Primary cilia are cellular surface projections enriched in receptors and signaling molecules, acting as signaling hubs that respond to stimuli. Malfunctions in primary cilia have been linked to human diseases, including retinopathies and ocular defects. Here, we focus on TMEM107, a protein localized to the transition zone of primary cilia. TMEM107 mutations were found in patients with Joubert and Meckel-Gruber syndromes. A mouse model lacking Tmem107 exhibited eye defects such as anophthalmia and microphthalmia, affecting retina differentiation. Tmem107 expression during prenatal mouse development correlated with phenotype occurrence, with enhanced expression in differentiating retina and optic stalk. TMEM107 deficiency in retinal organoids resulted in the loss of primary cilia, down-regulation of retina-specific genes, and cyst formation. Knocking out TMEM107 in human ARPE-19 cells prevented primary cilia formation and impaired response to Smoothened agonist treatment because of ectopic activation of the SHH pathway. Our data suggest TMEM107 plays a crucial role in early vertebrate eye development and ciliogenesis in the differentiating retina.
- MeSH
- Humans MeSH
- Membrane Proteins genetics metabolism MeSH
- Mice MeSH
- Polycystic Kidney Diseases * genetics MeSH
- Ciliary Motility Disorders * genetics metabolism MeSH
- Retina metabolism MeSH
- Retinitis Pigmentosa * metabolism MeSH
- Pregnancy MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Východiska: Nádorová onemocnění jsou druhou nejčastější příčinou úmrtí v České republice. Léčba tohoto typu onemocnění je pro pacienty velmi náročná a její úspěšnost je často limitovaná kvůli častým relapsům. Navíc se mohou objevit metastázy, nejčastěji v plicích a játrech, které zhoršují pacientovu prognózu na přežití. Signální dráha Hedgehog (Hh) je jednou z významných signalizačních kaskád, které ovlivňují rozvoj a následné udržování mnoha typů nádorů. Její aberantní signalizace pomáhá buňkám uniknout apoptóze, narušuje energetický metabolizmus buněk, má vliv na proces epiteliálně-mezenchymálního přechodu, pomáhá nádorovým buňkám uniknout imunitnímu systému, udržuje nádorové kmenové buňky a podílí se na tvorbě metastáz. Role signální dráhy Hh v rozvoji, udržování a progresi nádorů je intenzivně studovaná. Bylo vyvinuto několik typů inhibitorů této signální dráhy. Nejvíce studované byly inhibitory receptoru Smoothened, ale vzhledem k často vznikající rezistenci se nyní dostává do popředí výzkum dalších skupin inhibitorů, které cílí mimo receptor Smoothened. Zdá se, že tyto inhibitory by mohly pomoci překonat rezistenci inhibicí přímých efektorů dráhy, tj. transkripčních faktorů Gli, nezávisle na membránové signalizaci. Tyto nové léky dávají naději pacientům, u kterých v současné době léčba selhává. Cíl: Tento souhrnný článek se snaží shrnout poznatky o roli signální dráhy Hh v rozvoji nádorů a popisuje některé zásadní pokroky ve vývoji cílených inhibitorů této dráhy.
Background: Cancer is the second most common cause of death in the Czech Republic. The treatment of this disease is very exhausting for the patients and the treatment has often limited success only. The disease often relapses after a period of remission. Moreover, metastases often appear in lungs, liver or other organs and worsen patient's prognosis and probability of survival. The Hedgehog (Hh) signaling pathway is one of the important pathways that affects initiation and maintenance of various types of tumours. When aberrantly activated, Hh signaling pathway helps cells escape apoptosis, disturbs cell energy metabolism, influences the process of epithelial-mesenchymal transition, helps to escape immune system, maintains cancer stem cells and supports metastasis. The role of Hh signaling cascade in tumour initiation, maintenance and progression is intensively studied. Several types of inhibitors of this pathway were developed. The most intensively studied were inhibitors of the receptor Smoothened. Due to commonly occurring resistance, the research of other groups of inhibitors is in the centre of interest. These new drugs do not target receptor Smoothened but proteins standing downstream of Smoothened (inhibition of final Gli transcription factors). The drugs could give new hope to patients whose treatment fails. Purpose: This review summarizes the findings about the role of Hh signaling pathway in tumour development and describes the progress in the development of targeted inhibitors of this pathway.
- Keywords
- epiteliálně-mezenchymální přechod, signální dráha Hedgehog,
- MeSH
- Apoptosis * MeSH
- Drug Resistance, Neoplasm * MeSH
- Molecular Targeted Therapy MeSH
- Humans MeSH
- Neoplasm Metastasis MeSH
- Neoplastic Stem Cells MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
Neural stem cells are fundamental to development of the central nervous system (CNS)-as well as its plasticity and regeneration-and represent a potential tool for neuro transplantation therapy and research. This study is focused on examination of the proliferation dynamic and fate of embryonic neural stem cells (eNSCs) under differentiating conditions. In this work, we analyzed eNSCs differentiating alone and in the presence of sonic hedgehog (SHH) or triiodothyronine (T3) which play an important role in the development of the CNS. We found that inhibition of the SHH pathway and activation of the T3 pathway increased cellular health and survival of differentiating eNSCs. In addition, T3 was able to increase the expression of the gene for the receptor smoothened (Smo), which is part of the SHH signaling cascade, while SHH increased the expression of the T3 receptor beta gene (Thrb). This might be the reason why the combination of SHH and T3 increased the expression of the thyroxine 5-deiodinase type III gene (Dio3), which inhibits T3 activity, which in turn affects cellular health and proliferation activity of eNSCs.
- MeSH
- Iodide Peroxidase genetics metabolism MeSH
- Cells, Cultured MeSH
- Mouse Embryonic Stem Cells cytology metabolism MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Neural Stem Cells cytology metabolism MeSH
- Neurogenesis * MeSH
- Hedgehog Proteins genetics metabolism MeSH
- Smoothened Receptor genetics metabolism MeSH
- Triiodothyronine metabolism MeSH
- Thyroid Hormone Receptors beta genetics metabolism MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Silymarin is the standardized extract from the fruits of Silybum marianum (L.) Gaertn., a well-known hepatoprotectant and antioxidant. Recently, bioactive compounds of silymarin, i.e., silybins and their 2,3-dehydro derivatives, have been shown to exert anticancer activities, yet with unclear mechanisms. This study combines in silico and in vitro methods to reveal the potential interactions of optically pure silybins and dehydrosilybins with novel protein targets. The shape and chemical similarity with approved drugs were evaluated in silico, and the potential for interaction with the Hedgehog pathway receptor Smoothened (SMO) and BRAF kinase was confirmed by molecular docking. In vitro studies on SMO and BRAF V600E kinase activity and in BRAF V600E A-375 human melanoma cell lines were further performed to examine their effects on these proteins and cancer cell lines and to corroborate computational predictions. Our in silico results direct to new potential targets of silymarin constituents as dual inhibitors of BRAF and SMO, two major targets in anticancer therapy. The experimental studies confirm that BRAF kinase and SMO may be involved in mechanisms of anticancer activities, demonstrating dose-dependent profiles, with dehydrosilybins showing stronger effects than silybins. The results of this work outline the dual SMO/BRAF effect of flavonolignans from Silybum marianum with potential clinical significance. Our approach can be applied to other natural products to reveal their potential targets and mechanism of action.
- Publication type
- Journal Article MeSH
- MeSH
- Chemotherapy, Adjuvant methods MeSH
- Melanoma, Amelanotic MeSH
- Carcinoma, Basal Cell surgery classification therapy MeSH
- Immune Checkpoint Inhibitors administration & dosage therapeutic use MeSH
- Hutchinson's Melanotic Freckle MeSH
- Humans MeSH
- Melanoma surgery drug therapy radiotherapy MeSH
- Skin Neoplasms * diagnosis classification therapy MeSH
- Antineoplastic Agents therapeutic use MeSH
- Antineoplastic Protocols MeSH
- Proto-Oncogene Proteins B-raf antagonists & inhibitors MeSH
- Smoothened Receptor administration & dosage MeSH
- Practice Guidelines as Topic MeSH
- Carcinoma, Squamous Cell surgery classification therapy MeSH
- Check Tag
- Humans MeSH
Ultra-high molecular polyethylene (UHMWPE) is one of the most used materials of the acetabular liners in total tip arthroplasty (THA). Polyethylene has good tribological properties and biocompatibility. However, the lifetime of polyethylene implants is limited by wear related complications. Polyethylene material released into the periprosthetic environment induces osteolysis that can be followed by implant loosening. Wear of cup is influenced mainly by orientation of the cup in pelvis, by initial geometry before the material degradation and by tribological parameters. Aim of this study is to focus on the run-in-phase of the liner which is predictive for future life cycles of liner. Creep deformations of liners for 30°, 45°, 60° inclination angles surgically recommended for the positioning in pelvis were analyzed by the optical scanning method. Load tests were performed for 50,000 cycles. Creep deformations and surface changes were analyzed at each 10,000 cycles. The results showed that liners with 60° inclination angle had higher creep deformations. Penetration of femoral head was 0.04-0.05 mm and occupied bearing area was around 77%. The smallest creep was measured for the 45° angle. However, deformation in the superior quadrant of acetabular rim, which is vulnerable for potential fracture of a liner, was identified in this case. Topography of the surface bearing was also observed during the run-in-phase. The surface was smoothened and showed multidirectional scratches caused by the influence of third body particles. This phase was followed by early delamination. Flakes sized approximately 5-20 µm were observed on the UHMWPE surface. This is similar to the'flake' shape wear debris extracted in vivo. Detailed analysis of run-in phase of loading of modern polyethylene implants can help to distinguish between their creep deformation and true degradation. The latter contributes strongly to the development of wear related complications associated with THAs limiting substantially their time in service.
OBJECTIVES: Hedgehog signalling plays a critical role during the pathogenesis of fibrosis in systemic sclerosis (SSc). Besides canonical hedgehog signalling with smoothened (SMO)-dependent activation of GLI transcription factors, GLI can be activated independently of classical hedgehog ligands and receptors (so-called non-canonical pathways). Here, we aimed to evaluate the role of non-canonical hedgehog signalling in SSc and to test the efficacy of direct GLI inhibitors that target simultaneously canonical and non-canonical hedgehog pathways. METHODS: The GLI inhibitor GANT-61 was used to inhibit canonical as well as non-canonical hedgehog signalling, while the SMO inhibitor vismodegib was used to selectively target canonical hedgehog signalling. Furthermore, GLI2 was selectively depleted in fibroblasts using the Cre-LoxP system. The effects of pharmacological or genetic of GLI2 on transforming growth factor-β (TGF-β) signalling were analysed in cultured fibroblasts, in bleomycin-induced pulmonary fibrosis and in mice with overexpression of a constitutively active TGF-β receptor I. RESULTS: TGF-β upregulated GLI2 in a Smad3-dependent manner and induced nuclear accumulation and DNA binding of GLI2. Fibroblast-specific knockout of GLI2 protected mice from TBR(act)-induced fibrosis. Combined targeting of canonical and non-canonical hedgehog signalling with direct GLI inhibitors exerted more potent antifibrotic effects than selective targeting of canonical hedgehog signalling with SMO inhibitors in experimental dermal and pulmonary fibrosis. CONCLUSIONS: Our data demonstrate that hedgehog pathways and TGF-β signalling both converge to GLI2 and that GLI2 integrates those signalling to promote tissue fibrosis. These findings may have translational implications as non-selective inhibitors of GLI2 are in clinical use and selective molecules are currently in development.
- MeSH
- Anilides pharmacology MeSH
- Adult MeSH
- Fibroblasts drug effects metabolism MeSH
- Fibrosis MeSH
- Gene Knockout Techniques MeSH
- Plasminogen Activator Inhibitor 1 genetics MeSH
- Collagen Type I genetics MeSH
- Cells, Cultured MeSH
- Skin drug effects pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- RNA, Messenger metabolism MeSH
- Young Adult MeSH
- Mice, Knockout MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- Pulmonary Fibrosis chemically induced metabolism MeSH
- Smad3 Protein metabolism MeSH
- Protein Serine-Threonine Kinases antagonists & inhibitors genetics MeSH
- Hedgehog Proteins metabolism MeSH
- Pteridines pharmacology MeSH
- Pyridines pharmacology MeSH
- Pyrimidines pharmacology MeSH
- Smoothened Receptor antagonists & inhibitors MeSH
- Receptors, Transforming Growth Factor beta antagonists & inhibitors genetics MeSH
- Recombinant Proteins pharmacology MeSH
- Connective Tissue Growth Factor genetics MeSH
- Aged MeSH
- Signal Transduction drug effects MeSH
- Scleroderma, Systemic genetics metabolism MeSH
- Transforming Growth Factor beta metabolism pharmacology MeSH
- Kruppel-Like Transcription Factors antagonists & inhibitors genetics metabolism MeSH
- Animals MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Mice MeSH
- Aged MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Bazaliom nebo bazocelulární karcinom je nejčastějším kožním nádorem, který velmi výjimečně metastazuje, ale může způsobit značnou mutilaci při penetraci do okolních tkání. Postihuje především osoby se světlým fototypem a pozitivní rodinnou anamnézou. Léčbou volby je standardní chirurgická excize. Mohsova mikrografická chirurgie se provádí ambulantně nebo za hospitalizace, kdy se nádor exciduje a bezprostředně se vyšetří v mikroskopu. Kryoterapie je starší metoda, používaná pro velkou část kožních nádorů. Další možnosti, jako fotodynamická terapie, lokální imunoterapie, aktinoterapie nebo cílená terapie budou diskutovány.
Basal cell carcinoma (BCC) also known as basalioma or basal cell cancer, is the most common skin cancer. BCC has a very low metastatic risk. This tumor can cause significant disfigurement by invading surrounding tissues. It occurs mainly in fair-skinned patients with a family history of this cancer. Sunlight is a factor in about two-thirds of these cancers. Standard surgical excision is the treatment of choice. Mohs micrographic surgery is an outpatient or inpatient procedure in which the tumor is surgically excised and then immediately examined under a microscope. Cryosurgery is an old modality for the treatment of many skin cancers. Other treatment options incl. photodynamic therapy, topical imunotherapy, radiation or targeted therapy will be discussed.
- Keywords
- imiquimod, vismodegib,
- MeSH
- Adjuvants, Immunologic therapeutic use MeSH
- Aminoquinolines therapeutic use MeSH
- Anilides therapeutic use MeSH
- Carcinoma, Basal Cell * pathology therapy MeSH
- Photochemotherapy MeSH
- Humans MeSH
- Microsurgery MeSH
- Skin Neoplasms pathology therapy MeSH
- Antineoplastic Agents therapeutic use MeSH
- Pyridines therapeutic use MeSH
- Radiotherapy MeSH
- Smoothened Receptor MeSH
- Check Tag
- Humans MeSH
... Degradation of ß-Catenin 868 -- Hedgehog Proteins Bind to Patched, Relieving Its Inhibition of -- Smoothened ...
Sixth edition xxxiv, 1430 stran v různém stránkování : ilustrace (převážně barevné) ; 29 cm
- MeSH
- Cells * MeSH
- Molecular Biology MeSH
- Conspectus
- Biochemie. Molekulární biologie. Biofyzika
- NML Fields
- molekulární biologie, molekulární medicína
- NML Publication type
- učebnice vysokých škol
