• Klíčová slova
• Accessory pathway, CARTO, Catheter ablation, Mitral isthmus, Tachycardia,
• MeSH
• elektrokardiografie * MeSH
• katetrizační ablace škodlivé účinky   metody   MeSH
• lidé MeSH
• mladý dospělý MeSH
• pooperační komplikace * MeSH
• převodní systém srdeční patofyziologie   chirurgie   MeSH
• přídatný svazek chirurgie   MeSH
• srdeční frekvence fyziologie   MeSH
• tachykardie diagnóza   etiologie   patofyziologie   MeSH
• Check Tag
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

The copper(II), cobalt(II), and zinc(II) complexes with 2-(1H-benzimidazol-2-ylmethylsulfanylmethyl)-1H-benzimidazole (tbb) and 2-[2-[2-(1H-benzimidazol-2-yl)ethylsulfanyl]ethyl]-1H-benzimidazole (tebb), [Cu(tbb)Cl2] (1), [Co(tbb)Cl2] (2), [Zn(tbb)Cl2] (3), [Cu(tebb)Cl(H2O)]Cl (4), [Co(tebb)Cl2]n·nCH3OH (5) and [Zn(tebb)Cl(H2O)]Cl (6), have been prepared and evaluated for antiproliferative activity. The structure of (4) was proved by X-ray diffraction crystallography. The coordination compounds were tested for their cytotoxic activities in cancer cell lines in vitro. The lower IC50 values were obtained for Co(II), Cu(II), and Zn(II) complexes with tebb in comparison with tbb complexes. Complex 2 showed strong antiproliferative selectivity for leukemia CEM cells and nontoxicity towards other tested cell lines and normal human cells (BJ and RPE-1). Proapoptotic activity of 2 and 5 were weaker than positive control cisplatin, but the big advantage of these complexes was their zero-cytotoxicity for normal healthy cells in contrast to the high cytotoxicity of cisplatin. The activation of apoptotic initiation phase was detected in neuroblastoma cancer cell line SH-SY5Y where 5 was cytotoxic without fragmentation of cells. Interestingly, complexes 5, 6, and tebb, together with cisplatin, dramatically impaired the mitochondrial membrane potential of SH-SY5Y after 72 h. Taken together, we demonstrated that our compounds trigger apoptosis via the mitochondrial pathway.

• Klíčová slova
• Antiproliferative activity, Apoptosis, Benzimidazole, Biocompatibility, Coordination compound, Mitochondria,
• MeSH
• apoptóza * účinky léků   MeSH
• benzimidazoly * chemie   farmakologie   MeSH
• kobalt chemie   farmakologie   MeSH
• komplexní sloučeniny * farmakologie   chemie   chemická syntéza   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• měď chemie   farmakologie   MeSH
• mitochondrie * metabolismus   účinky léků   MeSH
• nádorové buněčné linie MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• zinek chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzimidazoly * MeSH
• kobalt MeSH
• komplexní sloučeniny * MeSH
• měď MeSH
• protinádorové látky * MeSH
• zinek MeSH

Wnt signaling cascade has developed together with multicellularity to orchestrate the development and homeostasis of complex structures. Wnt pathway components - such as β-catenin, Dishevelled (DVL), Lrp6, and Axin-- are often dedicated proteins that emerged in evolution together with the Wnt signaling cascade and are believed to function primarily in the Wnt cascade. It is interesting to see that in recent literature many of these proteins are connected with cellular functions that are more ancient and not limited to multicellular organisms - such as cell cycle regulation, centrosome biology, or cell division. In this review, we summarize the recent literature describing this crosstalk. Specifically, we attempt to find the answers to the following questions: Is the response to Wnt ligands regulated by the cell cycle? Is the centrosome and/or cilium required to activate the Wnt pathway? How do Wnt pathway components regulate the centrosomal cycle and cilia formation and function? We critically review the evidence that describes how these connections are regulated and how they help to integrate cell-to-cell communication with the cell and the centrosomal cycle in order to achieve a fine-tuned, physiological response.

• Klíčová slova
• Wnt, cell cycle, centrosome, cilium, crosstalk, planar cell polarity,
• MeSH
• buněčný cyklus * MeSH
• centrozom metabolismus   MeSH
• lidé MeSH
• mezibuněčná komunikace MeSH
• polarita buněk MeSH
• signální dráha Wnt * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: The mitogen-activated protein kinase (MAPK) pathway contributes to regulation of many cellular functions, such as cell proliferation and differentiation, mobility and apoptosis. Extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) /p38 and ERK5 construct the three main modules in this pathway. The Raf-ERK1/2 and JNK cascades contribute in cell proliferation, migration, and survival and are principal regulators of malignant phenotype. This pathway is itself regulated by several outside signals as well as lateral signals from other pathways, which construct a complex network. Long non-coding RNAs (lncRNAs) as principal modulators of gene expression at transcriptional and post-transcriptional levels also regulate this pathway. In addition, lncRNA signature can be used as biomarker and target of novel treatment strategies in cancer patients. AIM: To explore the role of lncRNAs in regulation of MAPK pathway. CONCLUSION: Considering the role of this pathway in the pathogenesis of several cancers, alterations in lncRNA expression lead to changes in MAPK pathway resulting in inhibition of apoptosis and induction of cell proliferation and migration. Moreover, some lncRNAs participate in cross-talk between MAPK and other cancer-related pathways, such as PI3K/Akt pathway through regulation of certain shared proteins between these pathways. Based on the availability of certain anticancer drugs that modulate this pathway, identification of lncRNAs that affect this pathway would help in establishment of effective therapies.Key words: RNA - long noncoding - mitogen-activated protein kinases - signal transduction.

• MeSH
• lidé MeSH
• MAP kinasový signální systém * MeSH
• nádory genetika   metabolismus   MeSH
• RNA dlouhá nekódující * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• RNA dlouhá nekódující * MeSH

Aberrations in various cellular signaling pathways are instrumental in regulating cellular metabolism, tumor development, growth, proliferation, metastasis and cytoskeletal reorganization. The fundamental cellular signaling cascade involved in these processes, the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR), closely related to the mitogen-activated protein kinase (MAPK) pathway, is a crucial and intensively explored intracellular signaling pathway in tumorigenesis. Various activating mutations in oncogenes together with the inactivation of tumor suppressor genes are found in diverse malignancies across almost all members of the pathway. Substantial progress in uncovering PI3K/AKT/mTOR alterations and their roles in tumorigenesis has enabled the development of novel targeted molecules with potential for developing efficacious anticancer treatment. Two approved anticancer drugs, everolimus and temsirolimus, exemplify targeted inhibition of PI3K/AKT/mTOR in the clinic and many others are in preclinical development as well as being tested in early clinical trials for many different types of cancer. This review focuses on targeted PI3K/AKT/mTOR signaling from the perspective of novel molecular targets for cancer therapy found in key pathway members and their corresponding experimental therapeutic agents. Various aberrant prognostic and predictive biomarkers are also discussed and examples are given. Novel approaches to PI3K/AKT/mTOR pathway inhibition together with a better understanding of prognostic and predictive markers have the potential to significantly improve the future care of cancer patients in the current era of personalized cancer medicine.

• Klíčová slova
• PI3K pathway, Predictive biomarkers, Targeted therapy,
• MeSH
• 1-fosfatidylinositol-3-kinasa metabolismus   MeSH
• cílená molekulární terapie * MeSH
• inhibitory fosfoinositid-3-kinasy * MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• nádory farmakoterapie   enzymologie   patologie   MeSH
• protinádorové látky terapeutické užití   MeSH
• protoonkogenní proteiny c-akt antagonisté a inhibitory   metabolismus   MeSH
• racionální návrh léčiv MeSH
• signální transdukce účinky léků   MeSH
• TOR serin-threoninkinasy antagonisté a inhibitory   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• 1-fosfatidylinositol-3-kinasa MeSH
• inhibitory fosfoinositid-3-kinasy * MeSH
• inhibitory proteinkinas MeSH
• protinádorové látky MeSH
• protoonkogenní proteiny c-akt MeSH
• TOR serin-threoninkinasy MeSH

BACKGROUND: Stroke is devastating cerebrovascular event which is responsible for 6.7 million deaths each year worldwide. Inflammation plays an important role in the pathophysiology of stroke. Targeting inflammation after stroke is highly actual topic for both experimental and clinical research. METHODS: Research articles related to cholinergic anti-inflammatory pathway (CHAIP) and stroke were reviewed. The first part of review describes the basic characteristics of inflammatory response after stroke, main components and function of CHAIP. The second part reviews studies focused on CHAIP as a therapeutic target for ischemic and hemorrhagic stroke. Both pharmacological stimulation of α7 nAChR and vagus nerve stimulation after stroke are reviewed. RESULTS: Cholinergic anti-inflammatory pathway (CHAIP) is a physiological mechanism by which central nervous system regulates immune response and controls inflammation. Vagus nerve, spleen and α7 nicotinic acetylcholine receptor (α7 nAChR) are the main components of CHAIP. CONCLUSION: Targeting cholinergic anti-inflammatory pathway is a promising way of immunomodulation which attenuates inflammation in a complex manner without causing immunosuppression.

• Klíčová slova
• Cerebral ischemia, Vagus nerve stimulation, cholinergic anti-inflammatory pathway, inflammation, intracerebral hemorrhage, stroke, subarachnoid hemorrhage, α7 nicotinic acetylcholine receptor (α7 nAChR),
• MeSH
• alfa7 nikotinové acetylcholinové receptory fyziologie   MeSH
• centrální nervový systém fyziologie   MeSH
• cévní mozková příhoda imunologie   patofyziologie   MeSH
• lidé MeSH
• nervus vagus fyziologie   MeSH
• slezina fyziologie   MeSH
• zánět patofyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• alfa7 nikotinové acetylcholinové receptory MeSH

African Trypanosomes have developed elaborate mechanisms to escape the adaptive immune response, but little is known about complement evasion particularly at the early stage of infection. Here we show that ISG65 of the human-infective parasite Trypanosoma brucei gambiense is a receptor for human complement factor C3 and its activation fragments and that it takes over a role in selective inhibition of the alternative pathway C5 convertase and thus abrogation of the terminal pathway. No deposition of C4b, as part of the classical and lectin pathway convertases, was detected on trypanosomes. We present the cryo-electron microscopy (EM) structures of native C3 and C3b in complex with ISG65 which reveal a set of modes of complement interaction. Based on these findings, we propose a model for receptor-ligand interactions as they occur at the plasma membrane of blood-stage trypanosomes and may facilitate innate immune escape of the parasite.

• MeSH
• aktivace komplementu MeSH
• alternativní dráha komplementu MeSH
• C3-C5-konvertasy komplementu metabolismus   MeSH
• elektronová kryomikroskopie MeSH
• komplement C3 * metabolismus   MeSH
• komplement C5 metabolismus   MeSH
• lidé MeSH
• Trypanosoma brucei gambiense * metabolismus   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• C3 protein, human MeSH Prohlížeč
• C3-C5-konvertasy komplementu MeSH
• komplement C3 * MeSH
• komplement C5 MeSH

Animals sense and respond to nutrient availability in their environments, a task coordinated in part by the mTOR complex 1 (mTORC1) pathway. mTORC1 regulates growth in response to nutrients and, in mammals, senses specific amino acids through specialized sensors that bind the GATOR1/2 signaling hub. Given that animals can occupy diverse niches, we hypothesized that the pathway might evolve distinct sensors in different metazoan phyla. Whether such customization occurs, and how the mTORC1 pathway might capture new inputs, is unknown. Here, we identify the Drosophila melanogaster protein Unmet expectations (CG11596) as a species-restricted methionine sensor that directly binds the fly GATOR2 complex in a fashion antagonized by S-adenosylmethionine (SAM). We find that in Dipterans GATOR2 rapidly evolved the capacity to bind Unmet and to thereby repurpose a previously independent methyltransferase as a SAM sensor. Thus, the modular architecture of the mTORC1 pathway allows it to co-opt preexisting enzymes to expand its nutrient sensing capabilities, revealing a mechanism for conferring evolvability on an otherwise conserved system.

• MeSH
• Drosophila melanogaster * metabolismus   MeSH
• mTORC1 metabolismus   MeSH
• multiproteinové komplexy metabolismus   MeSH
• S-adenosylmethionin MeSH
• savci metabolismus   MeSH
• TOR serin-threoninkinasy * metabolismus   MeSH
• živiny MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• mTORC1 MeSH
• multiproteinové komplexy MeSH
• S-adenosylmethionin MeSH
• TOR serin-threoninkinasy * MeSH

BACKGROUND: Autosomal-dominant mutations in the Park8 gene encoding Leucine-rich repeat kinase 2 (LRRK2) have been identified to cause up to 40% of the genetic forms of Parkinson's disease. However, the function and molecular pathways regulated by LRRK2 are largely unknown. It has been shown that LRRK2 serves as a scaffold during activation of WNT/β-catenin signaling via its interaction with the β-catenin destruction complex, DVL1-3 and LRP6. In this study, we examine whether LRRK2 also interacts with signaling components of the WNT/Planar Cell Polarity (WNT/PCP) pathway, which controls the maturation of substantia nigra dopaminergic neurons, the main cell type lost in Parkinson's disease patients. METHODS: Co-immunoprecipitation and tandem mass spectrometry was performed in a mouse substantia nigra cell line (SN4741) and human HEK293T cell line in order to identify novel LRRK2 binding partners. Inhibition of the WNT/β-catenin reporter, TOPFlash, was used as a read-out of WNT/PCP pathway activation. The capacity of LRRK2 to regulate WNT/PCP signaling in vivo was tested in Xenopus laevis' early development. RESULTS: Our proteomic analysis identified that LRRK2 interacts with proteins involved in WNT/PCP signaling such as the PDZ domain-containing protein GIPC1 and Integrin-linked kinase (ILK) in dopaminergic cells in vitro and in the mouse ventral midbrain in vivo. Moreover, co-immunoprecipitation analysis revealed that LRRK2 binds to two core components of the WNT/PCP signaling pathway, PRICKLE1 and CELSR1, as well as to FLOTILLIN-2 and CULLIN-3, which regulate WNT secretion and inhibit WNT/β-catenin signaling, respectively. We also found that PRICKLE1 and LRRK2 localize in signalosomes and act as dual regulators of WNT/PCP and β-catenin signaling. Accordingly, analysis of the function of LRRK2 in vivo, in X. laevis revelaed that LRKK2 not only inhibits WNT/β-catenin pathway, but induces a classical WNT/PCP phenotype in vivo. CONCLUSIONS: Our study shows for the first time that LRRK2 activates the WNT/PCP signaling pathway through its interaction to multiple WNT/PCP components. We suggest that LRRK2 regulates the balance between WNT/β-catenin and WNT/PCP signaling, depending on the binding partners. Since this balance is crucial for homeostasis of midbrain dopaminergic neurons, we hypothesize that its alteration may contribute to the pathophysiology of Parkinson's disease.

• Klíčová slova
• CELSR1, DVL, Dopaminergic neurons, Endocytosis, Immunoprecipitation, PRICKLE1, Parkinson’s disease, Signalosomes, Substantia nigra, WNT/planar cell polarity,
• MeSH
• beta-katenin metabolismus   MeSH
• dopaminergní neurony metabolismus   MeSH
• kadheriny metabolismus   MeSH
• lidé MeSH
• LRRK2 genetika   metabolismus   MeSH
• mutace genetika   MeSH
• polarita buněk fyziologie   MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• proteomika metody   MeSH
• signální dráha Wnt fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• beta-katenin MeSH
• CELSR1 cadherin, human MeSH Prohlížeč
• CTNNB1 protein, human MeSH Prohlížeč
• integrin-linked kinase MeSH Prohlížeč
• kadheriny MeSH
• LRRK2 protein, human MeSH Prohlížeč
• LRRK2 MeSH
• protein-serin-threoninkinasy MeSH

Significance: As the central metabolic organ, the liver is exposed to a variety of potentially cytotoxic, proinflammatory, profibrotic, and carcinogenic stimuli. To protect the organism from these deleterious effects, the liver has evolved a number of defense systems, which include antioxidant substrates and enzymes, anti-inflammatory tools, enzymatic biotransformation systems, and metabolic pathways. Recent Advances: One of the pivotal systems that evolved during phylogenesis was the heme catabolic pathway. Comprising the important enzymes heme oxygenase and biliverdin reductase, this complex pathway has a number of key functions including enzymatic activities, but also cell signaling, and DNA transcription. It further generates two important bile pigments, biliverdin and bilirubin, as well as the gaseous molecule carbon monoxide. These heme degradation products have potent antioxidant, immunosuppressive, and cytoprotective effects. Recent data suggest that the pathway participates in the regulation of metabolic and hormonal processes implicated in the pathogenesis of hepatic and other diseases. Critical Issues: This review discusses the impact of the heme catabolic pathway on major liver diseases, with particular focus on the involvement of cellular targeting and signaling in the pathogenesis of these conditions. Future Directions: To utilize the biological consequences of the heme catabolic pathway, several unique therapeutic strategies have been developed. Research indicates that pharmaceutical, nutraceutical, and lifestyle modifications positively affect the pathway, delivering potentially long-term clinical benefits. However, further well-designed studies are needed to confirm the clinical benefits of these approaches. Antioxid. Redox Signal. 35, 734-752.

• Klíčová slova
• bilirubin, biliverdin, carbon monoxide, heme catabolic pathway, heme oxygenase, oxidative stress,
• MeSH
• biliverdin metabolismus   MeSH
• hem * metabolismus   MeSH
• hemová oxygenasa (decyklizující) metabolismus   MeSH
• hemoxygenasa-1 metabolismus   MeSH
• lidé MeSH
• nemoci jater * MeSH
• oxid uhelnatý metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• biliverdin MeSH
• hem * MeSH
• hemová oxygenasa (decyklizující) MeSH
• hemoxygenasa-1 MeSH
• oxid uhelnatý MeSH