No description available.

<p><strong><p>Bakgrund:</p>Den dominerande cancerformen hos män över 75 år är prostatacancer. Kosten har en påverkan på många sjukdomstillstånd och på senare tid har man undersökt misstankarna kring om höga nivåer av IGF-1 kan öka risken för att utveckla prostatacancer. IGF-1 finns naturligt i kroppen men hormonet finns bland annat också i vissa livsmedel så som mejeriprodukter. <strong><p>Syfte:</p>Att granska tillgänglig evidens gällande samband mellan höga nivåer av IGF-1 och prostatacancer, samt att om ett samband går att finna, undersöka om en kostrekommendation kan göras för att sänka nivåerna av detta hormon i kroppen och på så vis minska risken för utveckling av prostatacancer. <strong><p>Metod:</p>Systematisk litteraturstudie. <strong><p>Resultat:</p>Det finns studier som talar för och emot ett samband mellan höga nivåer av IGF-1 och ökad risk för att drabbas av prostatacancer. Dock belyser samtliga studierna vikten av fortsatt granskning inom området för att helt kunna fastställa ett eventuellt samband. <strong><p>Slutsats:</p>Det krävs fler studier för att fastställa ett samband mellan höga nivåer av IGF-1 och ökad risk för prostatacancer. I nuläget anser författarna att det inte går att göra en kostrekommendation där man har för avsikt att sänka nivåerna av IGF-1 i serum på grund av olika presenterade studieresultat. </strong></strong></strong></strong></strong></p>

Increased circulating levels of glucocorticoids observed in many catabolic conditions play a major role in the induction of muscle atrophy. Indeed, inhibition of glucocorticoid action by glucocorticoid receptor antagonist attenuates and, in some cases, abolishes muscle atrophy. Circulating and tissue levels of IGF-I, a growth factor that stimulates the development of muscle mass, are frequently reduced in response to glucocorticoids. This decline could therefore trigger muscle atrophy in catabolic conditions. Indeed, systemic administration of IGF-I prevents glucocorticoid-induced muscle atrophy. However, use of systemic IGF-I administration is limited by its hypoglycemic and cardiac hypertrophic actions. Moreover, local IGF-I seems to play a more important role in the regulation of muscle mass than systemic IGF-I. Therefore, to limit loss of muscle mass observed in catabolic states, IGF-I administration must mimic as close as possible the autocrine production of IGF-I. The aim of this thesis was to investigate whether the restoration of IGF-I muscle content could reverse muscle atrophy induced by glucocorticoids. In this work we have tested the hypothesis that the local decrease in muscle IGF-I content might be responsible for the muscular atrophy induced by glucocorticoids. In our work, we have demonstrated that localized overexpression of IGF-I by gene electrotransfer prevents muscle atrophy in glucocorticoid-treated rats. High rate of fiber transfection and long term gene expression were obtained by combining multiple injection sites of DNA with electroporation. Human IGF-I gene electrotransfer using this optimised protocol resulted in increased muscle IGF-I mRNA and protein levels together with prevention of loss of skeletal muscle mass. Furthermore, alterations in the Akt/GSK-3â/â-catenin signaling pathway caused by glucocorticoids were prevented by local IGF-I gene overexpression. Finally, muscle overexpression of caAkt, dnGSK-3b and ÄNb-catenin was sufficient to mimic the anti-atrophic effect of IGF-I supporting the role of this signalling pathway in muscle atrophy caused by glucocorticoids. Taken together, our results show, for the first time in vivo, the role of the IGF-I/Akt/GSK-3b/b-catenin pathway in the skeletal muscle atrophy caused by glucocorticoids. In conclusion, our work highlights the crucial role of decreased muscle IGF-I in glucocorticoid-induced muscle atrophy. Indeed, the data presented in this thesis support the fact that the atrophic action of glucocorticoids is in part due to the downregulation of IGF-I, leading to the inhibition of its signalling pathways while restoration of muscle IGF-I levels is able to counteract totally muscle atrophy.

Background: Different types of cardiomyopathies are associated with variable hypertrophic response. A number of growth factors are thought to play a role in pathologic cardiac remodeling. Aims: We compared the modulation of the TGF-ƓÒ superfamily and IGF-1 signaling pathways and their target genes, the cell cycle regulatory proteins in tachycardia-induced dilated cardiomyopathy, a model with no detectable hypertrophy and in ischemic cardiomyopathy, a model with a marked hypertrophic reaction. Methods: In the first study, endomyocardial biopsies were obtained weekly in 15 dogs, during the development of tachycardiomyopaty. Genes involved in the myostatin-TGF-ƓÒ-Activin-A/Smad signaling pathway, p21 and cyclin D were quantified and correlated to echocardiographic measures of hypertrophy. In the second study, myocardial tissue samples were obtained in 8 dogs with a healed myocardial infarction, in 8 dogs with heart failure induced by overpacing and in 7 healthy dogs. We measured gene expression of IGF-1, its receptor (IGF-1R) and cyclins A, B, D1, D2, D3 and E and correlated them to the level of hypertrophy. Results: Tachycardiomyopathy was characterized by chambers dilation with no identifiable hypertrophy. Ischemic cardiomyopathy was characterized by eccentric hypertrophy. In tachycardiomyopathy, Activin-A mRNA was 4-fold higher than at baseline. Smad7 was overexpressed in severe heart failure; p21, a direct target gene of the Smad pathway was upregulated 8-fold and cyclin D1 was down-regulated. In that model, IGF-1 was overexpressed but neither IGF-1R nor any of the cyclins studied. In ischemic cardiomyopathy, IGF-1, IGF-R, and cyclins B, D1, D3 and E gene expression were upregulated. In tachycardiomyopathy, Activin-A and p21 were inversely correlated to the thickness of the interventricular septum. In normal dogs and in the both models of cardiomyopathy, IGF-1R was correlated to the thickness of the interventricular septum and to cyclins. Conclusions: Taken together, these results agree with the notion that Activin-A, IGF and cyclins are involved in the modulation of hypertrophic response observed in cardiomyopathies.

Bakgrund: Den dominerande cancerformen hos män över 75 år är prostatacancer. Kosten har en påverkan på många sjukdomstillstånd och på senare tid har man undersökt misstankarna kring om höga nivåer av IGF-1 kan öka risken för att utveckla prostatacancer. IGF-1 finns naturligt i kroppen men hormonet finns bland annat också i vissa livsmedel så som mejeriprodukter. Syfte: Att granska tillgänglig evidens gällande samband mellan höga nivåer av IGF-1 och prostatacancer, samt att om ett samband går att finna, undersöka om en kostrekommendation kan göras för att sänka nivåerna av detta hormon i kroppen och på så vis minska risken för utveckling av prostatacancer. Metod: Systematisk litteraturstudie. Resultat: Det finns studier som talar för och emot ett samband mellan höga nivåer av IGF-1 och ökad risk för att drabbas av prostatacancer. Dock belyser samtliga studierna vikten av fortsatt granskning inom området för att helt kunna fastställa ett eventuellt samband. Slutsats: Det krävs fler studier för att fastställa ett samband mellan höga nivåer av IGF-1 och ökad risk för prostatacancer. I nuläget anser författarna att det inte går att göra en kostrekommendation där man har för avsikt att sänka nivåerna av IGF-1 i serum på grund av olika presenterade studieresultat.

No description available.

No description available.

Skeletal muscle regeneration involves a tightly regulated coordination of cellular and signaling events to remodel and repair the site of injury. When this coordination is perturbed, the regenerative process is impaired. The expression of insulin-like growth factor-I (IGF-I) is robust in the typical muscle regenerative program, promoting cell survival and increasing myoblast activity. In this project, we found that severely depressed IGF-I expression and intracellular signaling in aged skeletal muscle coincided with impaired regeneration from ischemia/reperfusion (I/R). To hasten muscle regeneration, we developed the PEGylated fibrin gel (PEG-Fib) system as a means to intramuscularly deliver IGF-I in a controlled manner to injured muscle. This strategy resulted in greatly improved muscle function and histological assessment following 14 days of reperfusion, which are likely mediated by improved myofiber survival. Recent evidence suggests macrophages (MPs) are responsible for the upregulation of IGF-I following injury, therefore we developed a rapid, reproducible, and cost-effective model of investigating MP profiles in injured muscle via flow cytometry. Using information gathered from this model, we found that increasing the number of a non-inflammatory MP population improves the recovery of muscle from I/R. These data demonstrate that immunomodulatory therapies have the potential to greatly improve the recovery of skeletal muscle from injury. / text

Thioredoxin-1 (Trx-1) is a redox protein that is overexpressed in many tumors where it is associated with tumor growth, inhibited apoptosis and decreased patient survival. Through redox reactions, Trx-1 is able to reduce a number of proteins including transcription factors. Sp1 activation has been implicated in the regulation of many genes involved in cellular growth and survival and its overexpression in certain cancer correlates with decreased patient survival. We demonstrate that Trx-1 is able to activate Sp1 in a redox dependent manner. Trx-1 overexpression increases Sp1 transactivation and DNA binding whereas a redox inactive Trx-1 has no effect on Sp1 DNA binding.Sp1 has been implicated in vascular endothelial growth factor regulation and we have shown that Trx-1 expression results in increased hypoxic VEGF expression and increased tumor permeability in vivo. Trx-1 overexpression results in an increase in VEGF expression that is dependent upon Sp1, as inhibition of Sp1 expression with siRNA prevented the induction of VEGF expression by Trx-1. These results suggest that Trx-1 increases VEGF expression under normoxic conditions through a redox dependent increase in the DNA binding of the Sp1 transcription factor. VEGF regulation by Sp1 could increase angiogenesis in relatively perfused areas contributing to the stimulation of tumor growth by Trx-1.We hypothesized that Trx-1 regulation of Sp1 may be part of the mechanism of Trx-1 induction of cellular growth. Sp1 regulates many genes involved in cellular growth including epidermal growth factor receptor (EGFR) and insulin-like growth factor I receptor (IGF-IR). These two growth factor receptors are important for cellular growth and have been shown to be important therapeutic targets for cancer treatment. We report that treatment with the Trx-1 inhibitor PX-12 results in decreased Sp1 DNA binding as well as decreased Sp1 activation and transactivation of VEGF, EGFR, and IGF-IR. These results indicate that Trx-1 promotes cellular growth and survival, in part, through the redox regulation of Sp1 responsive growth genes EGFR and IGF-IR. Inhibition of Trx-1, via PX-12, results in a decrease in EGFR and IGF-IR expression and suggests a new mechanism by which Trx-1 inhibition is clinically effective for treating cancer.

Diss. (sammanfattning) Stockholm : Univ., 2004. / Härtill 4 uppsatser.