• Publikační typ
• abstrakt z konference MeSH

Apolipoprotein J (clusterin) is a component of high-density lipoproteins, the high level of which is reversely correlated with the risk of coronary heart disease. In addition, it exerts anti-inflammatory and anti-apoptotic effects on endothelial cells and inhibits smooth muscle cell migration and proliferation, indicating that it may play a protective role in cardiovascular disease. However, the exact mechanisms by which this occurs remain unclear. This study aimed to clarify these underlying protective mechanisms by researching the inhibitory effects of apolipoprotein J via the NOD-like receptor protein 3 pathway on the inflammation induced by cholesterol crystals in THP‐1 macrophages. In culture, THP-1 macrophages were infected with adenoviral vectors containing apolipoprotein J genes and subsequently treated with cholesterol crystals. The inflammatory cytokines interleukin‐1β, interleukin 18 and tumour necrosis factor α were quantitatively measured with ELISA kits. NOD-like receptor protein 3, cysteinyl aspartate specific proteinase 1 and interleukin 1β were evaluated by Western blot and PCR analysis. As a result, apolipoprotein J expression was found to remarkably decrease the levels of inflammatory cytokines, including tumour necrosis factor α, interleukin 18 and interleukin 1β, secreted by THP‐1 macrophages. It was also found capable of inhibiting the levels of NOD-like receptor protein 3, cysteinyl aspartate-specific proteinase 1 and interleukin 1β both at the protein and mRNA levels. In the current study, we revealed that over-expression of apolipoprotein J attenuated the inflammation induced by cholesterol crystals through inhibition of the NOD-like receptor protein 3 inflammasome pathway.

• MeSH
• cholesterol metabolismus   MeSH
• cytokiny metabolismus   MeSH
• endoteliální buňky metabolismus   patologie   MeSH
• inflamasomy * metabolismus   farmakologie   MeSH
• interleukin-18 metabolismus   MeSH
• interleukin-1beta metabolismus   MeSH
• klusterin metabolismus   farmakologie   MeSH
• kyselina aspartová metabolismus   farmakologie   MeSH
• lidé MeSH
• makrofágy metabolismus   MeSH
• proteasy metabolismus   farmakologie   MeSH
• protein NLRP3 * metabolismus   MeSH
• TNF-alfa metabolismus   MeSH
• zánět patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Chronic continuous normobaric hypoxia (CNH) increases cardiac tolerance to ischemia/reperfusion injury in vivo and this effect is mediated via µ and delta2 opioid receptors (ORs) activation. CNH has also been shown to be cardioprotective in isolated rat heart. In this study, we hypothesize that this cardioprotective effect of CNH is mediated by activation of µ and delta2 ORs and preservation of mitochondrial function. Hearts from rats adapted to CNH (12 % oxygen) for 3 weeks were extracted, perfused in the Langendorff mode and subjected to 45 min of global ischemia and 30 min of reperfusion. Intervention groups were pretreated for 10 min with antagonists for different OR types: naloxone (300 nmol/l), the selective delta OR antagonist TIPP(psi) (30 nmol/l), the selective delta1 OR antagonist BNTX (1 nmol/l), the selective delta2 OR antagonist naltriben (1 nmol/l), the selective peptide µ OR antagonist CTAP (100 nmol/l) and the selective delta OR antagonist nor-binaltorphimine (3 nmol/l). Creatine kinase activity in coronary effluent and cardiac contractile function were monitored to assess cardiac injury and functional impairment. Additionally, cardiac tissue was collected to measure ATP and to isolate mitochondria to measure respiration rate and calcium retention capacity. Adaptation to CNH decreased myocardial creatine kinase release during reperfusion and improved the postischemic recovery of contractile function. Additionally, CNH improved mitochondrial state 3 and uncoupled respiration rates, ADP/O, mitochondrial transmembrane potential and calcium retention capacity and myocardial ATP level during reperfusion compared to the normoxic group. These protective effects were completely abolished by naloxone, TIPP(psi), naltriben, CTAP but not BNTX or nor-binaltorphimine. These results suggest that cardioprotection associated with adaptation to CNH is mediated by µ and delta2 opioid receptors activation and preservation of mitochondrial function.

• MeSH
• hypoxie patofyziologie   MeSH
• krysa rodu rattus MeSH
• narkotika - antagonisté farmakologie   MeSH
• orgánové kultury - kultivační techniky MeSH
• potkani Wistar MeSH
• receptory opiátové delta antagonisté a inhibitory   fyziologie   MeSH
• receptory opiátové mu antagonisté a inhibitory   fyziologie   MeSH
• reperfuzní poškození myokardu patofyziologie   prevence a kontrola   MeSH
• srdeční mitochondrie účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Meniscus is a semilunar fibrocartilaginous tissue, serving important roles in load buffering, stability, lubrication, proprioception, and nutrition of the knee joint. The degeneration and damage of meniscus has been proved to be a risk factor of knee osteoarthritis. Mechanical stimulus is a critical factor of the development, maintenance and repair of the meniscus fibrochondrocytes. However, the mechanism of the mechano-transduction process remains elusive. Here we reported that cyclic hydrostatic compress force (CHCF) treatment promotes proliferation and inhibits apoptosis of the isolated primary meniscus fibrochondrocytes (PMFs), via upregulating the expression level of integrin ?5ß1. Consequently, increased phosphorylated-ERK1/2 and phosphorylated-PI3K, and decreased caspase-3 were detected. These effects of CHCF treatment can be abolished by integrin ?5ß1 inhibitor or specific siRNA transfection. These data indicate that CHCF regulates apoptosis of PMFs via integrin ?5ß1-FAK-PI3K/ERK pathway, which may be an important candidate approach during meniscus degeneration.

• MeSH
• apoptóza fyziologie   účinky léků   MeSH
• buněčný převod mechanických signálů fyziologie   MeSH
• chondrocyty metabolismus   účinky léků   MeSH
• fibroblasty metabolismus   účinky léků   MeSH
• hydrostatický tlak MeSH
• integrin alfa5beta1 antagonisté a inhibitory   metabolismus   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• malá interferující RNA aplikace a dávkování   MeSH
• meniskus cytologie   metabolismus   MeSH
• pevnost v tlaku fyziologie   MeSH
• potkani Sprague-Dawley MeSH
• proliferace buněk fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

One of the significant limiting complications of paclitaxel is painful peripheral neuropathy during its therapy for several types of cancers. Our recent study showed that impairment of Nrf2-antioxidant response element (Nrf2-ARE) and upregulation of oxidative signals in the dorsal root ganglion (DRG) of rats with treatment of paclitaxel result in neuropathic pain. The purpose of this study was to examine the beneficial role played by electroacupuncture (EA) in modifying neuropathic pain evoked by paclitaxel via Nrf2-ARE and oxidative mechanisms. Behavioral test was performed to determine mechanical and thermal sensitivity in rats. Western Blot analysis and ELISA were used to examine expression of Nrf2-ARE and superoxide dismutases (SOD); and the levels of products of oxidative stress in the DRG. Our data showed that paclitaxel increased mechanical and thermal sensitivity and this was accompanied with impaired Nrf2-ARE and SOD in the DRG and amplified products of oxidative stress (i.e. 8-isoprostaglandin F2alpha and 8-hydroxy-2'-deoxyguanosine). EA treatment largely restored the levels of Nrf2-ARE/SOD and inhibited products of oxidative stress and thereby attenuated mechanical and thermal hypersensitivity induced by paclitaxel. In conclusion, we revealed specific signaling pathways leading to paclitaxel-evoked neuropathic pain, including impairment of Nrf2-ARE and heightened oxidative signals. We further provided evidence for the role of EA in alleviating paclitaxel-neuropathic pain via these molecular mediators.

• MeSH
• antioxidancia * metabolismus   MeSH
• antitumorózní látky fytogenní toxicita   MeSH
• elektroakupunktura metody   MeSH
• krysa rodu rattus MeSH
• měření bolesti účinky léků   metody   MeSH
• neuralgie chemicky indukované   metabolismus   terapie   MeSH
• paclitaxel toxicita   MeSH
• potkani Sprague-Dawley MeSH
• signální transdukce účinky léků   fyziologie   MeSH
• spinální ganglia účinky léků   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Galanin and galanin receptors (GalRs) have been reported to be involved in the transmission and modulation of nociceptive information in the central nervous system (CNS). However, the underlying mechanism of the antinociception of GalRs in neuropathic pain remains unclear. This study investigated the antinociception induced by galanin receptor 1 (GalR1) via protein kinase A (PKA) signaling pathway in the nucleus accumbens (NAc) of rats with neuropathic pain. A mononeuropathy model was replicated by ligation of the left sciatic nerve, following which the expression of phospho-PKA (p-PKA) in the NAc were markedly up-regulated at 14(th) and 28(th) day after ligation of sciatic nerve, and p-PKA expression was down-regulated by intra-NAc injection of GalR1 agonist M617, but the GalR1 antagonist M35 did not have an effect. We also found that M35 in the NAc blocked the M617-induced increase in the hind paw withdrawal latencies (HWLs) of rats with mononeuropathy, but M35 alone had no effect on HWLs, and PKA inhibitor H-89 attenuated the M617-induced an increase in the HWLs. These results suggested that GalR1 induced an antinociception via inhibiting PKA activation, implying that GalR agonists may be potential and potent therapeutic options to treat chronic neuropathic pain.

• MeSH
• aktivace enzymů účinky léků   fyziologie   MeSH
• analgetika metabolismus   MeSH
• bradykinin analogy a deriváty   farmakologie   MeSH
• galanin analogy a deriváty   farmakologie   MeSH
• krysa rodu rattus MeSH
• měření bolesti účinky léků   metody   MeSH
• neuralgie metabolismus   prevence a kontrola   MeSH
• nucleus accumbens účinky léků   metabolismus   MeSH
• peptidové fragmenty farmakologie   MeSH
• potkani Sprague-Dawley MeSH
• proteinkinasy závislé na cyklickém AMP antagonisté a inhibitory   metabolismus   MeSH
• receptor galaninu typ 1 agonisté   antagonisté a inhibitory   biosyntéza   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Endothelin-1 (ET-1) and Nerve Growth Factor (NGF) are proteins, released from cancer-ridden tissues, which cause spontaneous pain and hypersensitivity to noxious stimuli. Here we examined the electrophysiological and behavioral effects of these two agents for evidence of their interactions. Individual small-medium cultured DRG sensory neurons responded to both ET-1 (50 nM, n=6) and NGF (100 ng/ml, n=4), with increased numbers of action potentials and decreased slow K(+) currents; pre-exposure to ET-1 potentiated NGF´s actions, but not vice versa. Behaviorally, single intraplantar (i.pl.) injection of low doses of ET-1 (20 pmol) or NGF (100 ng), did not increase hindpaw tactile or thermal sensitivity, but their simultaneous injections sensitized the paw to both modalities. Daily i.pl. injections of low ET-1 doses in male rats caused tactile sensitization after 21 days, and enabled further tactile and thermal sensitization from low dose NGF, in ipsilateral and contralateral hindpaws. Single injections of 100 ng NGF, without changing the paw's tactile sensitivity by itself, acutely sensitized the ipsilateral paw to subsequent injections of low ET-1. The sensitization from repeated low ET-1 dosing and the cross-sensitization between NGF and ET-1 were both significantly greater in female than in male rats. These findings reveal a synergistic interaction between cutaneously administered low doses of NGF and ET-1, which could contribute to cancer-related pain.

• MeSH
• bolest chemicky indukované   metabolismus   MeSH
• endotelin-1 aplikace a dávkování   metabolismus   toxicita   MeSH
• fyzikální stimulace škodlivé účinky   MeSH
• hmat účinky léků   fyziologie   MeSH
• injekce subkutánní MeSH
• krysa rodu rattus MeSH
• měření bolesti metody   MeSH
• nervový růstový faktor aplikace a dávkování   metabolismus   toxicita   MeSH
• potkani Sprague-Dawley MeSH
• vazba proteinů fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Bis(3)-tacrine is a dimeric AChE inhibitor derived from tacrine with a potential to treat Alzheimer's disease. It was recently been reported to act as a fast off-rate antagonist of NMDA receptors with moderate affinity. In the present study, we aimed to explore whether bis(3)-tacrine could modulate the function of native sustained potassium current in cultured rat hippocampal neurons using whole-cell patch-clamp technique. We found that bis(3)-tacrine inhibited the amplitude of sustained potassium current in a reversible and concentration-dependent manner, with a potency two orders of magnitude higher than that of tacrine. The inhibition was voltage-independent between 0 to +60 mV. The IC(50) values for bis(3)-tacrine and tacrine inhibition of sustained potassium current were 0.45+/-0.07 and 50.5+/-4.8 microM, respectively. I-V curves showed a more potent inhibition of sustained potassium current by bis(3)-tacrine (1 microM) compared to tacrine at the same concentration. Bis(3)-tacrine hyperpolarized the activation curve of the current by 11.2 mV, albeit leaving the steady-state inactivation of the current unaffected.

• MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• draslíkový kanál Kv1.2 antagonisté a inhibitory   fyziologie   MeSH
• elektrická stimulace metody   MeSH
• hipokampus účinky léků   fyziologie   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• membránové potenciály účinky léků   fyziologie   MeSH
• neurony účinky léků   fyziologie   MeSH
• potkani Sprague-Dawley MeSH
• takrin farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

5-hydroxytryptamine (5-HT) is involved in the stress-induced alteration of colonic functions, specifically motility and secretion, but its precise mechanisms of regulation remain unclear. In the present study, we have investigated the effects of 5-HT on rat colonic mucosal secretion after acute water immersion restraint stress, as well as the underlying mechanism of this phenomenon, using short circuit current recording (I(SC)), real-time polymerase chain reaction, Western blot analysis, and enzyme-linked immunosorbance assays. After 2 h of water immersion restraint stress, the baseline I(SC) and 5-HT-induced I(SC) responses of the colonic mucosa were significantly increased. Pretreatment with selective 5-HT(4) receptor antagonist, SB204070, inhibited the 5-HT-induced colonic I(SC) response by 96 % in normal rats and 91.2 % in acute-stress rats. However, pretreatment with the selective antagonist of 5-HT(3) receptor, MDL72222 or Y-25130, had no obvious effect on 5-HT-induced I(SC) responses under either set of conditions. Total protein expression of both the mucosal 5-HT(3) receptors and the 5-HT(4) receptors underwent no significant changes following acute stress. Both colonic basal cAMP levels and foskolin-induced I(SC) responses were significantly enhanced in acute stress rats. 5-HT significantly enhanced the intracellular cAMP level via 5-HT(4) receptors in the colonic mucosa from both control and stressed animals, and 5-HT-induced cAMP increase in stressed rats was not more than that in control rats. Taken together, the present results indicate that acute water immersion restraint stress enhances colonic secretory responses to 5-HT in rats, a process in which increased cellular cAMP accumulation is involved.

• MeSH
• AMP cyklický metabolismus   MeSH
• kolon účinky léků   sekrece   MeSH
• krysa rodu rattus MeSH
• ponoření MeSH
• potkani Sprague-Dawley MeSH
• psychický stres metabolismus   MeSH
• serotonin farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• střevní sliznice účinky léků   sekrece   MeSH
• upregulace účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In previous studies, it has been shown that recombinant human neuregulin-1(rhNRG-1) is capable of improving the survival rate in animal models of doxorubicin (DOX)-induced cardiomyopathy; however, the underlying mechanism of this phenomenon remains unknown. In this study, the role of rhNRG-1 in attenuating doxorubicin-induce apoptosis is confirmed. Neonatal rat ventricular myocytes (NRVMs) were subjected to various treatments, in order to both induce apoptosis and determine the effects of rhNRG-1 on the process. Activation of apoptosis was determined by observing increases in the protein levels of classic apoptosis markers (including cleaved caspase-3, cytochrome c, Bcl-2, BAX and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining). The activation of Akt was detected by means of western blot analysis. The study results showed that doxorubicin increased the number of TUNEL positive cells, as well as the protein levels of cleaved caspase-3 and cytochrome c, and reduced the ratio of Bcl-2/Bax. However, all of these effects were markedly antagonized by pretreament with rhNRG-1. It was then further demonstrated that the effects of rhNRG-1 could be blocked by the phosphoinositole-3-kinase inhibitor LY294002, indicating the involvement of the Akt process in mediating the process. RhNRG-1 is a potent inhibitor of doxorubicin-induced apoptosis, which acts through the PI3K-Akt pathway. RhNRG-1 is a novel therapeutic drug which may be effective in preventing further damage from occurring in DOX-induced damaged myocardium.

• MeSH
• aktivace enzymů MeSH
• antibiotika antitumorózní toxicita   MeSH
• apoptóza účinky léků   MeSH
• cytoprotekce MeSH
• doxorubicin toxicita   MeSH
• fosforylace MeSH
• inhibitory proteinkinas farmakologie   MeSH
• kardiomyocyty účinky léků   enzymologie   patologie   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• lidé MeSH
• neuregulin-1 farmakologie   MeSH
• novorozená zvířata MeSH
• ochranné látky farmakologie   MeSH
• potkani Sprague-Dawley MeSH
• proteiny regulující apoptózu metabolismus   MeSH
• protoonkogenní proteiny c-akt antagonisté a inhibitory   metabolismus   MeSH
• rekombinantní proteiny farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH