| 1. |
- Bellomo, Claudia, et al.
(författare)
-
Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma
- 2018
-
Ingår i: Cell Death and Differentiation. - : Springer Science and Business Media LLC. - 1350-9047 .- 1476-5403. ; 25:5, s. 885-903
-
Tidskriftsartikel (refereegranskat)abstract
- Understanding the complexity of changes in differentiation and cell survival in hepatocellular carcinoma (HCC) is essential for the design of new diagnostic tools and therapeutic modalities. In this context, we have analyzed the crosstalk between transforming growth factor β (TGFβ) and liver X receptor α (LXRα) pathways. TGFβ is known to promote cytostatic and pro-apoptotic responses in HCC, and to facilitate mesenchymal differentiation. We here demonstrate that stimulation of the nuclear LXRα receptor system by physiological and clinically useful agonists controls the HCC response to TGFβ. Specifically, LXRα activation antagonizes the mesenchymal, reactive oxygen species and pro-apoptotic responses to TGFβ and the mesenchymal transcription factor Snail mediates this crosstalk. In contrast, LXRα activation and TGFβ cooperate in enforcing cytostasis in HCC, which preserves their epithelial features. LXRα influences Snail expression transcriptionally, acting on the Snail promoter. These findings propose that clinically used LXR agonists may find further application to the treatment of aggressive, mesenchymal HCCs, whose progression is chronically dependent on autocrine or paracrine TGFβ.
|
|
| 2. |
- Carthy, Jon M., et al.
(författare)
-
Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation
- 2016
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Plasticity in epithelial tissues relates to processes of embryonic development, tissue fibrosis and cancer progression. Pharmacological modulation of epithelial transitions during disease progression may thus be clinically useful. Using human keratinocytes and a robotic high-content imaging platform, we screened for chemical compounds that reverse transforming growth factor beta (TGF-beta)-induced epithelial-mesenchymal transition. In addition to TGF-beta receptor kinase inhibitors, we identified small molecule epithelial plasticity modulators including a naturally occurring hydroxysterol agonist of the liver X receptors (LXRs), members of the nuclear receptor transcription factor family. Endogenous and synthetic LXR agonists tested in diverse cell models blocked alpha-smooth muscle actin expression, myofibroblast differentiation and function. Agonist-dependent LXR activity or LXR overexpression in the absence of ligand counteracted TGF-beta-mediated myofibroblast terminal differentiation and collagen contraction. The protective effect of LXR agonists against TGF-beta-induced pro-fibrotic activity raises the possibility that anti-lipidogenic therapy may be relevant in fibrotic disorders and advanced cancer.
|
|
| 3. |
- Chou, Wan-Chih, et al.
(författare)
-
Mechanism of a transcriptional cross talk between transforming growth factor-beta-regulated Smad3 and Smad4 proteins and orphan nuclear receptor hepatocyte nuclear factor-4
- 2003
-
Ingår i: Molecular Biology of the Cell. - 1059-1524 .- 1939-4586. ; 14:3, s. 1279-1294
-
Tidskriftsartikel (refereegranskat)abstract
- We have shown previously that the transforming growth factor-beta (TGFbeta)-regulated Sma-Mad (Smad) protein 3 and Smad4 proteins transactivate the apolipoprotein C-III promoter in hepatic cells via a hormone response element that binds the nuclear receptor hepatocyte nuclear factor 4 (HNF-4). In the present study, we show that Smad3 and Smad4 but not Smad2 physically interact with HNF-4 via their Mad homology 1 domains both in vitro and in vivo. The synergistic transactivation of target promoters by Smads and HNF-4 was shown to depend on the specific promoter context and did not require an intact beta-hairpin/DNA binding domain of the Smads. Using glutathione S-transferase interaction assays, we established that two regions of HNF-4, the N-terminal activation function 1 (AF-1) domain (aa 1-24) and the C-terminal F domain (aa 388-455) can mediate physical Smad3/HNF-4 interactions in vitro. In vivo, Smad3 and Smad4 proteins enhanced the transactivation function of various GAL4-HNF-4 fusion proteins via the AF-1 and the adjacent DNA binding domain, whereas a single tyrosine to alanine substitution in AF-1 abolished coactivation by Smads. The findings suggest that the transcriptional cross talk between the TGFbeta-regulated Smads and HNF-4 is mediated by specific functional domains in the two types of transcription factors. Furthermore, the specificity of this interaction for certain target promoters may play an important role in various hepatocyte functions, which are regulated by TGFbeta and the Smads.
|
|
| 4. |
- Grüner Sveälv, Bente, 1956, et al.
(författare)
-
Benefit of warm water immersion on biventricular function in patients with chronic heart failure
- 2009
-
Ingår i: Cardiovasc Ultrasound. - : Springer Science and Business Media LLC. - 1476-7120 .- 1476-7120. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Regular physical activity and exercise are well-known cardiovascular protective factors. Many elderly patients with heart failure find it difficult to exercise on land, and hydrotherapy (training in warm water) could be a more appropriate form of exercise for such patients. However, concerns have been raised about its safety.The aim of this study was to investigate, with echocardiography and Doppler, the acute effect of warm water immersion (WWI) and effect of 8 weeks of hydrotherapy on biventricular function, volumes and systemic vascular resistance. A secondary aim was to observe the effect of hydrotherapy on brain natriuretic peptide (BNP). METHODS: Eighteen patients [age 69 +/- 8 years, left ventricular ejection fraction 31 +/- 9%, peakVO2 14.6 +/- 4.5 mL/kg/min] were examined with echocardiography on land and in warm water (34 degrees C).Twelve of these patients completed 8 weeks of control period followed by 8 weeks of hydrotherapy twice weekly. RESULTS: During acute WWI, cardiac output increased from 3.1 +/- 0.8 to 4.2 +/- 0.9 L/min, LV tissue velocity time integral from 1.2 +/- 0.4 to 1.7 +/- 0.5 cm and right ventricular tissue velocity time integral from 1.6 +/- 0.6 to 2.5 +/- 0.8 cm (land vs WWI, p < 0.0001, respectively). Heart rate decreased from 73 +/- 12 to 66 +/- 11 bpm (p < 0.0001), mean arterial pressure from 92 +/- 14 to 86 +/- 16 mmHg (p < 0.01), and systemic vascular resistance from 31 +/- 7 to 22 +/- 5 resistant units (p < 0.0001).There was no change in the cardiovascular response or BNP after 8 weeks of hydrotherapy. CONCLUSION: Hydrotherapy was well tolerated by all patients. The main observed cardiac effect during acute WWI was a reduction in heart rate, which, together with a decrease in afterload, resulted in increases in systolic and diastolic biventricular function. Although 8 weeks of hydrotherapy did not improve cardiac function, our data support the concept that exercise in warm water is an acceptable regime for patients with heart failure.
|
|
| 5. |
- Kardassis, Dimitris
(författare)
-
Cardiovascular structure and function in obesity. The impact of body composition, sleep apnea and sustained weight loss
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Obesity is associated with disturbances in cardiovascular structure and function varying along with the degree of fatness, but the mechanisms underlying this co-variation are unclear. Short-term weight loss appears to have favourable effects on the cardiovascular system, but whether such improvements are maintained in the long run is unknown. Aims: To study how body composition, fat distribution and obstructive sleep apnoea relate to cardiovascular structure and function and to evaluate the effects of long-term sustained weight loss on the heart and vascular system. Methods: At the 10-year follow-up of the Swedish obese subjects (SOS) study cohort we identified 44 obese patients, who following bariatric surgery had displayed 10-year sustained weight losses (surgery group, BMI 31.5 kg/m2) and 44 matched obese patients, who during the same time period had maintained stable weight (obese group, BMI 42.5 kg/m2). We also included 44 matched subjects with normal weight (lean group, BMI 24.4 kg/m2). All study participants were evaluated with echocardiography, carotid ultrasonography, computed tomography, dual-energy X-ray absorptiometry (DXA) and analysis of blood tests. In addition, 19 patients from the surgery group and 20 from the obese group were examined with polysomnography. Results: As compared with obese controls, the surgery group showed lower left ventricular end-diastolic volume (87±12 vs. 114±24 ml, p<0.001), wall thickness (0,79±0.12 vs. 0,93±0.19 cm, p<0.001) and mass (158±21 vs. 201±22 g, p<0.01), and also improved estimates of systolic (SMV 10,6±1.0 vs. 9.3±1.6 cm/s, p<0.01) and diastolic (E/A ratio 1.24±1.10 vs. 1.05±0.20, p<0.01) left ventricular function. Further, surgery patients had lower apnoea hypopnoea index (20±22 vs. 38±28 n/h, p<0.05) and inflammatory activity (hsCRP 2.3±3.0 vs. 7.2±5.0 mg/L, p<0.001) than obese controls. Lumen diameter, intima-media thickness and total plaque area in the carotid artery did not, however, differ between the surgery and obese groups. In forward stepwise multivariate analysis including all subjects (n=132), stroke volume, left ventricular cavity size and carotid artery lumen diameter were mainly predicted by lean body mass, whereas blood pressure, left ventricular wall thickness and carotid artery intima-media thickness were more influenced by visceral adipose tissue. In multiple regression analyses including subjects examined with polysomnography (n=39) and controlling for BMI, the AHI remained independently associated with estimates of inflammation and diastolic dysfunction. Conclusions: Body composition and fat distribution are of importance with respect to cardiovascular structure and function in obesity. Whereas lean body mass determines stroke volume, left ventricular cavity size and carotid artery diameter, visceral adipose tissue is more relatedto blood pressure, left ventricular wall thickness and carotid artery intima-media thickness. Patients with sustained weight loss after bariatric surgery display lower left ventricular mass, enhanced cardiac function, less severe sleep apnoea and reduced inflammatory activity as compared to weight stable obese counterparts, but not less premature carotid artery atherosclerosis. Sleep apnoea that persist despite obesity intervention appears to limit the beneficial effect of weight loss on cardiac performance and inflammation.
|
|
| 6. |
|
|
| 7. |
- Kardassis, Dimitris, et al.
(författare)
-
Control of transforming growth factor beta signal transduction by small GTPases
- 2009
-
Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 276:11, s. 2947-2965
-
Forskningsöversikt (refereegranskat)abstract
- The integrated roles of small GTPases in executing the transforming growth factor beta (TGFbeta) signaling pathway have attracted increasing attention in recent years. In this review, we summarize recent findings on TGFbeta signaling during receptor endocytosis, Smad trafficking and actin cytoskeleton remodeling, and emphasize the role of small GTPases in these processes. First, we give an overview of the different endocytic routes taken by TGFbeta receptors, their impact on active TGFbeta signaling versus degradation and their regulation by the small GTPases Rab, RalA/Ral-binding protein 1 and Rap2. Second, we focus on the mechanisms and regulation of Smad trafficking in the cytoplasm, through the nuclear pores and into the nucleus, and the contribution of Ran GTPase to these events. Third, we summarize the role of Rho small GTPases in early and late cytoskeleton remodeling in various cell models and diseases, and the positive and negative cross-talk between Rho GTPases and the TGFbeta/Smad pathway. The biological significance of this exciting research field, the perspectives and critical open questions are discussed.
|
|
| 8. |
- Kardassis, Dimitris, et al.
(författare)
-
Impact of body composition, fat distribution and sustained weight loss on cardiac function in obesity.
- 2012
-
Ingår i: International Journal of Cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 159:2, s. 128-133
-
Tidskriftsartikel (refereegranskat)abstract
- Background Obesity is associated with alterations in left ventricular function varying along with the degree of fatness, but the mechanisms underlying this co-variation are not clear. In a case–control study we examined how sustained weight losses affect cardiac function and report on how body composition and fat distribution relate to the left ventricular performance. Methods At the 10-year follow-up of the Swedish obese subjects (SOS) study cohort we identified 44 patients with sustained weight losses after bariatric surgery (surgery group) and 44 matched obese control patients who remained weight stable (obese group). We also recruited 44 matched normal weight subjects (lean group). Dual-energy X-ray absorptiometry, computed tomography and echocardiography were performed to evaluate body composition, fat distribution and cardiac function. Results BMI was 42.5 kg/m2, 31.5 kg/m2 and 24.4 kg/m2 for the obese, surgery and lean groups respectively. Increasing degree of obesity was associated with larger left ventricular volumes (p < 0.001), higher cardiac output (p < 0.001), reduced systolic myocardial velocity (p < 0.001) and impaired ventricular relaxation (p = 0.015). In multivariate analyses, left ventricular volume, stroke volume and cardiac output primarily associated with lean body mass, whereas blood pressure, heart rate and variables reflecting cardiac dysfunction were more related to total body fat and visceral adiposity. Conclusion Obesity is associated with discrete but distinct disturbances in the left ventricular performance appearing to be related to both the total amount of body fat and degree of visceral adiposity. Patients with sustained weight losses display superior left ventricular systolic and diastolic functions as compared with their obese counterparts remaining weight stable.
|
|
| 9. |
- Kardassis, Dimitris, et al.
(författare)
-
Sleep apnea modifies the long-term impact of surgically induced weight loss on cardiac function and inflammation.
- 2013
-
Ingår i: Obesity (Silver Spring, Md.). - : Wiley. - 1930-739X .- 1930-7381. ; 21:4, s. 698-704
-
Tidskriftsartikel (refereegranskat)abstract
- Obesity is frequently associated with obstructive sleep apnea (OSA). Both conditions are proinflammatory and proposed to deteriorate cardiac function. We used a nested cohort study design to evaluate the long-term impact of bariatric surgery on OSA and how weight loss and OSA relate to inflammation and cardiac performance.
|
|
| 10. |
- Kardassis, Dimitris, et al.
(författare)
-
The Influence of Body Composition, Fat Distribution, and Sustained Weight Loss on Left Ventricular Mass and Geometry in Obesity
- 2012
-
Ingår i: Obesity. - : Wiley. - 1930-739X .- 1930-7381. ; 20:3, s. 605-611
-
Tidskriftsartikel (refereegranskat)abstract
- Alterations in left ventricular mass and geometry vary along with the degree of obesity, but mechanisms underlying such covariation are not clear. In a case–control study, we examined how body composition and fat distribution relate to left ventricular structure and examine how sustained weight loss affects left ventricular mass and geometry. At the 10-year follow-up of the Swedish obese subjects (SOS) study cohort, we identified 44 patients with sustained weight losses after bariatric surgery (surgery group) and 44 matched obese control patients who remained weight stable (obese group). We also recruited 44 matched normal weight subjects (lean group). Dual-energy X-ray absorptiometry, computed tomography, and echocardiography were performed to evaluate body composition, fat distribution, and left ventricular structure. BMI was 42.5 kg/m2, 31.5 kg/m2, and 24.4 kg/m2 for the obese, surgery, and lean groups, respectively. Corresponding values for left ventricular mass were 201.4 g, 157.7 g, and 133.9 g (P < 0.001). In multivariate analyses, left ventricular diastolic dimension was predicted by lean body mass (β = 0.03, P < 0.001); left ventricular wall thickness by visceral adipose tissue (β = 0.11, P < 0.001) and systolic blood pressure (β = 0.02, P = 0.019); left ventricular mass by lean body mass (β = 1.23, P < 0.001), total body fat (β = 1.15, P < 0.001) and systolic blood pressure (β = 2.72, P = 0.047); and relative wall thickness by visceral adipose tissue (β = 0.02, P < 0.001). Left ventricular adjustment to body size is dependent on body composition and fat distribution, regardless of blood pressure levels. Obesity is associated with concentric left ventricular remodeling and sustained 10-year weight loss results in lower cavity size, wall thickness and mass.
|
|
