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1.
J Comp Neurol ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31674015

RESUMO

Cognitive control is the coordination of mental operations under conditions of uncertainty in accordance with goal-directed behaviors, and plays a key role in the domains of executive control, working memory, and decision-making. Although there is emerging evidence of common involvement of the cognitive control network (CCN) of the brain in these domains, this network has mostly been linked to the processing of conflict, which is just one case of an increase in uncertainty. Here, we conducted an activation-likelihood-estimation-based large-scale meta-analysis of 289 functional magnetic resonance imaging studies in the three domains to examine the common involvement of the CCN in uncertainty processing by contrasting the high-uncertainty versus low-uncertainty conditions. We found a general association between increase in uncertainty and an activation increase in regions of the CCN, including the frontoparietal network (comprising the frontal eye fields, the areas near/along the intraparietal sulcus, and the dorsolateral prefrontal cortex), the cingulo-opercular network (including the anterior cingulate cortex/supplementary motor area, and the anterior insular cortex), and a subcortical structure (the striatum). These results demonstrate that the CCN is a domain-general construct underlying uncertainty processing to support goal-directed behaviors. This article is protected by copyright. All rights reserved.

2.
Adv Healthc Mater ; : e1900974, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31697035

RESUMO

Endoscopy is a clinical gold standard to exam the interior of a hollow organ or body cavity. For the first of time, this study presents the design and construction of a fluorescent endoscopic system that harnesses the power of the second near-infrared window II (NIR-II) fluorescence imaging. An NIR-II fluorescent molecular probe, indocyanine green (ICG) conjugated bevacizumab (Bev-ICG) that targets vascular endothelial growth factor (VEGF), is successfully synthesized and evaluated along with the NIR-II endoscopy imaging system. Simultaneous NIR-II fluorescence and white-light (WL) imaging of VEGF is validated in an orthotopic rat colorectal cancer model. This NIR-II endoscopy system is a generalizable design, and it is compatible with the most of current clinic endoscopies. Similar hardware upgrades are expected to greatly promote the application of NIR-II fluorescent imaging in the clinic.

3.
J Cell Biochem ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31709621

RESUMO

Preterm birth (PTB) is a major cause of neonatal mortality, with a poorly understood etiology. The regular contraction of the myometrium was considered as contributing to the etiology of the onset of labor, especially PTB. Thus, studying the mechanism of myometrium contraction is very important for understanding the initiation of labor and also for preventing PTB. Using liquid chromatography-mass spectrometry, we found 322 significantly differential peptides in myometrium tissues between term nonlabor and term labor groups (absolute fold change ≥ 2 and P < .05). We next analyzed length, molecular weights, isoelectric point, and cleavage site of all the different peptides. We, next, analyzed the functions of different peptides through their precursor proteins by Gene Ontology, enrichment and canonical pathway analysis. The results indicated that the extracellular matrix (ECM) played a major role in biological process, the cellular component, and molecular function categories, and revealed that ECM remodeling played a vital role in myometrial contraction. In addition, some known signaling, such as corticotropin-releasing hormone signaling and calcium signaling were proven to be involved in this process. Ingenuity Pathways Analysis upstream regulator analysis suggested that some of the known molecules, which reportedly were very important in labor onset, were included, for example, nuclear factor κB, tubulin, and phosphoinositide 3-kinase. We also identified 23 peptides derived from the precursor protein TITIN, of which 21 peptides sequences from TITIN were located in functional domains. These results suggested that peptides play an important role in labor onset and provide further insight into PTB therapy.

4.
Oncol Rep ; 42(6): 2309-2322, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31578594

RESUMO

Glioma is the most common and aggressive tumor type of the central nervous system and is associated with poor prognosis. To date, novel emerging immunotherapies have significantly improved outcomes for patients with various cancer types. Human endogenous retrovirus­H long terminal repeat­associating protein 2 (HHLA2), a newly discovered immune checkpoint molecule, has demonstrated its potential as a novel therapeutic target. Therefore, the present study aimed to investigate the clinical prognostic value of HHLA2 in gliomas and its mechanistic role. A systematic review of datasets from The Cancer Genome Atlas was performed. The RNA­seq data of a total of 669 cases were analyzed and the biological function of HHLA2 was predicted by Gene Ontology (GO) and pathway enrichment analysis. Immunohistochemistry labelling images for HHLA2 was obtained from the Human Protein Atlas. xCell was used to comprehensively analyze the model of tumor­infiltrating immune cell in glioma. The Cox proportional hazards regression model was used to predict outcomes for glioma patients. The results revealed that the expression levels of HHLA2 were significantly lower in high­grade glioma, as well as glioma with wild­type isocitrate dehydrogenase, no deletion of 1p/19q and telomerase reverse transcriptase promoter mutation. Receiver operating characteristic analysis revealed that HHLA2 was a predictor of the neural subtype. The tumor­infiltrating immune cell model indicated that HHLA2 was negatively associated with tumor­associated macrophages. GO analysis and pathway enrichment analysis revealed that HHLA2­associated genes were functionally involved in inhibition of neoplasia­associated processes. HHLA2 was significantly negatively correlated with certain genes, including interleukin­10, transforming growth factor­ß, vascular endothelial growth factor and δ­like canonical Notch ligand 4, and other immune checkpoint molecules, including programmed cell death 1, lymphocyte activating 3 and CD276. Survival analysis indicated that high expression of HHLA2 predicted a favorable prognosis. In conclusion, the present study revealed that upregulation of HHLA2 is significantly associated with a favorable outcome for patients with glioma. Targeting HHLA2 as an immune stimulator may become a valuable approach for the treatment of glioma in clinical practice.

5.
Org Lett ; 21(21): 8615-8619, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31613111

RESUMO

A method using aroyl chlorides as atom-transfer radical cyclization agents in a novel visible-light photocatalytic aroylchlorination reaction is developed. The overall transformation involves the formation of two new C-C bonds and one new C-Cl bond in a one-pot process. The advantages of this reaction include high atom/step/redox economy, mild conditions, operational simplicity, and broad substrate scopes.

6.
J Org Chem ; 84(22): 14760-14769, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31642323

RESUMO

An efficient method was successfully developed to obtain cyclic ß-amino ketones via visible-light photoredox catalysis. With this catalytic system, vinyl azides and N-Ph pyrrolidines react to form cyclic ß-amino ketones by α-amino radical addition. This method provides a simple, mild, straightforward, and novel paradigm to prepare important ß-amino ketones.

7.
J Med Chem ; 62(21): 9642-9657, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31603674

RESUMO

Glutaminase (GLS1) is a cancer energy metabolism protein which plays a predominant role in cell growth and proliferation. Because of its major involvement in malignant tumor, small-molecule GLS1 inhibitors are urgently needed to assess its therapeutic potential and for probing their underlying biology function. Recent studies showed that targeting the allosteric binding site represented a promising strategy for identifying potent and selective GLS1 inhibitors. Herein, we present the synthesis of two fluorescent probes targeting the allosteric binding site of GLS1 and their usage as mechanistic tools in multiple applicable assay platform. The fluorescence polarization (FP)-based binding assay enables easy, fast, and reliable screen of allosteric inhibitors from our in-house compound library obtained through click chemistry method. The obtained compound C147 (named as CPU-L1) has been proved to be more potent and with greater solubility than the control compound CB839, which could serve as promising leads for further optimization as novel GLS1 inhibitors.

8.
Cytotechnology ; 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31535308

RESUMO

ßKlotho as the major role is a necessary auxiliary protein when fibroblast growth factor 21 (FGF21) binds FGF21 receptors (FGFR) for activating intracellular signaling pathways that ultimately generate biological effects. To achieve the aim of high throughput screening of FGF21 analogues, we established 3T3-L1-ßKlotho cells that could stably express ßklotho protein. The glucose uptake, expression of GLUT1 mRNA and activation of FGF signaling molecules ERK1/2 phosphorylation were detected by GOD-POD assay, real-time PCR analysis and western blotting assay in 3T3-L1-ßKlotho cells and 3T3-L1 adipocytes, respectively. The results showed that FGF21 increased glucose uptake significantly in a dose-dependent and time-dependent manner in 3T3-L1-ßKlotho cells. 3T3-L1-ßKlotho cells stimulated with FGF21 up-regulated the transcriptional levels of GLUT1 mRNA obviously. FGF21 activated the FGF signaling molecules ERK1/2 in 3T3-L1-ßKlotho cells. In addition, the same results were obtained in 3T3-L1 adipocytes. Furthermore, FGF21-stimulated elevation of glucose uptake, GLUT1 mRNA transcription and the phosphorylation of ERK1/2 were dramatically attenuated by pretreatment of cells with FGFR specific inhibitor SU5402 in 3T3-L1-ßKlotho cells. This study demonstrated that the cell model could be applied to high throughput screen FGF21 analogues.

9.
Aging (Albany NY) ; 11(17): 6839-6850, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31479421

RESUMO

Data regarding the association between subclinical thyroid dysfunction and clinical outcomes in ischemic stroke patients with intravenous thrombolysis (IVT) are limited. We aimed to investigate the predictive value of subclinical thyroid dysfunction in END, functional outcome and mortality at 3 months among IVT patients. We prospectively recruited 563 IVT patients from 5 stroke centers in China. Thyroid function status was classified as subclinical hypothyroidism, subclinical hyperthyroidism (SHyper) and euthyroidism. The primary outcome was END, defined as ≥ 4 point in the NIHSS score within 24 h after IVT. Secondary outcomes included 3-month functional outcome and mortality. Of the 563 participants, END occurred in 14.7%, poor outcome in 50.8%, and mortality in 9.4%. SHyper was an independent predictor of END [odd ratio (OR), 4.35; 95% confidence interval [CI], 1.86-9.68, P = 0.003], 3-month poor outcome (OR, 3.24; 95% CI, 1.43-7.33, P = 0.005) and mortality [hazard ratio, 2.78; 95% CI, 1.55-5.36, P = 0.003]. Subgroup analysis showed that there was no significant relationship between SHyper and clinical outcomes in IVT patients with endovascular therapy. In summary, SHyper is associated with increased risk of END, and poor outcome and mortality at 3 months in IVT patients without endovascular therapy.

10.
J Org Chem ; 84(21): 13871-13880, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31553609

RESUMO

Herein, we describe a variety of chiral hybrid pyrroidine-indole polycyclic derivatives with quaternary and continuous chiral centers were synthesized in good yields with excellent stereoselectivities through an asymmetric, intermolecular, and formal [3 + 2] cyclization reaction catalyzed by a bifunctional catalyst. In addition, the selection of substituents of substrates is the key to success, and both the hydroxyl group and the trifluoromethyl group play essential roles in the reaction.

11.
Chemistry ; 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31536145

RESUMO

We report a general design strategy for a new class of luminogens with dual-state emission (DSEgens) that are brightly emissive in both the solution and solid state, with solvatochromism properties, by constructing a partially shared donor-acceptor pattern based on a twisted molecule. The DSEgens with bright fluorescence emission in both the solid and solution state demonstrate a unique solvatochromism behaviour depending on solvent polarity and thus may have applications in anti-counterfeiting.

12.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(8): 883-890, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31511206

RESUMO

OBJECTIVE: To investigate the effect of the chemoprotectant tempol on the anti-tumor activity of cisplatin (DDP). METHODS: The cellular toxicity of tempol in human colon cancer SW480 cells and mouse colon cancer CT26 cells were evaluated using MTT and cell counting kit-8 assays. CalcuSyn software analysis was used to determine the interaction between tempol and DDP in inhibition of the cell viability. A subcutaneous homograft mouse model of colon cancer was established. The mice were randomly divided into control group, tempol group, cisplatin group and tempol + DDP treatment group with intraperitoneal injections of the indicated agents. The tumor size, body weight and lifespan of the mice were measured, and HE staining was used to analyze the cytotoxic effect of the agents on the kidney and liver. Immunohistochemistry and Western blotting were performed to detect the expression of Bax and Bcl2 in the tumor tissue, and TUNEL staining was used to analyze the tumor cell apoptosis. The level of reactive oxygen species (ROS) in the tumor tissue was determined using flow cytometry. RESULTS: Tempol showed inhibitory effects on the viability of SW480 and CT26 cells. CalcuSyn software analysis showed that tempol had a synergistic anti-tumor effect with DDP (CI < 1). In the homograft mouse model, tempol treatment alone did not produce obvious anti-tumor effect. HE staining showed that the combined use of tempol and DDP alleviated DDP-induced fibrogenesis in the kidneys, but tempol also reduced the anti-tumor activity of DDP. Compared with the mice treated with DDP alone, the mice treated with both tempol and DDP had a significantly larger tumor size (P < 0.01) and a shorter lifespan (P < 0.05). Tempol significantly reversed DDP-induced expression of Bax and Bcl2 in the tumor tissue and tumor cell apoptosis (P < 0.001), and obviously reduced the elevation of ROS level in the tumor tissue induced by DDP treatment (P < 0.05). CONCLUSIONS: Tempol can attenuate the anti-tumor effect of DDP while reducing the side effects of DDP. Caution must be taken and the risks and benefits should be carefully weighed when considering the use of tempol as an anti-oxidant to reduce the toxicities of DDP.


Assuntos
Óxidos N-Cíclicos/farmacologia , Animais , Antineoplásicos , Antioxidantes , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Humanos , Camundongos , Marcadores de Spin
13.
Artigo em Inglês | MEDLINE | ID: mdl-31383996

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy has displayed potent anti-leukemia activity in acute lymphocytic leukemia (ALL), acting as a new ray of hope to refractory/relapsed patients. However, the influence of CAR-T therapy on host immune system has not been well elucidated. Thus, We applied high-throughput T cell receptor ß chain sequencing to track the dynamic change of T-cell repertoire induced by CAR-T therapy in B-cell ALL patients. Six Chinese patients achieving complete remission were under observation, whose blood samples, bone marrow samples and infused CAR-T samples were collected at serial time points before and after CAR-T therapy. We observed decreased TCR diversity and increased clonality of T-cell repertoire in both peripheral blood and bone marrow after CAR-T administration. The persistent T cell clones in blood and bone marrow expanded following leukemic cell destruction and were barely detected in CAR T-cell pool. For the first time, our results demonstrated CAR-T therapy could stimulate the clonal proliferation of CAR-negative T cells in patients. Considering other groups' animal results indicating that CAR-T therapy could facilitate the proliferation of tumor antigen-specific T cells and that the emergence of these T cell clones followed the destruction of leukemic cells, they are most likely tumor antigen-specific.

14.
Gene ; 715: 144005, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31376410

RESUMO

Members of the highly conserved pleiotropic CK1 family of serine/threonine-specific kinases are tightly regulated in the cell and play crucial regulatory roles in multiple cellular processes from protozoa to human. Since their dysregulation as well as mutations within their coding regions contribute to the development of various different pathologies, including cancer and neurodegenerative diseases, they have become interesting new drug targets within the last decade. However, to develop optimized CK1 isoform-specific therapeutics in personalized therapy concepts, a detailed knowledge of the regulation and functions of the different CK1 isoforms, their various splice variants and orthologs is mandatory. In this review we will focus on the stress-induced CK1 isoform delta (CK1δ), thereby addressing its regulation, physiological functions, the consequences of its deregulation for the development and progression of diseases, and its potential as therapeutic drug target.


Assuntos
Caseína Quinase Idelta/química , Caseína Quinase Idelta/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/enzimologia , Transdução de Sinais , Animais , Caseína Quinase Idelta/antagonistas & inibidores , Caseína Quinase Idelta/genética , Sistemas de Liberação de Medicamentos/métodos , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Relação Estrutura-Atividade
15.
Redox Biol ; 26: 101295, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31421410

RESUMO

Hypertension is one of the major predisposing factors for neurodegenerative disease characterized with activated renin-angiotensin system (RAS) in both periphery and brain. Vitamin D (VitD) is recently recognized as a pleiotropic hormone with strong neuroprotective properties. While multiple lines of evidence suggest that VitD can act on RAS, the evidence concerning the crosstalk between VitD and RAS in the brain is limited. Therefore, this study aims to evaluate whether VitD can modulate brain RAS to trigger neuroprotective actions in the brain of spontaneously hypertensive rats (SHR). Our data showed that calcitriol treatment induced VDR expression and inhibited neural death in the prefrontal cortex of SHR. Sustained calcitriol administration also inhibited microglia M1 polarization, but enhanced M2 polarization, accompanied with decreased expression of proinflammatory cytokines. We then further explored the potential mechanisms and showed that SHR exhibited overactivated classical RAS with increased expression of angiotensin II (Ang II) receptor type 1 (AT1), angiotensin converting enzyme (ACE) and Ang II production, whereas the counteracting arm of traditional RAS, ACE2/Ang(1-7)/MasR, was impaired in the SHR brain. Calcitriol nonsignificantly suppressed AT1 and ACE but markedly reduced Ang II formation. Intriguingly, calcitriol exerted pronouncedly impact on ACE2/Ang(1-7)/MasR axis with enhanced expression of ACE2, MasR and Ang(1-7) generation. Meanwhile, calcitriol ameliorated the overactivation of NADPH-oxidase (Nox), the downstream of RAS, in SHR, and also mitigated oxidative stress. In microglial (BV2) cells, we further found that calcitriol induced ACE2 and MasR with no significant impact on ACE and AT1. In accordance, calcitriol also attenuated Ang II-induced Nox activation and ROS production, and shifted the microglia polarization from M1 to M2 phenotype. However, co-treatment with A779, a specific MasR antagonist, abrogated the antioxidant and neuroimmune modulating actions of VitD. These findings strongly indicate the involvement of ACE2/Ang(1-7)/MasR pathway in the neuroprotective mechanisms of VitD in the hypertensive brain.

16.
J Org Chem ; 84(16): 10292-10305, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31321983

RESUMO

A sequential and general strategy has been successfully developed for the synthesis of spiropyrazolone scaffolds. This intriguing transformation of the asymmetric multicomponent catalysis process was realized with the combination of Michael addition/chlorination/nucleophilic substitution in a one-pot sequence, giving rise to a series of spiropyrazolones with fully substituted cyclopropanes and spiro-dihydrobenzofurans containing continuous stereogenic centers in good yields with excellent stereoselectivities.

17.
J Alzheimers Dis ; 71(1): 185-200, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31356201

RESUMO

Cognitive control for the coordination of mental operations is essential in normal cognitive functioning of daily life. Although the decline of cognitive control in older adults with mild cognitive impairment (MCI) has been demonstrated, whether this decline is a core deficit in MCI remains unclear. In this study, we employed a perceptual decision-making task to estimate the capacity of cognitive control (CCC) in older adults with MCI (n = 55) and the age-, sex-, and education-matched healthy controls (HC, n = 55) selected based on a commonly used battery of ten neuropsychological tests in five cognitive domains. We found that the CCC was significantly correlated to the neuropsychological measures of the battery. The mean CCC was significantly lower in the MCI group (3.06 bps) than in the HC group (3.59 bps) and significantly lower in the amnestic MCI subgroup (2.90 bps) than in the nonamnestic MCI subgroup (3.22 bps). In detecting and classifying MCI using machine learning, the classifier with the CCC as the input feature outperformed the overall classification with neuropsychological measures in a single cognitive domain. The classification performance was significantly increased when the CCC was included as a feature in addition to measures in a single domain, and the CCC served as a key feature in optimal classifiers with inputs from multiple domains. These results support the hypothesis that the decline in cognitive control is a core deficit in MCI and suggest that the CCC may serve as a key index in the diagnosis of MCI.

18.
Spectrochim Acta A Mol Biomol Spectrosc ; 223: 117335, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31288169

RESUMO

Luminogens with aggregation-induced emission (AIE) have been used to develop a new type of molecular probes based on analyte-triggered aggregation, but it still remains a challenge to design water-soluble AIE-active probe for specific detection of metal ions. Herein, we designed and synthesized a water-soluble molecular probe with AIE property for discriminative detection of aluminum ion and lead ion. Four carboxylic acid groups were incorporated into a tetraphenylethylene unit to enhance the coordination affinity and increase water-solubility in aqueous solution. The designed probe can be selectively lighted up by aluminum ion and lead ion via coordination-triggered AIE process. Discrimination of aluminum ion and lead ions based on the probe can be achieved in quantitative manner with the assistance of suitable masking reagents. This probe was further used to image aluminum ions in living cells of seedling roots of Arabidopsis, and the results showed that this probe is capable of imaging aluminum ions in living cells avoiding the interference of lead ions, and is suited for long-term imaging due to its excellent photostability. This work expands the application scope of AIE-active probes in discriminative detection of metal ions, and provides a design direction for water-soluble AIE probes to avoid the false signals from self-precipitation under physiological conditions.

19.
Molecules ; 24(14)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336903

RESUMO

It has been more than 36 years since peroxisome proliferator-activated receptors (PPARs) were first recognized as enhancers of peroxisome proliferation. Consequently, many studies in different fields have illustrated that PPARs are nuclear receptors that participate in nutrient and energy metabolism and regulate cellular and whole-body energy homeostasis during lipid and carbohydrate metabolism, cell growth, cancer development, and so on. With increasing challenges to human health, PPARs have attracted much attention for their ability to ameliorate metabolic syndromes. In our previous studies, we found that the complex functions of PPARs may be used as future targets in obesity and atherosclerosis treatments. Here, we review three types of PPARs that play overlapping but distinct roles in nutrient and energy metabolism during different metabolic states and in different organs. Furthermore, research has emerged showing that PPARs also play many other roles in inflammation, central nervous system-related diseases, and cancer. Increasingly, drug development has been based on the use of several selective PPARs as modulators to diminish the adverse effects of the PPAR agonists previously used in clinical practice. In conclusion, the complex roles of PPARs in metabolic networks keep these factors in the forefront of research because it is hoped that they will have potential therapeutic effects in future applications.

20.
Cell Death Dis ; 10(8): 555, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324751

RESUMO

Neuroinflammation is initiated in response to ischemic stroke, generally with the hallmarks of microglial activation and collateral brain injury contributed by robust inflammatory effects. Triggering receptor expressed on myeloid cells (TREM)-1, an amplifier of the innate immune response, is a critical regulator of inflammation. This study identified that microglial TREM-1 expression was upregulated following cerebral ischemic injury. After pharmacologic inhibition of TREM-1 with synthetic peptide LP17, ischemia-induced infarction and neuronal injury were substantially alleviated. Moreover, blockade of TREM-1 can potentiate cellular proliferation and synaptic plasticity in hippocampus, resulting in long-term functional improvement. Microglial M1 polarization and neutrophil recruitment were remarkably abrogated as mRNA levels of M1 markers, chemokines, and protein levels of myeloperoxidase and intracellular adhesion molecule-1 (ICAM-1) were decreased by LP17. Mechanistically, both in vivo and in vitro, we delineated that TREM-1 can activate downstream pro-inflammatory pathways, CARD9/NF-κB, and NLRP3/caspase-1, through interacting with spleen tyrosine kinase (SYK). In addition, TREM-1-induced SYK initiation was responsible for microglial pyroptosis by elevating levels of gasdermin D (GSDMD), N-terminal fragment of GSDMD (GSDMD-N), and forming GSDMD pores, which can facilitate the release of intracellular inflammatory factors, in microglia. In summary, microglial TREM-1 receptor yielded post-stroke neuroinflammatory damage via associating with SYK.

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