Revmatoidní artritida (RA) je nejčastější zánětlivé revmatické onemocnění postihující až 1 % populace, které prokazatelně zhoršuje kvalitu života. Bolest je obvykle označována za hlavní limitující symptom pacientů, může být přítomna neustále a úleva od ní je hodnocena jako nejvyšší priorita při zlepšování pocitu zdraví a kvality života. Bolest u RA má komplexní charakter, je způsobena více mechanismy a může být jak nociceptivního, tak neuropatického charakteru. Nociceptivní bolest, která u RA převažuje, vzniká na principu periferní senzitizace (zvýšení citlivosti periferních nervů) působením na periferní nervová zakončení, která jsou drážděna lokálními působky (zánětlivými cytokiny a dalšími mediátory) produkovanými imunitními buňkami a buňkami poškozené tkáně v místě zánětu. Mezi tyto působky řadíme prostaglandiny (zejména prostaglandin E2), interleukin-1, interleukin-6 a cyklooxygenázu typu 1 i 2. Přímý vliv na volná nervová zakončení mají dále kalium, bradykinin a serotonin. Zmíněné působky vedou k podráždění nociceptorů, které uvolňují substanci P a jiné neuropeptidy, jež způsobují degranulaci mastocytů a uvolnění histaminu. Substance P má dále vliv na vazodilataci okolních kapilár, vznik otoku a uvolnění dalších molekul bradykininu. V důsledku zmíněného mechanismu dochází k aktivaci intracelulárních signálních drah a fosforylačních kaskád. Vyjma periferní senzitizace se u RA uplatňuje i senzitizace centrální, tedy zvýšená citlivost nociceptivních neuronů centrálního nervového systému na normální či podprahové podněty. Výsledkem je perzistující bolest a zvýšení citlivosti na bolest i v oblastech mimo postižený kloub, distálních či vzdálených. Tento mechanismus se podílí též na vzniku fibromyalgie, která se vyskytuje až u 20 % pacientů s RA. Přehledné sdělení se zabývá klinickými aspekty bolesti u RA a současnými léčebnými možnostmi.
Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease, affecting up to 1% of the population, and has been shown to impair quality of life. Pain is usually identified as the main limiting symptom for patients, it can be present all the time, and relief from it is rated as the highest priority in improving health and quality of life. Pain in RA is complex, caused by multiple mechanisms, and can be both nociceptive and neuropathic in nature. Nociceptive pain, which is predominant in RA, is caused by peripheral sensitization (increased sensitivity of peripheral nerves) acting on peripheral nerve endings that are irritated by local agents (inflammatory cytokines and other mediators) produced by immune cells and cells of the damaged tissue at the site of inflammation. These agents include prostaglandins (especially prostaglandin E2), interleukin-1, interleukin-6, and both type 1 and type 2 cyclooxygenase. Potassium, bradykinin, and serotonin also have a direct effect on free nerve endings. These effects lead to irritation of nociceptors, which release substance P and other neuropeptides that cause mast cell degranulation and histamine release. Substance P also affects vasodilation of the surrounding capillaries, the development of edema, and the release of other bradykinin molecules. As a result of this mechanism, intracellular signaling pathways and phosphorylation cascades are activated. Apart from peripheral sensitization, RA also involves central sensitization, i.e. increased sensitivity of nociceptive neurons of the central nervous system to normal or subliminal stimuli. The result is persistent pain and increased sensitivity to pain even in areas outside the affected joint, distal or remote. This mechanism is also involved in the development of fibromyalgia, which occurs in up to 20% of RA patients. This review discusses the clinical aspects of pain in RA and current treatment options.
- MeSH
- analgetika farmakologie klasifikace terapeutické užití MeSH
- chronická bolest * diagnóza etiologie farmakoterapie patofyziologie MeSH
- kanabinoidy farmakologie klasifikace terapeutické užití MeSH
- kvalita života MeSH
- lidé MeSH
- management bolesti metody MeSH
- měření bolesti metody MeSH
- revmatoidní artritida * diagnóza farmakoterapie komplikace patofyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
The pregnane X receptor (PXR) is a ligand-activated nuclear receptor controlling hepatocyte expression of numerous genes. Although expression changes in xenobiotic-metabolizing, lipogenic, gluconeogenic and bile acid synthetic genes have been described after PXR activation, the temporal dynamics of their expression is largely unknown. Recently, 3D spheroids of primary human hepatocytes (PHHs) have been characterized as the most phenotypically relevant hepatocyte model. We used 3D PHHs to assess time-dependent expression profiles of 12 prototypic PXR-controlled genes in the time course of 168 h of rifampicin treatment (1 or 10 μM). We observed a similar bell-shaped time-induction pattern for xenobiotic-handling genes (CYP3A4, CYP2C9, CYP2B6, and MDR1). However, we observed either biphasic profiles for genes involved in endogenous metabolism (FASN, GLUT2, G6PC, PCK1, and CYP7A1), a decrease for SHP or oscillation for PDK4 and PXR. The rifampicin concentration determined the expression profiles for some genes. Moreover, we calculated half-lives of CYP3A4 and CYP2C9 mRNA under induced or basal conditions and we used a mathematical model to describe PXR-mediated regulation of CYP3A4 expression employing 3D PHHs. The study shows the importance of long-term time-expression profiling of PXR target genes in phenotypically stable 3D PHHs and provides insight into PXR function in liver beyond our knowledge from conventional 2D in vitro models.
Defective viral genomes (DVGs) are truncated and/or rearranged viral genomes produced during virus replication. Described in many RNA virus families, some of them have interfering activity on their parental virus and/or strong immunostimulatory potential, and are being considered in antiviral approaches. Chikungunya virus (CHIKV) is an alphavirus transmitted by Aedes spp. that infected millions of humans in the last 15 years. Here, we describe the DVGs arising during CHIKV infection in vitro in mammalian and mosquito cells, and in vivo in experimentally infected Aedes aegypti mosquitoes. We combined experimental and computational approaches to select DVG candidates most likely to have inhibitory activity and showed that, indeed, they strongly interfere with CHIKV replication both in mammalian and mosquito cells. We further demonstrated that some DVGs present broad-spectrum activity, inhibiting several CHIKV strains and other alphaviruses. Finally, we showed that pre-treating Aedes aegypti with DVGs prevented viral dissemination in vivo.
- MeSH
- Aedes virologie MeSH
- antivirové látky farmakologie MeSH
- defektní viry genetika MeSH
- genom virový * MeSH
- horečka chikungunya imunologie přenos virologie MeSH
- komáří přenašeči virologie MeSH
- lidé MeSH
- replikace viru * MeSH
- virus chikungunya genetika růst a vývoj izolace a purifikace MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Mathematical models of in vitro viral kinetics help us understand and quantify the main determinants underlying the virus-host cell interactions. We aimed to provide a numerical characterization of the Zika virus (ZIKV) in vitro infection kinetics, an arthropod-borne emerging virus that has gained public recognition due to its association with microcephaly in newborns. The mathematical model of in vitro viral infection typically assumes that degradation of extracellular infectious virus proceeds in an exponential manner, that is, each viral particle has the same probability of losing infectivity at any given time. We incubated ZIKV stock in the cell culture media and sampled with high frequency for quantification over the course of 96 h. The data showed a delay in the virus degradation in the first 24 h followed by a decline, which could not be captured by the model with exponentially distributed decay time of infectious virus. Thus, we proposed a model, in which inactivation of infectious ZIKV is gamma distributed and fit the model to the temporal measurements of infectious virus remaining in the media. The model was able to reproduce the data well and yielded the decay time of infectious ZIKV to be 40 h. We studied the in vitro ZIKV infection kinetics by conducting cell infection at two distinct multiplicity of infection and measuring viral loads over time. We fit the mathematical model of in vitro viral infection with gamma distributed degradation time of infectious virus to the viral growth data and identified the timespans and rates involved within the ZIKV-host cell interplay. Our mathematical analysis combined with the data provides a well-described example of non-exponential viral decay dynamics and presents numerical characterization of in vitro infection with ZIKV.
- MeSH
- Cercopithecus aethiops MeSH
- infekce virem zika virologie MeSH
- kinetika MeSH
- replikace viru * MeSH
- reprodukovatelnost výsledků MeSH
- teoretické modely * MeSH
- Vero buňky MeSH
- virová nálož MeSH
- virus zika růst a vývoj fyziologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
The search for mates is often accompanied with conspicuous behaviour or morphology that can be exploited by predators. Here we explore the evolutionary consequences of a trade-off that arises naturally between mate acquisition and risk of predation and study evolution of the rate at which male prey search for mates in a population subject to a mate-finding Allee effect and exposed to either generalist or specialist predators. Since we show that the mate search rate determines the strength of the mate-finding Allee effect, we can alternatively view this as evolution of the mate-finding Allee effect in prey. We contrast two different life histories and find that, predominantly, male prey either evolve towards the maximal mate search rate yielding the weakest possible mate-finding Allee effect (thus showing no adaptive response in mating behaviour to predation risk) or evolutionary bi-stability occurs. In the latter case, males evolve a relatively low mate search rate (hence a relatively strong mate-finding Allee effect, interpreted as an adaptive response of male prey to predation) when initially slow or the maximal mate search rate when initially fast. Disruptive selection does not occur in populations exposed to generalist predators but is possible when predators are specialists. The dimorphic phase, in which fast and conspicuous male prey coexist with slow and cryptic ones, is however but a transient in evolutionary dynamics as one branch goes extinct while the other evolves towards the maximal mate search rate.
- MeSH
- algoritmy MeSH
- biologická evoluce * MeSH
- biologické modely MeSH
- kompetitivní chování fyziologie MeSH
- predátorské chování fyziologie MeSH
- rozmnožování fyziologie MeSH
- sexuální chování zvířat fyziologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Sexually reproducing organisms require males and females to find each other. Increased difficulty of females finding mates as male density declines is the most frequently reported mechanism of Allee effects in animals. Evolving more effective mate search may alleviate Allee effects, but may depend on density regimes a population experiences. In particular, high-density populations may evolve mechanisms that induce Allee effects which become detrimental when populations are reduced and maintained at a low density. We develop an individual-based, eco-genetic model to study how mating systems and fitness trade-offs interact with changes in population density to drive evolution of the rate at which males or females search for mates. Finite mate search rate triggers Allee effects in our model and we explore how these Allee effects respond to such evolution. We allow a population to adapt to several population density regimes and examine whether high-density populations are likely to reverse adaptations attained at low densities. We find density-dependent selection in most of scenarios, leading to search rates that result in lower Allee thresholds in populations kept at lower densities. This mainly occurs when fecundity costs are imposed on mate search, and provides an explanation for why Allee effects are often observed in anthropogenically rare species. Optimizing selection, where the attained trait value minimizes the Allee threshold independent of population density, depended on the trade-off between search and survival, combined with monogamy when females were searching. Other scenarios led to runaway selection on the mate search rate, including evolutionary suicide. Trade-offs involved in mate search may thus be crucial to determining how density influences the evolution of Allee effects. Previous studies did not examine evolution of a trait related to the strength of Allee effects under density variation. We emphasize the crucial role that mating systems, fitness trade-offs and the evolving sex have in determining the density threshold for population persistence, in particular since evolution need not always take the Allee threshold to its minimum value.
- MeSH
- biologická evoluce * MeSH
- genetická zdatnost * MeSH
- hustota populace MeSH
- modely genetické MeSH
- sexuální výběr u zvířat * MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Early male-killing (MK) bacteria are vertically transmitted reproductive parasites which kill male offspring that inherit them. Whereas their incidence is well documented, characteristics allowing originally non-MK bacteria to gradually evolve MK ability remain unclear. We show that horizontal transmission is a mechanism enabling vertically transmitted bacteria to evolve fully efficient MK under a wide range of host and parasite characteristics, especially when the efficacy of vertical transmission is high. We also show that an almost 100% vertically transmitted and 100% effective male-killer may evolve from a purely horizontally transmitted non-MK ancestor, and that a 100% efficient male-killer can form a stable coexistence only with a non-MK bacterial strain. Our findings are in line with the empirical evidence on current MK bacteria, explain their high efficacy in killing infected male embryos and their variability within and across insect taxa, and suggest that they may have evolved independently in phylogenetically distinct species.
- MeSH
- Bacteria klasifikace genetika MeSH
- biologická evoluce * MeSH
- fyziologie bakterií MeSH
- hmyz embryologie mikrobiologie MeSH
- interakce hostitele a patogenu * MeSH
- poměr pohlaví MeSH
- přenos infekční nemoci * MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
