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Oxidative addition (OA) is a necessary step in mechanisms of widely used synthetic methodologies such as the Heck reaction, cross-coupling reactions, and the Buchwald-Hartwig amination. This study pioneers the exploration of OA of aryl halide to palladium nanoparticles (NPs), a process previously unaddressed in contrast to the activity of well-studied Pd(0) complexes. Employing DFT modeling and semi-empirical metadynamics simulations, the oxidative addition of phenyl bromide to Pd nanoparticles was investigated in detail. Energy profiles of oxidative addition to Pd NPs were analyzed and compared to those involving Pd(0) complexes forming under both ligand-stabilized (phosphines) and ligandless (amine base) conditions. Metadynamics simulations highlighted the edges of the (1 1 1) facets of Pd NPs as the key element of oxidative addition activity. We demonstrate that OA to Pd NPs is not only kinetically facile at ambient temperatures but also thermodynamically favorable. This finding accentuates the necessity of incorporating OA to Pd NPs in future investigations, thus providing a more realistic view of the involved catalytic mechanisms. These results enhance the understanding of aryl halide (cross-)coupling reactions, reinforcing the concept of a catalytic "cocktail". This concept posits dynamic interconversions between diverse active and inactive centers, collectively affecting the outcome of the reaction. High activity of Pd NPs in direct C-X activation paves the way for novel approaches in catalysis, potentially enhancing the field and offering new catalytic pathways to consider.
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Transient receptor potential vanilloid subtype 3 (TRPV3) is an ion channel implicated in skin physiology and itch. TRPV3 inhibitors can present a novel strategy for combating debilitating itch conditions, and medicinal plants are a natural pool of such compounds. Here, we report the isolation of a TRPV3-inhibiting compound from Andrographis paniculata, a medicinal plant with anti-inflammatory properties whose bioactive components are poorly characterized in terms of molecular targets. Using 1H and 13C NMR and high-resolution mass spectrometry, the compound was identified as a labdane-type diterpenoid, 14-deoxy-11,12-didehydroandrographolide (ddA). The activity of the compound was evaluated by fluorescent calcium assay and manual whole-cell patch-clamp technique. ddA inhibited human TRPV3 in stably expressing CHO and HaCaT keratinocytes, acting selectively among other TRP channels implicated in itch and inflammation and not showing toxicity to HaCaT cells. Antipruritic effects of the compound were evaluated in scratching behavior models on ICR mice. ddA suppressed itch induced by the TRPV3 activator carvacrol. Additionally, ddA potently suppressed histamine-induced itch with efficacy comparable to loratadine, a clinically used antihistamine drug. These results suggest the potential of ddA as a possible safe and efficacious alternative for antipruritic therapy.
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Andrographis , Diterpenos , Plantas Medicinais , Prurido , Canais de Cátion TRPV , Animais , Diterpenos/farmacologia , Diterpenos/química , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo , Prurido/tratamento farmacológico , Humanos , Camundongos , Plantas Medicinais/química , Andrographis/química , Estrutura Molecular , Camundongos Endogâmicos ICR , Queratinócitos/efeitos dos fármacos , Células CHO , Cricetulus , Antipruriginosos/farmacologia , Masculino , Pele/efeitos dos fármacos , Células HaCaTRESUMO
The article presents a rare case of human invasion by the trematode Clinostomum complanatum in the European part of Russia. The diagnosis was established based on a parasitological study of flukes removed from the tonsils and pharynx of a 42-year-old woman, a resident of the Tambov region of Russia.
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A novel modification of IP networks integrated optimization method for heterogeneous networks, for example, the seamless Wi-Fi network serving simultaneously mobile users and wireless sensors, has been developed in this article. The mutual influence of signal reception, frequency-territorial planning, and routing procedures in heterogeneous networks have been analyzed in the case of simultaneous data transmission by both mobile users and wireless sensors. New principles for the listed procedures interaction and the basic functions for their describing are formulated. A novel modification of the integrated optimization method and its algorithm have been developed. The developed method's effectiveness has been analyzed for the IEEE 802.11ax network segment. Its result showed that the network load was decreased by an average of 20%, the data rate over the network as a whole increased for users and sensors by an average of 25% and 40%, respectively, and the sensors' lifetime increased by an average of 20% compared to the novel modification of the Collective Dynamic Routing method.
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Tafalgin (Taf) is a tetrapeptide opioid used in clinical practice in Russia as an analgesic drug for subcutaneous administration as a solution (4 mg/mL; concentration of 9 mM). We found that the acid-sensing ion channels (ASICs) are another molecular target for this molecule. ASICs are proton-gated sodium channels that mediate nociception in the peripheral nervous system and contribute to fear and learning in the central nervous system. Using electrophysiological methods, we demonstrated that Taf could increase the integral current through heterologically expressed ASIC with half-maximal effective concentration values of 0.09 mM and 0.3 mM for rat and human ASIC3, respectively, and 1 mM for ASIC1a. The molecular mechanism of Taf action was shown to be binding to the channel in the resting state and slowing down the rate of desensitization. Taf did not compete for binding sites with both protons and ASIC3 antagonists, such as APETx2 and amiloride (Ami). Moreover, Taf and Ami together caused an unusual synergistic effect, which was manifested itself as the development of a pronounced second desensitizing component. Thus, the ability of Taf to act as a positive allosteric modulator of these channels could potentially cause promiscuous effects in clinical practice. This fact must be considered in patients' treatment.
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Canais Iônicos Sensíveis a Ácido , Analgésicos Opioides , Ratos , Humanos , Animais , Canais Iônicos Sensíveis a Ácido/metabolismo , Analgésicos Opioides/farmacologia , Amilorida/farmacologia , Prótons , Sítios de LigaçãoRESUMO
Alloys of gallium with transition metals have recently received considerable attention for their applications in microelectronics and catalysis. Here, we investigated the initial stages of the Ga-Cu alloy formation on Cu(111) and Cu(001) surfaces using scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy (XPS), and low energy electron diffraction (LEED). The results show that Ga atoms deposited using physical vapor deposition readily intermix with the Cu surface, leading to a random distribution of the Ga and Cu atoms within the surface layer, on both terraces and monolayer-thick islands formed thereon. However, as the Ga coverage increases, several ordered structures are formed. The (â3×â3)R30° structure is found to be thermodynamically most stable on Cu(111). This structure remains after vacuum annealing at 600 K, independent of the initial Ga coverage (varied between 0.5 and 3 monolayers), indicating a self-limited growth of the Ga-Cu alloy layer, with the rest of the Ga atoms migrating into the Cu crystal. For Ga deposited on Cu(001), we observed a (1 × 5)-reconstructed surface, which has never been observed for surface alloys on Cu(001). The experimental findings were rationalized on the basis of density functional theory (DFT) calculations, which provided structural models for the most stable surface Ga-Cu alloys on Cu(111) and Cu(001). The study sheds light on the complex interaction of Ga with transition metal surfaces and the interfaces formed thereon that will aid in a better understanding of surface alloying and chemical reactions on the Ga-based alloys.
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The Tibellus oblongus spider is an active hunter that does not spin webs and remains highly underinvestigated in terms of the venom composition. Here, we describe venom glands transcriptome and venom proteome analysis for unveiling the polypeptide composition of Tibellus oblongus spider venom. The resulting EST database includes 1733 records, including 1263 nucleotide sequences with ORFs, of these 942 have been identified as toxin-coding. The database of peptide sequences was built based on of the transcriptomics results. It contains 217 new toxins, 212 of them were detected in the T. oblongus venom by the proteomics.
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Venenos de Aranha , Transcriptoma , Sequência de Aminoácidos , Perfilação da Expressão Gênica/métodos , Proteômica/métodos , Venenos de Aranha/genética , Venenos de Aranha/química , Peçonhas , AnimaisRESUMO
Wound healing is a complex process and remains a considerable challenge in clinical trials due to the lack of ideal therapeutic drugs. Here, a new peptide TK-HR identified from the skin of the frog Hoplobatrachus rugulosus was tested for its ability to heal cutaneous wounds in mice. Topical application of TK-HR at doses of 50-200 µg/mL significantly accelerated wound closure without causing any adverse effects in the animals. In vitro and in vivo investigations proved the regulatory role of the peptide on neutrophils, macrophages, keratinocytes, and vein endothelial cells involved in the inflammatory, proliferative, and remodeling phases of wound healing. Notably, TK-HR activated the MAPK and TGF-ß-Smad signaling pathways by acting on NK1R in RAW264.7 cells and mice. The current work has identified that TK-HR is a potent wound healing regulator that can be applied for the treatment of wounds, including diabetic foot ulcers and infected wounds, in the future.
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Células Endoteliais , Receptores da Neurocinina-1 , Camundongos , Animais , Receptores da Neurocinina-1/metabolismo , Pele/metabolismo , Cicatrização , Peptídeos/farmacologia , Medicina TradicionalRESUMO
In-plane sulfur vacancies (Sv) in molybdenum disulfide (MoS2) were newly unveiled for CO2 hydrogenation to methanol, whereas edge Sv were found to facilitate methane formation. Thus, selective exposure and activation of basal plane is crucial for methanol synthesis. Here, we report a mesoporous silica-encapsulated MoS2 catalysts with fullerene-like structure and atomic copper (Cu/MoS2@SiO2). The main approach is based on a physically constrained topologic conversion of molybdenum dioxide (MoO2) to MoS2 within silica. The spherical curvature enables the generation of strain and Sv in inert basal plane. More importantly, fullerene-like structure of few-layer MoS2 can selectively expose in-plane Sv and reduce the exposure of edge Sv. After promotion by atomic copper, the resultant Cu/MoS2@SiO2 exhibits stable specific methanol yield of 6.11 molMeOH molMo-1 h-1 with methanol selectivity of 72.5% at 260 °C, much superior to its counterparts lacking the fullerene-like structure and copper decoration. The reaction mechanism and promoting role of copper are investigated by in-situ DRIFTS and in-situ XAS. Theoretical calculations demonstrate that the compressive strain facilitates Sv formation and CO2 hydrogenation, while tensile strain accelerates the regeneration of active sites, rationalizing the critical role of strain.
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Acid-sensing ion channels (ASICs) are proton-gated ion channels that mediate nociception in the peripheral nervous system and contribute to fear and learning in the central nervous system. Sevanol was reported previously as a naturally-occurring ASIC inhibitor from thyme with favorable analgesic and anti-inflammatory activity. Using electrophysiological methods, we found that in the high micromolar range, the compound effectively inhibited homomeric ASIC1a and, in sub- and low-micromolar ranges, positively modulated the currents of α1ß2γ2 GABAA receptors. Next, we tested the compound in anxiety-related behavior models using a targeted delivery into the hippocampus with parallel electroencephalographic measurements. In the open field, 6 µM sevanol reduced both locomotor and θ-rhythmic activity similar to GABA, suggesting a primary action on the GABAergic system. At 300 µM, sevanol markedly suppressed passive avoidance behavior, implying alterations in conditioned fear memory. The observed effects could be linked to distinct mechanisms involving GABAAR and ASIC1a. These results elaborate the preclinical profile of sevanol as a candidate for drug development and support the role of ASIC channels in fear-related functions of the hippocampus.
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Thymus (Planta) , Canais Iônicos Sensíveis a Ácido , Medo/efeitos dos fármacos , Ácido gama-Aminobutírico , Hipocampo/efeitos dos fármacos , Receptores de GABA-A/efeitos dos fármacos , Thymus (Planta)/químicaRESUMO
This review covers briefly the work carried out at our institute (IBCh), in many cases in collaboration with other Russian and foreign laboratories, for the last 50 years. It discusses the discoveries and studies of various animal toxins, including protein and peptide neurotoxins acting on the nicotinic acetylcholine receptors (nAChRs) and on other ion channels. Among the achievements are the determination of the primary structures of the α-bungarotoxin-like three-finger toxins (TFTs), covalently bound dimeric TFTs, glycosylated cytotoxin, inhibitory cystine knot toxins (ICK), modular ICKs, and such giant molecules as latrotoxins and peptide neurotoxins from the snake, as well as from other animal venoms. For a number of toxins, spatial structures were determined, mostly by 1H-NMR spectroscopy. Using this method in combination with molecular modeling, the molecular mechanisms of the interactions of several toxins with lipid membranes were established. In more detail are presented the results of recent years, among which are the discovery of α-bungarotoxin analogs distinguishing the two binding sites in the muscle-type nAChR, long-chain α-neurotoxins interacting with α9α10 nAChRs and with GABA-A receptors, and the strong antiviral effects of dimeric phospholipases A2. A summary of the toxins obtained from arthropod venoms includes only highly cited works describing the molecules' success story, which is associated with IBCh. In marine animals, versatile toxins in terms of structure and molecular targets were discovered, and careful work on α-conotoxins differing in specificity for individual nAChR subtypes gave information about their binding sites.
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Experimentação Animal , Toxinas Biológicas , Animais , Bungarotoxinas , Neurotoxinas/toxicidade , CitotoxinasRESUMO
Efficient DNA sample preparation from fungi with the rigid cell walls is still critical for successful polymerase chain reaction (PCR), one of the basic platforms in molecular diagnostics of fungi, especially in medical mycology. Common methods that involve different chaotropes to yield DNA samples have found a limited application for fungi. Here we describe a novel procedure for efficient production of permeable fungal cell envelopes with DNA inside as suitable templates for PCR. This procedure is facile, relies on boiling of fungal cells in aqueous solutions of selected chaotropic agents and additives and enables to remove RNA and proteins from PCR template samples. The use of chaotropic solutions containing 7 M urea, 1% sodium dodecyl sulfate (SDS), up to100 mM ammonia and/or 25 mM sodium citrate was the best option to yield highly purified DNA-containing cell envelopes from all fungal strains under study, including clinical Candida and Cryptococcusisolates. After treatment with the selected chaotropic mixtures, the fungal cell walls had undergone loosening and were no longer a barrier to release DNA in PCR as evident from electron microscopy examinations and successful target gene amplifications. Overall, the developed simple, fast, and low-cost approach to produce PCR-suitable templates in the form of DNA encased by permeable cell walls can find application in molecular diagnostics.
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Parede Celular , Reação em Cadeia da Polimerase , DNA Fúngico/química , DNA Fúngico/genética , DNA Fúngico/isolamento & purificação , Reação em Cadeia da Polimerase/métodos , RNA Fúngico/química , RNA Fúngico/genética , RNA Fúngico/isolamento & purificação , Parede Celular/químicaRESUMO
This study investigated von Willebrand factor (VWF)-mediated platelet adhesion at high shear rates in patients with premature coronary artery disease (CAD). The study included 84 patients with stable premature CAD and 64 patients without CAD. Whole blood samples were perfused through a microfluidic cell over a collagen-coated surface at a shear rate of 1300 s-1. Measurements were performed before and after the inhibition of VWF-specific platelet GPIb receptors with an anti-GPIb monoclonal antibody (mAb). Platelet adhesion decreased by 77.0% (55.9; 84.7) in patients with premature CAD and by 29.6% (0.0; 59.7) in control patients after the inhibition of VWF-platelet interaction with anti-GPIb mAb (p < 0.001). After adjusting for traditional risk factors, the odds ratio for premature CAD per 1% decrease in GPIb-mediated platelet adhesion was 1.03 (95% CI, 1.02-1.05; p < 0.001). The optimal cut-off level value of GPIb-mediated platelet adhesion was 62.8%, with 70.2% sensitivity and 81.2% specificity for CAD. The plasma levels of VWF or antiplatelet therapy did not affect the GPIb-mediated component of platelet adhesion. Thus, the GPIb-mediated component of platelet adhesion was more pronounced in patients with premature CAD. This may indicate the possible role of excessive VWF-platelet interactions in the development of premature CAD.
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Acid-sensing ion channels (ASICs) have been known as sensors of a local pH change within both physiological and pathological conditions. ASIC-targeting peptide toxins could be potent molecular tools for ASIC-manipulating in vitro, and for pathology treatment in animal test studies. Two sea anemone toxins, native Hmg 1b-2 and recombinant Hmg 1b-4, both related to APETx-like peptides, inhibited the transient current component of human ASIC3-Δ20 expressed in Xenopus laevis oocytes, but only Hmg 1b-2 inhibited the rat ASIC3 transient current. The Hmg 1b-4 action on rASIC3 as a potentiator was confirmed once again. Both peptides are non-toxic molecules for rodents. In open field and elevated plus maze tests, Hmg 1b-2 had more of an excitatory effect and Hmg 1b-4 had more of an anxiolytic effect on mouse behavior. The analgesic activity of peptides was similar and comparable to diclofenac activity in an acid-induced muscle pain model. In models of acute local inflammation induced by λ-carrageenan or complete Freund's adjuvant, Hmg 1b-4 had more pronounced and statistically significant anti-inflammatory effects than Hmg 1b-2. It exceeded the effect of diclofenac and, at a dose of 0.1 mg/kg, reduced the volume of the paw almost to the initial volume. Our data highlight the importance of a comprehensive study of novel ASIC-targeting ligands, and in particular, peptide toxins, and present the slightly different biological activity of the two similar toxins.
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Ansiolíticos , Proteína HMGB3 , Anêmonas-do-Mar , Toxinas Biológicas , Ratos , Camundongos , Humanos , Animais , Ansiolíticos/farmacologia , Anêmonas-do-Mar/química , Diclofenaco , Proteína HMGB2 , Peptídeos/farmacologia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Toxinas Biológicas/farmacologia , Fatores de Transcrição , Roedores , Anti-Inflamatórios/farmacologiaRESUMO
Chemoselective O-alkylation of 1-aryl-3-polyfluoroalkylpyrazol-5-oles under basic conditions resulted in a series of 5-alkoxypyrazoles (26 derivatives). They showed an acceptable ADME profile (in silico) and can be considered as drug-like. In experiments inâ vivo (CD-1 mice), it was found that the obtained compounds do not have toxic properties at a dose of more than 150â mg/kg (for most compounds at a dose of >300â mg/kg, and for lead compounds - >600â mg/kg). 22 Compounds from this series demonstrated from moderate to high analgesic effects (28-104 % at 1â h and 37-109 % at 2â h after administration) inâ vivo in the hot plate test (SD rats, 15â mg/kg, intraperitoneal (ip)). The lead compound was 4-([1-phenyl-3-(trifluoromethyl)pyrazol-5-yl]oxy)butan-1-ol, which not only increased the latent period in the hot plate test by 103 % at both measurement points but also showed a pronounced analgesic effect under conditions of capsaicin-induced nociception (CD-1 mice, 15â mg/kg, ip). According to molecular modeling, all synthesized compounds can interact with the TRPV1 ion channel. This biological target was confirmed in inâ vitro experiments on Chinese hamster ovary cells expressing rTRPV1. 5-Alkoxypyrazoles were partial agonists of the TRPV1 ion channel in various degree, and the most active was the same pyrazole as in inâ vivo tests.
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Analgésicos , Canais de Cátion TRPV , Cricetinae , Ratos , Camundongos , Animais , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Células CHO , Ratos Sprague-Dawley , CricetulusRESUMO
Atomically dispersed metal catalysts offer the advantages of efficient metal utilization and high selectivities for reactions of technological importance. Such catalysts have been suggested to be strong candidates for dry reforming of methane (DRM), offering prospects of high selectivity for synthesis gas without coke formation, which requires ensembles of metal sites and is a challenge to overcome in DRM catalysis. However, investigations of the structures of isolated metal sites on metal oxide supports under DRM conditions are lacking, and the catalytically active sites remain undetermined. Data characterizing the DRM reaction-driven structural evolution of a cerium oxide-supported catalyst, initially incorporating atomically dispersed platinum, and the corresponding changes in catalyst performance are reported. X-ray absorption and infrared spectra show that the reduction and agglomeration of isolated cationic platinum atoms to form small platinum clusters/nanoparticles are necessary for DRM activity. Density functional theory calculations of the energy barriers for methane dissociation on atomically dispersed platinum and on platinum clusters support these observations. The results emphasize the need for in-operando experiments to assess the active sites in such catalysts. The inferences about the catalytically active species are suggested to pertain to a broad class of catalytic conversions involving the rate-limiting dissociation of light alkanes.
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Purinergic P2X7 receptors (P2X7) have now been proven to play an important role and represent an important therapeutic target in many pathological conditions including neurodegeneration. Here, we investigated the impact of peptides on purinergic signaling in Neuro-2a cells through the P2X7 subtype in in vitro models. We have found that a number of recombinant peptides, analogs of sea anemone Kunitz-type peptides, are able to influence the action of high concentrations of ATP and thereby reduce the toxic effects of ATP. The influx of calcium, as well as the fluorescent dye YO-PRO-1, was significantly suppressed by the studied peptides. Immunofluorescence experiments confirmed that the peptides reduce the P2X7 expression level in neuronal Neuro-2a cells. Two selected active peptides, HCRG1 and HCGS1.10, were found to specifically interact with the extracellular domain of P2X7 and formed stable complexes with the receptor in surface plasmon resonance experiments. The molecular docking approach allowed us to establish the putative binding sites of the most active HCRG1 peptide on the extracellular domain of the P2X7 homotrimer and propose a mechanism for regulating its function. Thus, our work demonstrates the ability of the Kunitz-type peptides to prevent neuronal death by affecting signaling through the P2X7 receptor.
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Receptores Purinérgicos P2X7 , Anêmonas-do-Mar , Animais , Anêmonas-do-Mar/metabolismo , Simulação de Acoplamento Molecular , Peptídeos/química , Trifosfato de Adenosina/metabolismoRESUMO
Membrane-based alkaline water electrolyser is promising for cost-effective green hydrogen production. One of its key technological obstacles is the development of active catalyst-materials for alkaline hydrogen-evolution-reaction (HER). Here, we show that the activity of platinum towards alkaline HER can be significantly enhanced by anchoring platinum-clusters onto two-dimensional fullerene nanosheets. The unusually large lattice distance (~0.8 nm) of the fullerene nanosheets and the ultra-small size of the platinum-clusters (~2 nm) leads to strong confinement of platinum clusters accompanied by pronounced charge redistributions at the intimate platinum/fullerene interface. As a result, the platinum-fullerene composite exhibits 12 times higher intrinsic activity for alkaline HER than the state-of-the-art platinum/carbon black catalyst. Detailed kinetic and computational investigations revealed the origin of the enhanced activity to be the diverse binding properties of the platinum-sites at the interface of platinum/fullerene, which generates highly active sites for all elementary steps in alkaline HER, particularly the sluggish Volmer step. Furthermore, encouraging energy efficiency of 74% and stability were achieved for alkaline water electrolyser assembled using platinum-fullerene composite under industrially relevant testing conditions.
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This review aimed to trace the inflammatory pathway from the NLRP3 inflammasome to monomeric C-reactive protein (mCRP) in atherosclerotic cardiovascular disease. CRP is the final product of the interleukin (IL)-1ß/IL-6/CRP axis. Its monomeric form can be produced at sites of local inflammation through the dissociation of pentameric CRP and, to some extent, local synthesis. mCRP has a distinct proinflammatory profile. In vitro and animal-model studies have suggested a role for mCRP in: platelet activation, adhesion, and aggregation; endothelial activation; leukocyte recruitment and polarization; foam-cell formation; and neovascularization. mCRP has been shown to deposit in atherosclerotic plaques and damaged tissues. In recent years, the first published papers have reported the development and application of mCRP assays. Principally, these studies demonstrated the feasibility of measuring mCRP levels. With recent advances in detection techniques and the introduction of first assays, mCRP-level measurement should become more accessible and widely used. To date, anti-inflammatory therapy in atherosclerosis has targeted the NLRP3 inflammasome and upstream links of the IL-1ß/IL-6/CRP axis. Large clinical trials have provided sufficient evidence to support this strategy. However, few compounds target CRP. Studies on these agents are limited to animal models or small clinical trials.
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Aterosclerose , Doenças Cardiovasculares , Animais , Proteína C-Reativa/metabolismo , Inflamassomos , Interleucina-6 , Proteína 3 que Contém Domínio de Pirina da Família NLR , Inflamação/metabolismo , Aterosclerose/metabolismoRESUMO
Metal promotion is the most widely adopted strategy for enhancing the hydrogenation functionality of an oxide catalyst. Typically, metal nanoparticles or dopants are located directly on the catalyst surface to create interfacial synergy with active sites on the oxide, but the enhancement effect may be compromised by insufficient hydrogen delivery to these sites. Here, we introduce a strategy to promote a ZnZrOx methanol synthesis catalyst by incorporating hydrogen activation and delivery functions through optimized integration of ZnZrOx and Pd supported on carbon nanotube (Pd/CNT). The CNT in the Pd/CNT + ZnZrOx system delivers hydrogen activated on Pd to a broad area on the ZnZrOx surface, with an enhancement factor of 10 compared to the conventional Pd-promoted ZnZrOx catalyst, which only transfers hydrogen to Pd-adjacent sites. In CO2 hydrogenation to methanol, Pd/CNT + ZnZrOx exhibits drastically boosted activity-the highest among reported ZnZrOx-based catalysts-and excellent stability over 600 h on stream test, showing potential for practical implementation.