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Esculetin (ESC) is a coumarin-derived phytochemical prevalent in traditional Chinese medicine that exhibits anti-acute ischemic stroke activities. Our previous studies demonstrate that CKLF1 is a potential anti-stroke target for coumarin-derived compound. In this study we investigated whether CKLF1 was involved in the neuroprotective effects of ESC against photothrombotic stroke in mice. The mice were treated with ESC (20, 40 or 80 mg·kg-1·d-1, i.g.) for two weeks. The therapeutic effect of ESC was assessed using MRI, neurological function evaluation, and a range of behavioral tests on D1, 3, 7 and 14 of ESC administration. We showed that oral administration of ESC dose-dependently reduced the cerebral infarction volume within one week after stroke, improved behavioral performance, and alleviated neuropathological damage within two weeks. Functional MRI revealed that ESC significantly enhanced the abnormal low-frequency fluctuation (ALFF) value of the motor cortex and promoted functional connectivity between the supplementary motor area (SMA) and multiple brain regions. We demonstrated that ESC significantly reduced the protein levels of CKLF1 and CCR5, as well as the CKLF1/CCR5 protein complex in the peri-infarcted area. We showed that ESC (0.1-10 µM) dose-dependently blocked CKLF1-induced chemotactic movement of neutrophils in the Transwell assay, reducing the interaction of CKLF1/CCR5 on the surface of neutrophils, thereby reducing neutrophil infiltration, and decreasing the expression of ICAM-1, VCAM-1 and MMP-9 in the peri-infarct tissue. Knockout of CKLF1 reduced brain infarction volume and motor dysfunction after stroke but also negated the anti-stroke efficacy and neutrophil infiltration of ESC. These results suggest that the efficacy of ESC in promoting post-stroke neural repair depends on its inhibition on CKLF1-mediated neutrophil infiltration, which offering novel perspectives for elucidating the therapeutic properties of coumarins.
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Objectives. Anti-fungal agents are increasingly becoming less effective due to the development of resistance. In addition, it is difficult to treat Candida organisms that form biofilms due to a lack of ability of drugs to penetrate the biofilms. We are attempting to assess the effect of a new therapeutic agent, N-acetylcysteine (NAC), on adhesion and biofilm formation in Candida parapsilosis clinical strains. Meanwhile, to detect the transcription level changes of adhesion and biofilm formation-associated genes (CpALS6, CpALS7, CpEFG1 and CpBCR1) when administrated with NAC in C. parapsilosis strains, furthermore, to explore the mechanism of drug interference on biofilms.Hypothesis/Gap statement. N-acetylcysteine (NAC) exhibits certain inhibitory effects on adhesion and biofilm formation in C. parapsilosis clinical strains from CRBSIs through: (1) down-regulating the expression of the CpEFG1 gene, making it a highly potential candidate for the treatment of C. parapsilosis catheter-related bloodstream infections (CRBSIs), (2) regulating the metabolism and biofilm -forming factors of cell structure.Methods. To determine whether non-antifungal agents can exhibit inhibitory effects on adhesion, amounts of total biofilm formation and metabolic activities of C. parapsilosis isolates from candidemia patients, NAC was added to the yeast suspensions at different concentrations, respectively. Reverse transcription was used to detect the transcriptional levels of adhesion-related genes (CpALS6 and CpALS7) and biofilm formation-related factors (CpEFG1 and CpBCR1) in the BCR1 knockout strain, CP7 and CP5 clinical strains in the presence of NAC. To further explore the mechanism of NAC on the biofilms of C. parapsilosis, RNA sequencing was used to calculate gene expression, comparing the differences among samples. Gene Ontology (GO) enrichment analysis helps to illustrate the difference between two particular samples on functional levels.Results. A high concentration of NAC reduces the total amount of biofilm formation in C. parapsilosis. Following co-incubation with NAC, the expression of CpEFG1 in both CP7 and CP5 clinical strains decreased, while there were no significant changes in the transcriptional levels of CpBCR1 compared with the untreated strain. GO enrichment analysis showed that the metabolism and biofilm-forming factors of cell structure were all regulated after NAC intervention.Conclusions. The non-antifungal agent NAC exhibits certain inhibitory effects on clinical isolate biofilm formation by down-regulating the expression of the CpEFG1 gene, making it a highly potential candidate for the treatment of C. parapsilosis catheter-related bloodstream infections.
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Acetilcisteína , Biofilmes , Candida parapsilosis , Candidemia , Infecções Relacionadas a Cateter , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Acetilcisteína/farmacologia , Humanos , Candida parapsilosis/efeitos dos fármacos , Candida parapsilosis/genética , Candida parapsilosis/fisiologia , Infecções Relacionadas a Cateter/microbiologia , Candidemia/microbiologia , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Antifúngicos/farmacologiaRESUMO
AIMS: Ischaemia/reperfusion (I/R) injury is an important complication of reperfusion therapy for acute myocardial infarction, extremely compromising the cardiac benefits of revascularization; however, specific and efficient treatment for cardiac I/R injury is still lacking. Isthmin-1 (ISM1) is a novel adipokine and plays indispensable roles in regulating glycolipid metabolism and cell survival. The present study aims to investigate the potential role and molecular mechanism of ISM1 in cardiac I/R injury using gain- and loss-of-function approaches. METHODS AND RESULTS: Cardiac-specific ISM1 overexpression and silence were achieved using an adeno-associated virus serotype 9 system, and then these mice were subjected to I/R surgery, followed by biochemical test, echocardiography and histopathologic examinations, etc. Meanwhile, neonatal rat cardiomyocytes (NRCMs) with ISM1 silence or overexpression also received simulated I/R (sI/R) injury to further verify its role in vitro. The potential downstream pathways and molecular targets of ISM1 were screened by RNA sequencing. We also treated injured mice and NRCMs with recombinant ISM1 (rISM1) to explore whether supplementation with ISM1 was sufficient to protect against I/R injury. Furthermore, acute myocardial infarction patients with percutaneous coronary intervention (PCI) and paired healthy controls were included to reveal the clinical relevance of circulating ISM1. Cardiac-specific ISM1 silencing aggravated while ISM1 overexpression alleviated I/R-induced acute cardiac injury and cardiac remodelling and dysfunction. Mechanistically, ISM1 targeted αvß5 integrin to facilitate the nuclear accumulation of nuclear transcription factor Y subunit alpha, transcriptionally increased soluble guanylyl cyclase beta subunit expression, and eventually enhanced cGMP generation. Besides, we confirmed that treatment with rISM1 before or after reperfusion could confer cardioprotective effects in mice. Clinically, lower ISM1 levels post-PCI was associated with worse outcome in patients. CONCLUSION: ISM1 can protect against cardiac I/R injury through cGMP-PKG signalling pathway, and it is a promising therapeutic and predictive target of cardiac I/R injury.
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GMP Cíclico , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica , Miócitos Cardíacos , Transdução de Sinais , Animais , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Humanos , Masculino , GMP Cíclico/metabolismo , Células Cultivadas , Adipocinas/metabolismo , Adipocinas/genética , Função Ventricular Esquerda , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/genética , Estudos de Casos e Controles , Remodelação Ventricular , Ratos , Ratos Sprague-Dawley , Sistemas do Segundo Mensageiro , Camundongos , Proteínas de MembranaRESUMO
Aging-related cardiac dysfunction poses a major risk factor of mortality for elderly populations, however, efficient treatment for aging-related cardiac dysfunction is far from being known. Isthmin-1 (ISM1) is a novel adipokine that promotes glucose uptake and acts indispensable roles in restraining inflammatory and fibrosis. The present study aims to investigate the potential role and molecular mechanism of ISM1 in aging-related cardiac dysfunction. Aged and matched young mice were overexpressed or silenced with ISM1 to investigate the role of ISM1 in aging-related cardiac dysfunction. Moreover, H9C2 cells were stimulated with D-galactose (D-gal) to examine the role of ISM1 in vitro. Herein, we found that cardiac-specific overexpression of ISM1 significantly mitigated insulin resistance by promoting glucose uptake in aging mice. ISM1 overexpression alleviated while ISM1 silencing deteriorated cellular senescence, cardiac inflammation, and dysfunction in natural and accelerated cardiac aging. Mechanistically, ISM1 promoted glycolysis and activated Sirtuin-1 (SIRT1) through increasing glucose uptake. ISM1 increased glucose uptake via translocating GLUT4 to the surface, thereby enhancing glycolytic flux and hexosamine biosynthetic pathway (HBP) flux, ultimately leading to increased SIRT1 activity through O-GlcNAc modification. ISM1 may serve as a novel potential therapeutic target for preventing aging-related cardiac disease in elderly populations. ISM1 prevents aging-related cardiac dysfunction by promoting glycolysis and enhancing SIRT1 deacetylase activity, making it a promising therapeutic target for aging-related cardiac disease.
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Toxoplasma gondii is an opportunistic protozoan parasite that is highly prevalent in the human population and can lead to adverse health consequences in immunocompromised patients and pregnant women. Noncoding RNAs, such as microRNAs (miRNAs) and circular RNAs (circRNAs), play important regulatory roles in the pathogenesis of many infections. However, the differentially expressed (DE) miRNAs and circRNAs implicated in the host cell response during the lytic cycle of T. gondii are unknown. In this study, we profiled the expression of miRNAs and circRNAs in human foreskin fibroblasts (HFFs) at different time points after T. gondii infection using RNA sequencing (RNA-seq). We identified a total of 7, 7, 27, 45, 70, 148, 203, and 217 DEmiRNAs and 276, 355, 782, 1863, 1738, 6336, 1229, and 1680 DEcircRNAs at 1.5, 3, 6, 9, 12, 24, 36, and 48 h post infection (hpi), respectively. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed that the DE transcripts were enriched in immune response, apoptosis, signal transduction, and metabolism-related pathways. These findings provide new insight into the involvement of miRNAs and circRNAs in the host response to T. gondii infection.
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MicroRNAs , Toxoplasma , Gravidez , Humanos , Feminino , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Endógeno Competitivo , Perfilação da Expressão Gênica , Redes Reguladoras de GenesRESUMO
Cepharanthine (CEP), a bioactive compound derived from Stephania Cephalantha Hayata, is cytotoxic to various malignancies. However, the underlying mechanism of gastric cancer is unknown. CEP inhibited the cellular activity of gastric cancer AGS, HGC27 and MFC cell lines in this study. CEP-induced apoptosis reduced Bcl-2 expression and increased cleaved caspase 3, cleaved caspase 9, Bax, and Bad expression. CEP caused a G2 cell cycle arrest and reduced cyclin D1 and cyclin-dependent kinases 2 (CDK2) expression. Meanwhile, it increased oxidative stress, decreased mitochondrial membrane potential, and enhanced reactive oxygen species (ROS) accumulation in gastric cancer cell lines. Mechanistically, CEP inhibited Kelch-like ECH-associated protein (Keap1) expression while activating NF-E2 related factor 2 (Nrf2) nuclear translocations, increasing transcription of Nrf2 target genes quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), and glutamate-cysteine ligase modifier subunit (GCLM). Furthermore, a combined analysis of targeted energy metabolism and RNA sequencing revealed that CEP could alter the levels of metabolic substances such as D (+) - Glucose, D-Fructose 6-phosphate, citric acid, succinic acid, and pyruvic acid, thereby altering energy metabolism in AGS cells. In addition, CEP significantly inhibited tumor growth in MFC BALB/c nude mice in vivo, consistent with the in vitro findings. Overall, CEP can induce oxidative stress by regulating Nrf2/Keap1 and alter energy metabolism, resulting in anti-gastric cancer effects. Our findings suggest a potential application of CEP in gastric cancer treatment.
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In China, the prevalence of diabetic retinopathy (DR) is increasing, so it is necessary to provide convenient and effective community outreach screening programs for DR, especially in rural and remote areas. The purpose of this study was to use the results of ophthalmologists as the gold standard to evaluate the accuracy of community general practitioners' judgement and grading of DR to find a feasible and convenient DR screening method to reduce the risk of visual impairment and blindness in known diabetes patients. Retinal images of 1646 diabetic patients who underwent DR screening through teleophthalmology at Nanchang First Hospital were collected for 30 months (January 2020 to June 2022). Retinal images were collected without medication for mydriasis, stored by community general practitioner, and diagnosed by both community general practitioner and ophthalmologist of our hospital through teleophthalmology. The grading of ophthalmologist was used as a reference or gold standard for comparison with that of community general practitioner. A total of 1646 patients and 3185 eyes were examined, including 2310 eyes with DR. The evaluation by the community general practitioner had a Kappa value of 0.578, sensitivity of 80.58%, specificity of 89.94%, and accuracy of 83.38%% in 2020; a Kappa value of 0.685, sensitivity of 95.43%, specificity of 78.55%, and accuracy of 90.77% in 2021; and a Kappa value of 0.744, sensitivity of 93.99%, specificity of 88.97%, and accuracy of 92.86% in 2022. Teleophthalmology helped with large-scale screening of DR and made it possible for community general practitioner to grade images with high accuracy after appropriate training. It is possible to solve the current shortage of eye care personnel, promote the early recognition of disease and reduce the impact of diabetes-associated blindness.
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Diabetes Mellitus , Retinopatia Diabética , Oftalmologia , Telemedicina , Humanos , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/epidemiologia , Telemedicina/métodos , Oftalmologia/métodos , Programas de Rastreamento/métodos , Cegueira , FotografaçãoRESUMO
BACKGROUND: Heart failure (HF) is a global health problem characterized by impaired heart function. Cardiac remodeling and cell death contribute to the development of HF. Although treatments such as digoxin and angiotensin receptor blocker drugs have been used, their effectiveness in reducing mortality is uncertain. Researchers are exploring the use of adipose-derived mesenchymal stem cell (ADMSC) exosomes (Exos) as a potential therapy for HF. These vesicles, secreted by cells, may aid in tissue repair and regulation of inflammation and immune responses. However, further investigation is needed to understand the specific role of these vesicles in HF treatment. AIM: To investigate the mechanism of extracellular vesicles produced by ADMSC s in the treatment of HF. METHODS: Exogenous surface markers of ADMSCs were found, and ADMSCs were cultured. RESULTS: The identification of surface markers showed that the surface markers CD44 and CD29 of adipose-derived stem cells (ADSCs) were well expressed, while the surface markers CD45 and CD34 of ADSCs were negative, so the cultured cells were considered ADSCs. Western blotting detected the Exo surface marker protein, which expressed CD63 protein but did not express calnexin protein, indicating that ADSC-derived Exos were successfully extracted. CONCLUSION: The secretion of MSCs from adipose tissue can increase ATP levels, block cardiomyocyte apoptosis, and enhance the heart function of animals susceptible to HF. The inhibition of Bax, caspase-3 and p53 protein expression may be related to this process.
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Parkinson's disease (PD) is pathologically manifested by the aggregation of α-synuclein, which has been envisioned as a promising disease-modifying target for PD. Here, we identified 20C, a bibenzyl compound derived from Gastrodia elata, able to inhibit the aggregation of A53T variants of α-synuclein directly in vitro. Computational analysis revealed that 20C binds to cavities in mature α-synuclein fibrils, and it indeed displays a strong interaction with α-synuclein and reduced their ß-sheet structure by microscale thermophoresis and circular dichroism, respectively. Moreover, incubating neural cells with 20C reduced the amounts of α-synuclein inclusions significantly. The treatment of A53T α-Syn transgenic mice with 20C significantly reduces the toxic α-synuclein levels, improves behavioral performance, rescues dopaminergic neuron, and enhances functional connections between SNc and PD associated brain areas. The transcriptome analysis of SNc demonstrated that 20C improves mitochondrial dynamics, which protects mitochondrial morphology and function against α-synuclein induced degeneration. Overall, 20C appears to be a promising candidate for the treatment of PD.
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Gastrodia , Doença de Parkinson , Animais , Camundongos , alfa-Sinucleína/genética , Doença de Parkinson/tratamento farmacológico , Encéfalo , Neurônios Dopaminérgicos , Camundongos TransgênicosRESUMO
Stroke, the third leading cause of death and disability worldwide, is classified into ischemic or hemorrhagic, in which approximately 85% of strokes are ischemic. Ischemic stroke occurs as a result of arterial occlusion due to embolus or thrombus, with ischemia in the perfusion territory supplied by the occluded artery. The traditional concept that ischemic stroke is solely a vascular occlusion disorder has been expanded to include the dynamic interaction between microglia, astrocytes, neurons, vascular cells, and matrix components forming the "neurovascular unit." Acute ischemic stroke triggers a wide spectrum of neurovascular disturbances, glial activation, and secondary neuroinflammation that promotes further injury, ultimately resulting in neuronal death. Microglia, as the resident macrophages in the central nervous system, is one of the first responders to ischemic injury and plays a significant role in post-ischemic neuroinflammation. In this review, we reviewed the mechanisms of microglia in multiple stages of post-ischemic neuroinflammation development, including acute, sub-acute and chronic phases of stroke. A comprehensive understanding of the dynamic variation and the time-dependent role of microglia in post-stroke neuroinflammation could aid in the search for more effective therapeutics and diagnostic strategies for ischemic stroke.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Microglia , Doenças Neuroinflamatórias , Acidente Vascular Cerebral/terapia , MacrófagosRESUMO
Crystallization of organic steric molecules often leads to multiple polyhedral crystal morphologies. However, the relationships among the molecular structure, supramolecular interaction, aggregation mode and crystal morphology are still unclear. In this work, we elaborate two model crystals formed by spiro[fluorene-9,9'-xanthene] (SFX) and spiro[cyclopenta[1,2-b : 5,4-b']dipyridine-5,9'-xanthene] (SDAFX) to demonstrate the feasibility of morphology prediction by periodic bond chain (PBC) theory based on interaction energy (IE) values in terms of single point energy. With non-directional van der Waals forces, only one PBC direction is found in SFX crystal, leading to the irregular 1D rod-like structure. Compared with SFX, the extra N heteroatoms in SDAFX can bring additional hydrogen bonds and some other interactions into the bulky molecular skeletons, inducing 3-dimensionally oriented PBCs to form the explicit F-face network in SDAFX which leads to the final octahedral structure. A simple and accurate method has been provided to quantify PBC vector on the supramolecular level in the organic molecular system, and the PBC theory has also been further demonstrated and developed in the morphology prediction of organic spiro-molecules.
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The hexosamine biosynthetic pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) to facilitate O-linked GlcNAc (O-GlcNAc) protein modifications, and subsequently enhance cell survival under lethal stresses. Transcript induced in spermiogenesis 40 (Tisp40) is an endoplasmic reticulum membrane-resident transcription factor and plays critical roles in cell homeostasis. Here, we show that Tisp40 expression, cleavage and nuclear accumulation are increased by cardiac ischemia/reperfusion (I/R) injury. Global Tisp40 deficiency exacerbates, whereas cardiomyocyte-restricted Tisp40 overexpression ameliorates I/R-induced oxidative stress, apoptosis and acute cardiac injury, and modulates cardiac remodeling and dysfunction following long-term observations in male mice. In addition, overexpression of nuclear Tisp40 is sufficient to attenuate cardiac I/R injury in vivo and in vitro. Mechanistic studies indicate that Tisp40 directly binds to a conserved unfolded protein response element (UPRE) of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) promoter, and subsequently potentiates HBP flux and O-GlcNAc protein modifications. Moreover, we find that I/R-induced upregulation, cleavage and nuclear accumulation of Tisp40 in the heart are mediated by endoplasmic reticulum stress. Our findings identify Tisp40 as a cardiomyocyte-enriched UPR-associated transcription factor, and targeting Tisp40 may develop effective approaches to mitigate cardiac I/R injury.
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Hexosaminas , Traumatismo por Reperfusão , Animais , Masculino , Camundongos , Vias Biossintéticas , Hexosaminas/metabolismo , Isquemia/metabolismo , Miócitos Cardíacos/metabolismo , Traumatismo por Reperfusão/metabolismo , Espermatogênese , Fatores de Transcrição/metabolismoRESUMO
With the development and generalization of endoscopic technology and screening, clinical application of magnetically controlled capsule gastroscopy (MCCG) has been increasing. In recent years, various types of MCCG are used globally. Therefore, establishing relevant guidelines on MCCG is of great significance. The current guidelines containing 23 statements were established based on clinical evidence and expert opinions, mainly focus on aspects including definition and diagnostic accuracy, application population, technical optimization, inspection process, and quality control of MCCG. The level of evidence and strength of recommendations were evaluated. The guidelines are expected to guide the standardized application and scientific innovation of MCCG for the reference of clinicians.
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Gastroscopia , Humanos , Gastroscopia/métodos , MagnetismoRESUMO
Chemokine receptor 5 (CCR5) is one of the main co-receptors of HIV-1, and has been found to be a potential therapeutic target for stroke. Maraviroc is a classic CCR5 antagonist, which is undergoing clinical trials against stroke. As maraviroc shows poor blood-brain barrier (BBB) permeability, it is of interest to find novel CCR5 antagonists suitable for neurological medication. In this study we characterized the therapeutic potential of a novel CCR5 antagonist A14 in treating ischemic stroke mice. A14 was discovered in screening millions compounds in the Chemdiv library based on the molecular docking diagram of CCR5 and maraviroc. We found that A14 dose-dependently inhibited the CCR5 activity with an IC50 value of 4.29 µM. Pharmacodynamic studies showed that A14 treatment exerted protective effects against neuronal ischemic injury both in vitro and vivo. In a SH-SY5Y cell line overexpressing CCR5, A14 (0.1, 1 µM) significantly alleviated OGD/R-induced cell injury. We found that the expression of CCR5 and its ligand CKLF1 was significantly upregulated during both acute and recovery period in focal cortical stroke mice; oral administration of A14 (20 mg·kg-1·d-1, for 1 week) produced sustained protective effect against motor impairment. A14 treatment had earlier onset time, lower onset dosage and much better BBB permeability compared to maraviroc. MRI analysis also showed that A14 treatment significantly reduced the infarction volume after 1 week of treatment. We further revealed that A14 treatment blocked the protein-protein interaction between CCR5 and CKLF1, increasing the activity of CREB signaling pathway in neurons, thereby improving axonal sprouting and synaptic density after stroke. In addition, A14 treatment remarkably inhibited the reactive proliferation of glial cells after stroke and reduced the infiltration of peripheral immune cells. These results demonstrate that A14 is a promising novel CCR5 antagonist for promoting neuronal repair after ischemic stroke. A14 blocked the protein-protein interaction between CKLF1 and CCR5 after stroke by binding with CCR5 stably, improved the infarct area and promoted motor recovery through reversing the CREB/pCREB signaling which was inhibited by activated CCR5 Gαi pathway, and benefited to the dendritic spines and axons sprouting.
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Antagonistas dos Receptores CCR5 , AVC Isquêmico , Neuroblastoma , Acidente Vascular Cerebral , Animais , Humanos , Camundongos , AVC Isquêmico/tratamento farmacológico , Maraviroc/uso terapêutico , Maraviroc/farmacologia , Simulação de Acoplamento Molecular , Receptores CCR5/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/farmacologiaRESUMO
Ischemic stroke is characterized by the presence of reactive microglia. However, its precise involvement in stroke etiology is still unknown. We used metabolic profiling and showed that chemokine like factor 1 (CKLF1) causes acute microglial inflammation and metabolic reprogramming from oxidative phosphorylation to glycolysis, which was reliant on the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR)-hypoxia inducible factor 1α (HIF-1α) signaling pathway. Once activated, microglia enter a chronic tolerant state as a result of widespread energy metabolism abnormalities, which reduces immunological responses, including cytokine release and phagocytosis. Metabolically dysfunctional microglia were also found in mice using genome-wide RNA sequencing after chronic administration of CKLF1, and there was a decrease in the inflammatory response. Finally, we showed that the loss of CKLF1 reversed the defective immune response of microglia, as indicated by the maintenance its phagocytosis to neutrophils, thereby mitigating the long-term outcomes of ischemic stroke. Overall, CKLF1 plays a crucial role in the relationship between microglial metabolic status and immune function in stroke, which prepares a potential therapeutic strategy for ischemic stroke.
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AVC Isquêmico , Acidente Vascular Cerebral , Animais , Camundongos , Citocinas/metabolismo , Tolerância Imunológica , AVC Isquêmico/metabolismo , Mamíferos/metabolismo , Microglia/metabolismo , Acidente Vascular Cerebral/metabolismoRESUMO
BACKGROUND: Lugol chromoendoscopy (LCE) has served as a standard screening technique in high-risk patients with esophageal cancer. Nevertheless, LCE is not suitable for general population screening given its side effects. Linked color imaging (LCI) is a novel image-enhanced endoscopic technique that can distinguish subtle diff-erences in mucosal color. AIM: To compare the diagnostic performance of LCI with LCE in detecting esophageal squamous cell cancer and precancerous lesions and to evaluate whether LCE can be replaced by LCI in detecting esophageal neoplastic lesions. METHODS: In this prospective study, we enrolled 543 patients who underwent white light imaging (WLI), LCI and LCE successively. We compared the sensitivity and specificity of LCI and LCE in the detection of esophageal neoplastic lesions. Clinicopathological features and color analysis of lesions were assessed. RESULTS: In total, 43 patients (45 neoplastic lesions) were analyzed. Among them, 36 patients (38 neoplastic lesions) were diagnosed with LCI, and 39 patients (41 neoplastic lesions) were diagnosed with LCE. The sensitivity of LCI was similar to that of LCE (83.7% vs 90.7%, P = 0.520), whereas the specificity of LCI was greater than that of LCE (92.4% vs 87.0%, P = 0.007). The LCI procedure time in the esophageal examination was significantly shorter than that of LCE [42 (34, 50) s vs 160 (130, 189) s, P < 0.001]. The color difference between the lesion and surrounding mucosa in LCI was significantly greater than that observed with WLI. However, the color difference in LCI was similar in different pathological types of esophageal squamous cell cancer. CONCLUSION: LCI offers greater specificity than LCE in the detection of esophageal squamous cell cancer and precancerous lesions, and LCI represents a promising screening strategy for general populations.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Lesões Pré-Cancerosas , Humanos , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas/patologia , Estudos Prospectivos , Detecção Precoce de Câncer/métodos , Carcinoma de Células Escamosas do Esôfago/diagnóstico por imagem , Lesões Pré-Cancerosas/patologia , CorRESUMO
The exciplex-thermally activated delayed fluorescence (exciplex-TADF) system is an excellent candidate for the fabrication of high-efficiency organic light-emitting diodes (OLEDs) because of its more easily achieved small singlet-triplet energy splitting (ΔEST) and doping control. However, exciplex-TADF is still faced with the problems of low external quantum efficiency (ηext) and unclear effect of structure modification in electron acceptors. Herein, we provide a steric hindrance increase strategy to obtain high-efficiency exciplex emissions. Through introducing a 9-phenylfluorene group into N-ethylcarbazole of the dicyano-substituted 9-phenylfluorene, an electron acceptor material with increased steric hindrance is obtained, which helps the exciplex harvest a larger driving force and higher emission efficiencies. Encouragingly, the obtained OLED displays a maximum ηext of 25.8%, which is one of the best efficiency values among reported exciplex-OLEDs, simultaneously possessing excellent current efficiency of 83.6 cd A-1 and power efficiency of 93.7 lm W-1. It is expected that this work will offer a new avenue for designing electron acceptors for highly efficient exciplex emissions.
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[This corrects the article DOI: 10.3389/fonc.2022.929763.].