ALDH7A1 deficiency is an epileptic encephalopathy whose seizures respond to treatment with supraphysiological doses of pyridoxine. It arises as a result of damaging variants in ALDH7A1, a gene in the lysine catabolism pathway. α-Aminoadipic semialdehyde (α-AASA) and Δ1-piperideine-6-carboxylate (P6C), which accumulate because of the block in the lysine pathway, are diagnostic biomarkers for this disorder. Recently, it has been reported that 6-oxo-pipecolic acid (6-oxo-PIP) also accumulates in the urine, CSF and plasma of ALDH7A1-deficient individuals and that, given its improved stability, it may be a more suitable biomarker for this disorder. This study measured 6-oxo-PIP in urine from a cohort of 30 patients where α-AASA was elevated and showed that it was above the normal range in all those above 6 months of age. However, 6-oxo-PIP levels were within the normal range in 33% of the patients below 6 months of age. Levels increased with age and correlated with a decrease in α-AASA levels. Longitudinal analysis of urine samples from ALDH7A1-deficient patients who were on a lysine restricted diet whilst receiving supraphysiological doses of pyridoxine showed that levels of 6-oxo-PIP remained elevated whilst α-AASA decreased. Similar to α-AASA, we found that elevated urinary excretion of 6-oxo-PIP can also occur in individuals with molybdenum cofactor deficiency. This study demonstrates that urinary 6-oxo-PIP may not be a suitable biomarker for ALDH7A1 deficiency in neonates. However, further studies are needed to understand the biochemistry leading to its accumulation and its potential long-term side effects.
- MeSH
- aldehyddehydrogenasa nedostatek genetika MeSH
- biologické markery * moč MeSH
- dítě MeSH
- epilepsie moč MeSH
- kojenec MeSH
- kyselina 2-aminoadipová moč analogy a deriváty MeSH
- kyseliny pipekolové * moč MeSH
- lidé MeSH
- lysin nedostatek moč MeSH
- mitochondriální aldehyddehydrogenasa nedostatek genetika MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- pyridoxin nedostatek moč terapeutické užití MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Hydrogen sulfide (H2S) is a gas neurotransmitter that is synthesized in various mammalian tissues including vascular tissues and regulates vascular tone. The aim of this study is to investigate whether the endogenous L-cysteine/H2S pathway is impaired due to aging and endothelial denudation in mouse isolated thoracic aorta. For this purpose, young (3-4 months) and old (23-25 months) mice were used in the experiments. The effects of aging and endothelium on endogenous and exogenous H2S-induced vasorelaxation were investigated by cumulative L-cysteine-(1 microM-10 mM) and NaHS-(1 microM-3 mM) induced vasorelaxations, respectively. The L-cysteine-induced relaxations were reduced in old mice aorta compared to the young mice. Also, vasorelaxant responses to L-cysteine (1 microM-10 mM) were reduced on aorta rings with denuded-endothelium of young and old mice. However, the relaxation responses to NaHS were not altered by age or endothelium denudation. The loss of staining of CSE in the endothelial layer was observed in old thoracic aorta. Ach-induced (1-30 microM) relaxation almost abolished in endothelium-denuded rings from both mice group. Also, relaxation Ach reduced in intact endothelium tissue of old mice aorta. In conclusion, the vasorelaxant responses to L-cysteine but not NaHS decreased and the protein expression of CSE reduced in old thoracic aorta rings consistent with a decrease in H2S concentration with aging and endothelium damage, suggesting that aging may be lead to decrease in enzyme expression and H2S signaling system due to endothelium damage in mouse thoracic aorta. Key words Aging, Hydrogen sulfide, L-cysteine, Endothelium, Thoracic aorta.
- MeSH
- aorta thoracica * účinky léků metabolismus fyziologie MeSH
- cévní endotel * metabolismus účinky léků MeSH
- cystein metabolismus farmakologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- signální transdukce MeSH
- stárnutí * metabolismus MeSH
- sulfan * metabolismus MeSH
- vazodilatace * účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
An imbalance in coagulation is associated with cardiovascular events. For prevention and treatment, anticoagulants, currently mainly xabans and gatrans, are used. The purpose of the present study was to provide a head-to-head comparison since there are no studies directly evaluating these novel anticoagulants. An additional aim was to find whether selected anthropological and biochemical factors can affect their anticoagulant properties as they are used in fixed doses. In this cross-sectional study, blood from 50 generally healthy donors was collected, and coagulation responses to dabigatran, argatroban, rivaroxaban, and apixaban, at a concentration of 1 μM, were analyzed. Heparin was used as a positive control. Prothrombin time (PT) expressed as international normalized ratio (INR) and activated partial thromboplastin time (aPTT) were measured and compared. Rivaroxaban was the most active according to PT/INR while argatroban according to aPTT. The ex vivo anticoagulant effect measured by INR correlated inversely with body mass index (BMI) in all four anticoagulants tested. Shortening of aPTT was associated with higher cholesterol and triglyceride levels. No sex-related differences were observed in response to the anticoagulant treatments. As this was an ex vivo study and pharmacokinetic factors were not included, the influence of BMI is of high therapeutic importance.
- MeSH
- antikoagulancia * farmakologie MeSH
- arginin * analogy a deriváty MeSH
- dabigatran farmakologie MeSH
- dospělí MeSH
- hemokoagulace * účinky léků MeSH
- index tělesné hmotnosti MeSH
- INR MeSH
- kyseliny pipekolové * farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- parciální tromboplastinový čas MeSH
- protrombinový čas MeSH
- průřezové studie MeSH
- pyrazoly farmakologie MeSH
- pyridony farmakologie farmakokinetika MeSH
- rivaroxaban * farmakologie MeSH
- sulfonamidy farmakologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Karcinom prostaty je jedním z nejčastějších onkologických onemocnění mužů ve světě. Diagnostika a stratifikace pacientů jsou klíčové pro zajištění včasné a adekvátní terapie. Současné standardy se opírají převážně o PSA, jehož nádorová specificita je limitována. Tento přehled se zaměřuje na neinvazivní potenciální onkomarkery získané z moči včetně oxidačního stresu, metabolomiky a analýzy nukleových kyselin. V rámci některých studií se ukazuje, že zvýšené hladiny markerů jako F2-isoprostanáza, sarcosin a PCA3 mohou indikovat přítomnost a agresivitu karcinomu prostaty. Nové kombinované testy Prostarix, Mi-Prostate Score, SelectMDX nebo ExoDX nabízejí potenciál pro zlepšení stratifikace pacientů a snížení počtu negativních biopsií. Klinické využití těchto nových markerů je zatím omezené. Vzhledem k heterogenitě tohoto onemocnění je nezbytné pokračovat ve výzkumu, který usnadní personalizovaný přístup v léčbě.
Prostate cancer is one of the most common oncological diseases among men worldwide. Accurate diagnosis and patient stratification are crucial for ensuring timely and appropriate therapy. Current standards primarily rely on PSA, whose tumor specificity is limited. This review focuses on non-invasive potential oncological markers derived from urine, including oxidative stress, metabolomics and nucleic acid analysis. Some studies indicate that elevated levels of markers such as F2-isoprostane, sarcosine or PCA3 may signify the presence and aggressiveness of prostate cancer. New combined tests Prostarix, Mi-Prostate Score, SelectMDX and ExoDX offer potential for improved diagnosis and patient stratification, as well as a reduction in negative biopsies. However, the clinical application of these new markers remains limited. Considering the heterogeneity of this disease, ongoing research is essential to support a personalized approach to treatment.
- MeSH
- aminokyseliny moč MeSH
- biopsie metody MeSH
- časná detekce nádoru metody MeSH
- diagnostické techniky molekulární MeSH
- exozómy fyziologie MeSH
- lidé MeSH
- metabolomika metody MeSH
- mikro RNA moč MeSH
- nádorové biomarkery * moč MeSH
- nádory prostaty * diagnóza MeSH
- oxidační stres fyziologie MeSH
- prostatický specifický antigen krev MeSH
- Check Tag
- lidé MeSH
Patients with alcohol use disorder (AUD) who seek treatment show highly variable outcomes. A precision medicine approach with biomarkers responsive to new treatments is warranted to overcome this limitation. Promising biomarkers relate to prefrontal control mechanisms that are severely disturbed in AUD. This results in reduced inhibitory control of compulsive behavior and, eventually, relapse. We reasoned here that prefrontal dysfunction, which underlies vulnerability to relapse, is evidenced by altered neuroelectric signatures and should be restored by pharmacological interventions that specifically target prefrontal dysfunction. To test this, we applied our recently developed biocompatible neuroprosthesis to measure prefrontal neural function in a well-established rat model of alcohol addiction and relapse. We monitored neural oscillations and event-related potentials in awake alcohol-dependent rats during abstinence and following treatment with psilocybin or LY379268, agonists of the serotonin 2A receptor (5-HT2AR), and the metabotropic glutamate receptor 2 (mGluR2), that are known to reduce prefrontal dysfunction and relapse. Electrophysiological impairments in alcohol-dependent rats are reduced amplitudes of P1N1 and N1P2 components and attenuated event-related oscillatory activity. Psilocybin and LY379268 were able to restore these impairments. Furthermore, alcohol-dependent animals displayed a dominance in higher beta frequencies indicative of a state of hyperarousal that is prone to relapse, which particularly psilocybin was able to counteract. In summary, we provide prefrontal markers indicative of relapse and treatment response, especially for psychedelic drugs.
- MeSH
- alkoholismus * farmakoterapie patofyziologie MeSH
- aminokyseliny MeSH
- bicyklické sloučeniny heterocyklické * farmakologie MeSH
- biologické markery MeSH
- evokované potenciály účinky léků MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech * MeSH
- prefrontální mozková kůra * účinky léků patofyziologie metabolismus MeSH
- psilocybin * farmakologie MeSH
- receptory metabotropního glutamátu MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Juvenil, a nontoxic extract of bovine blood, is registered as a dietary supplement having no side effects. It contains a broad spectrum of free amino acids, as well as small proteins and oligopeptides (molecular weights up to 10 kDa), various nucleotides, and small amounts of phospholipids. The complex of these exclusively natural components has been shown to support physiological responses of supplemented organisms.Juvenil has been studied for several decades using a wide range of both experimental and clinical studies. Analyses have shown that it acts directly neither on individual functional systems of the body nor on individual metabolic processes. Current findings indicate that modulatory effects of Juvenil occur through modulation of gut microbiota composition, which is associated with the modulation of microbiota-gut-brain axis signaling. In murine model that modulatory effect is reflected in the expression of an early activation c-Fos marker in specific parts of the brain.In this review we present a set of findings about Juvenil, which has a wide range of positive effects on the functional systems of organisms. These effects can be used to strenghten the resistance, immunity, and regeneration of human beings. According to its effects Juvenil can be classified as a psychobiotics.
- MeSH
- aminokyseliny metabolismus MeSH
- biologické přípravky farmakologie MeSH
- imunitní systém * účinky léků MeSH
- lidé MeSH
- nukleotidy metabolismus MeSH
- oligopeptidy metabolismus MeSH
- osa mozek-střevo fyziologie účinky léků MeSH
- potravní doplňky * MeSH
- prebiotika MeSH
- probiotika farmakologie MeSH
- střevní mikroflóra * účinky léků MeSH
- Check Tag
- lidé MeSH
PURPOSE: We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS: Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS: On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION: Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.
- MeSH
- akrylamidy * MeSH
- aniliny terapeutické užití MeSH
- erbB receptory genetika MeSH
- indoly * MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- lidé MeSH
- mutace MeSH
- nádory centrálního nervového systému * diagnostické zobrazování farmakoterapie genetika MeSH
- nádory plic * farmakoterapie genetika patologie MeSH
- nemalobuněčný karcinom plic * farmakoterapie genetika patologie MeSH
- pemetrexed terapeutické užití MeSH
- platina terapeutické užití MeSH
- pyrimidiny * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
INTRODUCTION AND OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the nasal cavity, penetrates the nasal epithelial cells through the interaction of its spike protein with the host cell receptor angiotensin-converting enzyme 2 (ACE2) and then triggers a cytokine storm. We aimed to assess the biocompatibility of fullerenol nanoparticles C60(OH)40 and ectoine, and to document their effect on the protection of primary human nasal epithelial cells (HNEpCs) against the effects of interaction with the fragment of virus - spike protein. This preliminary research is the first step towards the construction of a intranasal medical device with a protective, mechanical function against SARS-CoV-2 similar to that of personal protective equipment (eg masks). METHODS: We used HNEpCs and the full-length spike protein from SARS-CoV-2 to mimic the first stage of virus infection. We assessed cell viability with the XTT assay and a spectrophotometer. May-Grünwald Giemsa and periodic acid-Schiff staining served to evaluate HNEpC morphology. We assessed reactive oxygen species (ROS) production by using 2',7'-dichlorofluorescin diacetate and commercial kit. Finally, we employed reverse transcription polymerase chain reaction, Western blotting and confocal microscopy to determine the expression of angiotensin-converting enzyme 2 (ACE2) and inflammatory cytokines. RESULTS: There was normal morphology and unchanged viability of HNEpCs after incubation with 10 mg/L C60(OH)40, 0.2% ectoine or their composite for 24 h. The spike protein exerted cytotoxicity via ROS production. Preincubation with the composite protected HNEpCs against the interaction between the spike protein and the host membrane and prevented the production of key cytokines characteristic of severe coronavirus disease 2019, including interleukin 6 and 8, monocyte chemotactic protein 1 and 2, tissue inhibitor of metalloproteinases 2 and macrophage colony-stimulating factor. CONCLUSION: In the future, the combination of fullerenol and ectoine may be used to prevent viral infections as an intranasal medical device for people with reduced immunity and damaged mucous membrane.
- MeSH
- aminokyseliny diaminové MeSH
- angiotensin-konvertující enzym 2 metabolismus MeSH
- COVID-19 * prevence a kontrola MeSH
- cytokiny metabolismus MeSH
- epitelové buňky * účinky léků virologie MeSH
- fullereny * farmakologie chemie MeSH
- glykoprotein S, koronavirus * metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- nanočástice * chemie MeSH
- nosní sliznice účinky léků cytologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- SARS-CoV-2 * účinky léků MeSH
- syndrom uvolnění cytokinů * prevence a kontrola MeSH
- viabilita buněk * účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
AIM OF STUDY: To determine whether a high dose of levodopa-carbidopa intestinal gel (LCIG), expressed as levodopa equivalent daily dose (LE daily dose), is a risk factor for acute polyneuropathy in patients treated with LCIG. CLINICAL RATIONALE FOR STUDY: Treatment with LCIG is an effective device-assisted therapy in the advanced stages of Parkinson's Disease (PD). Polyneuropathy is a well-known complication of PD treatment. Patients treated with oral levodopa usually suffer from sub-clinical or mild chronic sensory polyneuropathy. However, severe acute polyneuropathy occurs in patients treated with LCIG, which is causally related to the treatment and leads to its immediate discontinuation. The etiology is not yet clear, but some patients with acute polyneuropathy have been given high doses of LCIG. MATERIAL AND METHODS: A retrospective multicentre study of patients treated with LCIG was performed. Patients with acute polyneuropathy were subjected to a detailed analysis including statistical processing. RESULTS: Of 183 patients treated with LCIG in seven centres, six patients (five females, median age 63 years) developed acute polyneuropathy with LCIG discontinuation. The median (interquartile range) initial and final LE daily dose in patients with and without acute polyneuropathy was 3,015 (2,695-3,184) and 1,898 (1,484-2,167) mg, respectively. The final LE daily dose of 2,605 mg cut-off had 83% sensitivity and 93% specificity for the prediction of acute polyneuropathy. CONCLUSIONS AND CLINICAL IMPLICATIONS: The risk of acute polyneuropathy in LCIG-treated patients was associated with a daily LE dose of greater than 2,605 mg or with more than a 62% increase in the daily LE dose during LCIG treatment.
- MeSH
- antiparkinsonika * škodlivé účinky aplikace a dávkování MeSH
- fixní kombinace léků * MeSH
- gely * MeSH
- karbidopa * aplikace a dávkování škodlivé účinky MeSH
- levodopa * aplikace a dávkování škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- Parkinsonova nemoc * farmakoterapie MeSH
- polyneuropatie * chemicky indukované farmakoterapie MeSH
- retrospektivní studie MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
The purpose of this study was to determine the effects of resistance training (RT) alongside creatine-hydrochloride (Cr-HCl) or creatine monohydrate (CrM) supplementation on anabolic/catabolic hormones, strength, and body composition. Forty participants with an age range of 18-25 years were randomly divided into four groups (n=10): RT+Cr-HCl (0.03 g.kg-1 of body mass), RT+CrM-loading phase (CrM-LP) (0.3 g.kg-1 of body mass for five days (loading) and 0.03 g.kg-1 body mass for 51 days (maintenance)), RT+CrM-without loading phase (CrM-WLP) (0.03 g.kg-1 body mass), and RT+placebo (PL). The participants consumed supplements and performed RT with an intensity of 70-85 % 1RM for eight weeks. Before and after the training and supplementation period, strength (1RM), body composition (percent body fat (PBF), skeletal muscle mass (SMM), muscular cross-sectional area (MCSA)) and serum levels of testosterone, growth hormone (GH), insulin-like growth factor-1 (IGF-1), cortisol, adrenocorticotropic hormone (ACTH), follistatin and myostatin were measured. The results showed that in the supplementation groups, strength, arm and thigh MCSA, and SMM significantly increased, and PBF significantly decreased (P
- MeSH
- dospělí MeSH
- hydrokortison krev MeSH
- insulinu podobný růstový faktor I metabolismus MeSH
- kosterní svaly metabolismus účinky léků MeSH
- kreatin * MeSH
- lidé MeSH
- lidský růstový hormon krev MeSH
- mladiství MeSH
- mladý dospělý MeSH
- odporový trénink * metody MeSH
- potravní doplňky * MeSH
- složení těla * MeSH
- svalová síla * účinky léků MeSH
- testosteron krev MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
