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The cytotoxicity feature to eliminate malignant cells makes natural killer (NK) cells a candidate for tumor immunotherapy. However, this scenario is currently hampered by inadequate understanding of the regulatory mechanisms of NK cell development. Ten-Eleven-Translocation 2 (Tet2) is a demethylase whose mutation was recently shown to cause phenotypic defects in NK cells. However, the role of Tet2 in the development and maturation of NK cells is not entirely clear. Here we studied the modulatory role of Tet2 in NK cell development and maturation by generating hematopoietic Tet2 knockout mice and mice with Tet2 conditional deletion in NKp46+ NK cells. The results showed that both hematopoietic and NK cell conditional deletion of Tet2 had no effect on the early steps of NK cell development, but impaired the terminal maturation of NK cells defined by CD11b, CD43, and KLRG1 expression. In the liver, Tet2 deletion not only prevented the terminal maturation of NK cells, but also increased the proportion of type 1 innate lymphoid cells (ILC1s) and reduced the proportion of conventional NK cells (cNK). Moreover, hematopoietic deletion of Tet2 lowered the protein levels of perforin in NK cells. Furthermore, hematopoietic deletion of Tet2 downregulated the protein levels of Eomesodermin (Eomes), but not T-bet, in NK cells. In conclusion, our results demonstrate that Tet2 plays an important role in the terminal maturation of NK cells, and the Eomes transcription factor may be involved.
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Cu2+ accelerates the viral-like propagation of α-synuclein fibrils and plays a key role in the pathogenesis of Parkinson's disease (PD). Therefore, the accurate detection of Cu2+ is essential for the diagnosis of PD and other neurological diseases. The Cu2+ detection process is impeded by substances that have similar electrochemical properties. In this study, graphdiyne (GDY), a new kind of carbon allotrope with strong electron-donating ability, was utilized for the highly selective detection of Cu2+ by taking advantage of its outstanding adsorption capacity for Cu2+. Density functional theory (DFT) calculations show that Cu atoms are adsorbed in the cavity of GDY, and the absorption energy between Cu and C atoms is higher than that of graphene (GR), indicating that the cavity of GDY is favorable for the adsorption of Cu atoms and electrochemical sensing. The GDY-based electrochemical sensor can effectively avoid the interference of amino acids, metal ions and neurotransmitters and has a high sensitivity of 9.77 µA·µM-1·cm-2, with a minimum detectable concentration of 200 nM. During the investigating pathogenesis and therapeutic process of PD with α-synuclein as the diagnostic standard, the concentration of Cu2+ in cells before and after L-DOPA and GSH treatments were examined, and it was found that Cu2+ exhibits high potential as a biomarker for PD. This study not only harnesses the favorable adsorption of the GDY and Cu2+ to improve the specificity of ion detection but also provide clues for deeper understanding of the role of Cu2+ in neurobiology and neurological diseases.
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Cobre , Técnicas Eletroquímicas , Grafite , Doença de Parkinson , alfa-Sinucleína , Cobre/química , Doença de Parkinson/diagnóstico , Grafite/química , Humanos , Técnicas Eletroquímicas/métodos , alfa-Sinucleína/análise , alfa-Sinucleína/química , Teoria da Densidade Funcional , Levodopa/química , Limite de Detecção , Glutationa/químicaRESUMO
NK cells can be rapidly activated in response to cytokines during host defense against malignant cells or viral infection. However, it remains unclear what mechanisms precisely and rapidly regulate the expression of a large number of genes involved in activating NK cells. In this study, we discovered that NK-cell N6-methyladenosine (m6A) methylation levels were rapidly upregulated upon short-term NK-cell activation and were repressed in the tumor microenvironment (TME). Deficiency of methyltransferase-like 3 (METTL3) or METTL14 moderately influenced NK-cell homeostasis, while double-knockout of METTL3/14 more significantly impacted NK-cell homeostasis, maturation, and antitumor immunity. This suggests a cooperative role of METTL3 and METTL14 in regulating NK-cell development and effector functions. Using methylated RNA immunoprecipitation sequencing, we demonstrated that genes involved in NK-cell effector functions, such as Prf1 and Gzmb, were directly modified by m6A methylation. Furthermore, inhibiting mTOR complex 1 activation prevented m6A methylation levels from increasing when NK cells were activated, and this could be restored by S-adenosylmethionine supplementation. Collectively, we have unraveled crucial roles for rapid m6A mRNA methylation downstream of the mTOR complex 1-S-adenosylmethionine signal axis in regulating NK-cell activation and effector functions.
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Adenosina , Células Matadoras Naturais , Ativação Linfocitária , Metiltransferases , RNA Mensageiro , Transdução de Sinais , Serina-Treonina Quinases TOR , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , Metilação , Ativação Linfocitária/imunologia , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , RNA Mensageiro/genética , Camundongos , Humanos , Microambiente Tumoral/imunologia , Camundongos Knockout , Camundongos Endogâmicos C57BLRESUMO
Purpose: Premenstrual syndrome (PMS) is a cyclical psychosomatic disorder prevalent among women of reproductive age. However, research on the potential impact of PMS on routine nursing schedules and activities is limited. This study aims to identify the prevalence of PMS among female nursing staff and to examine the relationship between PMS and missed nursing care (MNC). Method: Between November 1, 2022, and April 30, 2023, this study was conducted among female nursing staff working in nine inpatient departments at Sun Yat-sen University Cancer Center. This study used a cross-sectional design. The participants were recruited through convenience sampling. Data were collected using the standardized Menstrual Distress Questionnaire, the Oncology Missed Nursing Care self-rating scale, and a sociodemographic questionnaire. One-way analysis of variance, Fisher's least significant difference test for post-hoc comparisons, and Spearman's correlation coefficient were utilized for data analysis. A trend test was also performed to explore patterns in the severity of PMS and MNC over time. Results: We collected a total of 224 questionnaires, with 154 (68.7%) female nursing staff reporting PMS. The most common symptoms were low back pain (91.1%), abdominal discomfort (90.6%), cold hands and feet (87.1%), and lethargy (87.1%). Moreover, 91.5% of the 224 female nursing staff reported at least one MNC activity. The nursing activities most frequently missed or left incomplete were liquid intake and output monitoring as ordered (43.3%), medication administration within 30 min before or after the scheduled time (43.3%), and electrocardiogram monitoring as ordered (42.9%). "Abdominal discomfort" from the Menstrual Distress Questionnaire was significantly correlated with the majority of MNC activities (p < 0.001). Conclusions: This study provides evidence for a strong association between PMS and MNC among female nursing staff, suggesting that administrators should take the premenstrual conditions of female nursing staff into consideration. It is necessary to provide appropriate understanding and support to mitigate the impact on patient care and safety.
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Single-atom (SA) nanoparticles exhibit considerable potential in terms of photothermal properties for bactericidal applications. Nevertheless, the restricted efficacy of their targeted and controlled antibacterial activity has hindered their practical implementation. This study aims to overcome this obstacle by employing chemical modifications to tailor SAs, thereby achieving targeted and light-controlled antimicrobial effects. By conducting atomic-level modifications on palladium SAs using glutathione (GSH) and mercaptophenylboronic acid (MBA), their superior targeted binding capabilities toward Escherichia coli cells are demonstrated, surpassing those of SAs modified with cysteine (Cys). Moreover, these modified SAs effectively inhibit wound bacteria proliferation and promote wound healing in rats, without inducing noticeable toxicity to major organs under 808 nm laser irradiation. This study highlights the significance of chemical engineering in tailoring the antibacterial properties of SA nanoparticles, opening avenues for combating bacterial infections and advancing nanoparticle-based therapies.
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Anti-Infecciosos , Nanopartículas , Ratos , Animais , Nanopartículas/química , Antibacterianos/químicaRESUMO
Adenosine triphosphate (ATP) is the major resource of energy supply in tumor activity. Therefore, improving ATP consumption efficiencies is a promising approach for cancer therapy. Herein, inspired by the H2O2-involved structure regulation effect during the catalysis of natural protein enzymes, we developed an artificial H2O2-driven ATP catalysis-promoting system, the Ce-based metal-organic framework (Ce-MOF), for catalytic cancer therapy. In the presence of H2O2, the hydrolysis ATP activity of Ce-MOF(H2O2) was enhanced by around 1.6 times. Taking advantage of the endogenous H2O2 in cancerous cells, catalytic hydrolysis for intracellular ATP of the Ce-MOF achieves the inhibition of cancerous cell growth, which involves damaged mitochondrial function and autophagy-associated cell death. Furthermore, in vivo studies suggest that the Ce-MOF has a good tumor inhibition effect. The artificial H2O2-driven ATP catalysis-promoting system not only demonstrates high catalytic ATP consumption efficiencies for cancer therapy but also highlights a bioinspired strategy to expedite nanozyme research in both design and applied sciences.
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Apirase , Estruturas Metalorgânicas , Peróxido de Hidrogênio/química , Estruturas Metalorgânicas/farmacologia , Estruturas Metalorgânicas/química , Catálise , Trifosfato de Adenosina/químicaRESUMO
The elevated antioxidant defense system in cancer cells can lead to resistance to treatments involving ROS. Breaking the redox balance of the cell system through a "open up the source and regulate the flow" strategy can inhibit the growth of cancer cells and thus design a cancer treatment strategy. Here, cobalt single atom-supported N-doped carbon nanozymes (Co SA-N/C) were synthesized via a simple sacrificial template method, which can mimic the properties of ascorbate oxidase and glutathione oxidase effectively. The synthesized Co SA-N/C can induce the generation of active oxygen by accelerating the oxidation of ascorbic acid (AA) and destroy the endogenous active oxygen scavenging system by consuming the main antioxidant, glutathione (GSH). In-depth in vitro and in vivo investigations indicate that compared with solo therapy, Co SA-N/C together with AA can significantly enhance the anti-tumor efficiency by simultaneously elevating oxidative stress and consuming the overexpressed glutathione (GSH) through the redox reaction catalyzed by Co SA-N/C. This work provides a promising route for developing nanozyme-guided and ascorbate-based antitumor agents.
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Antioxidantes , Ácido Ascórbico , Ácido Ascórbico/farmacologia , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio , Cobalto/farmacologia , Oxirredução , Glutationa/farmacologia , Glutationa/metabolismoRESUMO
Colorectal cancer (CRC) is the third leading cause of cancer-related mortality. 5-Fluorouracil (5-FU) is the first choice for treatment of CRC, but it cannot avoid the negative effects from local high glucose (Glu) in tumor. Recently, 5-FU therapy has been combined with other treatment modalities for CRC synergistic therapy. Although these combination therapy strategies are more effective in cancer therapy, the toxicity side effects to the liver and cause metabolic acidosis still exist. Herein, we report an emerging amorphous honeycomb-like nitrogen-doped carbon (N/C) nanozyme with nicotinamide adenine dinucleotide (NADH) oxidase and catalase (CAT) activity and cascade it with natural glucose dehydrogenase (GDH) to realize NAD+ regeneration and further hyperglycemia management. In this case, by the coupling of N/C nanozyme with natural GDH to form a N/C-GDH system, the electron transfer route can switch from Glu to a common but limited electron receptor, i.e., NAD+ to ubiquitous large amounts of oxygen, achieving the purpose of sustainable consumption of Glu under NAD+ circulation and regeneration, and importantly escaping the generation of toxic H2O2. The combination of the N/C-GDH system and 5-FU on CRC cells was investigated to assess their synergistic bioeffects. Notably, our results showed that the N/C-GDH system and 5-FU in combination significantly suppress the proliferation of human colon cancer cells (HCT-116) by reducing the sugar level and induced apoptosis compared with either material or drug used alone. This work expands the nanozymes in blood Glu management as well as the promising cancer cell inhibition and provides the possibility of nonmetallic nanomaterials in the realization of effective treatment of cancer.
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Neoplasias Colorretais , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , NAD/metabolismo , NAD/uso terapêutico , Peróxido de Hidrogênio , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Linhagem Celular TumoralRESUMO
Despite the extensive investigation of the nanozymes exhibit their favorable performance compared to natural enzymes, nevertheless, the highly specific nanozyme still needs to be developed so that it can meet the requirements of exploring the mechanism as well as administration of related diseases and selective monitoring in biological system. In this study, self-assembled glutathione-Cu/Cu2O nanoparticles (GSH-Cu/Cu2O NPs) that exhibits specific ascorbic acid (AA) oxidase-like catalytic activity were constructed for AA-activated and H2O2-reinforced cancer cell proliferation inhibition and selective neurochemical monitoring. Cu/Cu2O NPs demonstrates effective AA oxidase-like activity and no common characteristics of other redox mimic enzymes often present in nanozyme. In particular, we found that the AA oxidase-like activity of GSH-Cu/Cu2O nanozyme was significantly improved by about 40% by improving the activation ability toward oxygen. The synthesized nanozyme can induce the generation of active oxygen by accelerating the oxidation of AA, which effectively suppresses the proliferation of cancer cells. We constructed an online electrochemical system (OECS) though loading nanozyme with enhanced ascorbate oxidase activity into a microreactor and setting it in the upstream of the detector. This GSH-Cu/Cu2O NPs-integrated microreactor can completely eliminate AA interference of the physical level toward 3,4-dihydroxy phenylacetic acid (DOPAC) electrochemical measurement, and the nanozyme-based OECS is able to continuously capture DOPAC alteration in rat brain acidosis model. Our findings may inspire rational design of nanozymes with high specificity as well as nanozyme-based selectivity solution for in vivo detection and show promising opportunities for their involvement in neurochemistry investigation.
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Técnicas Biossensoriais , Neoplasias , Animais , Ratos , Ascorbato Oxidase , Ácido 3,4-Di-Hidroxifenilacético , Peróxido de Hidrogênio , Proliferação de Células , Ácido Ascórbico , GlutationaRESUMO
BACKGRUOUND: Chronic exposure to elevated levels of saturated fatty acids results in pancreatic ß-cell senescence. However, targets and effective agents for preventing stearic acid-induced ß-cell senescence are still lacking. Although melatonin administration can protect ß-cells against lipotoxicity through anti-senescence processes, the precise underlying mechanisms still need to be explored. Therefore, we investigated the anti-senescence effect of melatonin on stearic acid-treated mouse ß-cells and elucidated the possible role of microRNAs in this process. METHODS: ß-Cell senescence was identified by measuring the expression of senescence-related genes and senescence-associated ß-galactosidase staining. Gain- and loss-of-function approaches were used to investigate the involvement of microRNAs in stearic acid-evoked ß-cell senescence and dysfunction. Bioinformatics analyses and luciferase reporter activity assays were applied to predict the direct targets of microRNAs. RESULTS: Long-term exposure to a high concentration of stearic acid-induced senescence and upregulated miR-146a-5p and miR- 8114 expression in both mouse islets and ß-TC6 cell lines. Melatonin effectively suppressed this process and reduced the levels of these two miRNAs. A remarkable reversibility of stearic acid-induced ß-cell senescence and dysfunction was observed after silencing miR-146a-5p and miR-8114. Moreover, V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (Mafa) was verified as a direct target of miR-146a-5p and miR-8114. Melatonin also significantly ameliorated senescence and dysfunction in miR-146a-5pand miR-8114-transfected ß-cells. CONCLUSION: These data demonstrate that melatonin protects against stearic acid-induced ß-cell senescence by inhibiting miR-146a- 5p and miR-8114 and upregulating Mafa expression. This not only provides novel targets for preventing stearic acid-induced ß-cell dysfunction, but also points to melatonin as a promising drug to combat type 2 diabetes progression.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Melatonina , MicroRNAs , Camundongos , Animais , Melatonina/farmacologia , Melatonina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , MicroRNAs/farmacologia , Senescência Celular , Ácidos Esteáricos/farmacologia , Ácidos Esteáricos/metabolismo , Fatores de Transcrição Maf Maior/metabolismo , Fatores de Transcrição Maf Maior/farmacologiaRESUMO
Corilagin, a gallotannin, shows excellent antioxidant and anti-inflammatory effects. The NLRP3 inflammasome dysfunction has been implicated in a variety of inflammation diseases. However, it remains unclear how corilagin regulates the NLRP3 inflammasome to relieve gouty arthritis. In this study, bone marrow-derived macrophages (BMDMs) were pretreated with lipopolysaccharide (LPS) and then incubated with NLRP3 inflammasome agonists, such as adenine nucleoside triphosphate (ATP), nigericin, and monosodium urate (MSU) crystals. The MSU crystals were intra-articular injected to induce acute gouty arthritis. Here we showed that corilagin reduced lactate dehydrogenase (LDH) secretion and the proportion of propidium iodide- (PI-)stained cells. Corilagin suppressed the expression of N-terminal of the pyroptosis executive protein gasdermin D (GSDMD-NT). Corilagin restricted caspase-1 p20 and interleukin (IL)-1ß release. Meanwhile, corilagin attenuated ASC oligomerization and speck formation. Our findings confirmed that corilagin diminished NLRP3 inflammasome activation and macrophage pyroptosis. We further discovered that corilagin limited the mitochondrial reactive oxygen species (ROS) production and prevented the interaction between TXNIP and NLRP3, but ROS activator imiquimod could antagonize the inhibitory function of corilagin on NLRP3 inflammasome and macrophage pyroptosis. Additionally, corilagin ameliorated MSU crystals induced joint swelling, inhibited IL-1ß production, and abated macrophage and neutrophil migration into the joint capsule. Collectively, these results demonstrated that corilagin suppressed the ROS/TXNIP/NLRP3 pathway to repress inflammasome activation and pyroptosis and suggest its potential antioxidative role in alleviating NLRP3-dependent gouty arthritis.
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Artrite Gotosa , Piroptose , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Taninos Hidrolisáveis/farmacologia , Taninos Hidrolisáveis/uso terapêutico , Lipopolissacarídeos/farmacologia , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/metabolismo , Ácido Úrico/uso terapêutico , Antioxidantes/farmacologia , Nigericina/farmacologia , Nigericina/uso terapêutico , Imiquimode/farmacologia , Imiquimode/uso terapêutico , Propídio/farmacologia , Propídio/uso terapêutico , Nucleosídeos/farmacologia , Caspase 1/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Anti-Inflamatórios/farmacologia , Trifosfato de Adenosina/farmacologia , Adenina/farmacologia , Lactato DesidrogenasesRESUMO
Remote control of cells and the regulation of cell events at the molecular level are of great interest to the biomedical field. In addition to mechanical forces and genes, chemical compounds and light play pivotal roles in regulating cell fate, which have boosted the fast growth of biology. Herein, we synthesized light-regulated, atomically dispersed Fe-N4immobilized on a carbon substrate nanozyme (Fe-N/C single atom catalysts), whose peroxidase- and catalase-like properties can be enhanced by 120% and 135%, respectively, under 808-nm laser irradiation through the photothermal effect of Fe-N/C. Interestingly, a switch to love/switch to kill interaction between Fe-N/C dose and near-infrared (NIR) light co-regulating the Fe-N/C nanozyme to modulate cell fate was discovered. Based on this, we found that under NIR light irradiation, when the dose of Fe-N/C is low, it can scavenge more reactive oxygen species (ROS) and achieve cell protection; when the dose of Fe-N/C is too high, it tended to lead to cell apoptosis. This work not only provides an effective strategy for the regulation of nanozyme activity but also realizes the dual-functional application of nanozyme materials for the treatment of some specific diseases.
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Ferro , Carbono/química , Catalase , Ferro/química , Ferro/farmacologia , Espécies Reativas de OxigênioRESUMO
Cell mechanotransduction plays an important role in vascular regulation and disease development. Excessive accumulation of ROS, especially superoxide anion radicals (O2Ë-), is closely related to cardiovascular diseases. Lately, NADPH oxidases, which are the major source of O2Ë- production in vascular tissues, have been demonstrated to be involved in cardiovascular diseases. Therefore, in situ and real-time monitoring of superoxide anions (O2Ë-) is essential for exploring the mechanisms of mechanotransduction associated with NADPH oxidase function in living cells. Here we report a rationally designed ultrasonication-assisted approach for growing Au nanoflower films on a flexible surface, which serves as the desired interface for cysteine and superoxide dismutase (SOD) anchoring to form a flexible and stretchable electrode (SOD/Cys/Au SE). The SOD/Cys/Au SE shows good stretchability, fast electron-transfer rates, and high selectivity to measure O2Ë- released from cells during the stretching states. Our strategy provides a basis for developing more sophisticated stretchable biosensing tools to induce and monitor transient biochemical signals during cell mechanotransduction.
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Técnicas Biossensoriais , Doenças Cardiovasculares , Humanos , Mecanotransdução Celular , Superóxido Dismutase/metabolismo , Superóxidos/metabolismoRESUMO
Nanozymes have been designed to address the limitations of high cost and poor stability involving natural enzymes in analytical applications. However, the catalytic efficiency of the nanozyme still needs to be improved so that it can meet the selectivity and stability requirements of accurate biomolecule analysis. Here, we presented structure defects of metal-organic frameworks (MOFs) as a tuning strategy to regulate the catalytic efficiency of artificial nanozymes and investigated the roles of defects on the catalytic activity of oxidase-like MOFs. Structural defects were introduced into a novel Co-containing zeolitic imidazolate framework with gradually loosened morphology (ZIF-L-Co) by doping cysteine (Cys). It was found that with the increase in defect degree, the properties of materials such as ascorbate oxidase-like, glutathione oxidase-like, and laccase-like were obviously enhanced by over 5, 2, and 3 times, respectively. In-depth structural investigations indicate that the doping of sulfur inducing structural defects which may destroy the equilibrium state between cobalt and nitrogen in 2-methylimidazole and distort the crystal lattice, thereby enhancing the adsorption of oxygen and thus promoting the oxidase-like activity. The ZIF-L-Co-10 mg with enhanced ascorbate oxidase- and laccase-like activity was loaded into a microreactor and integrated into an online electrochemical system (OECS) in the upstream of the detector. This nanozyme-based microreactor can completely remove ascorbic acid, dopamine, and 3,4-dihydroxyphenylacetic acid which are the main interference toward uric acid (UA) electrochemical measurement, and the ZIF-L-Co-10 mg Cys-based OECS system is capable of continuously capturing UA change in rat brain following ischemia-reperfusion injury. Structure defect tuning of ZIF-L-Co not only provides a new regulatory strategy for artificial nanozyme activity but also provides a critical chemical platform for the investigation of UA-related brain function and brain diseases.
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Gallic acid is an active phenolic acid widely distributed in plants, and there is compelling evidence to prove its anti-inflammatory effects. NLRP3 inflammasome dysregulation is closely linked to many inflammatory diseases. However, how gallic acid affects the NLRP3 inflammasome remains unclear. Therefore, in the present study, we investigated the mechanisms underlying the effects of gallic acid on the NLRP3 inflammasome and pyroptosis, as well as its effect on gouty arthritis in mice. The results showed that gallic acid inhibited lactate dehydrogenase (LDH) release and pyroptosis in lipopolysaccharide (LPS)-primed and ATP-, nigericin-, or monosodium urate (MSU) crystal-stimulated macrophages. Additionally, gallic acid blocked NLRP3 inflammasome activation and inhibited the subsequent activation of caspase-1 and secretion of IL-1ß. Gallic acid exerted its inhibitory effect by blocking NLRP3-NEK7 interaction and ASC oligomerization, thereby limiting inflammasome assembly. Moreover, gallic acid promoted the expression of nuclear factor E2-related factor 2 (Nrf2) and reduced the production of mitochondrial ROS (mtROS). Importantly, the inhibitory effect of gallic acid could be reversed by treatment with the Nrf2 inhibitor ML385. NRF2 siRNA also abolished the inhibitory effect of gallic acid on IL-1ß secretion. The results further showed that gallic acid could mitigate MSU-induced joint swelling and inhibit IL-1ß and caspase 1 (p20) production in mice. Moreover, gallic acid could moderate MSU-induced macrophages and neutrophils migration into joint synovitis. In summary, we found that gallic acid suppresses ROS generation, thereby limiting NLRP3 inflammasome activation and pyroptosis dependent on Nrf2 signaling, suggesting that gallic acid possesses therapeutic potential for the treatment of gouty arthritis.
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Anti-Inflamatórios/uso terapêutico , Artrite Gotosa/tratamento farmacológico , Ácido Gálico/uso terapêutico , Inflamassomos/metabolismo , Macrófagos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Piroptose , Transdução de SinaisRESUMO
OBJECTIVES: Wedelolactone exhibits regulatory effects on some inflammatory diseases. However, the anti-inflammatory mechanism of wedelolactone has not been entirely unravelled. Therefore, the present study focuses on investigating the mechanism of wedelolactone on NLRP3 inflammasome in macrophages and its influence on MSU-induced inflammation. MATERIALS AND METHODS: BMDM, J774A.1 and PMA-differentiated THP-1 macrophages were primed with LPS and then stimulated with ATP or nigericin or MSU crystal in the presence or absence of wedelolactone. The cell lysates and supernatants were collected to detect NLRP3 inflammasome components such as NLRP3, ASC and caspase 1, as well as pyroptosis and IL-1ß production. In addition, the anti-inflammatory effects of wedelolactone on MSU-induced peritonitis and arthritis mice were also evaluated. RESULTS: We found that wedelolactone broadly inhibited NLRP3 inflammasome activation and pyroptosis and IL-1ß secretion. Wedelolactone also block ASC oligomerization and speck formation. The inhibitory effects of wedelolactone were abrogated by PKA inhibitor H89, which also attenuated wedelolactone-enhanced Ser/Thr phosphorylation of NLRP3 at PKA-specific sites. Importantly, wedelolactone could abate MSU-induced IL-1ß production and neutrophils migration into peritoneal cavity, and reduced caspase 1 (p20) and IL-1ß expression in the joint tissue of MSU-induced arthritis. CONCLUSION: Our results indicate that wedelolactone promotes the Ser/Thr phosphorylation of NLRP3 to inhibit inflammasome activation and pyroptosis partly through potentiating PKA signalling, thus identifying its potential use for treating MSU-induced peritonitis and gouty arthritis.
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Anti-Inflamatórios/farmacologia , Cumarínicos/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Humanos , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacosRESUMO
A novel electrochemical online system for indirect, highly sensitive and selective online monitoring of ATP in the cerebral microdialysate is presented based on the particular reaction of ATP with zeolitic imidazole framework-90 (ZIF-90) encapsulated laccase microcrystals (laccase@ZIF-90) and the natural catalytic activity of laccase.
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Trifosfato de Adenosina/análise , Técnicas Biossensoriais , Encéfalo/metabolismo , Técnicas Eletroquímicas , Lacase/química , Zeolitas/química , Trifosfato de Adenosina/metabolismo , Animais , Imidazóis/química , Imidazóis/metabolismo , Lacase/metabolismo , Estrutura Molecular , Tamanho da Partícula , Ratos , Propriedades de Superfície , Zeolitas/metabolismoRESUMO
Although most metal-organic coordination materials are promising materials used as templates to develop highly efficient electrocatalysts via pyrolysis in situ, few studies have explored the use of these materials for direct catalysis of oxygen evolution reaction (OER). Herein, inspired by the natural synthesis and the inherent properties of metal-organic coordination materials, the FeNi-tannic acid coordination crystal was in situ grown on Ni foam ((FeNi)-Tan/NF) to directly catalyze the OER. It was found that (FeNi)-Tan/NF exhibited predominant OER activity, which required a low overpotential of 208 mV to reach a current density of 50 mA·cm-2 under a small Tafel slope of 33.5 mV·dec-1, and it possessed robust stability. Density functional theory (DFT) calculations demonstrated that the active site change from Ni in Ni-Tan to the Fe atom in (FeNi)-Tan may provide a more favorable OER catalytic route. This application of such polyphenol coordination materials is promising for stimulating the exploration of functional metal-organic coordination materials toward applications in the energy conversion field.
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Mixed-matrix membranes (MMMs) have been drawing increasing attention due to the high permeability and high rejection capabilities for highly efficient wastewater treatment applications. Nonetheless, improving the water permeance while maintaining the high rejection capability is still an ongoing challenge for the practically state-of-the-art MMMs. Herein, a new class of poly(ether sulfone) (PES) based MMM containing metal-organic framework (MOF) nanofillers of HKUST-1 and blending with poly(methyl methacrylate- co-methacrylic acid) (PMMA- co-MAA) copolymer, designated as HKUST-1@mPES MMM, were developed for the highly efficient ultrafiltration (UF) process. In this study, the nanosized HKUST-1 nanofillers were removed by water dissolution as sacrificial templating materials, so that the additional nanovoids were deliberately generated throughout the dense polymer matrix. The introduction of PMMA- co-MAA copolymer facilitated the even dispersion of HKUST-1 nanofillers in a polymer matrix, by constructing the bridge connection between inorganic nanofillers and organic matrix. The resultant HKUST-1@mPES MMM exhibited a high pure water permeability (PWP) up to 490 L·m-2·h-1·bar-1, substantially reaching nearly 3 times higher than that of the mPES membrane without HKUST-1 nanofillers loading and maintaining a relatively high BSA rejection rate of 96% without obvious deterioration. The newly developed HKUST-1@mPES MMM thereby exhibited a comparable separation efficiency compared to the cutting-edge UF membranes reported so far. Overall, the nanovoid-generated approach provides new insight into developing advanced MMMs used for highly efficient water treatment applications.
RESUMO
In this study, a sensitive and facile method with wide linear range and low detection limit for detecting hydrogen sulfide in rat brain microdialysate was developed. The design of the sensor is based on the competitive binding reaction principle, in which cysteine was self-assembly immobilized on the surface of gold electrode, and then the Cu2+ as the electrochemical probe was anchored to the cysteine film through coordination bonding with carboxyl (-COOH) and amino group (-NH2) to form the Cu2+/Cys/Au electrode. The Cu2+/Cys/Au electrode can serve as an electrochemical H2S sensor through a ligand exchange reaction, which may come from the greater affinity of H2S than cysteine to the gold surface due to a steric hindrance reason. The hydrogen sulfide cuts off the S-Au bonds between cysteine and Au electrode and leads to the Cu2+ drop off from electrode, resulting in a decrease in the redox signal of Cu2+, thereby creating a current that is indirectly proportional to the logarithm of the concentration of H2S dissolved at the sensor surface. The current response, i.e., signal output, is in wide linearity to logarithm of the concentration of H2S in the range of 0.01-100.0 µM with ΔI/µA = 0.0857 lgCH2S(nM) +0.124 and very low detection limit 5 nM (S/N = 3). The assay demonstrated here is highly selective with respect to alleviating the interference of other thiol-containing species such as glutathione (GSH), homocysteine (Hcy), and cysteine commonly existing in the brain. The basal level of H2S in the microdialysate from the hippocampus of rats is determined to be around 8.6 ± 3.2 µM. The method demonstrated here is facile but reliable and durable and is envisaged to be applicable to understanding the chemical essence involved in physiological and pathological events associated with H2S. Graphical abstract By rationally tailoring the gold electrode surface through the competitive binding interaction of gold electrode between cysteine and H2S, we have successfully designed a simple, highly sensitive, and selective method for electrochemical sensing of H2S in brain microdialysate.