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TNF stimulation generates pro-survival signals through activation of NF-κB that restrict the build-in death signaling triggered by TNF. The competition between TNF-induced survival and death signals ultimately determines the fate of a cell. Here, we report the identification of Bclaf1 as a novel component of the anti-apoptotic program of TNF. Bclaf1 depletion in multiple cells sensitizes cells to TNF-induced apoptosis but not to necroptosis. Bclaf1 exerts its anti-apoptotic function by promoting the transcription of CFLAR, a caspase 8 antagonist, downstream of NF-κB activation. Bclaf1 binds to the p50 subunit of NF-κB, which is required for Bclaf1 to stimulate CFLAR transcription. Finally, in Bclaf1 siRNA administered mice, TNF-induced small intestine injury is much more severe than in control mice with aggravated signs of apoptosis and pyroptosis. These results suggest Bclaf1 is a key regulator in TNF-induced apoptosis, both in vitro and in vivo.
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Apoptose , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD , NF-kappa B , Proteínas Repressoras , Fator de Necrose Tumoral alfa , Animais , Apoptose/genética , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/biossíntese , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Intestino Delgado/lesões , Intestino Delgado/metabolismo , Intestino Delgado/fisiopatologia , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Repressoras/genética , Transdução de Sinais , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Excessive acetaminophen (APAP) can induce neutrophil activation and hepatocyte death. Along with hepatocyte dysfunction and death, NETosis (a form of neutrophil-associated inflammation) plays a vital role in the progression of acute liver injury (ALI) induced by APAP overdose. It has been shown that activated neutrophils tend to migrate towards the site of injury and participate in inflammatory processes via formation of neutrophil extracellular traps (NETs). In this study we investigated whether NETs were involved in hepatocyte injury and contributed to APAP-induced ALI progression. ALI mouse model was established by injecting overdose (350 mg/kg) of APAP. After 24 h, blood and livers were harvested for analyses. We showed that excessive APAP induced multiple programmed cell deaths of hepatocytes including pyroptosis, apoptosis and necroptosis, accompanied by significantly increased NETs markers (MPO, citH3) in the liver tissue and serum. Preinjection of DNase1 (10 U, i.p.) for two consecutive days significantly inhibited NETs formation, reduced PANoptosis and consequently alleviated excessive APAP-induced ALI. In order to clarify the communication between hepatocytes and neutrophils, we induced NETs formation in isolated neutrophils, and treated HepaRG cells with NETs. We found that NETs treatment markedly increased the activation of GSDMD, caspase-3 and MLKL, while pre-treatment with DNase1 down-regulated the expression of these proteins. Knockdown of AIM2 (a cytosolic innate immune receptor) abolished NETs-induced PANoptosis in HepaRG cells. Furthermore, excessive APAP-associated ALI was significantly attenuated in AIM2KO mice, and PANoptosis occurred less frequently. Upon restoring AIM2 expression in AIM2KO mice using AAV9 virus, both hepatic injury and PANoptosis was aggravated. In addition, we demonstrated that excessive APAP stimulated mtROS production and mitochondrial DNA (mtDNA) leakage, and mtDNA activated the TLR9 pathway to promote NETs formation. Our results uncover a novel mechanism of NETs and PANoptosis in APAP-associated ALI, which might serve as a therapeutic target.
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Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Proteínas de Ligação a DNA , Armadilhas Extracelulares , Hepatócitos , Camundongos Endogâmicos C57BL , Neutrófilos , Animais , Acetaminofen/toxicidade , Acetaminofen/efeitos adversos , Armadilhas Extracelulares/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Camundongos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Humanos , Camundongos Knockout , Piroptose/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Analgésicos não Narcóticos/toxicidadeRESUMO
Pericytes are present tight around the intervals of capillaries, play an essential role in stabilizing the blood-brain barrier, regulating blood flow and immunomodulation, and persistent contraction of pericytes eventually leads to impaired blood flow and poor clinical outcomes in ischemic stroke. We previously show that iptakalim, an ATP-sensitive potassium (K-ATP) channel opener, exerts protective effects in neurons, and glia against ischemia-induced injury. In this study we investigated the impacts of iptakalim on pericytes contraction in stroke. Mice were subjected to cerebral artery occlusion (MCAO), then administered iptakalim (10 mg/kg, ip). We showed that iptakalim administration significantly promoted recovery of cerebral blood flow after cerebral ischemia and reperfusion. Furthermore, we found that iptakalim significantly inhibited pericytes contraction, decreased the number of obstructed capillaries, and improved cerebral microcirculation. Using a collagen gel contraction assay, we demonstrated that cultured pericytes subjected to oxygen-glucose deprivation (OGD) consistently contracted from 3 h till 24 h during reoxygenation, whereas iptakalim treatment (10 µM) notably restrained pericyte contraction from 6 h during reoxygenation. We further showed that iptakalim treatment promoted K-ATP channel opening via suppressing SUR2/EPAC1 complex formation. Consequently, it reduced calcium influx and ET-1 release. Taken together, our results demonstrate that iptakalim, targeted K-ATP channels, can improve microvascular disturbance by inhibiting pericyte contraction after ischemic stroke. Our work reveals that iptakalim might be developed as a promising pericyte regulator for treatment of stroke.
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AVC Isquêmico , Acidente Vascular Cerebral , Trifosfato de Adenosina , Animais , Camundongos , Microcirculação , Pericitos , Propilaminas , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
The typical electron-deficiency of the boron element renders fascinating architectures and chemical bonding to boron-based nanoclusters. We theoretically predict two di-Ca-doped boron clusters, B6Ca2 (D2h, 1Ag) and B8Ca2 (D8h, 1A1g), and both adopt interesting inverse sandwich geometries, showing an elongated D2h B6 or perfectly planar D8h B8 ring being sandwiched by two Ca atoms only, respectively. Natural atomic charge analyses indicate that the Ca atoms donate nearly all the 4s electrons to the B6 (or B8) ring, forming [Ca]2+[B6]4-[Ca]2+ and [Ca]2+[B8]4-[Ca]2+ charge transfer complexes. The interaction between the two Ca atoms and the boron rings is governed by robust electrostatics albeit by weaker B-Ca covalent interaction. Chemical bonding analyses show that B6Ca2 has 4σ and 6π delocalized electrons on the elongated B6 ring, leading to a conflicting aromatic system. B8Ca2, possessing 6σ and 6π delocalized electrons on the B8 ring, is doubly aromatic. Additionally, the B6Ca2 and B8Ca2 clusters show noticeable structural and electronic transmutation relative to their equivalent electronic B6Be2 and B8Mg2 clusters, respectively. The intrinsic reasons behind the transmutations are elucidated via in-depth bonding analyses.
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Therapeutic hypothermia is a promising strategy for acute cerebral ischemia via physical or pharmacological methods. In this study, we pharmacologically induced hypothermia on Sprague Dawley rats by intraperitoneally injecting PD149163. We found that mild hypothermia was induced by PD149163 treatment without local cerebral blood flow (LCBF) alteration. To evaluate the neuroprotective effects of PD149163, TTC staining, HE staining and Nissl's staining were performed in our study. We found that PD149163 could prevent neuronal damage, and inhibit proliferation and activation of glial cells induced by ischemia. Simultaneously, we observed PD149163 ameliorated apoptosis characterized by down-regulated caspase-3 and Bax, but elevated Bcl-2. Moreover, PD149163 dramatically reduced JNK and AMPK/mTOR signaling pathway activation, and thereby inhibited autophagy by increased P62 expression, decreased the ratio of LC3-â ¡ to LC3-â and the expression of Beclin. Taken together, the present findings reveal the therapeutic effects of PD149163-induced hypothermia in brain ischemia, and provide a new strategy for stroke treatment.
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Isquemia Encefálica/complicações , Hipotermia Induzida , Hipóxia Encefálica/etiologia , Hipóxia Encefálica/prevenção & controle , Fármacos Neuroprotetores , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , Doença Aguda , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Autofagia/genética , Proliferação de Células/efeitos dos fármacos , Injeções Intraperitoneais , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Neuroglia/citologia , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To explore the role of NADPH oxidase 4( NOX4) in transforming growth factor-ß( TGF-ß)-induced A549 cells migration. METHODS: The A549 cells were allocated into five groups: TGF-ß( stimulation) group, Normal control group, DPI( NOX4 inhibitor) group, TGF-ß + DPI group, and DMSO( solvent control)group. The level of ROS were detected by flow cytometry instrument. The level of NOX4, snail and E-cadherin protein were detected by western blot. Use scratches experiment to express the change of A549 cells migration. RESULTS: After the quantification by Quantity One software, the expression of NOX4 in TGF-ß group is( 1. 80 ± 0. 07), the TGF-ß +DPI group is( 0. 49 ± 0. 03)( F = 327. 071, P < 0. 001). The change of EMT related protein: the expression of snail protein in TGF-ß group is( 9. 0 ± 0. 6), the TGF-ß + DPI group is( 1. 8 ± 0. 3)( F = 119. 097, P < 0. 001), the expression of E-cadherin protein in TGF-ß group is( 0. 5 ± 0. 1), the TGF-ß + DPI group is( 3. 3 ± 0. 3)( F = 71. 063, P <0. 001). These aboveresult indicate that DPI can inhibit the expression of NOX4 and EMTprogress in A549 cells. Then TGF-ß + DPI group compared with the TGF-ß group, the scratch healing rate is decreased( F = 33. 899, P < 0. 001). It illustrates that DPI can inhibit migration ability of A549 cells. CONCLUSION: After the NOX4 was inhibited by DPI, TGF-ß-induced migration of A549 cells was inhibited. And this phenomenon is associated with the progress of TGF-ß-induced EMT.
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Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , NADPH Oxidase 4/farmacologia , Fator de Crescimento Transformador beta1/fisiologia , Linhagem Celular Tumoral , Humanos , Oxirredutases , Fosfatos , Fatores de Crescimento TransformadoresRESUMO
A series of chiral aryl amide compounds bearing peptide pendants have been investigated as low molecular weight gelators. A mechanistic study reveals that complementary hydrogen bonding from peptide pendants is the main driving force for the formation of organogels. This new class of organogels can exhibit multi-stimuli-responsive behavior upon applying (1) thermal, (2) pH, (3) enantiomeric purity, and (4) fluoride anion stimuli. Enantiomeric purity as a new external stimulus displays sensitive stimuli-responsiveness; only 0.02 equiv. of the enantiomer can completely disassemble the gel aggregate. They will serve as excellent smart materials with potential applications in chiral sensors, recognition, and separation.
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Amidas/química , Géis/química , Peptídeos/química , Ligação de Hidrogênio , EstereoisomerismoRESUMO
As wireless communication devices gain popularity, concerns about the potential risks of environmental exposure to complex frequency electromagnetic radiation (EMR) on mental health have become a public health issue. Historically, EMR research has predominantly focused on single- frequency electromagnetic waves, neglecting the study of multi-frequency electromagnetic waves, which more accurately represent everyday life. To address these concerns, our study compared the emotional effects of single-frequency and dual-frequency EMR while exploring potential molecular mechanisms and intervention targets. Our results revealed that single-frequency EMR at 2.65 or 0.8 GHz did not induce anxiety-like behavior in mice. However, exposure to dual-frequency EMR at 2.65/0.8 GHz significantly led to anxiety-like behavior in mice. Further analysis of mouse sera revealed substantial increases in corticosterone and corticotrophin releasing hormone levels following exposure to 2.65/0.8 GHz EMR. Transcriptome sequencing indicated a significant decrease in the expression of Cnr1, encoding cannabinoid receptor 1 Type (CB1R), in the cerebral. This finding was consistently verified through western blot analysis, revealing a substantial reduction in CB1R content. Additionally, a significant decrease in the endocannabinoid 2-arachidonoylglycerol was observed in the cerebral cortex. Remarkably, administering the cannabinoid receptor agonist Win55-212-2 significantly alleviated the anxiety-like behavior, and the cannabinoid receptor antagonist AM251 effectively counteracted the anti-anxiety effects of Win55-212-2. In summary, our research confirmed that dual-frequency EMR is more likely to induce anxiety-like behavior in mice than single-frequency EMR, with implications for the hypothalamic-pituitary-adrenal axis and the endocannabinoid system. Furthermore, our findings suggest that Win55-212-2 may represent a novel avenue for researching and developing anti-EMR drugs.
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Upcycling of CO2 into fuels by virtually unlimited solar energy provides an ultimate solution for addressing the substantial challenges of energy crisis and climate change. In this work, we report an efficient nanostructured Ru/MnOx catalyst composed of well-defined Ru/MnO/Mn3O4 for photo-thermal catalytic CO2 hydrogenation to CH4, which is the result of a combination of external heating and irradiation. Remarkably, under relatively mild conditions of 200 °C, a considerable CH4 production rate of 166.7 mmol g-1 h-1 was achieved with a superior selectivity of 99.5% at CO2 conversion of 66.8%. The correlative spectroscopic and theoretical investigations suggest that the yield of CH4 is enhanced by coordinating photon energy with thermal energy to reduce the activation energy of reaction and promote formation of key intermediate COOH* species over the catalyst. This work opens up a new strategy for CO2 hydrogenation toward CH4.
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Introduction: Multiple system atrophy (MSA) is a rapidly progressing neurodegenerative disorder. Although diverse biomarkers have been established for Parkinson's disease (PD), no widely accepted markers have been identified in MSA. Pyruvate and lactate are the end-product of glycolysis and crucial for brain metabolism. However, their correlation with MSA remains unclear. Moreover, it is elusive how lifestyles modify these metabolites. Methods: To investigate the correlation and diagnostic value of plasma pyruvate and lactate levels in MSA and PD. Moreover, we explored how lifestyle-related metabolites interact with these metabolites in determining the disease risk. We assayed the 3 metabolites in pyruvate/lactate and 6 in the tea/coffee metabolic pathways by targeted mass spectrometry and evaluate their interactions and performance in diagnosis and differentiation between MSA and PD. Results: We found that 7 metabolites were significantly different between MSA, PD and healthy controls (HCs). Particularly, pyruvate was increased in PD while significantly decreased in MSA patients. Moreover, the tea/coffee metabolites were negatively associated with the pyruvate level in HCs, but not in MSA and PD patients. Using machine-learning models, we showed that the combination of pyruvate and tea/coffee metabolites diagnosed MSA (AUC = 0.878) and PD (AUC = 0.833) with good performance. Additionally, pyruvate had good performance in distinguishing MSA from PD (AUC = 0.860), and the differentiation increased (AUC = 0.922) when combined with theanine and 1,3-dimethyluric acid. Conclusions: This study demonstrates that pyruvate correlates reversely with MSA and PD, and may play distinct roles in their pathogenesis, which can be modified by lifestyle-related tea/coffee metabolites.
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BACKGROUND: Identifying the risk factors associated with perioperative mortality is crucial, particularly in older patients. Predicting 6-month mortality risk in older patients based on large datasets can assist patients and surgeons in perioperative clinical decision-making. This study aimed to develop a risk prediction model of mortality within 6 months after noncardiac surgery using the clinical data from 11 894 older patients in China. MATERIALS AND METHODS: A multicentre, retrospective cohort study was conducted in 20 tertiary hospitals. The authors retrospectively included 11 894 patients (aged ≥65 years) who underwent noncardiac surgery between April 2020 and April 2022. The least absolute shrinkage and selection operator model based on linear regression was used to analyse and select risk factors, and various machine learning methods were used to build predictive models of 6-month mortality. RESULTS: The authors predicted 12 preoperative risk factors associated with 6-month mortality in older patients after noncardiac surgery. Including laboratory-associated risk factors such as mononuclear cell ratio and total blood cholesterol level, etc. Also including medical history associated risk factors such as stroke, history of chronic diseases, etc. By using a random forest model, the authors constructed a predictive model with a satisfactory accuracy (area under the receiver operating characteristic curve=0.97). CONCLUSION: The authors identified 12 preoperative risk factors associated with 6-month mortality in noncardiac surgery older patients. These preoperative risk factors may provide evidence for a comprehensive preoperative anaesthesia assessment as well as necessary information for clinical decision-making by anaesthesiologists.
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Acidente Vascular Cerebral , Humanos , Idoso , Estudos Retrospectivos , Medição de Risco/métodos , Fatores de Risco , Tomada de Decisão ClínicaRESUMO
Drug resistance is still a big challenge for cancer patients. We previously demonstrated that inhibiting peptidylarginine deiminase 2 (PADI2) enzyme activity with Cl-amine increases the efficacy of docetaxel (Doc) on tamoxifen-resistant breast cancer cells with PADI2 expression. However, it is not clear whether this effect applies to other tumour cells. Here, we collected four types of tumour cells with different PADIs expression and fully evaluated the inhibitory effect of the combination of PADIs inhibitor (BB-Cla) and Doc in vitro and in vivo on tumour cell growth. Results show that inhibiting PADIs combined with Doc additively inhibits tumour cell growth across the four tumour cells. PADI2-catalysed citrullination of MEK1 Arg 189 exists in the four tumour cells, and blocking the function of MEK1 Cit189 promotes the anti-tumour effect of Doc in these tumour cells. Further analysis shows that inhibiting MEK1 Cit189 decreases the expression of cancer cell stemness factors and helps prevent cancer cell stemness maintenance. Importantly, this combined treatment can partially restore the sensitivity of chemotherapy-resistant cells to docetaxel or cisplatin in tumour cells. Thus, our study provides an experimental basis for the combined therapeutic approaches using docetaxel- and PADIs inhibitors-based strategies in tumour treatment. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.
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Antineoplásicos , Citrulinação , Docetaxel , Resistencia a Medicamentos Antineoplásicos , MAP Quinase Quinase 1 , Humanos , Docetaxel/farmacologia , Tamoxifeno , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , Antineoplásicos/farmacologiaRESUMO
Accumulation of evidences suggested that excessive amounts of AChE and BuChE in the brain of AD patients at the different stage of AD, which could hydrolyze ACh and accelerated Aß aggregation. To develop new "hidden" multifunctional agents through AChE/BuChE would be a promising strategy to treat AD. To this end, firstly, a series of chalcone derivatives with chelating property was designed and synthesized. The in vitro results showed that compound 3f indicated significant selective MAO-B inhibitory activity (IC50 = 0.67 µM) and remarkable anti-inflammatory property. It also significantly inhibited self-induced Aß1-42 aggregation and showed remarkable neuroprotective effects on Aß25-35-induced PC12 cell injury. Furthermore, compound 3f was a selective metal chelator and could inhibit Cu2+-induced Aß1-42 aggregation. Based on this, the carbamate fragment was introduced to compound 3f to obtain carbamate derivatives. The biological activity results exhibited that compound 4b showed good BBB permeability, good AChE inhibitory potency (IC50 = 5.3 µM), moderate BuChE inhibitory potency (IC50 = 12.4 µM), significant MAO-B inhibitory potency, anti-inflammation potency on LPS-induced BV-2 cells and neuroprotective effects on Aß25-35-induced PC12 cell injury. Compared with 3f, compound 4b did not show obvious chelation property. Significantly, compound 4b could be activated by AChE/BuChE following inhibition of AChE/BuChE to liberate an active multifunctional chelator 3f, which was consistent with our original intention. More importantly, compounds 3f and 4b presented favorable ADME properties and good stability in artificial gastrointestinal fluid, blood plasma and rat liver microsomes. The in vivo results suggested that compound 4b (0.0195 µg/mL) could significantly improve dyskinesia and reaction capacity of the AlCl3-induced zebrafish AD model by increasing the level of ACh. Together our data suggest that compound 4b was a promising "hidden" multifunctional agent by AChE/BuChE, and this strategy deserved further development for the treatment of AD.
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Doença de Alzheimer , Fármacos Neuroprotetores , Ratos , Animais , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Peixe-Zebra , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Desenho de Fármacos , Monoaminoxidase , Quelantes/farmacologia , Quelantes/uso terapêutico , Dor , Ligantes , Carbamatos/uso terapêutico , Acetilcolinesterase/uso terapêuticoRESUMO
Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of acute neonatal death and chronic neurological damage, and severe HIE can have secondary sequelae such as cognitive impairment and cerebral palsy, for which effective interventions are lacking. In this study, we found that continuous 30-day intake of Acer truncatum Bunge seed oil (ASO) reduced brain damage and improved cognitive ability in HIE rats. Using lipidomic strategies, we observed that HIE rats had decreased unsaturated fatty acids and increased lysophospholipids in the brain. However, after 30 days of ASO treatment, phospholipids, plasmalogens, and unsaturated fatty acids increased, while lysophospholipids and oxidized glycerophospholipids decreased in both serum and the brain. Enrichment analysis showed that ASO intake mainly affected sphingolipid metabolism, fat digestion and absorption, glycerolipid metabolism and glycerophospholipid metabolic pathways in serum and the brain. Cluster, correlation, and confirmatory factor analyses showed that cognitive improvement after ASO administration was attributed to increased essential phospholipids and ω3/6/9 fatty acids, coupled with decreased oxidized glycerophospholipids in HIE rats. Our findings indicate that ASO has the potential to be developed as an effective food supplement for ischemic hypoxic newborns.
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Acer , Hipóxia-Isquemia Encefálica , Ratos , Animais , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/metabolismo , Lipidômica , Cognição , Glicerofosfolipídeos , Óleos de Plantas/farmacologiaRESUMO
BACKGROUND AND AIMS: Carotid atherosclerosis is an important cause of ischemic stroke. Lipids play a key role in the progression of atherosclerosis. To date, the spatial lipid profile of carotid atherosclerotic plaques related to histology has not been systematically investigated. METHODS: Carotid atherosclerosis samples from 12 patients were obtained and classified into four classical pathological stages (preatheroma, atheroma, fibroatheroma and complicated lesion) by histological staining. Desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) was used to investigate the lipid profile of carotid atherosclerosis, and correlated it with histological information. Bioinformatics technology was used to process MSI data among different pathological stages of atherosclerosis lesions. RESULTS: A total of 55 lipids (26 throughout cross-section regions [TCSRs], 13 in lipid-rich regions [LRRs], and 16 in collagen-rich regions [CRRs]) were initially identified in carotid plaque from one patient. Subsequently, 32 of 55 lipids (12 in TCSRs, eight in LRRs, and 12 in CRRs) were further screened in 11 patients. Pathway enrichment analysis showed that multiple metabolic pathways, such as fat digestion and absorption, cholesterol metabolism, lipid and atherosclerosis, were enriched in TCSRs; sphingolipid signaling pathway, necroptosis pathway were enriched in LRRs; and glycerophospholipid metabolism, ether lipid metabolism pathway were mainly enriched in CRRs. CONCLUSIONS: This study comprehensively showed the spatial lipid metabolism footprint in human carotid atherosclerotic plaques. The lipid profiles and related metabolism pathways in three regions of plaque with disease progression were different markedly, suggesting that the different metabolic mechanisms in these regions of carotid plaque may be critical in atherosclerosis progression.
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Aterosclerose , Doenças das Artérias Carótidas , Placa Aterosclerótica , Humanos , Placa Aterosclerótica/patologia , Doenças das Artérias Carótidas/patologia , Aterosclerose/patologia , Artérias Carótidas/patologia , Lipídeos/químicaRESUMO
BACKGROUND: The diagnosis of cerebral thrombosis origin is challenging and remains unclear. This study aims to identify thrombosis due to cardioembolism (CE) and large artery atherosclerosis (LAA) from a new perspective of distinct metabolites. METHODS: Distinct metabolites between 26 CE and 22 LAA origin thrombi, which were extracted after successful mechanical thrombectomy in patients with acute ischemic stroke in the anterior circulation, were analyzed with a ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) system. Enriched metabolic pathways related to the metabolites were identified. Least absolute shrinkage selection operator regression analyses and a filtering method were used to select potential predictors. Furthermore, four machine learning classifiers, including decision tree, logistic regression, random forest (RF), and k means unsupervised classification model, were used to evaluate the predictive ability of the selected metabolites. RESULTS: UPLC-QTOF-MS analysis revealed that levels of 88 and 55 metabolites were elevated in LAA and CE thrombi, respectively. Kyoto Encyclopedia of Genes and Genomes analysis revealed a significant difference between the pathways enriched in the two types of thrombi. Six metabolites (diglyceride (DG, 18:3/24:0), DG (22:0/24:0), phytosphingosine, galabiosylceramide (18:1/24:1), triglyceride (15:0/16:1/o-18:0), and glucosylceramide (18:1/24:0)) were finally selected to build a predictive model. The predictive RF model was confirmed to be the best, with a satisfactory stability and prediction capacity (area under the curve=0.889). CONCLUSIONS: Six metabolites as potential predictors for distinguishing between cerebral thrombi of CE and LAA origin were identified. The results are useful for understanding the pathogenesis and for secondary stroke prevention.
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Aterosclerose , AVC Isquêmico , Acidente Vascular Cerebral , Trombose , Humanos , AVC Isquêmico/complicações , Aterosclerose/complicações , Aterosclerose/diagnóstico , Acidente Vascular Cerebral/complicações , Trombose/complicações , Artérias/patologiaRESUMO
Well supported: stable hemin-graphene conjugates formed by immobilization of monomeric hemin on graphene, showed excellent catalytic activity, more than 10 times better than that of the recently developed hemin-hydrogel system and 100 times better than that of unsupported hemin. The catalysts also showed excellent binding affinities and catalytic efficiencies approaching that of natural enzymes.
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Materiais Biomiméticos/química , Grafite/química , Hemina/química , Catálise , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Cinética , Oxirredução , Óxidos/químicaRESUMO
Purpose: Although classical techniques for image segmentation may work well for some images, they may perform poorly or not work at all for others. It often depends on the properties of the particular image segmentation task under study. The reliable segmentation of brain tumors in medical images represents a particularly challenging and essential task. For example, some brain tumors may exhibit complex so-called "bottle-neck" shapes which are essentially circles with long indistinct tapering tails, known as a "dual tail." Such challenging conditions may not be readily segmented, particularly in the extended tail region or around the so-called "bottle-neck" area. In those cases, existing image segmentation techniques often fail to work well. Methods: Existing research on image segmentation using wormhole and entangle theory is first analyzed. Next, a random positioning search method that uses a quantum-behaved particle swarm optimization (QPSO) approach is improved by using a hyperbolic wormhole path measure for seeding and linking particles. Finally, our novel quantum and wormhole-behaved particle swarm optimization (QWPSO) is proposed. Results: Experimental results show that our QWPSO algorithm can better cluster complex "dual tail" regions into groupings with greater adaptability than conventional QPSO. Experimental work also improves operational efficiency and segmentation accuracy compared with current competing reference methods. Conclusion: Our QWPSO method appears extremely promising for isolating smeared/indistinct regions of complex shape typical of medical image segmentation tasks. The technique is especially advantageous for segmentation in the so-called "bottle-neck" and "dual tail"-shaped regions appearing in brain tumor images.
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BACKGROUND: The homeostasis of mesenchymal stem cells (MSCs) is modulated by both their own intracellular molecules and extracellular milieu signals. Hematopoiesis in the bone marrow is maintained by niche cells, including MSCs, and it is indispensable for life. The role of MSCs in maintaining hematopoietic homeostasis has been fully elucidated. However, little is known about the mechanism by which hematopoietic cells reciprocally regulate niche cells. The present study aimed to explore the close relationship between MSCs and hematopoietic cells, which may be exploited for the development of new therapeutic strategies for related diseases. METHODS: In this study, we isolated cells from the offspring of Tie2Cre + and Ptenflox/flox mice. After cell isolation and culture, we investigated the effect of hematopoietic cells on MSCs using various methods, including flow cytometry, adipogenic and osteogenic differentiation analyses, quantitative PCR, western bloting, and microCT analysis. RESULTS: Our results showed that when the phosphatase and tensin homolog deleted on chromosome 10 (Pten) gene was half-deleted in hematopoietic cells, hematopoiesis and osteogenesis were normal in young mice; the frequency of erythroid progenitor cells in the bone marrow gradually decreased and osteogenesis in the femoral epiphysis weakened as the mice grew. The heterozygous loss of Pten in hematopoietic cells leads to the attenuation of osteogenic differentiation and enhanced adipogenic differentiation of MSCs in vitro. Co-culture with normal hematopoietic cells rescued the abnormal differentiation of MSCs, and in contrast, MSCs co-cultured with heterozygous null Pten hematopoietic cells showed abnormal differentiation activity. Co-culture with erythroid progenitor cells also revealed them to play an important role in MSC differentiation. CONCLUSION: Our data suggest that hematopoietic cells function as niche cells of MSCs to balance the differentiation activity of MSCs and may ultimately affect bone development.
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Células-Tronco Mesenquimais , Osteogênese , Animais , Células da Medula Óssea , Diferenciação Celular/fisiologia , Células Cultivadas , Hematopoese/genética , CamundongosRESUMO
BACKGROUND AND PURPOSE: Radiotherapy is a standard treatment for head and neck tumors that significantly increases patients' long-term survival rates. However, late cerebrovascular complications, especially carotid artery stenosis (CAS), have gained increasing attention. Investigation of biomarkers of radiation-induced CAS may help to elucidate the mechanism by which radiation induces damage to blood vessels and identify possible preventive measures against such damage. MATERIALS AND METHODS: In this study, we used lipidomics strategy to characterize the lipids present in 8 radiation-induced carotid plaques (RICPs) and 12 atherosclerotic carotid plaques (ASCPs). We also used desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) to map the spatial distribution of the screened lipids from 2 RICPs samples and 2 ASCPs samples. RESULTS: The results showed that 31 metabolites in RICPs were significantly higher than that in ASCPs, 24 of which were triglycerides (TGs). We used four machine learning models to select potential indicators from the 31 metabolites. Six TGs [TG(17:2/17:2/18:0), TG(17:1/17:2/18:0), TG(17:0/17:2/18:0), TG(17:2/17:2/20:0), TG(17:1/17:2/20:0), TG(15:0/22:0/22:2)] were found to be the potential markers for distinguishing RICPs and ASCPs (AUC = 0.83). The DESI-MSI results suggested that the 6 TGs were localized in the collagen fiber regions and confirmed the differences of these TGs between the two kinds of plaques. CONCLUSIONS: The 6 TGs primarily localized in the collagen fiber regions of plaques are likely to be potential indicators for the differentiation of RICPs from ASCPs which may have implications in the mechanisms and possible preventive measures against RICPs.