Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here, we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From these data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.
- MeSH
- Ergothioneine * metabolism pharmacology MeSH
- Physical Conditioning, Animal * MeSH
- Humans MeSH
- Mitochondria * metabolism MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Sulfurtransferases * metabolism MeSH
- Mitochondria, Muscle * metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
PURPOSE OF STUDY: Total joint replacements (TJR) have become the cornerstone of modern orthopedic surgery. A great majority of TJR employs ultrahigh molecular weight polyethylene (UHMWPE) liners. TJR manufacturers use many different types of UHMWPE, which are modified by various combinations of crosslinking, thermal treatment, sterilization and/or addition of biocompatible stabilizers. The UHMWPE modifications are expected to improve the polymer's resistance to oxidative degradation and wear (release of microparticles from the polymer surface). This manuscript provides an objective, non-commercial comparison of current UHMWPE formulations currently employed in total knee replacements. MATERIALS AND METHODS: UHMWPE liners from 21 total knee replacements (TKR) were collected which represent the most implanted liners in the Czech Republic in the period 2020-2021. The UHMWPEs were characterized using several methods: infrared microspectroscopy (IR), non-instrumented and instrumented microindentation hardness testing (MH and MHI), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solubility measurements. The above-listed methods yielded quite complete information about the structure and properties of each UHMWPE type, including its potential long-term oxidation resistance. RESULTS: For each UHMWPE liner, IR yielded information about immediate oxidative degradation (in the form of oxidation index, OI), level of crosslinking (trans-vinylene index, VI) and crystallinity (CI). The MH and MHI testing gave information about the impact of structure changes on mechanical properties. The remaining methods (DSC, TGA, and solubility measurements) provided additional information regarding the structure changes and resistance to long-term oxidative degradation. Statistical evaluation showed significant differences among the samples as well as interesting correlations among the UHMWPE modifications, structural changes, and mechanical performance. DISCUSSION: Surprisingly enough, UHMWPE materials from different manufacturers showed quite different properties, including the resistance against the long-term oxidative degradation, which is regarded as one of the main reasons of TJR failures. The most promising UHMWPE types were crosslinked materials with biocompatible stabilizers. CONCLUSIONS: Current UHMWPE liners from different manufactures used in total knee replacements exhibit significantly different structure and properties. From the point of view of clinical practice, the traditional UHMWPE types, which contained residual radicals from irradiation and/or gamma sterilization, showed inferior resistance to oxidative degradation and should be avoided. The best properties were observed in modern UHMWPE types, which combined crosslinking, biocompatible stabilizers, and sterilization by ethylenoxide or gas plasma. KEY WORDS: UHMWPE; knee replacements; oxidative degradation; infrared spectroscopy; microhardness.
- MeSH
- Biocompatible Materials chemistry MeSH
- Calorimetry, Differential Scanning MeSH
- Humans MeSH
- Polyethylenes * chemistry MeSH
- Prosthesis Design MeSH
- Knee Prosthesis * MeSH
- Thermogravimetry MeSH
- Materials Testing * methods MeSH
- Arthroplasty, Replacement, Knee * instrumentation methods MeSH
- Check Tag
- Humans MeSH
- Publication type
- English Abstract MeSH
- Journal Article MeSH
- Comparative Study MeSH
A family of new compounds with sulfonamide and amide functional groups as potential Alzheimer's disease drugs were prepared by multistep synthesis. Thermal stability measurements recorded the initial decomposition in the range of 200-220°C, close above the melting point. The final compounds were tested for their ability to inhibit acetylcholinesterase and butyrylcholinesterase, and the in vitro dissolution behavior of selected compounds was studied through both lipophilic and hydrophilic matrix tablets. All nine tested derivatives were even more active in inhibiting acetylcholinesterase than the clinically used rivastigmine. Regression analysis of the obtained dissolution profiles was performed, and the effects of the pH and the release mechanism were determined. Some substances showed remarkable biological activity and became a subject of interest for further extensive study.
- MeSH
- Acetylcholinesterase metabolism MeSH
- Alzheimer Disease * drug therapy MeSH
- Butyrylcholinesterase * metabolism MeSH
- Cholinesterase Inhibitors * pharmacology chemical synthesis chemistry MeSH
- Hydrogen-Ion Concentration MeSH
- Humans MeSH
- Molecular Structure MeSH
- Rivastigmine pharmacology chemical synthesis chemistry MeSH
- Solubility MeSH
- Sulfonamides * pharmacology chemistry chemical synthesis MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
The objective of this study was to evaluate whether RSV inhibits neutrophil extracellular traps (NETs) that induce joint hyperalgesia in C57BL/6 mice after adjuvant-induced arthritis. A subplantar injection of Freund's complete adjuvant was administered to C57BL/6 mice on day 0 for immunization in the AIA model. Resveratrol (RSV, 25 mg/kg) was administered intraperitoneally once daily starting on day 22 and continuing for two weeks. The effects of mechanical hyperalgesia and edema formation have been assessed in addition to histopathological scoring. Mice were sacrificed on day 35 to determine cytokine levels and PADI4 and COX-2 expression levels. ELISA was used to quantify neutrophil extracellular traps (NETs) along with neutrophil elastase-DNA and myeloperoxidase-DNA complexes in neutrophils. An immunohistochemical stain was performed on knee joints to determine the presence of nuclear factor kappa B p65 (NF-kappaB p65). AIA mice were found to have higher levels of NET in joints and their joint cells demonstrated an increased expression of the PADI4 gene. Treatment with RSV in AIA mice (25 mg/kg, i.p.) significantly (P<0.05) inhibited joint hyperalgesia, resulting in a significant increase in mechanical threshold, a decrease in articular edema, a decrease in the production of inflammatory cytokines, increased COX-2 expression, and a decrease in the immunostaining of NF-kappaB. Furthermore, treatment with RSV significantly reduced the amount of neutrophil elastase (NE)-DNA and MPO-DNA complexes, which were used as indicators of NET formation (P<0.05). This study indicates that RSV reduces NET production and hyperalgesia by reducing inflammation mediated by PADI4 and COX-2. According to these data, NETs contribute to joint pain and resveratrol can be used to treat pain in RA through this pathway.
- MeSH
- Cyclooxygenase 2 MeSH
- Cytokines metabolism MeSH
- DNA metabolism MeSH
- Edema metabolism MeSH
- Extracellular Traps * metabolism MeSH
- Hyperalgesia drug therapy metabolism MeSH
- Leukocyte Elastase metabolism pharmacology MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Neutrophils metabolism MeSH
- NF-kappa B metabolism MeSH
- Resveratrol pharmacology therapeutic use metabolism MeSH
- Arthritis, Rheumatoid * metabolism MeSH
- Toll-Like Receptor 4 metabolism MeSH
- Inflammation metabolism MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: During atrial fibrillation ablations using thermal energy, the treatment effect is attributed to not just pulmonary vein isolation (PVI), but also to modulation of the autonomic nervous system by ablation of cardiac ganglionated plexi (GP). OBJECTIVES: This study sought to assess the impact of pulsed field ablation (PFA) on the GP in patients undergoing PVI. METHODS: In the retrospective phase, heart rate was assessed pre- versus post-PVI using PFA, cryoballoon ablation, or radiofrequency ablation. In the prospective phase, a pentaspline PFA catheter was used in a protocol: 1) pre-PFA, high-frequency stimulation (HFS) identified GP sites by vagal effects; 2) PVI was performed assessing for repetitive vagal effects over each set of PF applications; 3) mapping defined PVI extent to identify those GP in the ablation zone; and 4) repeat HFS at GP sites to assess for persistence of vagal effects. RESULTS: Between baseline and 3 months, heart rates in the retrospective radiofrequency ablation (n = 40), cryoballoon (n = 40), and PFA (n = 40) cohorts increased by 8.9 ± 11.4, 11.1 ± 9.4, and -0.1 ± 9.2 beats/min, respectively (P= 0.01 PFA vs radiofrequency ablation; P= 0.01 PFA vs cryoballoon ablation). In the prospective phase, pre-PFA HFS in 20 additional patients identified 65 GP sites. During PFA, vagal effects were noted in 45% of first PF applications, persisting through all applications in 83%. HFS post-PFA reproduced vagal effects in 29 of 38 sites (76%) in low-voltage tissue. CONCLUSIONS: PFA has minimal effect on GP. Unlike with thermal ablation, the mechanism by which PFA treats atrial fibrillation is mediated solely by durable PVI.
- MeSH
- Atrial Fibrillation * MeSH
- Catheter Ablation * adverse effects MeSH
- Humans MeSH
- Vagus Nerve surgery MeSH
- Prospective Studies MeSH
- Retrospective Studies MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Telomeres are environment-sensitive regulators of health and aging. Here,we present telomere DNA length analysis of two reef-building coral genera revealing that the long- and short-term water thermal regime is a key driver of between-colony variation across the Pacific Ocean. Notably, there are differences between the two studied genera. The telomere DNA lengths of the short-lived, more stress-sensitive Pocillopora spp. colonies were largely determined by seasonal temperature variation, whereas those of the long-lived, more stress-resistant Porites spp. colonies were insensitive to seasonal patterns, but rather influenced by past thermal anomalies. These results reveal marked differences in telomere DNA length regulation between two evolutionary distant coral genera exhibiting specific life-history traits. We propose that environmentally regulated mechanisms of telomere maintenance are linked to organismal performances, a matter of paramount importance considering the effects of climate change on health.
- MeSH
- DNA genetics MeSH
- Anthozoa * genetics MeSH
- Coral Reefs MeSH
- Seasons MeSH
- Temperature MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: Pulsed field ablation is a novel nonthermal cardiac ablation modality using ultra-rapid electrical pulses to cause cell death by a mechanism of irreversible electroporation. Unlike the traditional ablation energy sources, pulsed field ablation has demonstrated significant preferentiality to myocardial tissue ablation, and thus avoids certain thermally mediated complications. However, its safety and effectiveness remain unknown in usual clinical care. METHODS: MANIFEST-PF (Multi-National Survey on the Methods, Efficacy, and Safety on the Post-Approval Clinical Use of Pulsed Field Ablation) is a retrospective, multinational, patient-level registry wherein patients at each center were prospectively included in their respective center registries. The registry included all patients undergoing postapproval treatment with a multielectrode 5-spline pulsed field ablation catheter to treat atrial fibrillation (AF) between March 1, 2021, and May 30, 2022. The primary effectiveness outcome was freedom from clinical documented atrial arrhythmia (AF/atrial flutter/atrial tachycardia) of ≥30 seconds on the basis of electrocardiographic data after a 3-month blanking period (on or off antiarrhythmic drugs). Safety outcomes included the composite of acute (<7 days postprocedure) and latent (>7 days) major adverse events. RESULTS: At 24 European centers (77 operators) pulsed field ablation was performed in 1568 patients with AF: age 64.5±11.5 years, female 35%, paroxysmal/persistent AF 65%/32%, CHA2DS2-VASc 2.2±1.6, median left ventricular ejection fraction 60%, and left atrial diameter 42 mm. Pulmonary vein isolation was achieved in 99.2% of patients. After a median (interquartile range) follow-up of 367 (289-421) days, the 1-year Kaplan-Meier estimate for freedom from atrial arrhythmia was 78.1% (95% CI, 76.0%-80.0%); clinical effectiveness was more common in patients with paroxysmal AF versus persistent AF (81.6% versus 71.5%; P=0.001). Acute major adverse events occurred in 1.9% of patients. CONCLUSIONS: In this large observational registry of the postapproval clinical use of pulsed field technology to treat AF, catheter ablation using pulsed field energy was clinically effective in 78% of patients with AF.
- MeSH
- Atrial Fibrillation * diagnosis surgery drug therapy MeSH
- Atrial Flutter * etiology MeSH
- Ventricular Function, Left MeSH
- Catheter Ablation * adverse effects methods MeSH
- Middle Aged MeSH
- Humans MeSH
- Recurrence MeSH
- Registries MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Stroke Volume MeSH
- Pulmonary Veins * MeSH
- Treatment Outcome MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
These days, explorations have focused on designing two-dimensional (2D) nanomaterials with useful (photo)catalytic and environmental applications. Among them, MXene-based composites have garnered great attention owing to their unique optical, mechanical, thermal, chemical, and electronic properties. Various MXene-based photocatalysts have been inventively constructed for a variety of photocatalytic applications ranging from pollutant degradation to hydrogen evolution. They can be applied as co-catalysts in combination with assorted common photocatalysts such as metal sulfide, metal oxides, metal-organic frameworks, graphene, and graphitic carbon nitride to enhance the function of photocatalytic removal of organic/pharmaceutical pollutants, nitrogen fixation, photocatalytic hydrogen evolution, and carbon dioxide conversion, among others. High electrical conductivity, robust photothermal effects, large surface area, hydrophilicity, and abundant surface functional groups of MXenes render them as attractive candidates for photocatalytic removal of pollutants as well as improvement of photocatalytic performance of semiconductor catalysts. Herein, the most recent developments in photocatalytic degradation of organic and pharmaceutical pollutants using MXene-based composites are deliberated, with a focus on important challenges and future perspectives; techniques for fabrication of these photocatalysts are also covered.
BACKGROUND: Quantitative sensory testing (QST) assesses the functional integrity of small and large nerve fibre afferents and central somatosensory pathways; QST was assumed to provide insight into the mechanisms of neuropathy. We analysed QST profiles and phenotypes in patients with diabetes mellitus to study whether these could differentiate patients with and without pain and neuropathy. METHODS: A standardized QST protocol was performed and 'loss and gain of function' abnormalities were analysed in four groups of subjects: diabetic patients with painful (pDSPN; n = 220) and non-painful distal symmetric polyneuropathy (nDSPN; n = 219), diabetic patients without neuropathy (DM; n = 23) and healthy non-diabetic subjects (n = 37). Based on the QST findings, diabetic subjects were further stratified into four predefined prototypic phenotypes: sensory loss (SL), thermal hyperalgesia (TH), mechanical hyperalgesia (MH) and healthy individuals. RESULTS: Patients in the pDSPN group showed the greatest hyposensitivity ('loss of function'), and DM patients showed the lowest, with statistically significant increases in thermal, thermal pain, mechanical and mechanical pain sensory thresholds. Accordingly, the frequency of the SL phenotype was significantly higher in the pDSPN subgroup (41.8%), than expected (p < 0.0042). The proportion of 'gain of function' abnormalities was low in both pDSPN and nDSPN patients without significant differences. CONCLUSIONS: There is a continuum in the sensory profiles of diabetic patients, with a more pronounced sensory loss in pDSPN group probably reflecting somatosensory nerve fibre degeneration. An analysis of 'gain of function' abnormalities (allodynia, hyperalgesia) did not offer a key to understanding the pathophysiology of spontaneous diabetic peripheral neuropathic pain. SIGNIFICANCE: This article, using quantitative sensory testing profiles in large cohorts of diabetic patients with and without polyneuropathy and pain, presents a continuum in the sensory profiles of diabetic patients, with more pronounced 'loss of function' abnormalities in painful polyneuropathy patients. Painful diabetic polyneuropathy probably represents a 'more progressed' type of neuropathy with more pronounced somatosensory nerve fibre degeneration. The proportion of 'gain of function' sensory abnormalities was low, and these offer limited understanding of pathophysiological mechanisms of spontaneous neuropathic pain.
PURPOSE OF THE STUDY In clinical practice UHMWPE is the most commonly used material for manufacturing articular components of joint replacements. The purpose of this study is to find out whether repeated ethylene oxide sterilization results in oxidative degradation of UHMWPE or not and also whether the oxidative degradation of various types of ethylene oxide-sterilized UHMWPE depends on storage time or not. MATERIAL AND METHODS The set included 12 samples of UHMWPE (three samples with different modifications (virgin PE, with E vitamin and cross-linked with thermal treatment) and different number of sterilizations (0×-3×)). The set also included 8 samples of commercial components of hip or knee replacements sterilized with ethylene oxide and stored for different storage periods. The oxidative degradation was assessed by infrared microspectroscopy, based on which the oxidation index (OI), transvinylene index (VI), crystallinity index (CI) and E vitamin index (EI) were calculated. Mechanical properties of UHMWPE were obtained through microhardness measurements. Statistical processing of the results was performed. RESULTS In all the samples, very low oxidative degradation values were reported (most OI values < 0.1). All radiation crosslinked UHMWPE samples showed an increased VI index and a slightly lower crystallinity index. All unmodified samples (irrespective of whether or not and how many times or how long ago the samples were sterilized with EtO) had almost zero value of VI. Changes in crystallinity were negligible (in the rage of 0.56-0.63), which required very accurate measurements of micromechanical properties. Yet, linear correlation was established between microhardness and crystallinity. DISCUSSION All the mentioned indices changed as anticipated: OIs were very low and slightly increased with time of storage, VIs of radiation crosslinked samples grew in proportion to the total gama radiation dose, CIs decreased in samples thermally treated by remelting, and EIs were very low due to negligible concentration of stabiliser (0.1%) in the samples of medical grade UHMWPE. CONCLUSIONS All samples showed zero or minimum oxidative degradation. This confirmed that neither ethylene oxide sterilization, nor multiple EtO sterilization or longer storage of polymer after ethylene oxide sterilization result in major oxidative degradation. Key words: UHMWPE, ethylene oxide, sterilization, oxidation, infrared spectroscopy, microhardness.
- MeSH
- Arthroplasty, Replacement * MeSH
- Ethylene Oxide * MeSH
- Humans MeSH
- Polyethylenes MeSH
- Sterilization methods MeSH
- Vitamins MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
