BACKGROUND: Mechanistic data indicate the benefit of short-chain fatty acids (SCFA) produced by gut microbial fermentation of fiber on colorectal cancer, but direct epidemiologic evidence is limited. A recent study identified SNPs for two SCFA traits (fecal propionate and butyrate-producing microbiome pathway PWY-5022) in Europeans and showed metabolic benefits. METHODS: We conducted a two-sample Mendelian randomization analysis of the genetic instruments for the two SCFA traits (three SNPs for fecal propionate and nine for PWY-5022) in relation to colorectal cancer risk in three large European genetic consortia of 58,131 colorectal cancer cases and 67,347 controls. We estimated the risk of overall colorectal cancer and conducted subgroup analyses by sex, age, and anatomic subsites of colorectal cancer. RESULTS: We did not observe strong evidence for an association of the genetic predictors for fecal propionate levels and the abundance of PWY-5022 with the risk of overall colorectal cancer, colorectal cancer by sex, or early-onset colorectal cancer (diagnosed at <50 years), with no evidence of heterogeneity or pleiotropy. When assessed by tumor subsites, we found weak evidence for an association between PWY-5022 and risk of rectal cancer (OR per 1-SD, 0.95; 95% confidence intervals, 0.91-0.99; P = 0.03) but it did not surpass multiple testing of subgroup analysis. CONCLUSIONS: Genetic instruments for fecal propionate levels and the abundance of PWY-5022 were not associated with colorectal cancer risk. IMPACT: Fecal propionate and PWY-5022 may not have a substantial influence on colorectal cancer risk. Future research is warranted to comprehensively investigate the effects of SCFA-producing bacteria and SCFAs on colorectal cancer risk.
- MeSH
- butyráty * analýza metabolismus MeSH
- feces * chemie mikrobiologie MeSH
- kolorektální nádory * epidemiologie genetika metabolismus MeSH
- kyseliny mastné těkavé analýza genetika metabolismus MeSH
- lidé MeSH
- mendelovská randomizace MeSH
- propionáty * analýza metabolismus MeSH
- riziko MeSH
- střevní mikroflóra * genetika fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Geografické názvy
- Evropa MeSH
Aryl hydrocarbon receptor (AHR) plays pivotal roles in intestinal physiology and pathophysiology. Intestinal AHR is activated by numerous dietary, endogenous, and microbial ligands. Whereas the effects of individual compounds on AHR are mostly known, the effects of real physiological mixtures occurring in the intestine have not been studied. Using reporter gene assays and RT-PCR, we evaluated the combinatorial effects (3520 combinations) of 11 microbial catabolites of tryptophan (MICTs) on AHR. We robustly (n = 30) determined the potencies and relative efficacies of single MICTs. Synergistic effects of MICT binary mixtures were observed between low- or medium-efficacy agonists, in particular for combinations of indole-3-propionate and indole-3-lactate. Combinations comprising highly efficacious agonists such as indole-3-pyruvate displayed rather antagonist effects, caused by saturation of the assay response. These synergistic effects were confirmed by RT-PCR as CYP1A1 mRNA expression. We also tested mimic multicomponent and binary mixtures of MICTs, prepared based on the metabolomic analyses of human feces and colonoscopy aspirates, respectively. In this case, AHR responsiveness did not correlate with type of diet or health status, and the indole concentrations in the mixtures were determinative of gross AHR activity. Future systematic research on the synergistic activation of AHR by microbial metabolites and other ligands is needed.
- MeSH
- cytochrom P-450 CYP1A1 genetika metabolismus MeSH
- indoly metabolismus farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- messenger RNA metabolismus MeSH
- propionáty MeSH
- pyruváty MeSH
- receptory aromatických uhlovodíků * metabolismus MeSH
- střeva MeSH
- tryptofan * metabolismus farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Despite the importance of drug release testing of parenteral depot formulations, the current in vitro methods still require ameliorations in biorelevance. We have investigated here the use of muscle tissue components to better mimic the intramuscular administration. For convenient handling, muscle tissue was used in form of a freeze-dried powder, and a reproducible process of incorporation of tested microspheres to an assembly of muscle tissue of standardized dimensions was successfully developed. Microspheres were prepared from various grades of poly(lactic-co-glycolic acid) (PLGA) or ethyl cellulose, entrapping flurbiprofen, lidocaine, or risperidone. The deposition of microspheres in the muscle tissue or addition of only isolated lipids into the medium accelerated the release rate of all model drugs from microspheres prepared from ester-terminated PLGA grades and ethyl cellulose, however, not from the acid-terminated PLGA grades. The addition of lipids into the release medium increased the solubility of all model drugs; nonetheless, also interactions of the lipids with the polymer matrix (ad- and absorption) might be responsible for the faster drug release. As the in vivo drug release from implants is also often faster than in simple buffers in vitro, these findings suggest that interactions with the tissue lipids may play an important role in these still unexplained observations.
- MeSH
- celulosa analogy a deriváty MeSH
- flurbiprofen aplikace a dávkování MeSH
- kopolymer kyseliny glykolové a mléčné MeSH
- léky s prodlouženým účinkem * MeSH
- lidokain aplikace a dávkování MeSH
- mikrosféry MeSH
- nosiče léků MeSH
- parenterální infuze * MeSH
- pomocné látky MeSH
- prasata MeSH
- příprava léků MeSH
- risperidon aplikace a dávkování MeSH
- svaly metabolismus MeSH
- techniky in vitro MeSH
- uvolňování léčiv MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
How the acetate and propionate accumulation impact anaerobic syntrophy during methane formation is not well understood. To investigate such effect, continuous acetate (35 g/L), propionate (11.25 g/L) and bicarbonate (30 g/L) supplementation were used during mesophilic anaerobic digestion. The high throughput sequencing (16S rRNA and mcrA), Real-Time quantitative PCR, and stable carbon isotope fingerprinting were applied to investigate the structure and activity of microbial community members. The results demonstrated that the abundance of syntrophic acetate oxidizing bacteria exhibited a gradual decrease coupled with heavier stable carbon isotopic signature of methane (δ 13CH4) in the three reagents impacted reactors. The increased acetate and propionate concentrations exerted negative influence on biogas production but the relatively stable hydrogenotrophic methanogens together with syntrophic acetate/propionate oxidizing bacteria kept the stable methane formation facing acetate and propionate accumulation. The functional genes copy number of the hydrogenotrophic Methanocellaceae and Methanomicrobiaceae correlated significantly with δ 13CH4 (R2 > 0.74), but only the abundance of Methanocellaceae fitted well with δ 13CH4 (p < 0.05). The δ 13CH4 signatures can predict methanogenesis, as it directly reflects the main methanogenic pathway; yet, further investigation of isotope fractionation in acetate/propionate coupled with δ 13CH4 is needed. Collectively, these results provide deep insight into anaerobic syntrophy and reveal changes of synergistic relationships, both of which may contribute to the stability of biogas reactors.
- MeSH
- acetáty MeSH
- anaerobióza MeSH
- bioreaktory * MeSH
- methan MeSH
- propionáty * MeSH
- RNA ribozomální 16S genetika MeSH
- Publikační typ
- časopisecké články MeSH
We aimed to evaluate the regulatory effects of propofol on high-dose remifentanil-induced hyperalgesia. A total of 180 patients receiving laparoscopic cholecystectomy were randomly divided into sevoflurane + high-dose remifentanil (SH) group, sevoflurane + low-dose remifentanil (SL) group and propofol + high-dose remifentanil group (PH) group (n=60). After intravenous administration of midazolam, SH and SL groups were induced with sevoflurane and remifentanil, and PH group was induced with propofol and remifentanil. During anesthesia maintenance, SH and SL groups were given 0.3 microg/kg/min and 0.1 microg/kg/min sevoflurane and remifentanil respectively, and PH group was given 0.3 microg/kg/min propofol and remifentanil. The three groups had significantly different awakening time, extubation time and total dose of remifentanil (P<0.001). Compared with SL group, periumbilical mechanical pain thresholds 6 h and 24 h after surgery significantly decreased in SH group (P<0.05), and the visual analog scale (VAS) scores significantly increased 30 min, 2 h and 6 h after surgery (P<0.05). Compared with SH group, periumbilical mechanical thresholds 6 h and 24 h after surgery were significantly higher in PH group (P<0.05), and VAS scores 30 min, 2 h and 6 h after surgery were significantly lower (P<0.05). PH group first used patient-controlled intravenous analgesia pump significantly later than SL group did (P<0.05). The total consumptions of sufentanil in PH and SL groups were significantly lower than that of SH group (P<0.05). The incidence rates of bradycardia and postoperative chill in PH and SH groups were significantly higher than those of SL group (P<0.05). Anesthesia by infusion of high-dose remifentanil plus sevoflurane caused postoperative hyperalgesia which was relieved through intravenous anesthesia with propofol.
- MeSH
- anestetika inhalační farmakologie MeSH
- anestetika intravenózní farmakologie MeSH
- cholecystektomie laparoskopická škodlivé účinky MeSH
- dospělí MeSH
- hyperalgezie chemicky indukované prevence a kontrola MeSH
- lidé středního věku MeSH
- lidé MeSH
- opioidní analgetika aplikace a dávkování škodlivé účinky MeSH
- pooperační bolest prevence a kontrola MeSH
- propofol farmakologie MeSH
- remifentanil aplikace a dávkování škodlivé účinky MeSH
- sevofluran farmakologie MeSH
- sufentanil aplikace a dávkování MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
BACKGROUND AND AIMS: Dexmedetomidine and remifentanil use in obstetric general anesthesia is controversial. This study aimed to compare the effects of remifentanil and dexmedetomidine on mothers and neonates during cesarean section under general anesthesia. METHODS: A total of 120 patients scheduled for elective cesarean section under general anesthesia were randomly allocated to dexmedetomidine (D), remifentanil (R), and control (C) groups. Anesthesia was induced with propofol and muscle relaxants in all groups. Anesthesia in groups D and R was induced with dexmedetomidine (induction, 0.5 µg/kg; maintenance, 0.5 µg/kg.h) and remifentanil (induction, 0.5 µg/kg; maintenance, 2 µg/kg.h), respectively, until birth. Group C received equivalent volumes of normal saline. Mean arterial blood pressure (MAP), heart rate (HR), plasma catecholamine, visual analog pain score (VAS), and total tramadol consumption at 1, 2, and 3 hours after extubation were recorded. Neonatal effects were assessed by Apgar scores and umbilical blood gas analysis. RESULTS: Post induction, MAP was significantly higher in group D compared to groups C and R, and significantly lower in group R than in group C. At intubation/skin incision and delivery, MAP, HR, and plasma epinephrine and norepinephrine concentrations were significantly lower in groups D and R than in group C. Compared to group R, MAP was significantly higher, and HR, plasma epinephrine, and norepinephrine concentrations were significantly lower in group D. Compared with groups C and D, the percentage of neonates with Apgar score < 7 was higher in group R at 1 min after delivery. Compared with groups C and R, the VAS was significantly lower in group D at 1 and 2 h postoperatively. Total tramadol consumption was significantly lower in group D at 3 hours postoperatively. CONCLUSION: During general anesthesia for cesarean section, remifentanil demonstrated better control of hemodynamic stability, while dexmedetomidine demonstrated better neonatal Apgar scores, postoperative analgesia, and decreased catecholamine release. TRIAL REGISTRATION: Chinese Clinical Trial Register (ChiCTR) - ChiCTR1800017125.
- MeSH
- celková anestezie metody MeSH
- císařský řez metody MeSH
- dexmedetomidin aplikace a dávkování MeSH
- dospělí MeSH
- hypnotika a sedativa aplikace a dávkování MeSH
- lidé MeSH
- matky MeSH
- novorozenec MeSH
- opioidní analgetika aplikace a dávkování MeSH
- remifentanil aplikace a dávkování MeSH
- těhotenství MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- novorozenec MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
The effective concentration of a drug in the blood, i.e. the concentration of a free drug in the blood, is influenced by the strength of drug binding onto plasma proteins. Besides its efficacy, these interactions subsequently influence the liberation, absorption, distribution, metabolism, excretion, and toxicological properties of the drug. It is important to not only determine the binding strength and stoichiometry, but also the binding site of a drug on the plasma protein molecule, because the co-administration of drugs with the same binding site can affect the above-mentioned concentration and as a result the pharmacological behavior of the drugs and lead to side effects caused by the change in free drug concentration, its toxicity. In this study, the binding characteristics of six drugs with human serum albumin, the most abundant protein in human plasma, were determined by capillary electrophoresis-frontal analysis, and the obtained values of binding parameters were compared with the literature data. The effect of several drugs and site markers on the binding of l-tryptophan and lidocaine to human serum albumin was investigated in subsequent displacement studies which thus demonstrated the usability of capillary electrophoresis as an automated high-throughput screening method for drug-protein binding studies.
- MeSH
- chlorpropamid analýza farmakologie MeSH
- diklofenak analýza farmakologie MeSH
- elektroforéza kapilární MeSH
- fenylbutazon analýza farmakologie MeSH
- flurbiprofen analýza farmakologie MeSH
- ibuprofen analýza farmakologie MeSH
- lidé MeSH
- lidokain antagonisté a inhibitory chemie MeSH
- lidský sérový albumin chemie MeSH
- tolbutamid analýza farmakologie MeSH
- tryptofan antagonisté a inhibitory chemie MeSH
- vazebná místa účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Highly persistent, toxic and bioaccumulative per - and polyfluoroalkyl substances (PFAS) represents a serious problem for the environment and their concentrations and fate remain largely unknown. The present study consists of a PFAS screening in sludges originating from 43 wastewater treatment plants (WWTPs) in the Czech Republic. To analyze an extended group of PFAS consisting of 32 PFAS, including GenX and other new replacements of older and restricted PFAS in sludge, a new method was optimized and validated using pressurized solvent extraction, followed by the SPE clean-up step to eliminate the observed matrix effects and LC-MS/MS. The results revealed high PFAS contamination of sewage sludge, reaching values from 5.6 to 963.2 ng g-1. The results showed that in the majority of the samples (about 60%), PFOS was the most abundant among the targeted PFAS, reaching 932.9 ng g-1. Approximately 20% of the analyzed samples contained more short-chain PFAS, suggesting the replacement of long-chain PFAS (especially restricted PFOA and PFOS). GenX was detected in 9 samples, confirming the trend in the use of new PFAS. The results revealed that significantly higher contamination was detected in the samples from large WWTPs (population equivalent > 50,000; p-value <0.05). Concerning the application of sludge in agriculture, our prediction using the respective PFAS bioconcentration factors, the observed concentrations, and the legislatively permitted management of biosolids in Czech Republic agriculture revealed that PFAS can cause serious contamination of cereals and vegetables (oat, celery shoots and lettuce leaves), as well as general secondary contamination of the environment.
- MeSH
- bioakumulace MeSH
- biosolidy MeSH
- chromatografie kapalinová MeSH
- čištění vody MeSH
- fluorokarbony analýza metabolismus MeSH
- kontaminace potravin analýza MeSH
- kyseliny alkansulfonové analýza metabolismus MeSH
- látky znečišťující půdu analýza metabolismus MeSH
- odpadní voda chemie MeSH
- odpadní vody chemie MeSH
- propionáty analýza metabolismus MeSH
- průmyslová hnojiva analýza MeSH
- tandemová hmotnostní spektrometrie MeSH
- zelenina chemie růst a vývoj metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Remifentanil is ultrashort-acting opioid with a unique pharmacokinetic profile. It is used exclusively intravenously. While considering its rapid onset of action and other pharmacokinetic properties, we decided to assess its effects following administration via non-traditional routes. Rabbits (n=10 per each group) were randomized into six groups: remifentanil 1 microg/kg and 3 microg/kg IM, 5.0 and 10.0 microg/kg conjunctivally, and 10 microg/kg and 25.0 microg/kg intranasally. Sedating effects were assessed via a loss of the righting reflex. Secondary, mean arterial blood pressure, arterial oxygen saturation of hemoglobin, and pulse rate was monitored in all rabbits. Non-traditional routes of administration were shown to provide a rapid onset of action as well as fast recovery. Importantly, the administration of remifentanil did not result in any deterioration of cardiovascular functions.
- MeSH
- akutní bolest farmakoterapie MeSH
- aplikace intranazální MeSH
- aplikace oční MeSH
- hemoglobiny metabolismus MeSH
- hypnotika a sedativa MeSH
- injekce intramuskulární MeSH
- konjunktiva účinky léků MeSH
- králíci MeSH
- krevní tlak účinky léků MeSH
- kyslík krev MeSH
- opioidní analgetika aplikace a dávkování MeSH
- polohový reflex účinky léků MeSH
- remifentanil aplikace a dávkování farmakokinetika MeSH
- srdeční frekvence MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
In this study, the ionic profile and pH of exhaled breath condensate (EBC) in a group of patients with acid and weakly acid reflux and no-reflux controls were compared. A portable sampler was used for non-invasive EBC collection from five exhalations. The ionic profile (anions, cations, organic acids) and pH of the collected EBC samples were measured by capillary electrophoresis with contactless conductivity detection and a pH microelectrode, respectively. Several ions were elevated in the patient groups. Sodium cation was elevated in weakly acid reflux (significance level p < 0.01) and acid reflux (p < 0.05) compared to no-reflux controls. Butyrate and propionate were elevated in both acid reflux and weakly acid reflux compared to no-reflux controls (butyrate: p < 0.01, propionate: p < 0.05). The median values of pH (after de-aeration with N2) were also significantly higher (p < 0.01) in groups with acid reflux and weakly acid reflux than in the control group with no reflux. The ionic analysis and simultaneous pH measurement offer a simple, cheap, fast, and non-invasive approach in gastroesophageal reflux disease diagnostics.
- MeSH
- butyráty analýza MeSH
- dechové testy metody MeSH
- dospělí MeSH
- elektroforéza kapilární metody MeSH
- gastroezofageální reflux diagnóza metabolismus MeSH
- ionty analýza metabolismus MeSH
- koncentrace vodíkových iontů MeSH
- lidé středního věku MeSH
- lidé MeSH
- propionáty analýza MeSH
- senioři MeSH
- sodík analýza MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
