1,720,972 research outputs found
Six1 is down-regulated in end-stage human dilated cardiomyopathy independently of Ezh2
No full textackground Recently, it was shown that a knock-out (KO) of the polycomb histone methyltransferase Ezh2 leads to cardiac hypertrophy in mice, which was driven by the homeodom ain transcription factor Six1. Here, we analyzed the expression of Six1 and its regulating factor Ezh2 in cardiac tissue of pa- tients with end-stage dilative cardiomyopathy (DCM). Methods Tissue samples of patients with end-stage DCM (n = 35) were com- pared with control s (n = 12) for the protein expression of Ezh1, Ezh2, Six1, and a marker of protein expression p70S6K. Results Contrary to the Ezh2-KO mouse model, we found a down-regulation of Six1 (26%) and an up-regulation of Ezh2 (76%) in DCM hearts, (both P < 0.05). Expression of Ezh2 and Six1 did not correlate in human tissue (DCM: r 2 : 0.03, P = 0.31 and donor: r 2 : 0.05, P = 0.45). Expression of Six1 weakly correlated with left ventricula r end-systolic diameter and fractional shortening. In DCM, Six1 also showed a positive correlation to the expression of the ribosomal protein p70S6K (r: 0.39, P = 0.02 9), which is involved in pro- tein synthesis. This correlation was not seen in donor tissue, whic h showed a trend for a negative correlation (r: 0.49, P = 0.08 ). Conclusion Our data indicate that the Ezh2/Six1 axis might be involved in human DCM. However, Six1 expression may be regulated by factors other t han Ezh2, and more research is needed to determine the precise role of Ezh2/Six1 in human DCM
A selective angiotensin-II type 2 receptor agonist reduced cancer cachexia-induced cardiomyopathy
No full textFebuxostat improves outcome in a rat model of cancer cachexia
No full textBackground Activity of xanthine oxidase is induced in cancer cachexia, and its inhibition by allopurinol or oxypurinol improves survival and reduces wasting in the Yoshida hepatoma cancer cachexia model. Here, we tested the effects of the second-generation xanthine oxidase inhibitor febuxostat compared with placebo in the same model as used previously by our group. Methods Wistar rats (similar to 200g) were treated daily with febuxostat at 5mg/kg/day or placebo via gavage for a maximum of 17days. Weight change, quality of life, and body composition were analysed. After sacrifice, proteasome activity in the gastrocnemius muscle was measured. Muscle-specific proteins involved in metabolism were analysed by western blotting. Results Treatment of the tumour-bearing rats with febuxostat led to a significantly improved survival compared with placebo (hazard ratio: 0.45, 95% confidence interval: 0.22-0.93, P=0.03). Loss of body weight was reduced (-26.312.4g) compared with placebo (-50.2 +/- 2.1g, P<0.01). Wasting of lean mass was attenuated (-12.7 +/- 10.8g) vs. placebo (-31.9 +/- 2.1g, P<0.05). While we did not see an effect of febuxostat on proteasome activity at the end of the study, the pAkt/Akt ratio was improved by febuxostat (0.94 +/- 0.09) vs. placebo (0.41 +/- 0.05, P<0.01), suggesting an increase in protein synthesis. Conclusions Febuxostat attenuated cachexia progression and improved survival of tumour-bearing rats.Sumitomo Life Welfare and Culture Foundatio
Influence of cancer cachexia on drug liver metabolism and renal elimination in rats.
No full textBACKGROUND: Body wasting and cachexia change body composition and organ function, with effects on drug pharmacokinetics. The aim of this study was to investigate how cancer and cancer cachexia modify liver metabolism and renal drug elimination in rats. METHODS: Nine male Wistar-Han rats received a single oral dose of midazolam and propranolol (markers of hepatic metabolism), and 10 rats received single intravenous dose of iohexol, a marker of glomerular filtration rate. After drug delivery, multiple dried blood samples were obtained within 2 h post-dose to evaluate drug pharmacokinetic profiles. After baseline sampling (D0), rats were injected with tumour cells. Drug application and blood sampling were repeated when rats developed tumours (Day 5-D5), and when rats were severely cachectic (Day 10-D10). Clearance (CL) and volume of distribution (Vd) of drugs were assessed with non-linear mixed effects modelling. Weight and body composition were measured on D0 and D10 and were related to pharmacokinetic parameters. RESULTS: All three drugs showed non-significant trend towards increased CL and Vd on D5. On D10, midazolam and propranolol CL and midazolam Vd significantly decreased from baseline (-80.5%, -79.8%, and -72.0%, respectively, P < 0.05 for all). Iohexol CL decreased by 29.8% from baseline value on D10, which was related to body weight loss (Pearson's r = 0.837, P = 0.019). CONCLUSIONS: Hepatic metabolism and renal drug elimination are significantly reduced in cachexia, which could increase risk of dose-related adverse events
Vergleich der Einflussnahme herzinsuffizienzbedingter sowie tumorassoziierter Kachexie auf Parameter der kardialen Morphologie und Funktion im Rattenmodell
No full text
Comparison of heart failure induced cachexia with cancer associated cachexia and its impact on cardiac morphology and function in a rat model
No full textIn der vorliegenden Dissertation wurden die Induktion und Progression der
Kachexie sowie deren Auswirkungen auf die Herzmorphologie und –funktion in dem
AH-130 Yoshida Hepatoma Modell (Tumormodell) mit dem LAD-Modell
(Myokardinfarktmodell) in jungen männlichen Ratten miteinander verglichen.
Danach erfolgte eine kardiovaskuläre Behandlung von mit AH-130 Yoshida
Hepatoma Zellen inokulierten Ratten. Als letztes wurden Daten bezüglich der
Herzmorphologie von kachektischen Tumorkachexiepatienten analysiert. Dabei
ergaben sich folgende Erkenntnisse: 1) Vergleich von tumorassoziierter
Kachexie (AH-130 Yoshida Hepatoma Modell) mit kardialer Kachexie
(Myokardinfarktmodell): • Während Tumortiere frühzeitig eine Kachexie,
gekennzeichnet durch Verlust von Fettmasse und Skelettmuskelmasse, aufwiesen,
entwickelten die Infarkttiere keine Kachexie. Bei den Tumortieren zeigte sich
insbesondere auch eine Atrophie der Organe, vor allem des Myokards. •
Desweiteren war die Entwicklung einer kardialen Dysfunktion in den Tumortieren
feststellbar, die sich durch verschlechterte echokardiographische Parameter
wie zum Beispiel dem Schlagvolumen, der Verkürzungsfraktion und dem
Herzminutenvolumen äußerte. Auch der Blutdruck und die Erregungsleitung im
Herzen nahmen durch Tumorinokulation ab. Biomarker bestätigten die Schädigung
des Herzens sowie ventrikuläres Remodelling. Die Infarkttiere wiesen aufgrund
der induzierten Herzinsuffizienz Ödeme auf. Ferner kam es durch die
Infarktinduktion zu einer Zunahme des Herzgewichtes, einer Dilatation des
Ventrikels und es zeigte sich ein Trend hinsichtlich einer Erhöhung der
Herzrate. Im Gegensatz dazu nahmen der ventrikuläre Diameter und die Herzrate
in den Tumortieren ab, wodurch sich diese Kardiomyopathie von einer
klassischen Herzinsuffizienz unterschied. • Die Analyse des Herzgewebes zeigte
eine Zunahme von Apoptose, Autophagie und der Ubiquitin-Proteasomaktivität in
den Tumortieren. Ferner wiesen diese Tiere eine reduzierte anabole
Signaltransduktion auf. Hingegen wurden durch Infarktinduktion Hypertrophie-
vermittelnde Signalwege induziert. 2) Behandlung von Tumortieren (AH-130
Modell) mit kardiovaskulären Medikamenten: • Der spezifische β1-Blocker
Bisoprolol (5mg/kg/d) oder der Aldosteronantagonist Spironolacton (50mg/kg/d)
konnten das Überleben von Tumortieren verlängern, während der unspezifische
β-Blocker Carvedilol (30mg/kg/d) oder der ACE- (Angiotensin-konvertierendes-
Enzym)-Inhibitor Imidapril (0,4mg/kg/d) keinen positiven Effekt auf das
Überleben zeigten. • Bisoprolol oder Spironolacton konnten den Verlust von
Skelettmuskelmasse, Fettmasse und des linksventrikulären Gewebes verringern.
Die Behandlung mit Spironolacton führte sogar zu einer Zunahme der
linksventrikulären Masse und zu einer verbesserten Herzfunktion. Imidapril
konnte zwar den Verlust von Körpergewicht verhindern, jedoch hatte es keinen
Einfluss auf die in Tumortieren verschlechterte Herzfunktion. Carvedilol
konnte weder die Kachexie mildern, noch die Kardiomyopathie verhindern. •
Bisoprolol oder Spironolacton konnten den Katabolismus reduzieren und den
Anabolismus in den Tumortieren steigern, Carvedilol und Imidapril hingegen
nicht. 3) Analyse von humanen Daten kachektischer Tumorpatienten: • Die
Ergebnisse zeigten eine Atrophie des Herzens mit Abnahme der Hinterwandstärke
und Fibrose. Erhöhtes BNP ließ eine Schädigung des Myokards vermuten. Die
Daten deuten auf eine eventuell verschlechterte Herzfunktion hin.In this dissertation the induction and progression of cachexia and its impact
on the heart were investigated and compared in a tumor model (AH-130 Yoshida
Hepatoma) and a myocardial infarction model (LAD) in young male rats. In
AH-130 study the treatment of tumor-bearing rats with cardiovascular drugs was
made. The analysis of cardiac data of cachectic cancer patients was presented
in this research as well. The following scientific findings were shown: 1)
Comparison of a cancer cachexia model (AH-130 Yoshida Hepatoma) with an
cardiac cachexia model (myocardial infarction): • While tumor animals
developed a real cachexia characterized by a loss of fat mass and skeletal
muscle mass, infarct animals did not. Tumor animals had also atrophic organs,
especially the heart. • Tumor animals showed a myocardial dysfunction visible
by echocardiographic parameters like stroke volume, fractional shortening and
cardiac output. Blood pressure and repolarization decreased in the heart due
to the tumor inoculation. Biomarkers confirmed the damage of the heart and
ventricular remodeling. Infarct animals developed heart failure induced edema.
In addition, myocardial induction led to a gain of heart weight, dilatation of
the ventricle and there was a trend to an increase of the heart rate. In
contrast the ventricular diameter and the heart rate decreased in tumor-
bearing rats distinguishing this cardiomyopathy from classical heart failure.
• Analysis of the heart revealed more apoptosis, autophagy and a higher
ubiquitin proteasome activity in the tumor animals. Furthermore, these animals
showed a reduced anabolic signaling. In contrast myocardial infarction induced
hypertrophic signaling. 2) Treatment of tumor-bearing rats with cardiovascular
drugs (AH-130): • The specific β1-blocker bisoprolol (5mg/kg/d) or the
aldosterone antagonist spironolactone (50mg/kg/d) showed an increase in the
survival of tumor-bearing animals, while the unspecific β-blocker carvedilol
(30mg/kg/d) or the angiotensin- converting-enzyme inhibitor imidapril
(0,4mg/kg/d) showed no positive effect. • Bisoprolol or spironolactone could
prevent the loss of skeletal muscle mass, fat mass and left ventricular
tissue. Treatment with spironolactone increased the left ventricular mass and
led to an improved heart function. Imidapril inhibited the loss of body
weight, but had no effect on the impaired heart function in tumor-bearing
animals. Carvedilol could neither attenuate the cachexia nor the
cardiomyopathy. • Bisoprolol or spironolacton reduced the catabolism and
increased anabolism in Tumor-bearing animals, but carvedilol or imidapril did
not. 3) Analysis of heart data of cachectic cancer patients: • The results
revealed atrophy of the heart with a reduced posterior wall and elevated
fibrosis. Higher BNP supposed a damaged heart. These data may indicate an
impaired heart function of cachectic cancer patients
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
- …
