Desmin mutations cause familial and sporadic cardiomyopathies. In addition to perturbing the contractile apparatus, both desmin deficiency and mutated desmin negatively impact mitochondria. Impaired myocardial metabolism secondary to mitochondrial defects could conceivably exacerbate cardiac contractile dysfunction. We performed metabolic myocardial phenotyping in left ventricular cardiac muscle tissue in desmin knock-out mice. Our analyses revealed decreased mitochondrial number, ultrastructural mitochondrial defects, and impaired mitochondria-related metabolic pathways including fatty acid transport, activation, and catabolism. Glucose transporter 1 and hexokinase-1 expression and hexokinase activity were increased. While mitochondrial creatine kinase expression was reduced, fetal creatine kinase expression was increased. Proteomic analysis revealed reduced expression of proteins involved in electron transport mainly of complexes I and II, oxidative phosphorylation, citrate cycle, beta-oxidation including auxiliary pathways, amino acid catabolism, and redox reactions and oxidative stress. Thus, desmin deficiency elicits a secondary cardiac mitochondriopathy with severely impaired oxidative phosphorylation and fatty and amino acid metabolism. Increased glucose utilization and fetal creatine kinase upregulation likely portray attempts to maintain myocardial energy supply. It may be prudent to avoid medications worsening mitochondrial function and other metabolic stressors. Therapeutic interventions for mitochondriopathies might also improve the metabolic condition in desmin deficient hearts.

• MeSH
• aminokyseliny metabolismus   MeSH
• citráty metabolismus   MeSH
• desmin * genetika   metabolismus   MeSH
• glukosa metabolismus   MeSH
• hexokinasa * genetika   metabolismus   MeSH
• kardiomyopatie * genetika   metabolismus   MeSH
• kreatinkinasa, mitochondriální forma metabolismus   MeSH
• mastné kyseliny metabolismus   MeSH
• myokard metabolismus   MeSH
• myši knockoutované MeSH
• myši MeSH
• oxidativní fosforylace MeSH
• přenašeč glukosy typ 1 metabolismus   MeSH
• proteomika MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The glucose transporter-1 (Glut-1) is a cell membrane glycoprotein involved in glucose uptake. An increased expression of Glut-1 is an important cell adaptation mechanism against hypoxia. An upregulation of Glut-1 can be found in several types of malignant tumors, which are able to reprogram their metabolism from oxidative phosphorylation to aerobic glycolysis (Warburg effect). However, the data regarding melanocytic lesions is equivocal. We performed comprehensive immunohistochemical analysis of the Glut-1 expression in 225 malignant melanomas (MM) and 175 benign nevi. Only the membranous expression of Glut-1 was regarded as positive. The expression of Glut-1 (the cut-off for positivity was determined as H-score 15) was found in 69/225 malignant melanomas. The number of positive cases and the H-score of Glut-1 increased where there was a higher Breslow thickness (p < 0.00001) when comparing pT1- pT4 MM groups. All benign nevi were classified as negative. In conclusion, the membranous expression of Glut-1 is a common feature of a malignant melanoma but this type of expression is very rare in benign melanocytic nevi. Our results suggest that the membranous expression of Glut-1 can be used as a surrogate marker in the assessing of the biological nature of benign and malignant melanocytic lesions. However, despite its high specificity, the sensitivity of this marker is relatively low. Moreover, due to the fact that the increased expression of Glut-1 correlates with a shorter survival period (10-year disease free survival, recurrence free survival and metastasis free survival and MFS), it can be used as a prognostically adverse factor.

• MeSH
• dospělí MeSH
• imunohistochemie metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• melanom metabolismus   patologie   MeSH
• míra přežití MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové biomarkery metabolismus   MeSH
• následné studie MeSH
• pigmentový névus metabolismus   patologie   MeSH
• přenašeč glukosy typ 1 metabolismus   MeSH
• prognóza MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Cardiac atrophy is the most common complication of prolonged application of the left ventricle (LV) assist device (LVAD) in patients with advanced heart failure (HF). Our aim was to evaluate the course of unloading-induced cardiac atrophy in rats with failing hearts, and to examine if increased isovolumic loading obtained by intraventricular implantation of an especially designed spring expander would attenuate this process. Heterotopic abdominal heart transplantation (HTx) was used as a rat model of heart unloading. HF was induced by volume overload achieved by creation of the aorto-caval fistula (ACF). The degree of cardiac atrophy was assessed as the weight ratio of the heterotopically transplanted heart (HW) to the control heart. Isovolumic loading was increased by intraventricular implantation of a stainless steel three-branch spring expander. The course of cardiac atrophy was evaluated on days 7, 14, 21, and 28 after HTx Seven days unloading by HTx in failing hearts sufficed to substantially decrease the HW (-59 ± 3%), the decrease progressed when measured on days 14, 21, and 28 after HTx Implantation of the spring expander significantly reduced the decreases in whole HW at all the time points (-39 ± 3 compared with -59 ± 3, -52 ± 2 compared with -69 ± 3, -51 ± 2 compared with -71 ± 2, and -44 ± 2 compared with -71 ± 3%, respectively; P<0.05 in each case). We conclude that the enhanced isovolumic heart loading obtained by implantation of the spring expander attenuates the development of unloading-induced cardiac atrophy in the failing rat heart.

• MeSH
• aorta chirurgie   MeSH
• atriální natriuretický faktor genetika   metabolismus   MeSH
• atrofie metabolismus   patofyziologie   prevence a kontrola   chirurgie   MeSH
• biologické markery metabolismus   MeSH
• design vybavení MeSH
• experimentální implantáty MeSH
• exprese genu MeSH
• fibroblastový růstový faktor 2 genetika   metabolismus   MeSH
• heterotopická transplantace MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• píštěle MeSH
• potkani inbrední LEW MeSH
• přenašeč glukosy typ 1 genetika   metabolismus   MeSH
• sarkoplazmatická Ca2+-ATPáza genetika   metabolismus   MeSH
• srdce patofyziologie   MeSH
• srdeční komory patofyziologie   chirurgie   MeSH
• srdeční selhání metabolismus   patofyziologie   chirurgie   terapie   MeSH
• tkáňové expandéry * MeSH
• transplantace srdce * MeSH
• vena cava superior chirurgie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Glucose transporter-1 (Glut-1) is a membrane glycoprotein that is, together with other glucose transporters, responsible for the regulation of glucose uptake. An increased expression of this protein seems to be a general feature of several malignant tumors that are able to reprogram their metabolism and switch from oxidative phosphorylation to aerobic glycolysis. METHODS: We performed comprehensive immunohistochemical analysis of Glut-1 expression in 336 endometrial samples, including tumors, nontumor lesions, and normal tissues. RESULTS: Expression of Glut-1 was found in 87% of endometrioid carcinomas (160/184 cases), 100% of serous carcinomas (29/29 cases), 100% of clear cell carcinomas (17/17 cases), 50% of polyps with atypical hyperplasia (8/16 cases), 12.5% of polyps with non-atypical hyperplasia (3/24 cases), 77% of hyperplasias with atypias (10/13 cases), 9% of hyperplasias without atypias (1/11 cases), 87% of secretory endometrium samples (13/15 cases), and in none of the nonsecretory endometrium samples (0/27 cases). In endometrioid carcinomas, Glut-1 was expressed in a marked geographical pattern. In nontumor lesions, its expression was more common in atypical hyperplasia and polyps with atypical hyperplasia compared with polyps with non-atypical hyperplasia and hyperplasias without atypia ( P = .00032). CONCLUSION: Our study confirms the high expression of Glut-1 not only in endometrioid carcinomas but also in other carcinomas of endometrium including clear cell and serous types. Glut-1 expression can be used as a surrogate marker in differential diagnosis between hyperplasia with and without atypia. Because of common Glut-1 expression in malignant tumors, therapeutic strategies influencing this protein or its signaling pathways can be beneficial.

• MeSH
• adenokarcinom z jasných buněk diagnóza   patologie   MeSH
• biopsie MeSH
• diferenciální diagnóza MeSH
• dospělí MeSH
• endometrium patologie   MeSH
• endometroidní karcinom diagnóza   patologie   MeSH
• hyperplazie endometria diagnóza   patologie   MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádorové biomarkery metabolismus   MeSH
• nádory endometria diagnóza   patologie   MeSH
• polypy diagnóza   patologie   MeSH
• prekancerózy diagnóza   patologie   MeSH
• přenašeč glukosy typ 1 metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The general mechanism underlying the tumor suppressor activity of the Hippo signaling pathway remains unclear. In this study, we explore the molecular mechanisms connecting the Hippo signaling pathway with glucose metabolism. We have found that two key regulators of glycolysis, C-MYC and GLUT1, are targets of the Hippo signaling pathway in human leukemia cells. Our results revealed that activation of MST1 by the natural compound shikonin inhibited the expression of GLUT1 and C-MYC. Furthermore, RNAi experiments confirmed the regulation of GLUT1 and C-MYC expression via the MST1-YAP1-TEAD1 axis. Surprisingly, YAP1 was found to positively regulate C-MYC mRNA levels in complex with TEAD1, while it negatively regulates C-MYC levels in cooperation with MST1. Hence, YAP1 serves as a rheostat for C-MYC, which is regulated by MST1. In addition, depletion of MST1 stimulates lactate production, whereas the specific depletion of TEAD1 has an opposite effect. The inhibition of lactate production and cellular proliferation induced by shikonin also depends on the Hippo pathway activity. Finally, a bioinformatic analysis revealed conserved TEAD-binding motifs in the C-MYC and GLUT1 promoters providing another molecular data supporting our observations. In summary, regulation of glucose metabolism could serve as a new tumor suppressor mechanism orchestrated by the Hippo signaling pathway.

• MeSH
• adaptorové proteiny signální transdukční účinky léků   MeSH
• apoptóza účinky léků   genetika   MeSH
• DNA vazebné proteiny účinky léků   MeSH
• fosfoproteiny účinky léků   metabolismus   MeSH
• geny myc účinky léků   MeSH
• hepatocytární růstový faktor MeSH
• jaderné proteiny účinky léků   MeSH
• lidé MeSH
• naftochinony farmakologie   MeSH
• přenašeč glukosy typ 1 metabolismus   MeSH
• proliferace buněk účinky léků   genetika   MeSH
• protoonkogenní proteiny účinky léků   MeSH
• signální transdukce účinky léků   fyziologie   MeSH
• transkripční faktory účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Glucose is molecule usually studied in relation to metabolism. Except for this traditional view, it is known that under certain conditions glucose can serve as a signal molecule for the circadian system. The circadian system is entrained by relevant synchronizing cues that can be tissue-dependent. Central oscillator is synchronized mainly by light-dark cycle, while peripheral oscillators can be entrained by food intake. Glucose transport in the organism is controlled by insulin dependent and independent mechanism. Therefore, we employed streptozotocin-induced diabetes to elucidate the influence of metabolic changes on glucose transporter (glut1, glut4) 24-h expression profile in peripheral oscillators in tissues, inside (frontal cortex, cerebellum) and outside (heart) the blood-brain barrier. Diabetes was induced by streptozotocin injection. Seventeen days later, sampling was performed during a 24-h cycle. Gene expression was measured using real-time PCR. We observed down-regulation of glut1 and glut4 expression in the heart of diabetic rats. The expression of glut1 and glut4 in brain areas was not down-regulated, however, we observed trend to phase advance in glut1 expression in the cerebellum. These results may indicate higher glucose levels in diabetic brain, which might influence regulation of clock gene expression in different manner in brain compared to periphery.

• MeSH
• cirkadiánní hodiny * MeSH
• cirkadiánní rytmus * MeSH
• experimentální diabetes mellitus chemicky indukované   metabolismus   MeSH
• glukosa metabolismus   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• přenašeč glukosy typ 1 metabolismus   MeSH
• přenašeč glukosy typ 4 metabolismus   MeSH
• streptozocin MeSH
• tkáňová distribuce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

It was demonstrated that estrogen deficiency and consuming high fat (HF) diet enhanced orexigenic activity of ghrelin. Therefore, we hypothesized that antagonizing of ghrelin action would attenuate food intake and body weight in mice obese both from ovariectomy (OVX) and feeding a HF diet. Ghrelin receptor antagonist [D-Lys(3)]GHRP-6 after seven days of subcutaneous treatment markedly decreased food intake in OVX mice fed both HF and standard diets; furthermore, it reduced body weight and blood glucose, insulin and leptin, and increased β-hydroxybutyrate level and uncoupling-protein-1 mRNA in brown adipose tissue. Pair-feeding revealed that effect of [D-Lys(3)]GHRP-6 was primary anorexigenic. Estrogen supplementation reduced anorexigenic effects of [D-Lys(3)]GHRP-6. OVX [D-Lys(3)]GHRP-6 treatment in mice on HF diet resulted in markedly increased circulating level and liver expression of a major metabolic regulator, fibroblast growth factor 21. Our data suggest that ghrelin antagonists could be especially beneficial in individuals with common obesity combined with estrogen deficiency.

• MeSH
• adipozita účinky léků   MeSH
• chování zvířat účinky léků   MeSH
• dieta s vysokým obsahem tuků MeSH
• estrogeny aplikace a dávkování   nedostatek   MeSH
• ghrelin metabolismus   MeSH
• hnědá tuková tkáň metabolismus   MeSH
• iontové kanály genetika   metabolismus   MeSH
• lidé MeSH
• mitochondriální proteiny genetika   metabolismus   MeSH
• modely u zvířat MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• obezita patofyziologie   MeSH
• oligopeptidy farmakologie   MeSH
• ovarektomie MeSH
• pohybová aktivita účinky léků   MeSH
• postmenopauza metabolismus   MeSH
• PPAR alfa genetika   metabolismus   MeSH
• přenašeč glukosy typ 1 genetika   metabolismus   MeSH
• přijímání potravy účinky léků   MeSH
• receptory ghrelinu antagonisté a inhibitory   genetika   metabolismus   MeSH
• tělesná hmotnost účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH