based on small studies and is subject to confounding by lifestyle factors, such as obesity and physical inactivity. This collaborative study examined whether stress...... at work, defined as "job strain," is associated with incident type 2 diabetes independent of lifestyle factors. RESEARCH DESIGN AND METHODS: We extracted individual-level data for 124,808 diabetes-free adults from 13 European cohort studies participating in the IPD-Work Consortium. We measured job strain...... with baseline questionnaires. Incident type 2 diabetes at follow-up was ascertained using national health registers, clinical screening, and self-reports. We analyzed data for each study using Cox regression and pooled the study-specific estimates in fixed-effect meta-analyses. RESULTS: There were 3,703 cases...

  10. Increased cholesterol efflux from cultured fibroblasts to plasma from hypertriglyceridemic type 2 diabetic patients: roles of pre beta-HDL, phospholipid transfer protein and cholesterol esterification.

    Science.gov (United States)

    de Vries, R; Groen, A K; Perton, F G; Dallinga-Thie, G M; van Wijland, M J A; Dikkeschei, L D; Wolffenbuttel, B H R; van Tol, A; Dullaart, R P F

    2008-02-01

    We tested whether hypertriglyceridemia associated with type 2 diabetes mellitus is accompanied by alterations in pre beta-HDL, which are considered to be initial acceptors of cell-derived cholesterol, and by changes in the ability of plasma to promote cellular cholesterol efflux. In 28 hypertriglyceridemic and 56 normotriglyceridemic type 2 diabetic patients, and in 56 control subjects, we determined plasma lipids, HDL cholesterol and phospholipids, plasma pre beta-HDL and pre beta-HDL formation, phospholipid transfer protein (PLTP) activity, plasma cholesterol esterification (EST) and cholesteryl ester transfer (CET) and the ability of plasma to stimulate cholesterol efflux out of cultured human fibroblasts. HDL cholesterol and HDL phospholipids were lower, whereas plasma PLTP activity, EST and CET were higher in hypertriglyceridemic diabetic patients than in the other groups. Pre beta-HDL levels and pre beta-HDL formation were unaltered, although the relative amount of pre beta-HDL (expressed as % of total plasma apo A-I) was increased in hypertriglyeridemic diabetic patients. Cellular cholesterol efflux to plasma from hypertriglyceridemic diabetic patients was increased compared to efflux to normotriglyceridemic diabetic and control plasma, but efflux to normotriglyceridemic diabetic and control plasma did not differ. Multiple linear regression analysis demonstrated that cellular cholesterol efflux to plasma was positively and independently related to pre beta-HDL formation, PLTP activity and EST (multiple r=0.48), but not to the diabetic state. In conclusion, cholesterol efflux from fibroblasts to normotriglyceridemic diabetic plasma is unchanged. Efflux to hypertriglyceridemic diabetic plasma is enhanced, in association with increased plasma PLTP activity and cholesterol esterification. Unaltered pre beta-HDL formation in diabetic hypertriglyceridemia, despite low apo A-I, could contribute to maintenance of cholesterol efflux.

  11. Induction of transforming growth factor beta receptors following focal ischemia in the rat brain.

    Directory of Open Access Journals (Sweden)

    Gabriella Pál

    Full Text Available Transforming growth factor-βs (TGF-βs regulate cellular proliferation, differentiation, and survival. TGF-βs bind to type I (TGF-βRI and II receptors (TGF-βRII, which are transmembrane kinase receptors, and an accessory type III receptor (TGF-βRIII. TGF-β may utilize another type I receptor, activin-like kinase receptor (Alk1. TGF-β is neuroprotective in the middle cerebral artery occlusion (MCAO model of stroke. Recently, we reported the expression pattern of TGF-β1-3 after MCAO. To establish how TGF-βs exert their actions following MCAO, the present study describes the induction of TGF-βRI, RII, RIII and Alk1 at 24 h, 72 h and 1 mo after transient 1 h MCAO as well as following 24 h permanent MCAO using in situ hybridization histochemistry. In intact brain, only TGF-βRI had significant expression: neurons in cortical layer IV contained TGF-βRI. At 24 h after the occlusion, no TGF-β receptors showed induction. At 72 h following MCAO, all four types of TGF-β receptors were induced in the infarct area, while TGF-βRI and RII also appeared in the penumbra. Most cells with elevated TGF-βRI mRNA levels were microglia. TGF-βRII co-localized with both microglial and endothelial markers while TGF-βRIII and Alk1 were present predominantly in endothels. All four TGF-β receptors were induced within the lesion 1 mo after the occlusion. In particular, TGF-βRIII was further induced as compared to 72 h after MCAO. At this time point, TGF-βRIII signal was predominantly not associated with blood vessels suggesting its microglial location. These data suggest that TGF-β receptors are induced after MCAO in a timely and spatially regulated fashion. TGF-β receptor expression is preceded by increased TGF-β expression. TGF-βRI and RII are likely to be co-expressed in microglial cells while Alk1, TGF-βRII, and RIII in endothels within the infarct where TGF-β1 may be their ligand. At later time points, TGF-βRIII may also appear in glial cells

  12. Betting Against Beta

    DEFF Research Database (Denmark)

    Frazzini, Andrea; Heje Pedersen, Lasse

    .S. equities, 20 international equity markets, Treasury bonds, corporate bonds, and futures; (2) A betting-against-beta (BAB) factor, which is long leveraged low beta assets and short high-beta assets, produces significant positive risk-adjusted returns; (3) When funding constraints tighten, the return...

  13. Low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin increase transforming growth factor {beta} and cause myocardial fibrosis in marmosets (Callithrix jacchus)

    Energy Technology Data Exchange (ETDEWEB)

    Riecke, K.; Grimm, D.; Kossmehl, P.; Paul, M.; Stahlmann, R. [Inst. of Clinical Pharmacology and Toxicology, Benjamin Franklin Medical Center, Freie Univ. Berlin, Berlin (Germany); Shakibaei, M.; Schulze-Tanzil, G. [Inst. of Anatomy, Benjamin Franklin Medical Center, Freie Univ. Berlin, Berlin (Germany)

    2002-06-01

    Epidemiological studies have suggested an association between exposure to dioxins and cardiovascular morbidity and mortality. However, cardiotoxic effects of low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in animals have not been reported so far. We studied the hearts of male marmosets (Callithrix jacchus) after treatment with single subcutaneous doses of 1, 10 or 100 ng TCDD/kg body weight or vehicle (toluene/DMSO 1+2 v/v, 100 {mu}l/kg body weight). The animals were killed 2 or 4 weeks after treatment. Tissue samples of left ventricular myocardium were stained with picrosirius red and examined histologically along with quantitative image analysis. Extracellular matrix proteins were additionally analysed by western blotting. Monkeys showed no overt signs of toxicity nor did their relative heart weights differ significantly depending on treatment. Histology revealed an increase of picrosirius red-positive area above control values in 2 of 4 (1 ng TCDD/kg body weight), 6 of 12 (10 ng/kg) and 6 of 10 (100 ng/kg) marmosets. Western blotting confirmed these histological findings showing an increase of collagen, fibronectin and laminin in the hearts of TCDD-treated animals. Western blotting additionally showed an increased concentration of transforming growth factor {beta}1 (TGF-{beta}1) as well as TGF-{beta} receptor type I which could be a functional link to the effects on extracellular matrix. Our findings might explain the association of TCDD exposure with increased cardiovascular mortality observed in epidemiological studies and should stimulate further research on the role of changes in the extracellular matrix in the toxic effects of dioxins and related substances on other organs. (orig.)

  14. Type 2 diabetes in children: Clinical aspects and risk factors.

    Science.gov (United States)

    Rao, P V

    2015-04-01

    A strong link between obesity, insulin resistance, and metabolic syndrome has been reported with development of a new paradigm to type 2 diabetes mellitus (T2DM), with some evidence suggesting that beta-cell dysfunction is present before the onset of impaired glucose tolerance. Differentiating type 1 diabetes mellitus (T1DM) from T2DM is actually not very easy and there exists a number of overlapping characteristics. The autoantibody frequencies of seven antigens in T1DM patients may turn out to be actually having T2DM patients (pre-T2DM). T2DM patients generally have increased C-peptide levels (may be normal at time of diagnosis), usually no auto-antibodies, strong family history of diabetes, obese and show signs of insulin resistance (hypertension, acanthosis, PCOS). The American Academy of Paediatrics recommends lifestyle modifications ± metformin when blood glucose is 126-200 mg/dL and hemoglobin A1c (HbA1c) 200 mg/dL and HbA1c >8.5, with or without ketosis. Metformin is not recommended if the patient is ketotic, because this increases the risk of lactic acidosis. Metformin is currently the only oral hypoglycemic that has been approved for use in children. Knowing these subtle differences in mechanism, and knowing how to test patients for which mechanism (s) are causing their diabetes mellitus, may help us eventually tailor treatment programs on an individual basis.

  15. Type 2 diabetes in children: Clinical aspects and risk factors

    Directory of Open Access Journals (Sweden)

    P V Rao

    2015-01-01

    Full Text Available A strong link between obesity, insulin resistance, and metabolic syndrome has been reported with development of a new paradigm to type 2 diabetes mellitus (T2DM, with some evidence suggesting that beta-cell dysfunction is present before the onset of impaired glucose tolerance. Differentiating type 1 diabetes mellitus (T1DM from T2DM is actually not very easy and there exists a number of overlapping characteristics. The autoantibody frequencies of seven antigens in T1DM patients may turn out to be actually having T2DM patients (pre-T2DM. T2DM patients generally have increased C-peptide levels (may be normal at time of diagnosis, usually no auto-antibodies, strong family history of diabetes, obese and show signs of insulin resistance (hypertension, acanthosis, PCOS. The American Academy of Paediatrics recommends lifestyle modifications ± metformin when blood glucose is 126-200 mg/dL and hemoglobin A1c (HbA1c 200 mg/dL and HbA1c >8.5, with or without ketosis. Metformin is not recommended if the patient is ketotic, because this increases the risk of lactic acidosis. Metformin is currently the only oral hypoglycemic that has been approved for use in children. Knowing these subtle differences in mechanism, and knowing how to test patients for which mechanism (s are causing their diabetes mellitus, may help us eventually tailor treatment programs on an individual basis.

  16. Ulcerative enterocolitis in two goats associated with enterotoxin- and beta2 toxin-positive Clostridium perfringens type D.

    Science.gov (United States)

    Uzal, Francisco A; Fisher, Derek J; Saputo, Juliann; Sayeed, Sameera; McClane, Bruce A; Songer, Glenn; Trinh, Hien T; Fernandez Miyakawa, Mariano E; Gard, Sharon

    2008-09-01

    Enterotoxemia caused by Clostridium perfringens type D in sheep is believed to result from the action of epsilon toxin (ETX). However, the sole role of ETX in the intestinal changes of the acute and chronic forms of enterotoxemia in goats remains controversial, and the synergistic action of other C. perfringens toxins has been suggested previously. The current study examined 2 goats that were found dead without premonitory clinical signs. Gross lesions at necropsy consisted of multifocal fibrinonecrotic enterocolitis, edematous lungs, and excess pleural fluid. Histologically, there were multifocal fibrinonecrotic and ulcerative ileitis and colitis, edema of the colonic serosa, and proteinaceous interstitial edema of the lungs. Clostridium perfringens type D carrying the genes for enterotoxin (CPE) and beta2 toxin (CPB2) was cultured from intestinal content and feces of 1 of 2 goats, while C. perfringens type D CPB2-positive was isolated from the other animal. When multiple colonies of the primary isolations from both animals were tested by Western blot, most of the isolates expressed CPB2, and only a few isolates from the first case expressed CPE. Alpha toxin and ETX were detected in ileal and colonic contents and feces of both animals by antigen capture enzyme-linked immunosorbent assay. CPB2, but not CPE, was identified in the small and large intestines of both goats by immunohistochemistry. These findings indicate that CPB2 may have contributed to the necrotic changes observed in the intestine, possibly assisting ETX transit across the intestinal mucosa.

  17. Development of hormone-dependent prostate cancer models for the evaluation of inhibitors of 17beta-hydroxysteroid dehydrogenase type 3.

    Science.gov (United States)

    Day, Joanna M; Tutill, Helena J; Foster, Paul A; Bailey, Helen V; Heaton, Wesley B; Sharland, Christopher M; Vicker, Nigel; Potter, Barry V L; Purohit, Atul; Reed, Michael J

    2009-03-25

    17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) are responsible for the pre-receptor reduction/oxidation of steroids at the 17-position into active/inactive hormones, and the 15 known enzymes vary in their substrate specificity, localisation, and directional activity. 17beta-HSD Type 3 (17beta-HSD3) has been seen to be over-expressed in prostate cancer, and catalyses the reduction of androstenedione (Adione) to testosterone (T), which stimulates prostate tumour growth. Specific inhibitors of 17beta-HSD3 may have a role in the treatment of hormone-dependent prostate cancer and benign prostate hyperplasia, and also have potential as male anti-fertility agents. A 293-EBNA-based cell line with stable expression of transfected human 17beta-HSD3 was created and used to develop a whole cell radiometric TLC-based assay to assess the 17beta-HSD3 inhibitory potency of a series of compounds. STX2171 and STX2624 (IC(50) values in the 200-450nM range) were two of several active inhibitors identified. In similar TLC-based assays these compounds were found to be inactive against 17beta-HSD1 and 17beta-HSD2, indicating selectivity. A novel proof of concept model was developed to study the efficacy of the compounds in vitro using the androgen receptor positive hormone-dependent prostate cancer cell line, LNCaPwt, and its derivative, LNCaP[17beta-HSD3], transfected and selected for stable expression of 17beta-HSD3. The proliferation of the parental cell line was most efficiently stimulated by 5alpha-dihydrotestosterone (DHT), but the LNCaP[17beta-HSD3] cells were equally stimulated by Adione, indicating that 17beta-HSD3 efficiently converts Adione to T in this model. Adione-stimulated proliferation of LNCaP[17beta-HSD3] cells was inhibited in the presence of either STX2171 or STX2624. The compounds alone neither stimulated proliferation of the cells nor caused significant cell death, indicating that they are non-androgenic with low cytotoxicity. STX2171 inhibited Adione

  18. Role of LncRNA-activated by transforming growth factor beta in the progression of hepatitis C virus-related liver fibrosis.

    Science.gov (United States)

    Fu, Na; Niu, Xuemin; Wang, Yang; Du, Huijuan; Wang, Baoyu; Du, Jinghua; Li, Ya; Wang, Rongqi; Zhang, Yuguo; Zhao, Suxian; Sun, Dianxing; Qiao, Liang; Nan, Yuemin

    2016-08-01

    Long non-coding RNA (LncRNA)-activated by transforming growth factor-beta (LncRNA-ATB) is a key regulator of transforming growth factor-beta (TGF-β) signaling pathway, and is positively correlated with the development of liver cirrhosis and vascular invasion of hepatocellular carcinoma (HCC). However, the role of LncRNA-ATB in hepatitis C virus (HCV)-related liver fibrosis remains largely unknown. In the present study, we confirmed a high expression level of LncRNA-ATB in the liver tissues and plasma samples of patients with HCV-related hepatic fibrosis, and the plasma level of LncRNA-ATB was significantly correlated with liver fibrosis stages. Furthermore, increased expression level of LncRNA-ATB was also present in activated hepatic stellate cells (HSCs), and knockdown of LncRNA-ATB inhibited the expression of alpha-smooth muscle actin (α-SMA) and alpha-1 type I collagen (Col1A1). LncRNA-ATB was found to share the common miRNA responsive element of miR-425-5p with TGF-β type II receptor (TGF-βRII) and SMAD2. Ectopic expression of LncRNA-ATB in HSCs could upregulate the protein expression of TGF-βRII and SMAD2 by inhibiting the endogenous miR-425-5p. Moreover, overexpression of miR-425-5p could partly abrogate the expression of TGF-βRII and SMAD2 induced by LncRNA-ATB. Hence, we conclude that LncRNA-ATB promotes HCV-induced liver fibrogenesis by activating HSCs and increasing collagen I production through competitively binding to miR-425-5p. LncRNA-ATB may be a novel diagnostic biomarker and a potential therapeutic target for HCV-related hepatic fibrosis.

  19. HDL and LDL cholesterol significantly influence beta-cell function in type 2 diabetes mellitus

    NARCIS (Netherlands)

    Kruit, Janine K; Brunham, Liam R; Verchere, C Bruce; Hayden, Michael R

    2010-01-01

    PURPOSE OF REVIEW: Patients with type 2 diabetes mellitus (T2DM) display significant abnormalities in both LDL and HDL particles. Recent data suggest that these changes in lipoprotein particles could contribute to the pathogenesis of T2DM. In this review, we focus on these abnormalities and discuss

  20. Innovative Approaches to Treating Type 1 Diabetes Addressed in Beta-Cell Replacement Presentations

    Science.gov (United States)

    ... Starchy Vegetables Fats Alcohol What Can I Drink? Fruit Dairy Food Tips Eating Out Quick Meal Ideas Snacks Nutrient Content Claims Understanding Carbohydrates Types of Carbohydrates Carbohydrate Counting Make Your Carbs Count Glycemic Index Low-Calorie Sweeteners Sugar and Desserts Fitness Exercise & ...

  1. Whole-genome multilocus sequence typing of extended-spectrum-beta-lactamase-producing enterobacteriaceae

    NARCIS (Netherlands)

    Kluytmans-Van Den Bergh, Marjolein F Q; Rossen, John W A; Bruijning-Verhagen, Patricia C J; Bonten, Marc J M; Friedrich, Alexander W.; Vandenbroucke-Grauls, Christina M J E; Willems, Rob J L; Kluytmans, Jan A.J.W.

    2016-01-01

    Molecular typing has become indispensable in the detection of nosocomial transmission of bacterial pathogens and the identification of sources and routes of transmission in outbreak settings, but current methods are labor-intensive, are difficult to standardize, or have limited resolution. Whole-gen

  2. Whole-Genome Multilocus Sequence Typing of Extended-Spectrum-Beta-Lactamase-Producing Enterobacteriaceae

    NARCIS (Netherlands)

    Kluytmans-van den Bergh, Marjolein F. Q.; Rossen, John W. A.; Bruijning-Verhagen, Patricia C. J.; Bonten, Marc J. M.; Friedrich, Alexander W.; Vandenbroucke-Grauls, Christina M. J. E.; Willems, Rob J. L.; Kluytmans, Jan A. J. W.

    2016-01-01

    Molecular typing has become indispensable in the detection of nosocomial transmission of bacterial pathogens and the identification of sources and routes of transmission in outbreak settings, but current methods are labor-intensive, are difficult to standardize, or have limited resolution. Whole-gen

  3. Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonists on 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men.

    Science.gov (United States)

    Wake, Deborah J; Stimson, Roland H; Tan, Garry D; Homer, Natalie Z M; Andrew, Ruth; Karpe, Fredrik; Walker, Brian R

    2007-05-01

    In animals, peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARgamma agonists down-regulate 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA and activity in liver and adipose tissue, respectively, and PPARgamma agonists reduce ACTH secretion from corticotrope cells. Our objective was to test whether PPAR agonists alter cortisol secretion and peripheral regeneration by 11beta-HSD1 in humans and whether reduced cortisol action contributes to metabolic effects of PPARgamma agonists. Three randomized placebo-controlled crossover studies were conducted at a clinical research facility. Healthy men and patients with type 2 dia