• MeSH
• autoradiografie metody   využití   MeSH
• axony MeSH
• barvení a značení metody   využití   MeSH
• experimenty na zvířatech MeSH
• histocytochemie metody   využití   MeSH
• interferenční mikroskopie metody   využití   MeSH
• leucin diagnostické užití   MeSH
• nervová vlákna MeSH
• proteosyntéza MeSH
• ryby MeSH
• statistika jako téma MeSH
• transport proteinů MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH

• MeSH
• atrofie MeSH
• axony účinky léků   MeSH
• bílá hmota patologie   účinky léků   MeSH
• cílená molekulární terapie MeSH
• kongresy jako téma MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• randomizované kontrolované studie jako téma MeSH
• roztroušená skleróza * farmakoterapie   patofyziologie   MeSH
• šedá hmota patologie   účinky léků   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• Publikační typ
• novinové články MeSH

Mammalian neurons lose the ability to regenerate their central nervous system axons as they mature during embryonic or early postnatal development. Neuronal maturation requires a transformation from a situation in which neuronal components grow and assemble to one in which these components are fixed and involved in the machinery for effective information transmission and computation. To regenerate after injury, neurons need to overcome this fixed state to reactivate their growth programme. A variety of intracellular processes involved in initiating or sustaining neuronal maturation, including the regulation of gene expression, cytoskeletal restructuring and shifts in intracellular trafficking, have been shown to prevent axon regeneration. Understanding these processes will contribute to the identification of targets to promote repair after injury or disease.

• MeSH
• axony * fyziologie   MeSH
• lidé MeSH
• neurogeneze * fyziologie   MeSH
• neurony fyziologie   MeSH
• regenerace nervu * fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Investigating the molecular mechanisms governing developmental axon growth has been a useful approach for identifying new strategies for boosting axon regeneration after injury, with the goal of treating debilitating conditions such as spinal cord injury and vision loss. The picture emerging is that various axonal organelles are important centers for organizing the molecular mechanisms and machinery required for growth cone development and axon extension, and these have recently been targeted to stimulate robust regeneration in the injured adult central nervous system (CNS). This review summarizes recent literature highlighting a central role for organelles such as recycling endosomes, the endoplasmic reticulum, mitochondria, lysosomes, autophagosomes and the proteasome in developmental axon growth, and describes how these organelles can be targeted to promote axon regeneration after injury to the adult CNS. This review also examines the connections between these organelles in developing and regenerating axons, and finally discusses the molecular mechanisms within the axon that are required for successful axon growth.

• MeSH
• lidé MeSH
• organely metabolismus   patologie   MeSH
• poranění míchy * metabolismus   patologie   terapie   MeSH
• regenerace nervu * MeSH
• růstové kužele metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: The emergence of new SARS-CoV-2 variants of concern B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) that harbor mutations in the viral S protein raised concern about activity of current vaccines and therapeutic antibodies. Independent studies have shown that mutant variants are partially or completely resistant against some of the therapeutic antibodies authorized for emergency use. METHODS: We employed hybridoma technology, ELISA-based and cell-based S-ACE2 interaction assays combined with authentic virus neutralization assays to develop second-generation antibodies, which were specifically selected for their ability to neutralize the new variants of SARS-CoV-2. FINDINGS: AX290 and AX677, two monoclonal antibodies with non-overlapping epitopes, exhibit subnanomolar or nanomolar affinities to the receptor binding domain of the viral Spike protein carrying amino acid substitutions N501Y, N439K, E484K, K417N, and a combination N501Y/E484K/K417N found in the circulating virus variants. The antibodies showed excellent neutralization of an authentic SARS-CoV-2 virus representing strains circulating in Europe in spring 2020 and also the variants of concern B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). In addition, AX677 is able to bind Omicron Spike protein just like the wild type Spike. The combination of the two antibodies prevented the appearance of escape mutations of the authentic SARS-CoV-2 virus. Prophylactic administration of AX290 and AX677, either individually or in combination, effectively reduced viral burden and inflammation in the lungs, and prevented disease in a mouse model of SARS-CoV-2 infection. INTERPRETATION: The virus-neutralizing properties were fully reproduced in chimeric mouse-human versions of the antibodies, which may represent a promising tool for COVID-19 therapy. FUNDING: The study was funded by AXON Neuroscience SE and AXON COVIDAX a.s.

• MeSH
• angiotensin-konvertující enzym 2 chemie   genetika   metabolismus   MeSH
• antigenní drift a shift MeSH
• COVID-19 virologie   MeSH
• farmakoterapie COVID-19 MeSH
• glykoprotein S, koronavirus genetika   imunologie   metabolismus   MeSH
• imunodominantní epitopy imunologie   MeSH
• kinetika MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• monoklonální protilátky imunologie   terapeutické užití   MeSH
• mutace MeSH
• myši MeSH
• neutralizační testy MeSH
• plíce patologie   MeSH
• protinádorové látky imunologicky aktivní imunologie   terapeutické užití   MeSH
• SARS-CoV-2 genetika   imunologie   izolace a purifikace   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Obsahem sdělení je přehled nejnovějších poznatků, týkajících se patofyziologie traumatického axonálního postižení a z toho vyplývajících forenzních a klinických implikací. Oproti mechanistické představě je zdůrazněna dynamická kaskáda biochemických pochodů na subcelulární úrovni, ve svém konečném důsledku vedoucím k axonotmesi. Diskutovány jsou i možnosti zásahu do této kaskády, především pokud se týče toxických látek. V závěru je zdůrazněna nutnost zohlednění těchto poznatků v znalecké činnosti.

The paper presents the most recent knowledge related to the patophysiology of traumatic axonal injury and resulting forensic and clinical implications. The mechanistic idea is replaced by the idea of dynamic cascade of biochemical events on subcellular level, finally leading to axonotmesis. Interventions targeted to the cascade are discussed with respect to toxic drugs. Finally a necessity to consider the new knowledge in forensic problems is outlined.

• MeSH
• axony fyziologie   patologie   MeSH
• bezvědomí komplikace   MeSH
• biochemické jevy MeSH
• difuzní axonální poranění patofyziologie   patologie   MeSH
• imunohistochemie využití   MeSH
• kraniocerebrální traumata komplikace   patofyziologie   patologie   MeSH
• lidé MeSH
• nežádoucí účinky léčiv komplikace   patofyziologie   patologie   MeSH
• poranění mozku patofyziologie   patologie   MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH

Neurons lose intrinsic axon regenerative ability with maturation, but the mechanism remains unclear. Using an in-vitro laser axotomy model, we show a progressive decline in the ability of cut CNS axons to form a new growth cone and then elongate. Failure of regeneration was associated with increased retraction after axotomy. Transportation into axons becomes selective with maturation; we hypothesized that selective exclusion of molecules needed for growth may contribute to regeneration decline. With neuronal maturity rab11 vesicles (which carry many molecules involved in axon growth) became selectively targeted to the somatodendritic compartment and excluded from axons by predominant retrograde transport However, on overexpression rab11 was mistrafficked into proximal axons, and these axons showed less retraction and enhanced regeneration after axotomy. These results suggest that the decline of intrinsic axon regenerative ability is associated with selective exclusion of key molecules, and that manipulation of transport can enhance regeneration.

• MeSH
• axony fyziologie   MeSH
• biologický transport MeSH
• buněčná diferenciace MeSH
• cytoplazmatické vezikuly metabolismus   MeSH
• potkani Sprague-Dawley MeSH
• rab proteiny vázající GTP metabolismus   MeSH
• regenerace * MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Přestože návykové látky mají rozdílnou chemickou strukturu i metabolizmus a působí v různých mozkových oblastech i na různých buněčných strukturách, vyvíjejí závislost, která má charakteristické společné znaky. Některé látky vyvolávající závislost působí na cílová místa přímo, jiná prostřednictvím svých metabolitů nebo biogenních aminů. Alkohol sám ovlivňuje fluiditu buněčných membrán, facilituje funkci GABA receptoru, inhibuje funkci NMDA receptoru a jeho reaktivní metabolit acetaldehyd tvoří s biogenními aminy kondenzační produkty, které mají strukturu podobnou opioidům. Opioidy působí na noradrenergních buňkách nucleus coeruleus, interneuronech i dopaminergních neuronech ventrálního tegmenta (VTA), a také přímo na buňkách nucleus accumbens. Účinky návykových látek vyúsťují v aktivaci mezolimbické a mezokortikální dráhy. Na buněčné úrovni dochází k aktivaci cAMP signální dráhy, transkripčních faktorů a genové exprese. Tyto neuroplastické změny jsou dlouhodobé a přetrvávají po dobu desetiletí i celoživotně.

Although addictive drugs have different chemical structures, metabolism and exert their effect in different brain areas and different cellular structures, they develop dependence which has common characteristics. Some addictive drugs influence their target sites directly, the other through their metabolites or biogenic amines. Alcohol oneself influences fluidity of cell membranes, facilitates GABA and inhibits NMDA receptor function. Its reactive metabolite acetaldehyde also combine with biogenic amines to create substances with chemical structure similar to that of opioides. Opioides influence noradrenergic cells of ncl. coeruleus, interneurons and dopaminergic neurons of ventral tegmentum and cells of ncl. accumbens. All effects of addictive drugs lead in activation of mesolimbic an mesocortical pathways. On the cellular level develops acti- vation of cAMP pathway, transscription factors and gene expression. These neuroplastic changes are long lasting and persisting for many decades or even for the rest of life.

• Klíčová slova
• návykové látky, cílová místa, závislost, bažení,
• MeSH
• neuroplasticita MeSH
• Publikační typ
• abstrakty MeSH

Fragile X syndrome (FXS) is the most frequently inherited form of intellectual disability and prevalent single-gene cause of autism. A priority of FXS research is to determine the molecular mechanisms underlying the cognitive and social functioning impairments in humans and the FXS mouse model. Glutamate ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate a majority of fast excitatory neurotransmission in the central nervous system and are critically important for nearly all aspects of brain function, including neuronal development, synaptic plasticity, and learning and memory. Both preclinical and clinical studies have indicated that expression, trafficking, and functions of AMPARs are altered and result in altered synapse development and plasticity, cognitive impairment, and poor mental health in FXS. In this review, we discuss the contribution of AMPARs to disorders of FXS by highlighting recent research advances with a specific focus on change in AMPARs expression, trafficking, and dependent synaptic plasticity. Since changes in synaptic strength underlie the basis of learning, development, and disease, we suggest that the current knowledge base of AMPARs has reached a unique point to permit a comprehensive re-evaluation of their roles in FXS.

• MeSH
• AMPA receptory genetika   metabolismus   MeSH
• lidé MeSH
• mentální retardace genetika   metabolismus   MeSH
• mutace fyziologie   MeSH
• neuroplasticita fyziologie   MeSH
• syndrom fragilního X genetika   metabolismus   MeSH
• transport proteinů fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Multiple sclerosis (MS) is a neurologic autoimmune disorder featured by chronic inflammation of the central nervous system, demyelination and axonal damage. Recently, the term "oxinflammation" has been proposed to depict the vicious circle of chronic inflammation and oxidative stress (OS). OS promotes demyelination and neurodegeneration directly, by oxidation of lipids, proteins, and DNA but also indirectly, by inducing a dysregulation of the immunity and favoring the state of pro-inflammatory response. Many of the actors of this delicately tuned network are controlled by Keap1/Nrf2/ARE signaling pathway, a principal regulator of antioxidant and phase II detoxification genes. This pathway also has a pivotal role in inflammation, and therefore possesses a great potential in the treatment of MS. The aim of this review is to provide the newest insights in the preclinical and clinical evidence of Nrf2 induction in the regeneration of the antioxidant response and attenuation of inflammation in MS. Preclinical studies have indicated that activators of this pathway, such as epigallocatechin gallate (EGCG), curcumin, melatonin, resveratrol, and sulforaphane might be a promising therapeutic option in amelioration of MS symptoms, nevertheless, the efficacy and safety of these compounds have to be confirmed in future clinical trials.

• MeSH
• faktor 2 související s NF-E2 účinky léků   MeSH
• KEAP-1 účinky léků   MeSH
• lidé MeSH
• roztroušená skleróza farmakoterapie   MeSH
• signální transdukce účinky léků   MeSH
• vezikulární transportní proteiny účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH