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1.
Microb Pathog ; 175: 105957, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36572196

RESUMO

African swine fever (ASF) is an infectious disease caused by the African swine fever virus (ASFV), and has a high mortality rate. It has caused serious socioeconomic consequences worldwide. Currently, there are no available commercial vaccines or antiviral drug interventions. D1133L is one of the key genes for ASFV replication and antiviral drug screening. In this study, a virtual screening software program, PyRx, was used to screen libraries of compounds against the potential drug target D1133L. Twelve compounds with a high affinity for ASFV D1133L were screened, and cyproheptadine hydrochloride (periactin) was identified as a candidate drug. The periactin has little cytotoxicity, and which dose-dependently inhibited ASFV replication in vitro. Further research indicated that periactin could significantly down-regulate D1133L at the transcriptional and protein levels with RT-qPCR and western blot methods. This study has provided important candidate drugs for the prevention and treatment of ASF, as well as biological materials and new fields of view for the research and development of vaccines and drugs for ASFV.


Assuntos
Vírus da Febre Suína Africana , Febre Suína Africana , Vacinas , Suínos , Animais , Vírus da Febre Suína Africana/genética , Febre Suína Africana/tratamento farmacológico , Febre Suína Africana/prevenção & controle , Replicação Viral , Antivirais/farmacologia , Antivirais/metabolismo , Ciproeptadina/metabolismo , Ciproeptadina/farmacologia
2.
Int Wound J ; 21(3): e14502, 2023 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-37973551

RESUMO

Diabetic foot ulcers (DFUs) pose significant clinical challenges, representing severe complications in diabetes mellitus patients and contributing to non-traumatic amputations. Identifying reliable biomarkers can optimize early diagnosis and improve therapeutic outcomes. This study focused on evaluating the association between serum levels of 25-hydroxyvitamin D [25-(OH)D], Serum Retinol Binding Protein (RBP), and Cyclooxygenase-2 (COX-2) in elderly DFU patients. A retrospective study involving 240 participants, from March 2020 to March 2023. The participants were segmented into three cohorts: 80 with DFUs, 80 diabetic patients without DFUs, and 80 healthy controls. Serum concentrations of the three biomarkers were assayed using methods like enzyme-linked immunosorbent assay (ELISA), chemiluminescence immunoassay, and an automated biochemistry analyser. Comparisons were made both between groups and within the DFU group based on disease severity. Statistical analysis revealed significant differences in biomarker levels across the groups (p < 0.05). COX-2 and RBP concentrations were highest in the DFU group, followed by the non-DFU diabetic group, and lowest in the control group. Conversely, 25(OH)D levels were highest in the control group, followed by the non-DFU diabetic group, and lowest in the DFU group. Within the DFU group, RBP and COX-2 levels increased with disease severity, while 25(OH)D levels decreased. These variations were especially pronounced in patients with the most severe Wagner grading. A significant positive correlation was observed between disease severity and levels of RBP (r = 0.651, p < 0.05) and COX-2 (r = 0.356, p < 0.05). Conversely, a significant negative correlation was identified between disease severity and 25(OH)D levels (r = -0.658, p < 0.05). Assessing 25(OH)D, RBP, and COX-2 serum levels offers a promising tool for evaluating the severity and progression of DFUs. Monitoring these biomarkers can enrich our understanding of the metabolic and inflammatory pathways of the disease and potentially refine therapeutic strategies.

3.
Vet Res ; 53(1): 24, 2022 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-35313983

RESUMO

Circular RNAs (circRNAs) are a new type of endogenous noncoding RNA that exhibit a variety of biological functions. However, it is not clear whether they are involved in foot-and-mouth disease virus (FMDV) infection and host response. In this study, we established circRNA expression profiles in FMDV-infected PK-15 cells using RNA-seq (RNA-sequencing) technology analysis. The biological function of the differentially expressed circRNAs was determined by protein interaction network, Gene Ontology (GO), and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment. We found 1100 differentially expressed circRNAs (675 downregulated and 425 upregulated) which were involved in various biological processes such as protein ubiquitination modification, cell cycle regulation, RNA transport, and autophagy. We also found that circRNAs identified after FMDV infection may be involved in the host cell immune response. RNA-Seq results were validated by circRNAs qRT-PCR. In this study, we analyzed for the first time circRNAs expression profile and the biological function of these genes after FMDV infection of host cells. The results provide new insights into the interactions between FMDV and host cells.


Assuntos
Vírus da Febre Aftosa , MicroRNAs , Animais , Vírus da Febre Aftosa/genética , Perfilação da Expressão Gênica/veterinária , Ontologia Genética , MicroRNAs/genética , RNA Circular/genética
4.
Small ; 17(25): e2101655, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34028968

RESUMO

The detection of autoantibodies is critical for diagnosis of autoimmune diseases. However, the sensitivity is often limited by the properties of the antigens and the detection systems such as enzyme-linked immunosorbent assay (ELISA). Here, employing the multidisplay ability of ferritin, a highly sensitive nanocage-based capture-detection system is designed, of which the sensitivity is 100-1000-fold higher than that of conventional ELISA methods. The capture nanocages are constructed by displaying the primary Sjögren's syndrome (pSS)-related antigenic peptides on ferritin nanocage, which present epitopes effectively and high affinity, leading to tenfold higher capture capability for autoantibodies. Human IgG Fc-binding peptides are also engineered on ferritin nanocage, which enable high binding affinity and efficient horseradish peroxidase (HRP)-labeling. Compared with commercial HRP-conjugated anti-human IgG antibody, the nanocage-based detecting probe exhibited more than tenfold increased sensitivity. Autoantibodies are then examined in 91 sera from patients with pSS, 51 from rheumatoid arthritis, 54 from systemic lupus erythematosus, and 55 from healthy individuals by using the nanocage-based ELISA. The results indicate that the nanocage-based capture-detection system is an effective detection platform and provide a novel and more sensitive method for the diagnosis of autoimmune diseases.


Assuntos
Artrite Reumatoide , Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Síndrome de Sjogren , Autoanticorpos , Doenças Autoimunes/diagnóstico , Ensaio de Imunoadsorção Enzimática , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico
5.
Virol J ; 18(1): 170, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34412678

RESUMO

BACKGROUND: African swine fever virus (ASFV) is a highly lethal virus that can infect porcine alveolar macrophages (PAMs). Since ASFV, China has dealt with a heavy blow to the pig industry. However, the effect of infection of ASFV strains isolated from China on PAM transcription level is not yet clarified. METHODS: In this study, RNA sequencing (RNA-seq) was used to detect the differential expression of genes in PAMs at different time points after ASFV-CN/GS/2018 infection. The fluorescent quantitative polymerase chain reaction (qPCR) method was used to confirm the altered expression of related genes in PAMs infected with ASFV. RESULTS: A total of 1154 differentially expressed genes were identified after ASFV-CN/GS/2018 infection, of which 816 were upregulated, and 338 were downregulated. GO and KEGG analysis showed that these genes were dynamically enriched in various biological processes, including innate immune response, inflammatory response, chemokines, and apoptosis. Furthermore, qPCR verified that the DEAD box polypeptide 58 (DDX58), Interferon-induced helicase C domain-containing protein 1 (IFIH1), Toll-like receptor 3 (TLR3), and TLR7 of PAMs were upregulated after ASFV infection, while TLR4 and TLR6 had a significant downward trend during ASFV infection. The expression of some factors related to antiviral and inflammation was altered significantly after ASFV infection, among which interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), IFIT2, Interleukin-6 (IL-6) were upregulated, and Ewing's tumor-associated antigen 1 homolog (ETAA1) and Prosaposin receptor GPR37 (GPR37) were downregulated. In addition, we discovered that ASFV infection is involved in the regulation of chemokine expression in PAMs, and the chemokines, such as C-X-C motif chemokine 8 (CXCL8) and CXCL10, were upregulated after infection. However, the expression of chemokine receptor C-X-C chemokine receptor type 2 (CXCR2) is downregulated. Also, that the transcriptional levels of pro-apoptotic and anti-apoptotic factors changed after infection. CONCLUSIONS: After ASFV-CN/GS/2018 infection, the expression of some antiviral and inflammatory factors in PAMs changed significantly. The ASFV infection may activates the RLR and TLR signaling pathways. In addition, ASFV infection is involved in regulating of chemokine expression in PAMs and host cell apoptosis.


Assuntos
Febre Suína Africana , Expressão Gênica , Interações Hospedeiro-Patógeno , Macrófagos/virologia , Vírus da Febre Suína Africana , Animais , Quimiocinas/imunologia , Imunidade Inata , Macrófagos/imunologia , Receptores de Quimiocinas/imunologia , Suínos , Receptores Toll-Like
6.
Langmuir ; 35(9): 3524-3533, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30580526

RESUMO

Cell adhesion is ubiquitous and plays an important role in various scientific and engineering problems. Herein, a quantitative criterion to predict cell adhesion was proposed by identifying the dominant interaction between microorganisms and abiotic surfaces. According to the criterion, the dominant interaction in cell adhesion could be identified as a Lewis acid-base (AB) interaction or electrostatic (EL) interaction via comparison of two expressions containing the electron-donor characteristics of the microorganism (γmv-) and abiotic surface (γsv-) and their ζ potentials (ζm, ζs). The results revealed that when dominated by the AB interaction, adhesion would decrease with increasing [Formula: see text]. However, when the EL interaction was dominant, adhesion would decrease with increasing (ζm + ζs)2. We have verified the criterion based on the adhesion of microalgae, bacteria, and fungi onto various surfaces obtained via our experiments and available in literature studies. The results demonstrated that the criterion had important implications in the prediction of cell adhesion in various applications.


Assuntos
Aderência Bacteriana/fisiologia , Adesão Celular/fisiologia , Modelos Biológicos , Chlorella/fisiologia , Enterococcus faecalis/fisiologia , Ácidos de Lewis/química , Bases de Lewis/química , Scenedesmus/fisiologia , Staphylococcus epidermidis/fisiologia , Eletricidade Estática , Estramenópilas/fisiologia , Propriedades de Superfície
7.
AJR Am J Roentgenol ; 211(2): 369-378, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29894216

RESUMO

OBJECTIVE: The purpose of this study was to perform a systematic review and meta-analysis to estimate the diagnostic performance of biparametric MRI (bpMRI) for detection of prostate cancer (PCa). MATERIALS AND METHODS: Two independent reviewers performed a systematic review of the literature published from January 2000 to July 2017 by using predefined search terms. The standard of pathologic reference was established at prostatectomy or prostate biopsy. The numbers of true- and false-positive and true- and false-negative results were extracted. The Quality Assessment of Diagnostic Accuracy Studies tool was used to assess the quality of the selected studies. Statistical analysis included pooling of diagnostic accuracy, meta-regression, subgroup analysis, head-to-head comparison, and identification of publication bias. RESULTS: Thirty-three studies were used for general data pooling. The overall sensitivity was 0.81 (95% CI, 0.76-0.85), and overall specificity was 0.77 (95% CI, 0.69-0.84). As for clinically relevant PCa, bpMRI maintained high diagnostic value (AUC, 0.85; 95% CI, 0.82-0.88). There was no evidence of publication bias (p = 0.67). From head-to-head comparison for detection of PCa, multiparametric MRI (mpMRI) had significantly higher pooled sensitivity (0.85; 95% CI, 0.78-0.93) than did bpMRI (0.80; 95% CI, 0.71-0.90) (p = 0.01). However, the pooled specificity values were not significantly different (mpMRI, 0.77 [95% CI, 0.58-0.95]; bpMRI, 0.80 [95% CI, 0.64-0.96]; p = 0.82). CONCLUSION: The results of this meta-analysis suggest that bpMRI has high diagnostic accuracy in the detection of PCa and maintains a high detection rate for clinically relevant PCa. However, owing to high heterogeneity among the included studies, caution is needed in applying the results of the meta-analysis.


Assuntos
Imageamento por Ressonância Magnética/métodos , Neoplasias da Próstata/diagnóstico por imagem , Humanos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Neoplasias da Próstata/patologia , Sensibilidade e Especificidade
9.
SAGE Open Med ; 12: 20503121241248044, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38711464

RESUMO

Background: Studies have linked gut microbiota dysbiosis with sleep apnea; however, no causal relationship was found in human subjects. Finding new targets for the pathophysiology of sleep apnea might be made possible by systematically investigating the causal relationship between the human gut microbiota and sleep apnea. Methods: A two-sample Mendelian randomization analysis was conducted. The human gut microbiome composition data, spanning five taxonomic levels, were acquired from a genome-wide association study that included 18,340 participants from 24 cohorts. Genome-wide association study data for sleep apnea were obtained from the Sleep Disorder Knowledge Portal for primary analysis and the FinnGen consortium for meta-analysis. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. Results: Using inverse-variance weighted analysis, eight microbial taxa were initially found to be substantially linked with the apnea-hypopnea index. Only three microbial taxa remained significant associations with sleep apnea when combined with the FinnGen consortium (the class Bacilli: B = 8.21%, 95% CI = 0.93%-15.49%; p = 0.03; the order Lactobacillales: B = 7.55%, 95% CI = 0.25%-4.85%; p = 0.04; the genus RuminococcaceaeUCG009: B = -21.63%, 95% CI = -41.47% to -1.80%; p = 0.03). Conclusions: Sleep apnea may lead to gut dysbiosis as significant reductions in butyrate-producing bacteria and increases in lactate-producing bacteria. By integrating genomes and metabolism, the evidence that three microbiome species are causally linked to sleep apnea may offer a fresh perspective on the underlying mechanisms of the condition.

10.
Food Chem ; 441: 138293, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38183718

RESUMO

Developing a straightforward method to remove pesticide residues from fruits is essential for food safety. In this study, ozone microbubble treatment was performed on three fruits (strawberry, cherry, and apricot) to remove four pesticide residues (emamectin benzoate, azoxystrobin, boscalid, and difenoconazole) while comparing removal efficiency. The concentration of hydroxyl radicals in different washing orientations was homogeneous at a concentration ranging between 8.9 and 10.2 µmol·L-1. Under long washing time (18 min), strawberry, cherry, and apricot obtained higher removal rates of 51 %∼65 %, 51 %∼59 % and 24 %∼70 %, respectively. Moreover, scanning electron microscopy (SEM) and contact angle (CA) revealed that apricot has better hydrophobicity, leading to a higher pesticide removal of 45 âˆ¼ 84 % with less water and more vigorous washing. Notably, vitamin C content in fruits remain largely unchanged following ozone microbubble treatment. This study demonstrated the effectiveness of ozone microbubble treatment as pollution-free method for enhancing food safety by removing pesticide residues on fruits.


Assuntos
Ozônio , Resíduos de Praguicidas , Praguicidas , Resíduos de Praguicidas/análise , Frutas/química , Ozônio/química , Microbolhas , Praguicidas/análise , Contaminação de Alimentos/análise
11.
ACS Nano ; 18(17): 11217-11233, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38627234

RESUMO

Due to its intrinsic tumor-targeting attribute, limited immunogenicity, and cage architecture, ferritin emerges as a highly promising nanocarrier for targeted drug delivery. In the effort to develop ferritin cage-encapsulated cisplatin (CDDP) as a therapeutic agent, we found unexpectedly that the encapsulation led to inactivation of the drug. Guided by the structural information, we deciphered the interactions between ferritin cages and CDDP, and we proposed a potential mechanism responsible for attenuating the antitumor efficacy of CDDP encapsulated within the cage. Six platinum prodrugs were then designed to avoid the inactivation. The antitumor activities of these ferritin-platinum prodrug complexes were then evaluated in cells of esophageal squamous cell carcinoma (ESCC). Compared with free CDDP, the complexes were more effective in delivering and retaining platinum in the cells, leading to increased DNA damage and enhanced cytotoxic action. They also exhibited improved pharmacokinetics and stronger antitumor activities in mice bearing ESCC cell-derived xenografts as well as patient-derived xenografts. The successful encapsulation also illustrates the critical significance of comprehending the interactions between small molecular drugs and ferritin cages for the development of precision-engineered nanocarriers.


Assuntos
Antineoplásicos , Cisplatino , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Ferritinas , Pró-Fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Humanos , Ferritinas/química , Ferritinas/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/química , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/metabolismo , Camundongos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Cisplatino/farmacologia , Cisplatino/química , Desenho de Fármacos , Platina/química , Platina/farmacologia , Camundongos Nus , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sistemas de Liberação de Medicamentos
12.
Food Chem ; 404(Pt B): 134695, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36323035

RESUMO

The theoretical screening and design of green solvents to reduce organic solvents and to develop green and efficient sample pretreatment methods have attracted extensive attention. Here, benzimidazoles (BZDs) with potential reproductive toxicity were used as target compounds, and amino acid ionic liquids (AAILs) were designed and selected via a theoretical calculation. With the functionalized AAIL as monomers, and POSS as the crosslinking agent, novel specific magnetic nanoparticles (Fe3O4@SiO2@MAPs@AAIL-POSS) were prepared and used to develop the magnetic dispersive solid-phase extraction (MDSPE) of trace BZDs from fruit juice and human serum. In the evaluation of the method, Fe3O4@SiO2@MAPs@AAIL-POSS showed specific adsorption, recyclable ability, high adsorption efficiency, a good recovery rate, and a low coefficient of variation. In addition, the adsorption behavior of Fe3O4@SiO2@MAPs@AAIL-POSS on BZDs was verified by investigating the kinetic and thermodynamic of the adsorption process. The study design provides ideas for green rapid detection methods of other food pollutants.


Assuntos
Líquidos Iônicos , Humanos , Líquidos Iônicos/química , Sucos de Frutas e Vegetais , Dióxido de Silício/química , Aminoácidos , Extração em Fase Sólida/métodos , Adsorção , Solventes , Fenômenos Magnéticos , Benzimidazóis , Limite de Detecção , Cromatografia Líquida de Alta Pressão/métodos
13.
Front Immunol ; 14: 1241791, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37731484

RESUMO

Glioma is the most common primary intracranial tumor in adults with poor prognosis. Current clinical treatment for glioma includes surgical resection along with chemoradiotherapy. However, the therapeutic efficacy is still unsatisfactory. The invasive nature of the glioma makes it impossible to completely resect it. The presence of blood-brain barrier (BBB) blocks chemotherapeutic drugs access to brain parenchyma for glioma treatment. Besides, tumor heterogeneity and hypoxic tumor microenvironment remarkably limit the efficacy of radiotherapy. With rapid advances of nanotechnology, the emergence of a new treatment approach, namely, reactive oxygen species (ROS)-based nanotherapy, provides an effective approach for eliminating glioma via generating large amounts of ROS in glioma cells. In addition, the emerging nanotechnology also provides BBB-crossing strategies, which allows effective ROS-based nanotherapy of glioma. In this review, we summarized ROS-based nanomedicine and their application in glioma treatment, including photodynamic therapy (PDT), photothermal therapy (PTT), chemodynamic therapy (CDT), sonodynamic therapy (SDT), radiation therapy, etc. Moreover, the current challenges and future prospects of ROS-based nanomedicine are also elucidated with the intention to accelerate its clinical translation.


Assuntos
Glioma , Nanomedicina , Adulto , Humanos , Barreira Hematoencefálica , Espécies Reativas de Oxigênio , Glioma/terapia , Estresse Oxidativo , Microambiente Tumoral
14.
Accid Anal Prev ; 186: 107051, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37019035

RESUMO

Facing the currently large quantity of intelligent transportation data, missing ones is often inevitable. Some previous works have shown the advantages of tensor decomposition-based approaches in solving multi-dimensional data imputation problems. However, a research gap still exists in examining the effect of applying these methods on imputation performance and their application to accident detection. Thus, referring to a two-month spatiotemporal traffic speed dataset, collected on the national trunk highway in Shandong, China, this paper employs the Bayesian Gaussian CANDECOMP/PARAFAC (BGCP) to impute missing speed data in different missing rates and missing scenarios. Moreover, the dataset is built while considering both the temporal and the road functions. Applying the generated results of data imputation in accident detection is also of the main targets of this work. Thus, while combining multiple sources of data, such as traffic operation status and weather, eXtreme Gradient Boosting (XGBoost) is deployed to build accident detection models. The generated results show that the BGCP model can produce accurate imputations even under temporally correlated data corruption. Added to that, it is also suggested that, when there are continuous periods of missing speed data (missing rate greater than 10%), pre-processing of data imputation is imperative to maintain the accuracy of accident detection. Thus, the objective of this work is to provide insights into traffic management and academics when performing spatiotemporal data imputation tasks.


Assuntos
Acidentes de Trânsito , Meios de Transporte , Humanos , Acidentes de Trânsito/prevenção & controle , Teorema de Bayes , Tempo (Meteorologia) , China
15.
Artigo em Inglês | MEDLINE | ID: mdl-38009048

RESUMO

Renal artery stenosis (RAS) hypertension is a common type of secondary hypertension. This paper aimed to explore how unilateral renal artery stenosis (Uni-RAS) and bilateral renal artery stenosis (Bi-RAS) caused renovascular hypertension with the fluid-structure interaction (FSI) method. Based on a real RAS model, 20 ideal models with different stenosis degrees were established by modifying the stenosis segment. The hemodynamic parameters at different degrees of stenosis, mass flow rate (MFR), pressure drop (PD), fractional flow reserve (FFR), oscillatory shear index (OSI), and relative residence time (RRT), were numerically calculated by the computational fluid dynamics (CFD) method. The numerical results showed that RAS caused the decrease of MFR, and the increase of PD and the proportion of high OSI and high RRT. In the case of RAS, it could not be regarded as a reference indicator for causing renovascular hypertension that the value of FFR was greater than 0.9. In addition, the results of the statistical analysis indicated that Uni-RAS and Bi-RAS were statistically different for MFR, PD and the proportion of high RRT.

16.
Cancer Commun (Lond) ; 43(11): 1244-1266, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37856423

RESUMO

BACKGROUND: As a rapid-progressing tumor, breast malignant phyllodes tumors (PTs) are challenged by the lack of effective therapeutic strategies and suitable prognostic markers. This study aimed to clarify the role and mechanism of CD146 on promoting PTs malignant progression, and to identify a novel prognosis marker and treatment target of breast malignant PTs. METHODS: The expression and prognostic significance of CD146 in PTs was detected through single-cell RNA-sequencing (scRNA-seq), immunostaining, real-time PCR and other methodologies. Functional experiments including proliferation assay, colony formation assay, transwell assay, and collagen contraction assay were conducted to validate the role of CD146 in malignant progression of PTs. The efficacy of anti-CD146 monoclonal antibody AA98 against malignant PTs was corroborated by a malignant PT organoid model and a PT patient-derived xenograft (PDX) model. Transcriptome sequencing, proteomic analysis, co-immunoprecipitation, and pull-down assay was employed to identify the modulating pathway and additional molecular mechanism. RESULTS: In this study, the scRNA-seq analysis of PTs disclosed a CD146-positive characteristic in the α-SMA+ fibroblast subset. Furthermore, a progressive elevation in the level of CD146 was observed with the malignant progression of PTs. More importantly, CD146 was found to serve as an independent predictor for recurrence in PT patients. Furthermore, CD146 was found to augment the viability and invasion of PTs. Mechanistically, CD146 acted as a protective "shield" to prevent the degradation of Discoidin, CUB, and LCCL domain-containing protein 2 (DCBLD2), thereby activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and enhancing malignant behaviors of PT cells. In the malignant PT organoid and PDX model, a significant suppression of malignant PT growth was observed after the application of AA98. CONCLUSIONS: These findings suggested that CD146 served as an efficacious marker for predicting PT malignant progression and showed promise as a prognosis marker and treatment target of breast malignant PTs. The study further unveiled the essential role of the CD146-DCBLD2/PI3K/AKT axis in the malignant progression of PTs.


Assuntos
Neoplasias da Mama , Tumor Filoide , Animais , Feminino , Humanos , Neoplasias da Mama/patologia , Antígeno CD146/genética , Modelos Animais de Doenças , Proteínas de Membrana , Fosfatidilinositol 3-Quinases , Tumor Filoide/genética , Tumor Filoide/metabolismo , Tumor Filoide/patologia , Proteômica , Proteínas Proto-Oncogênicas c-akt
17.
Cell Mol Immunol ; 20(8): 908-923, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37308559

RESUMO

As one of the main tumor-infiltrating immune cell types, tumor-associated macrophages (TAMs) determine the efficacy of immunotherapy. However, limited knowledge about their phenotypically and functionally heterogeneous nature restricts their application in tumor immunotherapy. In this study, we identified a subpopulation of CD146+ TAMs that exerted antitumor activity in both human samples and animal models. CD146 expression in TAMs was negatively controlled by STAT3 signaling. Reducing this population of TAMs promoted tumor development by facilitating myeloid-derived suppressor cell recruitment via activation of JNK signaling. Interestingly, CD146 was involved in the NLRP3 inflammasome-mediated activation of macrophages in the tumor microenvironment, partially by inhibiting transmembrane protein 176B (TMEM176B), an immunoregulatory cation channel. Treatment with a TMEM176B inhibitor enhanced the antitumor activity of CD146+ TAMs. These data reveal a crucial antitumor role of CD146+ TAMs and highlight the promising immunotherapeutic approach of inhibiting CD146 and TMEM176B.


Assuntos
Inflamassomos , Neoplasias , Animais , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Antígeno CD146/metabolismo , Macrófagos , Microambiente Tumoral
18.
FASEB J ; 25(5): 1577-84, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21282208

RESUMO

Isoprenoid precursors, which are a large group of natural products and play key roles in many biological pathways, can only be biosynthesized by the 2-C-methyl-d-erythritol 4-phosphate pathway in Mycobacterium tuberculosis. The 4-diphosphocytidyl-2-C-methyl-d-erythritol kinase (IspE), which is an essential enzyme in the isoprenoid precursor biosynthesis pathway, catalyzes ATP-dependent phosphorylation of 4-diphosphocytidyl-2-C-methyl-d-erythritol (CDP-ME) to 4-diphosphocytidyl-2C-methyl-d-erythritol-2-phosphate and plays a crucial role in M. tuberculosis survival. Therefore, IspE is characterized as an attractive and potential target for antimicrobial drug discovery. However, no experimental structure of M. tuberculosis IspE has been reported, which has hindered our understanding of its structural details and mechanism of action. Here, we report the expression and purification of fully active full-length M. tuberculosis IspE and solve the high-resolution crystal structures of IspE alone and in complex with either the substrate CDP-ME or nonhydrolyzable ATP analog or ADP. The structures present a characteristic galactose/homoserine/mevalonate/phosphomevalonate kinase superfamily α/ß-fold with a catalytic center located in a cleft between 2 domains and display clear substrate and ATP binding pockets. Our results also indicate distinct differences in ligand binding of M. tuberculosis IspE with other reported IspEs. Combined with the results of mutagenesis and enzymatic studies, our results provide useful information on the structural basis of IspE for future anti-M. tuberculosis drug discovery targeting this kinase.


Assuntos
Proteínas de Bactérias/química , Cristalografia por Raios X/métodos , Mycobacterium tuberculosis/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/química , Sequência de Aminoácidos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Dados de Sequência Molecular , Mycobacterium tuberculosis/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Homologia de Sequência de Aminoácidos
19.
Endocr J ; 59(7): 579-87, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22572547

RESUMO

The aim of the current study is to investigate the effects of growth hormone releasing hormone (GHRH) antagonist on acetaminophen (APAP)-induced acute liver injury in mice. Healthy C57/B6L mice were orally treated with 200 mg/kg APAP with or without a 30-min pre-treatment with 300 µg/kg GHRH antagonist MZ-5-156. After 12 hours, serum, plasma, and liver samples from each mouse were collected for analyses. Our results showed that twelve-hour treatment with APAP caused obvious liver injury, elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, increased oxidative stress, reduced expressions of antioxidant enzymes, accumulated expression of pro-inflammatory cytokines, and increased circulating levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I). Pre-treatment with MZ-5-156 aggravated liver injury, further increased serum ALT and AST levels, exacerbated oxidative stress and inflammation induced by APAP. Treatment of MZ-5-156 also blocked the phosphorylation form and total form of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5). Treatment of GHRH super-agonist JI-38 immediately after MZ-5-156 treatment partly reversed the liver injury caused by APAP and MZ-5-156. In conclusion, GHRH plays essential protective role in APAP-induced acute liver injury in vivo. The protective properties of GHRH are partially through GH/IGF-I axis and JAK/STAT pathway.


Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Hormônio Liberador de Hormônio do Crescimento/antagonistas & inibidores , Hormônio do Crescimento/fisiologia , Antagonistas de Hormônios/farmacologia , Fator de Crescimento Insulin-Like I/fisiologia , Doença Aguda , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Hormônio do Crescimento/metabolismo , Hormônio do Crescimento/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sermorelina/análogos & derivados , Sermorelina/farmacologia , Transdução de Sinais/efeitos dos fármacos
20.
Micromachines (Basel) ; 13(9)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36144049

RESUMO

In order to study the microstructure and properties of stainless steel after laser surface remelting, based on the theory of laser surface remelting, a simulation model of nanosecond-pulsed laser surface remelted stainless steel was established to study the evolution law of the Marangoni force of the molten pool during laser surface remelting. A single-lane laser remelting experiment was performed to study the variation of the scanning speed on the remelting width, roughness, and layer microtopography. The "S" scanning path was used to remelt the stainless steel surface to investigate the bonding force between the remelted layer and the substrate, the hardness, microscopic morphology, and corrosion resistance. The results show that the viscosity of the liquid metal in the molten pool increases with the increase of the scanning speed. Larger liquid viscosity and smaller surface tension temperature gradients promote a weaker flow of liquid metal, which reduces the velocity of the liquid metal flow in the molten pool. With the increase of scanning speed, the remelting width gradually decreases, but the roughness gradually increases. When the element content of Cr increases, the element content of Fe and O decreases. The surface is covered with an oxide film, the main components of which are oxides of Cr and Fe, the remelted layer is greater than that of the substrate, and the corrosion resistance is improved. Laser surface remelting technology can improve the structure and properties of 304 stainless steel.

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