Paradoxical growth
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Somatic mutations in receptor tyrosine kinase FGFR3 cause excessive cell proliferation, leading to cancer or skin overgrowth. Remarkably, the same mutations inhibit chondrocyte proliferation and differentiation in developing bones, resulting in skeletal dysplasias, such as hypochondroplasia, achondroplasia, SADDAN and thanatophoric dysplasia. A similar phenotype is observed in Noonan syndrome, Leopard syndrome, hereditary gingival fibromatosis, neurofibromatosis type 1, Costello syndrome, Legius syndrome and cardiofaciocutaneous syndrome. Collectively termed RASopathies, the latter syndromes are caused by germline mutations in components of the RAS/ERK MAP kinase signaling pathway. This article considers the evidence suggesting that FGFR3 activation in chondrocytes mimics the activation of major oncogenes signaling via the ERK pathway. Subsequent inhibition of chondrocyte proliferation in FGFR3-related skeletal dysplasias and RASopathies is proposed to result from activation of defense mechanisms that originally evolved to safeguard mammalian organisms against cancer.
- MeSH
- buněčná diferenciace genetika MeSH
- chondrocyty cytologie metabolismus MeSH
- geny ras genetika MeSH
- lidé MeSH
- nádory kostí genetika patologie MeSH
- proliferace buněk MeSH
- receptor fibroblastových růstových faktorů, typ 3 genetika metabolismus MeSH
- signální transdukce MeSH
- vývoj kostí genetika MeSH
- vývojové onemocnění kostí genetika patologie MeSH
- zárodečné mutace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Uncoupling protein 1 (UCP1) executes thermogenesis in brown adipose tissue, which is a major focus of human obesity research. Although the UCP1-knockout (UCP1 KO) mouse represents the most frequently applied animal model to judge the anti-obesity effects of UCP1, the assessment is confounded by unknown anti-obesity factors causing paradoxical obesity resistance below thermoneutral temperatures. Here we identify the enigmatic factor as endogenous FGF21, which is primarily mediating obesity resistance. The generation of UCP1/FGF21 double-knockout mice (dKO) fully reverses obesity resistance. Within mild differences in energy metabolism, urine metabolomics uncover increased secretion of acyl-carnitines in UCP1 KOs, suggesting metabolic reprogramming. Strikingly, transcriptomics of metabolically important organs reveal enhanced lipid and oxidative metabolism in specifically white adipose tissue that is fully reversed in dKO mice. Collectively, this study characterizes the effects of endogenous FGF21 that acts as master regulator to protect from diet-induced obesity in the absence of UCP1.
- MeSH
- bílá tuková tkáň metabolismus MeSH
- energetický metabolismus MeSH
- fibroblastové růstové faktory genetika metabolismus MeSH
- hnědá tuková tkáň metabolismus MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- obezita genetika metabolismus MeSH
- signální transdukce MeSH
- uncoupling protein 1 genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The response of the pituitary- thyroid axis, reverse triiodothyronine (rT3), prolactin, and growth hormone (GH) levels following TRH stimulus (Relefact TRH 200 microg 2 amp. i.v.) was examined in patients with autoimmune diabetes type 1 (DM1, n=30), with autoimmune thyroiditis (AT, n=25), and with concurrent DM1 and AT (n=22) to evaluate the influence of DM1 and AT of autoimmune pathogenesis on the above-mentioned hormonal parameters. Statistical analysis (ANOVA) showed that: a) the response of TSH did not differ from control groups (C); b) free triiodothyronine (fT3), free thyroxine (fT4) and their ratio in DM1, DM1+AT and C rose in 120 and 180 min, while a similar increase was not seen in AT (p<0.000001); c) rT3 was not present in any group, with rT3 levels higher in AT (p<0.00002) and lower in DM1 (p<0.02); d) the response of GH had a paradoxical character in some patients in all groups, most often in DM1 (52 %, DM1 vs C, p <0.01). The characteristic response difference was not in the peak GH level, but the delayed return to basal levels in DM1 (p<0.0001) and an abrupt one in AT (p<0.0001). The major findings in DM1 were the differences in GH response, while significant impairment of pituitary-thyroid axis and PRL response to TRH was absent. AT was associated with impairment of TRH stimulated fT3, fT4, fT3/fT4 response and changes in rT3 levels, in spite of preserved TRH-stimulated TSH secretion. GH response in AT patients was also altered.
- MeSH
- autoimunitní tyreoiditida diagnóza metabolismus MeSH
- diabetes mellitus 1. typu diagnóza metabolismus MeSH
- dospělí MeSH
- hormon uvolňující thyreotropin diagnostické užití MeSH
- hormony krev MeSH
- hypofýza metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidský růstový hormon krev MeSH
- prolaktin krev MeSH
- štítná žláza metabolismus MeSH
- thyroxin krev MeSH
- trijodthyronin reverzní krev MeSH
- trijodthyronin krev MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- ceruletid MeSH
- krysa rodu rattus MeSH
- pankreas růst a vývoj sekrece účinky léků MeSH
- Check Tag
- krysa rodu rattus MeSH
Supraphysiological levels of IL-7 induce increase counts of pre-B cells, naive T cells and memory phenotype CD8+ T cells. Immunocomplexes of IL-7 and αIL-7 mAb M25 (IL-7/M25) were described as IL-7 superagonist in vivo. Thus, treatment of mice with IL-7/M25 remarkably increases the size of the T cell pool. We decided to use IL-7/M25 in order to expand the T cell population prior to the administration of αCTLA-4 and αPD-1 mAbs in tumor-bearing mice and in turn boost the immunotherapy based on a combination of CTLA-4 and PD-1 blockage. We found that just four doses of IL-7/M25 increased the absolute numbers of splenocytes approximately fivefold and significantly shifted the CD4+:CD8+ T cell ratio in favor of CD8+ T cells. There was also a substantive increase in relative counts of memory phenotype CD8+ T cells (approximately threefold) within CD8+ T cells but a significant decrease (approximately 30%) in relative counts of Treg cells within CD4+ T cells. All these data suggest that IL-7/M25 offer a suitable approach to potentiate tumor immunotherapy through CTLA-4 and PD-1 blockage. Unexpectedly, IL-7/M25 significantly abrogated the antitumor activity of αCTLA-4 plus αPD-1 mAbs in the following mouse tumor models: MC-38 and CT26 colon carcinoma and B16F10 melanoma. This paradoxical effect of IL-7/M25 on the antitumor activity of CTLA-4 and PD-1 blockage was not mediated via either increased levels of IL-10 or TGF-β in the sera or increased counts of IL-10-producing B or T cells in the spleen of mice injected with IL-7/M25. Thus, our work shows that caution should be exercised when combining two immunotherapy approaches together.
- MeSH
- antigen CTLA-4 imunologie MeSH
- antigeny CD279 imunologie MeSH
- CD4-pozitivní T-lymfocyty imunologie MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- imunoterapie metody MeSH
- interleukin-10 imunologie MeSH
- interleukin-7 imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- melanom imunologie MeSH
- modely nemocí na zvířatech MeSH
- monoklonální protilátky imunologie MeSH
- myši inbrední BALB C MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory tračníku imunologie MeSH
- protinádorové látky imunologie MeSH
- regulační T-lymfocyty imunologie MeSH
- transformující růstový faktor beta imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A curious hemodynamic phenomenon emerging as a consequence of the treatment of varicose veins can offer a reasonable explanation why varicose vein and reflux recurrences occur tenaciously irrespective of the applied therapeutic procedure. Saphenous reflux is the most important hemodynamic factor in varicose vein disease: it is responsible for the hemodynamic disturbance, ambulatory venous hypertension, clinical symptoms, and chronic venous insufficiency. Abolition of saphenous reflux eliminates the hemodynamic disturbance and restores physiological hemodynamic and pressure conditions, but at the same time it unavoidably evokes a pressure difference between the femoral vein and the incompetent superficial veins in the thigh during calf pump activity. The pressure difference increases flow and enhances fluid shear stress on the endothelium in pre-existing minor communicating channels between the femoral vein and the saphenous system in the thigh, which triggers release of biochemical agents nitride oxide and vascular endothelial growth factor; the consequence is enlargement (vascular remodeling) of the communicating channels, and ultimately reflux recurrence. Hence, the abolition of saphenous reflux creates preconditions for the comeback of the previous pathological situation. This phenomenon-starting the same trouble while fixing the problem-has been called hemodynamic paradox; is explains why varicose vein and reflux recurrence can occur after any mode of therapy.
- Publikační typ
- časopisecké články MeSH
The aim of the study was to investigate the influence of flaxseed and lactobacilli supplementation to the diet of piglets during the time period between 10 days before and 21 days after weaning. The morphometry of the jejunal mucosa and proliferative ratio of both epithelial and lamina propria cells were compared with those found in a group of piglets fed with the usual diet added with sunflower oil during the same time period. The addition of flaxseed oil to the diet significantly increased the crypt depth in comparison with both groups supplemented with sunflower (P < 0.05 and 0.001 respectively) on the weaning day. Moreover, the flaxseed addition caused a significant decrease in villus height (P < 0.01) and crypt depth (P < 0.01) 21 days postweaning in comparison with the sunflower group. The proliferative ratio of the epithelial cells in the sunflower group on the weaning day was significantly higher than in both flaxseed groups (P < 0.01). Paradoxically, significantly higher proliferative activity in the mucosal connective tissue in the group with flaxseed supplementation in comparison with the sunflower group was observed on the day of weaning, as well as 3 days later (P < 0.05 both). A combination of flaxseed with lactobacilli showed significantly lower proliferative activity in the connective tissue cells from weaning up to 7 days after weaning (P < 0.05 all) in comparison with the flaxseed group.
- MeSH
- časové faktory MeSH
- fyziologie výživy zvířat MeSH
- jejunum účinky léků růst a vývoj mikrobiologie MeSH
- krmivo pro zvířata * MeSH
- Lactobacillus fyziologie MeSH
- lněný olej aplikace a dávkování MeSH
- odstavení MeSH
- prasata MeSH
- probiotika * MeSH
- proliferace buněk účinky léků MeSH
- střevní sliznice účinky léků růst a vývoj mikrobiologie MeSH
- věkové faktory MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
