Cell communication systems based on polypeptide ligands use transmembrane receptors to transmit signals across the plasma membrane. In their biogenesis, receptors depend on the endoplasmic reticulum (ER)-Golgi system for folding, maturation, transport and localization to the cell surface. ER stress, caused by protein overproduction and misfolding, is a well-known pathology in neurodegeneration, cancer and numerous other diseases. How ER stress affects cell communication via transmembrane receptors is largely unknown. In disease models of multiple myeloma, chronic lymphocytic leukemia and osteogenesis imperfecta, we show that ER stress leads to loss of the mature transmembrane receptors FGFR3, ROR1, FGFR1, LRP6, FZD5 and PTH1R at the cell surface, resulting in impaired downstream signaling. This is caused by downregulation of receptor production and increased intracellular retention of immature receptor forms. Reduction of ER stress by treatment of cells with the chemical chaperone tauroursodeoxycholic acid or by expression of the chaperone protein BiP resulted in restoration of receptor maturation and signaling. We show a previously unappreciated pathological effect of ER stress; impaired cellular communication due to altered receptor processing. Our findings have implications for disease mechanisms related to ER stress and are particularly important when receptor-based pharmacological approaches are used for treatment.
- MeSH
- chaperon endoplazmatického retikula BiP MeSH
- kyselina taurochenodeoxycholová farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- receptory buněčného povrchu * metabolismus MeSH
- signální transdukce * účinky léků MeSH
- stres endoplazmatického retikula * účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Antimicrobial lock therapy is recommended for preventing and treating catheter-related bloodstream infections, but different solutions have uncertain efficacy. METHODS: Two locks, 1.35% taurolidine and 4% ethylenediaminetetraacetic acid (EDTA), were tested on Staphylococcus epidermidis, Staphylococcus aureus, methicillin-resistant S. aureus, Pseudomonas aeruginosa, multidrug-resistant P. aeruginosa, vancomycin-resistant Enterococcus faecium, Klebsiella oxytoca (carbapenemase producing), K. pneumoniae (extended-spectrum β-lactamase producing), Candida albicans, and Candida glabrata. Broviac catheter segments were incubated with these organisms and then exposed to various lock solutions. Colony-forming units (CFUs) were counted after 2, 4, and 24 h of incubation. RESULTS: Taurolidine showed a significant decrease in CFUs after 2 h in S. aureus, S. epidermidis, methicillin-resistant S. aureus, vancomycin-resistant E. faecium, P. aeruginosa (both sensitive and multidrug-resistant strains), K. oxytoca, C. albicans, and C. glabrata. After 4 h, significant reductions were noted in S. aureus, S. epidermidis, methicillin-resistant S. aureus, P. aeruginosa, multidrug-resistant P. aeruginosa, K. pneumoniae, K. oxytoca, and C. albicans. Taurolidine was also effective after 24 h, especially against methicillin-resistant S. aureus and multidrug-resistant P. aeruginosa. Four percent EDTA acid showed a significant reduction in CFUs after 2 h in S. aureus, vancomycin-resistant E. faecium, P. aeruginosa, K. oxytoca, C. albicans, and C. glabrata. After 4 h, reductions occurred in P. aeruginosa, multidrug-resistant P. aeruginosa, K. oxytoca, and C. albicans and after 24 h in methicillin-resistant S. aureus, P. aeruginosa, and K. oxytoca. CONCLUSION: Taurolidine is more effective than 4% EDTA acid in eradicating Gram-positive and Gram-negative microorganisms and fungi.
- MeSH
- antiinfekční látky * farmakologie MeSH
- Candida albicans účinky léků MeSH
- EDTA * farmakologie MeSH
- katétrové infekce * prevence a kontrola mikrobiologie MeSH
- lidé MeSH
- methicilin rezistentní Staphylococcus aureus účinky léků MeSH
- mikrobiální testy citlivosti MeSH
- počet mikrobiálních kolonií MeSH
- Pseudomonas aeruginosa účinky léků MeSH
- Staphylococcus aureus účinky léků MeSH
- Staphylococcus epidermidis účinky léků MeSH
- taurin * analogy a deriváty farmakologie MeSH
- thiadiaziny * farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
Effective treatment of patients with autism spectrum disorder (ASD) is still absent so far. Taurine exhibits therapeutic effects towards the autism-like behaviour in ASD model animals. Here, we determined the mechanism of taurine effect on hippocampal neurogenesis in genetically inbred BTBR T+ tf/J (BTBR) mice, a proposed model of ASD. In this ASD mouse model, we explored the effect of oral taurine supplementation on ASD-like behaviours in an open field test, elevated plus maze, marble burying test, self-grooming test, and three-chamber test. The mice were divided into four groups of normal controls (WT) and models (BTBR), who did or did not receive 6-week taurine supplementation in water (WT, WT+ Taurine, BTBR, and BTBR+Taurine). Neurogenesis-related effects were determined by Ki67 immunofluorescence staining. Western blot analysis was performed to detect the expression of phosphatase and tensin homologue deleted from chromosome 10 (PTEN)/mTOR/AKT pathway-associated proteins. Our results showed that taurine improved the autism-like behaviour, increased the proliferation of hippocampal cells, promoted PTEN expression, and reduced phosphorylation of mTOR and AKT in hippocampal tissue of the BTBR mice. In conclusion, taurine reduced the autism-like behaviour in partially inherited autism model mice, which may be associa-ted with improving the defective neural precursor cell proliferation and enhancing the PTEN-associated pathway in hippocampal tissue.
- MeSH
- autistická porucha * metabolismus farmakoterapie MeSH
- chování zvířat účinky léků MeSH
- fosfohydroláza PTEN * metabolismus MeSH
- hipokampus * metabolismus účinky léků MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- neurogeneze * účinky léků MeSH
- poruchy autistického spektra metabolismus farmakoterapie MeSH
- proliferace buněk účinky léků MeSH
- protoonkogenní proteiny c-akt * metabolismus MeSH
- signální transdukce * účinky léků MeSH
- taurin * farmakologie MeSH
- TOR serin-threoninkinasy * metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The purpose of this study was to investigate the acute effect of low, moderate, or high doses of taurine on anaerobic and physiological performance in female rugby players. A total of 16 sub-elite female rugby athletes (21.3 ± 1.5 yr, 168.0 ± 4.9 cm, 62.1 ± 3.5 kg mean ± SD) participated in this research. Following familiarization, participants attended 4 successive tests separated by 72 h in a randomized, counter-balanced, crossover research design. Following an over night fast, participants completed a 5-min 60 Watt warm-up followed by a 30-s Wingate anaerobic test on a cycle ergometer after ingestion of either 2 g taurine (LOWTAU), 4 g (MODTAU), 6 g (HIGHTAU) or placebo (PLA) 1 h before the test. Peak (PP) and mean power (MP) along with heart rate (HR), rating of perceived exertion (RPE), capillary lactate and blood glucose were measured. LOWTAU did not affect PP, MP, HR, lactate and glucose compared to PLA (p > 0.05), while MODTAU improved MP and HIGHTAU improved PP and MP compared to PLA and LOWTAU (p < 0.05). MODTAU and HIGHTAU had little effect on HR, blood lactate and glucose (p > 0.05). A single dose of taurine (MODTAU or HIGHTAU) 1 h prior to competition or training would provide an ergogenic effect on subsequent power output.
- MeSH
- americký fotbal * fyziologie MeSH
- anaerobní práh účinky léků MeSH
- dvojitá slepá metoda MeSH
- klinické křížové studie * MeSH
- krevní glukóza účinky léků metabolismus MeSH
- kyselina mléčná * krev MeSH
- látky zvyšující výkon aplikace a dávkování farmakologie MeSH
- lidé MeSH
- mladý dospělý MeSH
- potravní doplňky MeSH
- sportovní výkon * fyziologie MeSH
- srdeční frekvence * účinky léků MeSH
- taurin * aplikace a dávkování farmakologie MeSH
- tělesná námaha fyziologie účinky léků MeSH
- zahřívací cvičení MeSH
- zátěžový test MeSH
- Check Tag
- lidé MeSH
- mladý dospělý MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC50 = 0.101 ± 0.003 μM and HssBChE IC50 = 0.036 ± 0.002 μM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound.
- MeSH
- acetylcholinesterasa MeSH
- antidota farmakologie MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory toxicita MeSH
- fosfor MeSH
- krysa rodu rattus MeSH
- kyslík MeSH
- lidé MeSH
- oximy farmakologie MeSH
- pralidoximové sloučeniny * MeSH
- pyridinové sloučeniny farmakologie MeSH
- reaktivátory cholinesterasy * farmakologie MeSH
- taurin analogy a deriváty MeSH
- trimedoxim farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND & AIMS: Severity of portal hypertension is usually quantified by measuring the hepatic venous pressure gradient (HVPG). However, due to its invasiveness, alternative markers are being sought. Bile acids (BA), being synthesized, metabolized, and transported by the liver, seem to have the potential to serve as endogenous markers. The aim of the present study was to determine whether serum BA reflect the severity of portal hypertension. METHODS: We correlated serum concentrations of individual BA with portal pressure (as HVPG) in an exploratory cohort of 21 cirrhotic patients with portal hypertension. The predictive potential of selected candidates was then confirmed in an independent validation cohort (n = 214). Additionally, nine previously published noninvasive markers were added to the stepwise logistic regression model to identify the most relevant ones, which were eventually used to create a prognostic index of portal hypertension. RESULTS: Serum levels of taurochenodeoxycholic acid (TCDCA) significantly correlated with HVPG and showed a high potential to predict clinically significant portal hypertension (HVPG ≥ 10 mm Hg: AUROC = 0.97 ± 0.06). This was confirmed in the validation cohort (AUROC = 0.96 ± 0.01). The predictive index (constructed based on AST/ALT, spleen diameter, and TCDCA concentration) was able to distinguish clinically significant portal hypertension with 95% sensitivity and 76% specificity. CONCLUSIONS: TCDCA seems to be a promising noninvasive marker of clinically significant portal hypertension. Its predictive potential may be further enhanced when it is combined with both the AST/ALT ratio and spleen diameter.
BACKGROUND: Plasma sulfur amino acids (SAAs), i.e., methionine, total cysteine (tCys), total homocysteine (tHcy), cystathionine, total glutathione (tGSH), and taurine, are potential risk factors for obesity and cardiometabolic disorders. However, except for plasma tHcy, little is known about how dietary intake modifies plasma SAA concentrations. OBJECTIVE: To investigate whether the intake of SAAs and proteins or diet quality is associated with plasma SAAs. METHODS: Data from a cross-sectional subset of The Maastricht Study (n = 1145, 50.5% men, 61 interquartile range: [55, 66] y, 22.5% with prediabetes and 34.3% with type 2 diabetes) were investigated. Dietary intake was assessed using a validated food frequency questionnaire. The intake of SAAs (total, methionine, and cysteine) and proteins (total, animal, and plant) was estimated from the Dutch and Danish food composition tables. Diet quality was assessed using the Dutch Healthy Diet Index, the Mediterranean Diet Score, and the Dietary Approaches to Stop Hypertension score. Fasting plasma SAAs were measured by liquid chromatography (LC) tandem mass spectrometry (MS) (LC/MS-MS). Associations were investigated with multiple linear regressions with tertiles of dietary intake measures (main exposures) and z-standardized plasma SAAs (outcomes). RESULTS: Intake of total SAAs and total proteins was positively associated with plasma tCys and cystathionine. Associations were stronger in women and in those with normal body weight. Higher intake of cysteine and plant proteins was associated with lower plasma tHcy and higher cystathionine. Higher methionine intake was associated with lower plasma tGSH, whereas cysteine intake was positively associated with tGSH. Higher intake of methionine and animal proteins was associated with higher plasma taurine. Better diet quality was consistently related to lower plasma tHcy concentrations, but it was not associated with the other SAAs. CONCLUSION: Targeted dietary modifications might be effective in modifying plasma concentrations of tCys, tHcy, and cystathionine, which have been associated with obesity and cardiometabolic disorders.
- MeSH
- aminokyseliny sírové * MeSH
- cystathionin MeSH
- cystein MeSH
- diabetes mellitus 2. typu * MeSH
- dieta MeSH
- homocystein MeSH
- kardiovaskulární nemoci * MeSH
- lidé MeSH
- methionin MeSH
- obezita MeSH
- průřezové studie MeSH
- taurin MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- chování při pití MeSH
- dítě MeSH
- energetické nápoje * analýza škodlivé účinky zákonodárství a právo MeSH
- kofein škodlivé účinky MeSH
- lidé MeSH
- mladiství MeSH
- ochrana veřejného zdraví MeSH
- sacharosa škodlivé účinky MeSH
- taurin škodlivé účinky MeSH
- zdravotně rizikové chování MeSH
- zranitelné populace MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- Geografické názvy
- Česká republika MeSH
- Polsko MeSH
