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1.
Invest Ophthalmol Vis Sci ; 65(4): 38, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38656280

RESUMO

Purpose: Fuchs endothelial corneal dystrophy (FECD) is characterized by Descemet's membrane (DM) abnormalities, namely an increased thickness and a progressive appearance of guttae and fibrillar membranes. The goal of this study was to identify abnormal extracellular matrix (ECM) proteins expressed in FECD DMs and to evaluate their impact on cell adhesion and migration. Methods: Gene expression profiles from in vitro (GSE112039) and ex vivo (GSE74123) healthy and FECD corneal endothelial cells were analyzed to identify deregulated matrisome genes. Healthy and end-stage FECD DMs were fixed and analyzed for guttae size and height. Immunostaining of fibronectin, tenascin-C, osteopontin, and type XIV collagen was performed on ex vivo specimens, as well as on tissue-engineered corneal endothelium reconstructed using healthy and FECD cells. An analysis of ECM protein expression according to guttae and fibrillar membrane was performed using immunofluorescent staining and phase contrast microscopy. Finally, cell adhesion was evaluated on fibronectin, tenascin-C, and osteopontin, and cell migration was studied on fibronectin and tenascin-C. Results: SPP1 (osteopontin), FN1 (fibronectin), and TNC (tenascin-C) genes were upregulated in FECD ex vivo cells, and SSP1 was upregulated in both in vitro and ex vivo FECD conditions. Osteopontin, fibronectin, tenascin-C, and type XIV collagen were expressed in FECD specimens, with differences in their location. Corneal endothelial cell adhesion was not significantly affected by fibronectin or tenascin-C but was decreased by osteopontin. The combination of fibronectin and tenascin-C significantly increased cell migration. Conclusions: This study highlights new abnormal ECM components in FECD, suggests a certain chronology in their deposition, and demonstrates their impact on cell behavior.


Assuntos
Movimento Celular , Endotélio Corneano , Fibronectinas , Distrofia Endotelial de Fuchs , Osteopontina , Tenascina , Humanos , Tenascina/metabolismo , Tenascina/genética , Fibronectinas/metabolismo , Fibronectinas/genética , Osteopontina/metabolismo , Osteopontina/genética , Distrofia Endotelial de Fuchs/genética , Distrofia Endotelial de Fuchs/metabolismo , Endotélio Corneano/metabolismo , Endotélio Corneano/patologia , Idoso , Adesão Celular , Células Cultivadas , Feminino , Masculino , Regulação da Expressão Gênica , Pessoa de Meia-Idade , Lâmina Limitante Posterior/metabolismo , Lâmina Limitante Posterior/patologia
2.
Front Immunol ; 15: 1368465, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38646526

RESUMO

HIV-infection of microglia and macrophages (MMs) induces neuronal injury and chronic release of inflammatory stimuli through direct and indirect molecular pathways. A large percentage of people with HIV-associated neurologic and psychiatric co-morbidities have high levels of circulating inflammatory molecules. Microglia, given their susceptibility to HIV infection and long-lived nature, are reservoirs for persistent infection. MMs and neurons possess the molecular machinery to detect pathogen nucleic acids and proteins to activate innate immune signals. Full activation of inflammasome assembly and expression of IL-1ß requires a priming event and a second signal. Many studies have demonstrated that HIV infection alone can activate inflammasome activity. Interestingly, secreted phosphoprotein-1 (SPP1/OPN) expression is highly upregulated in the CNS of people infected with HIV and neurologic dysfunction. Interestingly, all evidence thus far suggests a protective function of SPP1 signaling through mammalian target of rapamycin (mTORC1/2) pathway function to counter HIV-neuronal injury. Moreover, HIV-infected mice knocked down for SPP1 show by neuroimaging, increased neuroinflammation compared to controls. This suggests that SPP1 uses unique regulatory mechanisms to control the level of inflammatory signaling. In this mini review, we discuss the known and yet-to-be discovered biological links between SPP1-mediated stimulation of mTOR and inflammasome activity. Additional new mechanistic insights from studies in relevant experimental models will provide a greater understanding of crosstalk between microglia and neurons in the regulation of CNS homeostasis.


Assuntos
Infecções por HIV , Inflamassomos , Microglia , Neurônios , Osteopontina , Transdução de Sinais , Serina-Treonina Quinases TOR , Humanos , Inflamassomos/metabolismo , Microglia/metabolismo , Microglia/imunologia , Animais , Serina-Treonina Quinases TOR/metabolismo , Neurônios/metabolismo , Neurônios/virologia , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Osteopontina/metabolismo
3.
Georgian Med News ; (347): 131-135, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38609129

RESUMO

Thyroid hormones are critical regulators of bone maintenance in adulthood and play an important part in the development of bones. They also play a function in the formation of bones. Childhood hypothyroidism leads to delayed skeletal development, limited linear growth, and impaired bone mineral accumulation. This research aims to assess the serum concentration of sclerostin, osteocalcin, and osteopontin in women diagnosed with hypothyroidism. Additionally, it seeks to examine the impact of medical treatment on the levels of sclerostin, osteocalcin, and osteopontin in individuals with hypothyroidism. This research examined a total of 180 women, divided into three groups: 70 women before treatment, 70 women after treatment, and 40 control subjects. The age range of the participants was between 15 and 54 years. The participants in this research are categorized into three distinct groups: The first cohort consisted of 70 women diagnosed with hypothyroidism, as confirmed by medical professionals. The second group consisted of 70 women who had undergone treatment for hypothyroidism. The research included a control group consisting of healthy women with no family history of thyroid illness. These women were in good health and their ages were similar to those of the women with hypothyroidism. According to the presented data show a decrease in the mean of the serum level of sclerostin, and osteocalcin in hypothyroidism women before and after treatment compared with the control group (13.4±4.9 versus 19.8±5.1 and 21.5±5.0), (9.8±4.7 versus 14.35±12.63 and 15.20±14.73), respectively. The result was significant (p<0.01), with no differences in osteopontin levels between study groups. It was concluded that the sclerostin, and osteocalcin decreased in women with hypothyroidism before treatment in comparison with women after treatment and healthy women, while Furthermore no differences in Osteopontin levels between the three groups.


Assuntos
Hipotireoidismo , Osteopontina , Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Hipotireoidismo/tratamento farmacológico , Osteocalcina , Pacientes
4.
Clinics (Sao Paulo) ; 79: 100352, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38574573

RESUMO

BACKGROUND: The aim of this study was to compare metabolic parameters, plasma Osteopontin (OPN) and Hepatocyte Growth Factor (HGF) levels between Sleeve Gastrectomy (SG) patients in their 6th post-operation month and healthy control patients. METHODS: Height, weight, Body Mass Index (BMI) and laboratory parameters of 58 SG patients aged 18‒65 years (Group 1) and 46 healthy control patients (Group 2) were compared. In addition, preoperative and postoperative sixth-month BMI and laboratory parameters of the patients in Group 1 were compared. RESULTS: The mean age and gender distributions of the groups were similar (p > 0.05). Mean BMI was 28.9 kg/m2 in Group 1 and 27 kg/m2 in Group 2 (p < 0.01). While plasma HGF levels were similar between both groups, plasma OPN levels were higher in Group 2 (p < 0.001). Fasting plasma glucose, total cholesterol, triglyceride, fasting plasma insulin and insulin resistance values were higher in Group 1, while alanine aminotransferase and aspartate aminotransferase levels were higher in Group 2 (p < 0.05). There was a strong correlation between plasma HGF and OPN levels in Group 1, but not in Group 2 (Rho = 0.805, p < 0.001). CONCLUSION: OPN and HGF are promising biomarkers that can be used to better understand and detect problems related to obesity. The fact that patients in the early post-SG period had lower plasma OPN and similar plasma HGF compared to non-surgical patients of similar age and gender with higher BMI may be another favorable and previously unknown metabolic effect of SG.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Laparoscopia , Obesidade Mórbida , Humanos , Gastrectomia , Obesidade , Obesidade Mórbida/cirurgia , Osteopontina , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso
5.
Sci Rep ; 14(1): 8670, 2024 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622371

RESUMO

Hypoxic pulmonary hypertension (HPH) is a pulmonary vascular disease primarily characterized by progressive pulmonary vascular remodeling in a hypoxic environment, posing a significant clinical challenge. Leveraging data from the Gene Expression Omnibus (GEO) and human autophagy-specific databases, osteopontin (OPN) emerged as a differentially expressed gene, upregulated in cardiovascular diseases such as pulmonary arterial hypertension (PAH). Despite this association, the precise mechanism by which OPN regulates autophagy in HPH remains unclear, prompting the focus of this study. Through biosignature analysis, we observed significant alterations in the PI3K-AKT signaling pathway in PAH-associated autophagy. Subsequently, we utilized an animal model of OPNfl/fl-TAGLN-Cre mice and PASMCs with OPN shRNA to validate these findings. Our results revealed right ventricular hypertrophy and elevated mean pulmonary arterial pressure (mPAP) in hypoxic pulmonary hypertension model mice. Notably, these effects were attenuated in conditionally deleted OPN-knockout mice or OPN-silenced hypoxic PASMCs. Furthermore, hypoxic PASMCs with OPN shRNA exhibited increased autophagy compared to those in hypoxia alone. Consistent findings from in vivo and in vitro experiments indicated that OPN inhibition during hypoxia reduced PI3K expression while increasing LC3B and Beclin1 expression. Similarly, PASMCs exposed to hypoxia and PI3K inhibitors had higher expression levels of LC3B and Beclin1 and suppressed AKT expression. Based on these findings, our study suggests that OPNfl/fl-TAGLN-Cre effectively alleviates HPH, potentially through OPN-mediated inhibition of autophagy, thereby promoting PASMCs proliferation via the PI3K-AKT signaling pathway. Consequently, OPN emerges as a novel therapeutic target for HPH.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Camundongos , Humanos , Animais , Hipertensão Pulmonar/tratamento farmacológico , Osteopontina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Artéria Pulmonar/metabolismo , Hipóxia/complicações , Hipóxia/genética , Hipóxia/metabolismo , Hipertensão Arterial Pulmonar/metabolismo , RNA Interferente Pequeno/metabolismo , Autofagia/genética , Proliferação de Células , Miócitos de Músculo Liso/metabolismo , Remodelação Vascular
6.
BMC Infect Dis ; 24(1): 398, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38609845

RESUMO

BACKGROUND: This study aims to explore the potential of utilizing the expression levels of cannabinoid receptor 2 (CB2), µ-opioid receptor (MOR), MCP-1, IL-17, IFN-γ, and osteopontin as predictors for the severity of SARS-CoV-2 infection. The overarching goal is to delineate the pathogenic mechanisms associated with SARS-CoV-2. METHODS: Using quantitative Real-time PCR, we analyzed the gene expression levels of CB2 and MOR in nasopharynx specimens obtained from patients diagnosed with SARS-CoV-2 infection, with 46 individuals classified as having severe symptoms and 46 as non-severe. Additionally, we measured the circulating levels of MCP-1, IL-17, IFN-γ, and osteopontin using an ELISA assay. We examined the predictive capabilities of these variables and explored their correlations across all patient groups. RESULTS: Our results demonstrated a significant increase in MOR gene expression in the epithelium of patients with severe infection. The expression of CB2 receptor was also elevated in both male and female patients with severe symptoms. Furthermore, we observed concurrent rises in MCP-1, IL-17, IFN-γ, and osteopontin levels in patients, which were linked to disease severity. CB2, MOR, MCP-1, IL-17, IFN-γ, and osteopontin showed strong predictive abilities in distinguishing between patients with varying degrees of SARS-CoV-2 severity. Moreover, we identified a significant correlation between CB2 expression and the levels of MOR, MCP-1, osteopontin, and IFN-γ. CONCLUSIONS: These results underline the interconnected nature of molecular mediators in a sequential manner, suggesting that their overexpression may play a role in the development of SARS-CoV-2 infections.


Assuntos
COVID-19 , Humanos , Feminino , Masculino , Prognóstico , COVID-19/diagnóstico , Receptores de Canabinoides , Analgésicos Opioides , Interleucina-17 , Osteopontina , SARS-CoV-2 , Fatores Imunológicos
7.
BMC Pulm Med ; 24(1): 173, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38609925

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) induced by smoking poses a significant global health challenge. Recent findings highlight the crucial role of extracellular vesicles (EVs) in mediating miRNA regulatory networks across various diseases. This study utilizes the GEO database to uncover distinct expression patterns of miRNAs and mRNAs, offering a comprehensive understanding of the pathogenesis of smoking-induced COPD. This study aims to investigate the mechanisms by which extracellular vesicles (EVs) mediate the molecular network of miR-422a-SPP1 to delay the onset of COPD caused by smoking. METHODS: The smoking-related miRNA chip GSE38974-GPL7723 was obtained from the GEO database, and candidate miRs were retrieved from the Vesiclepedia database. Downstream target genes of the candidate miRs were predicted using mRNA chip GSE38974-GPL4133, TargetScan, miRWalk, and RNA22 databases. This prediction was integrated with COPD-related genes from the GeneCards database, downstream target genes predicted by online databases, and key genes identified in the core module of WGCNA analysis to obtain candidate genes. The candidate genes were subjected to KEGG functional enrichment analysis using the "clusterProfiler" package in R language, and a protein interaction network was constructed. In vitro experiments involved overexpressing miRNA or extracting extracellular vesicles from bronchial epithelial cell-derived exosomes, co-culturing them with myofibroblasts to observe changes in the expression levels of the miR-422a-SPP1-IL-17 A regulatory network, and assessing protein levels of fibroblast differentiation-related factors α-SMA and collagen I using Western blot analysis. RESULTS: The differential gene analysis of chip GSE38974-GPL7723 and the retrieval results from the Vesiclepedia database identified candidate miRs, specifically miR-422a. Subsequently, an intersection was taken among the prediction results from TargetScan, miRWalk, and RNA22 databases, the COPD-related gene retrieval results from GeneCards database, the WGCNA analysis results of chip GSE38974-GPL4133, and the differential gene analysis results. This intersection, combined with KEGG functional enrichment analysis, and protein-protein interaction analysis, led to the final screening of the target gene SPP1 and its upstream regulatory gene miR-422a. KEGG functional enrichment analysis of mRNAs correlated with SPP1 revealed the IL-17 signaling pathway involved. In vitro experiments demonstrated that miR-422a inhibition targets suppressed the expression of SPP1 in myofibroblasts, inhibiting differentiation phenotype. Bronchial epithelial cells, under cigarette smoke extract (CSE) stress, could compensate for myofibroblast differentiation phenotype by altering the content of miR-422a in their Extracellular Vesicles (EVs). CONCLUSION: The differential gene analysis of Chip GSE38974-GPL7723 and the retrieval results from the Vesiclepedia database identified candidate miRs, specifically miR-422a. Further analysis involved the intersection of predictions from TargetScan, miRWalk, and RNA22 databases, gene search on COPD-related genes from the GeneCards database, WGCNA analysis from Chip GSE38974-GPL4133, and differential gene analysis, combined with KEGG functional enrichment analysis and protein interaction analysis. Ultimately, the target gene SPP1 and its upstream regulatory gene miR-422a were selected. KEGG functional enrichment analysis on mRNAs correlated with SPP1 revealed the involvement of the IL-17 signaling pathway. In vitro experiments showed that miR-422a targeted inhibition suppressed the expression of SPP1 in myofibroblast cells, inhibiting differentiation phenotype. Furthermore, bronchial epithelial cells could compensate for myofibroblast differentiation phenotype under cigarette smoke extract (CSE) stress by altering the miR-422a content in their extracellular vesicles (EVs).


Assuntos
Vesículas Extracelulares , MicroRNAs , Humanos , Vesículas Extracelulares/genética , Interleucina-17/genética , MicroRNAs/genética , Osteopontina , Transdução de Sinais , Fumar/efeitos adversos
8.
Arthritis Res Ther ; 26(1): 85, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38610060

RESUMO

INTRODUCTION: Immunoglobulin A vasculitis (IgAV) in adults has a variable disease course, with patients often developing gastrointestinal and renal involvement and thus contributing to higher mortality. Due to understudied molecular mechanisms in IgAV currently used biomarkers for IgAV visceral involvement are largely lacking. Our aim was to search for potential serum biomarkers based on the skin transcriptomic signature. METHODS: RNA sequencing analysis was conducted on skin biopsies collected from 6 treatment-naïve patients (3 skin only and 3 renal involvement) and 3 healthy controls (HC) to get insight into deregulated processes at the transcriptomic level. 15 analytes were selected and measured based on the transcriptome analysis (adiponectin, lipopolysaccharide binding protein (LBP), matrix metalloproteinase-1 (MMP1), C-C motif chemokine ligand (CCL) 19, kallikrein-5, CCL3, leptin, C-X-C motif chemokine ligand (CXCL) 5, osteopontin, interleukin (IL)-15, CXCL10, angiopoietin-like 4 (ANGPTL4), SERPIN A12/vaspin, IL-18 and fatty acid-binding protein 4 (FABP4)) in sera of 59 IgAV and 22 HC. Machine learning was used to assess the ability of the analytes to predict IgAV and its organ involvement. RESULTS: Based on the gene expression levels in the skin, we were able to differentiate between IgAV patients and HC using principal component analysis (PCA) and a sample-to-sample distance matrix. Differential expression analysis revealed 49 differentially expressed genes (DEGs) in all IgAV patient's vs. HC. Patients with renal involvement had more DEGs than patients with skin involvement only (507 vs. 46 DEGs) as compared to HC, suggesting different skin signatures. Major dysregulated processes in patients with renal involvement were lipid metabolism, acute inflammatory response, and extracellular matrix (ECM)-related processes. 11 of 15 analytes selected based on affected processes in IgAV skin (osteopontin, LBP, ANGPTL4, IL-15, FABP4, CCL19, kallikrein-5, CCL3, leptin, IL-18 and MMP1) were significantly higher (p-adj < 0.05) in IgAV serum as compared to HC. Prediction models utilizing measured analytes showed high potential for predicting adult IgAV. CONCLUSION: Skin transcriptomic data revealed deregulations in lipid metabolism and acute inflammatory response, reflected also in serum analyte measurements. LBP, among others, could serve as a potential biomarker of renal complications, while adiponectin and CXCL10 could indicate gastrointestinal involvement.


Assuntos
Vasculite por IgA , Adulto , Humanos , Vasculite por IgA/diagnóstico , Vasculite por IgA/genética , Interleucina-18 , Leptina , Metaloproteinase 1 da Matriz , Osteopontina , Adiponectina , Ligantes , Inflamação , Calicreínas , Quimiocinas
9.
BMC Musculoskelet Disord ; 25(1): 195, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38443806

RESUMO

BACKGROUND: First-degree relatives (FDRs) of rheumatoid arthritis (RA) patients are known to have increased risk of developing the disease. The detection of altered bone metabolism in FDRs could be a predictor of the disease. Musculoskeletal ultrasound (MSUS) is known for its ability to detect subclinical joint inflammation in RA, but changes in FDRs are not yet described. We aimed to study serum Osteopontin (OPN) and Osteoprotegerin (OPG) levels in FDRs of RA patients as markers of altered bone metabolism in relation to clinical, laboratory and musculoskeletal ultrasound (MSUS) findings. METHODS: Fifty-five individuals were included, 20 had definite RA, 25 were first degree relatives (FDRs) of RA patients, and 10 healthy controls. Clinical evaluation for joint swelling/tenderness was performed for all. ESR, CRP, rheumatoid factor (RF), anti-citrullinated antibodies (ACPA), OPN, OPG, and Musculoskeletal ultrasound (MSUS) by the US7 score were evaluated. RESULTS: Osteoprotegerin was significantly higher in RA (143.89 pg/ml ± 365.47) than in FDRs (22.23 pg/ml ± 65.73; p = 0.009) and controls (6.20 pg/ml ± 12.43; p = 0.003). OPN was also higher in RA (3.66 ng/ml ± 4.20) than in FDRs (1.97 ng/ml ± 1.04) and controls (2.81 ng/ml ± 1.31), though not significant (p = 0.102). Eight of 25 FDRs (32%) had arthralgia without clinical arthritis and 17/25 (68%) were asymptomatic. FDRs with arthralgia had significantly higher ESR and CRP levels than asymptomatic FDRs (9.82 mm/h ± 4.13; p = 0.003, and 3.93 mg/l ± 3.58; p = 0.003). Osteoprotegerin was higher in FDRs than in controls, and also in those with arthralgia (51.55 pg/ml ± 114.68) than in those without (8.44 pg/ml ± 9.67), though without significant difference. OPN was higher in FDRs with arthralgia (2.09 ng/ml ± 1.19) than in asymptomatic (1.70 ng/ml ± 0.55), also without significant difference. Pathologic findings by US7 were detected in 10/25 (40%) FDRs, of which three (12%) had arthralgia and seven (28%) were asymptomatic. CONCLUSIONS: The raised OPG and lower OPN in FDRs than in controls reflect an altered bone metabolism which could precede clinical disease phase. OPN and OPG could serve as markers of altered preclinical bone metabolism in FDRs of RA. US7 score might be a useful screening tool to identify 'at-risk' individuals.


Assuntos
Artrite Reumatoide , Osteopontina , Humanos , Artralgia , Artrite Reumatoide/diagnóstico por imagem , Osteoprotegerina , Fator Reumatoide
10.
Lung ; 202(2): 197-210, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38480620

RESUMO

PURPOSE: Pembrolizumab-based regimens are conditioned by the expression of PD-L1, but durable response rate is limited by innate and acquired resistance mechanisms. Here, we focus on osteopontin (OPN), an upfront biomarker of senescence, which closely associated with natural history of non-small cell lung cancer (NSCLC). METHODS: Seventy-nine patients eligible to pembrolizumab regimens-alone or in combination with chemotherapy-as first-line treatment of advanced NSCLC were enrolled. Predictive value of OPN toward iRECIST progression disease (PD) was set as first outcome. Secondary ones included performance status (ECOG) at baseline, early (first and best) responses, and overall survival (OS). RESULTS: High Serum OPN characterized patients with worse ECOG-PS (p = 0.015) at baseline and subjects experienced PD/death at first (OR 1.17 [1.02 to 1.35]; p = 0.030) and best responses (0.04 [0.00 to 0.81]; p = 0.035). OPN was associated with time-to-progression (B -2.74 [-4.46 to -1.01]) and time-to death (-0.13 [-0.20 to -0.05]). Cox regression models unveil a predictive value for iRECIST-PD (HR 1.01 [1.00 to 1.02]; p = -0.005), RECIST-PD (HR 1.01 [1.00 to 1.02]; p = 0.017), and OS (HR 1.02 [1.01 to 1.03]; p = 0.001). These models were internally validated through bootstrap resampling and characterized by relevant discrimination ability at ROC curve analyses. CONCLUSION: Baseline levels of serum OPN is closely associated with performance status and short/long term outcomes in patients with advanced NSCLC, which are candidate to pembrolizumab-based regimens. As upfront biomarker of senescence, OPN may pave the way for future studies focusing on senescence patterns in NSCLC.


Assuntos
Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Osteopontina/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores
11.
Front Immunol ; 15: 1285813, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38426091

RESUMO

Background: Vulnerable plaque was associated with recurrent cardiovascular events. This study was designed to explore predictive biomarkers of vulnerable plaque in patients with coronary artery disease. Methods: To reveal the phenotype-associated cell type in the development of vulnerable plaque and to identify hub gene for pathological process, we combined single-cell RNA and bulk RNA sequencing datasets of human atherosclerotic plaques using Single-Cell Identification of Subpopulations with Bulk Sample Phenotype Correlation (Scissor) and Weighted gene co-expression network analysis (WGCNA). We also validated our results in an independent cohort of patients by using intravascular ultrasound during coronary angiography. Results: Macrophages were found to be strongly correlated with plaque vulnerability while vascular smooth muscle cell (VSMC), fibrochondrocyte (FC) and intermediate cell state (ICS) clusters were negatively associated with unstable plaque. Weighted gene co-expression network analysis showed that Secreted Phosphoprotein 1 (SPP1) in the turquoise module was highly correlated with both the gene module and the clinical traits. In a total of 593 patients, serum levels of SPP1 were significantly higher in patients with vulnerable plaques than those with stable plaque (113.21 [73.65 - 147.70] ng/ml versus 71.08 [20.64 - 135.68] ng/ml; P < 0.001). Adjusted multivariate regression analysis revealed that serum SPP1 was an independent determinant of the presence of vulnerable plaque. Receiver operating characteristic curve analysis indicated that the area under the curve was 0.737 (95% CI 0.697 - 0.773; P < 0.001) for adding serum SPP1 in predicting of vulnerable plaques. Conclusion: Elevated serum SPP1 levels confer an increased risk for plaque vulnerability in patients with coronary artery disease.


Assuntos
Doença da Artéria Coronariana , Placa Aterosclerótica , Humanos , Biomarcadores , Angiografia Coronária , Osteopontina/genética , Placa Aterosclerótica/patologia
12.
Front Immunol ; 15: 1271926, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38426086

RESUMO

Natural components of breast milk, human milk oligosaccharides (HMOs) and osteopontin (OPN) have been shown to have a variety of functional activities and are widely used in infant formulas. However, the preventive and therapeutic effects of both on influenza viruses are not known. In this study, antiviral assays using a human laryngeal carcinoma cell line (HEP-2) showed that 3'-sialyllactose (3'-SL) and OPN had the best antiviral ability with IC50 values of 33.46 µM and 1.65 µM, respectively. 3'-SL (10 µM) and OPN (4 µM) were used in combination to achieve 75% inhibition. Further studies found that the combination of 200 µg/mL of 3'-SL with 500 µg/mL of OPN exerted the best antiviral ability. The reason for this was related to reduced levels of the cytokines TNF-α, IL-6, and iNOS in relation to mRNA expression. Plaque assay and TCID50 assay found the same results and verified synergistic effects. Our research indicates that a combination of 3'-SL and OPN can effectively reduce inflammatory storms and exhibit anti-influenza virus effects through synergistic action.


Assuntos
Influenza Humana , Orthomyxoviridae , Lactente , Feminino , Humanos , Osteopontina/genética , Influenza Humana/tratamento farmacológico , Leite Humano/metabolismo , Oligossacarídeos/farmacologia , Antivirais
13.
J Cancer Res Clin Oncol ; 150(3): 155, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38526702

RESUMO

PURPOSE: Triple-negative breast cancer (TNBC) features high aggressiveness, metastasis rate, drug resistance as well as poor prognosis. Osteopontin (OPN) is a key protein in the process of osteogenesis and has emerged as a new tumor marker in recent years. METHODS: Cell viability was tested with the CCK-8 kit. Transwell and wound healing were adopted to test cell invasive and migratory abilities. Tumor sphere formation was detected by tumor sphere formation assay. Human umbilical vein endothelial cell (HUVEC) tube formation assay was used to measure the angiogenesis of tumor cells. Western blot was applied for the estimation of the expression of cancer stem cell markers, angiogenesis-, signaling pathway-related proteins as well as OPN. Bioinformatics tools predicted OPN expression in breast cancer tissues. The levels of oxidative stress-related markers were assessed with ELISA. Following the overexpression of OPN in MD-MB-436 cells and the addition of the PI3K/AKT/mTOR pathway inhibitor LY294002, the aforementioned functional experiments were implemented again to investigate the mechanism. Finally, in vivo experiments of tumor-bearing mice were performed for further verification. RESULTS: The proliferative, invasive, migratory and tumor sphere formation capabilities as well as angiogenesis of TNBC cells were conspicuously increased in contrast to non-TNBC cell lines. OPN expression in TNBC tissues and cells was dramatically enhanced. OPN upregulation significantly elevated cell proliferative, invasive and migratory capabilities as well as tumor sphere formation and angiogenesis. The mechanism might be achieved by activating PI3K/AKT/mTOR signaling to regulate glutathione peroxidase 4 (GPX4)-mediated anti-lipid peroxidation. CONCLUSION: OPN promoted tumor sphere formation and angiogenesis in TNBC by activating the PI3K/AKT/mTOR pathway to regulate GPX4-mediated anti-lipid peroxidation levels.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Osteopontina/metabolismo , Linhagem Celular Tumoral , Serina-Treonina Quinases TOR/metabolismo , Proliferação de Células , Movimento Celular/fisiologia
14.
Aging (Albany NY) ; 16(3): 2953-2977, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38329443

RESUMO

OBJECTIVE: The extracellular phosphoprotein, secreted phosphoprotein 1 (SPP1), plays a crucial role in various tumors and regulating the immune system. This study aimed to evaluate its prognostic value and relationship to immune infiltration in lung adenocarcinoma (LUAD). METHODS: In the TCGA and GEO datasets, the information on clinic and transcriptome analysis of SPP1 in non-small-cell lung cancer (NSCLC) was examined accordingly. The association of SPP1 expression with overall survival and clinicopathologic characteristics was investigated by univariate and multivariate analysis. CancerSEA database was utilized to investigate the role of SPP1 at the cellular level by single-cell analysis. Additionally, the CIBERSORT algorithm was utilized to assess the correlation among the immune cells that infiltrated. RESULTS: NSCLC tissues exhibited a notable rise in SPP1 expression compared with that of normal tissues. Furthermore, the overexpression of SPP1 was substantially associated with clinicopathological features and unfavorable survival outcomes in individuals with LUAD, whereas no such correlation was observed in lung squamous cell carcinoma. Immune cells that infiltrate tumors and their corresponding genes were associated with SPP1 expression levels in LUAD. CONCLUSIONS: SPP1 is a reliable indicator for assessing LUAD immune infiltration status and prognosis. With this approach, SPP1 can help earlier LUAD diagnosis and act as a possible immunotherapy target.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Osteopontina/genética , Prognóstico , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/genética
15.
J Pediatr Surg ; 59(5): 839-846, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38365473

RESUMO

BACKGROUND: Pulmonary vascular disease (PVD) complicated with pulmonary hypertension (PH) is a leading cause of mortality in congenital diaphragmatic hernia (CDH). Unfortunately, CDH patients are often resistant to PH therapy. Using the nitrogen CDH rat model, we previously demonstrated that CDH-associated PVD involves an induction of elastase and matrix metalloproteinase (MMP) activities, increased osteopontin and epidermal growth factor (EGF) levels, and enhanced smooth muscle cell (SMC) proliferation. Here, we aimed to determine whether the levels of the key members of this proteinase-induced pathway are also elevated in the pulmonary arteries (PAs) of CDH patients. METHODS: Neutrophil elastase (NE), matrix metalloproteinase-2 (MMP-2), epidermal growth factor (EGF), tenascin-C, and osteopontin levels were assessed by immunohistochemistry in the PAs from the lungs of 11 CDH patients and 5 normal age-matched controls. Markers of proliferation (proliferating cell nuclear antigen (PCNA)) and apoptosis (cleaved (active) caspase-3) were also used. RESULTS: While expressed by both control and CDH lungs, the levels of NE, MMP-2, EGF, as well as tenascin-C and osteopontin were significantly increased in the PAs from CDH patients. The percentage of PCNA-positive PA SMCs were also enhanced, while those positive for caspase-3 were slightly decreased. CONCLUSIONS: These results suggest that increased elastase and MMPs, together with elevated tenascin-C and osteopontin levels in an EGF-rich environment may contribute to the PVD in CDH infants. The next step of this study is to expand our analysis to a larger cohort, and determine the potential of targeting this pathway for the treatment of CDH-associated PVD and PH. TYPE OF STUDY: Therapeutic. LEVEL OF EVIDENCE: LEVEL III.


Assuntos
Hérnias Diafragmáticas Congênitas , Hipertensão Pulmonar , Doenças Vasculares , Humanos , Ratos , Animais , Hérnias Diafragmáticas Congênitas/complicações , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 2 da Matriz/metabolismo , Artéria Pulmonar , Osteopontina/metabolismo , Caspase 3/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Elastase Pancreática/metabolismo , Fator de Crescimento Epidérmico , Tenascina/metabolismo , Pulmão/metabolismo , Hipertensão Pulmonar/complicações , Metaloproteinases da Matriz , Doenças Vasculares/complicações , Éteres Fenílicos/metabolismo
16.
Immunity ; 57(2): 349-363.e9, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38309272

RESUMO

Microglial reactivity to injury and disease is emerging as a heterogeneous, dynamic, and crucial determinant in neurological disorders. However, the plasticity and fate of disease-associated microglia (DAM) remain largely unknown. We established a lineage tracing system, leveraging the expression dynamics of secreted phosphoprotein 1(Spp1) to label and track DAM-like microglia during brain injury and recovery. Fate mapping of Spp1+ microglia during stroke in juvenile mice revealed an irreversible state of DAM-like microglia that were ultimately eliminated from the injured brain. By contrast, DAM-like microglia in the neonatal stroke models exhibited high plasticity, regaining a homeostatic signature and integrating into the microglial network after recovery. Furthermore, neonatal injury had a lasting impact on microglia, rendering them intrinsically sensitized to subsequent immune challenges. Therefore, our findings highlight the plasticity and innate immune memory of neonatal microglia, shedding light on the fate of DAM-like microglia in various neuropathological conditions.


Assuntos
Lesões Encefálicas , Acidente Vascular Cerebral , Animais , Camundongos , Microglia , Encéfalo/metabolismo , Osteopontina/metabolismo
17.
Spine (Phila Pa 1976) ; 49(10): E142-E151, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38329420

RESUMO

STUDY DESIGN: Basic science study using a hemisection spinal cord injury (SCI) model. OBJECTIVE: We sought to assess the effect of blocking osteopontin (OPN) upregulation on motor function recovery and pain behavior after SCI and to further investigate the possible downstream target of OPN in the injured spinal cord. SUMMARY OF BACKGROUND DATA: OPN is a noncollagenous extracellular matrix protein widely expressed across different tissues. Its expression substantially increases following SCI. A previous study suggested that this protein might contribute to locomotor function recovery after SCI. However, its neuroprotective potential was not fully explored, nor were the underlying mechanisms. MATERIALS AND METHODS: We constructed a SCI mouse model and analyzed the expression of OPN at different time points and the particular cell distribution in the injured spinal cord. Then, we blocked OPN upregulation with lentivirus-delivering siRNA targeting OPN specifically and examined its effect on motor function impairment and neuropathic pain after SCI. The underlying mechanisms were explored in the OPN-knockdown mice model and cultured vascular endothelial cells. RESULTS: The proteome study revealed that OPN was the most dramatically increased protein following SCI. OPN in the spinal cord was significantly increased three weeks after SCI. Suppressing OPN upregulation through siRNA exacerbated motor function impairment and neuropathic pain. In addition, SCI resulted in an increase in vascular endothelial growth factor (VEGF), AKT phosphorylation, and angiogenesis within the spinal cord, all of which were curbed by OPN reduction. Similarly, OPN knockdown suppressed VEGF expression, AKT phosphorylation, cell migration, invasion, and angiogenesis in cultured vascular endothelial cells. CONCLUSION: OPN demonstrates a protective influence against motor function impairment and neuropathic pain following SCI. This phenomenon may result from the proangiogenetic effect of OPN, possibly due to activation of the VEGF and/or AKT pathways.


Assuntos
Neuralgia , Osteopontina , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal , Medula Espinal , Osteopontina/metabolismo , Animais , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Neuralgia/etiologia , Neuralgia/metabolismo , Neuralgia/prevenção & controle , Camundongos , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/metabolismo , Neovascularização Fisiológica/fisiologia , Neovascularização Fisiológica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Regulação para Cima , Masculino , Fator A de Crescimento do Endotélio Vascular/metabolismo , 60489
18.
Viruses ; 16(2)2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38400081

RESUMO

Nephropathis epidemica (NE), a mild form of hemorrhagic fever with renal syndrome (HFRS), is an acute zoonotic disease endemic in the Republic of Tatarstan. This study aimed to assess the impact of rosuvastatin on the clinical and laboratory results of NE. A total of 61 NE patients and 30 controls were included in this study; 22 NE patients and 7 controls received a daily dose of rosuvastatin (10 mg) for ten consecutive days. Serum samples were collected on days 1, 5, and 10 after admission to the hospital. These samples were analyzed to determine the levels of lipids, cytokines, and kidney toxicity markers. Our findings indicate that rosuvastatin reduced the duration of the second wave of fever and alleviated back pain and headache symptoms. Additionally, low-density lipoprotein cholesterol (LDL-C) serum levels were significantly decreased on days 5 and 10 upon rosuvastatin treatment. Furthermore, rosuvastatin decreased the levels of cytokines in the serum, particularly proinflammatory cytokines IL-1ß and IL-8. NE patients had significantly altered levels of the kidney toxicity markers albumin and osteopontin. The data from our study provide evidence supporting the therapeutic potential of rosuvastatin in NE cases.


Assuntos
Febre Hemorrágica com Síndrome Renal , Humanos , Febre Hemorrágica com Síndrome Renal/diagnóstico , Rosuvastatina Cálcica/uso terapêutico , Citocinas , Osteopontina , LDL-Colesterol
19.
Biomarkers ; 29(2): 105-113, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38376506

RESUMO

BACKGROUND: Although Osteopontin (OPN) has been reported to be associated with many different human cancers, the data on non-small cell lung cancer (NSCLC) are not definitive. This study aimed to explore the prognostic effect of OPN expression and clinicopathological characteristics in patients with NSCLC. METHODS: This study followed all aspects of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) report. PubMed, Embase and the Cochrane Library were searched to identify the relative studies. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to estimate the prognostic value of the OPN in patients with NSCLC. The odds ratio (OR) was calculated to represent the relationship between OPN expression and clinicopathological parameters. RESULTS: A total of fifteen studies with 2173 participants were finally included. The results revealed that high expression of OPN was significantly associated with poorer overall survival (OS) (HR = 1.89; 95%CI = 1.68-2.11; p < 0.001). Moreover, a significant correlation was observed between increased OPN expression and poorly differentiated (well and moderately differentiated vs. poorly differentiated; pooled OR = 0.38; 95% CI = 0.23-0.64; p < 0.001), lymph node metastasis (absence vs. presence; pooled OR = 0.49; 95%CI = 0.32-0.74; p < 0.001), and distant metastasis (absence vs. presence; pooled OR = 0.18; 95%CI = 0.11-0.29; p < 0.001). CONCLUSION: This meta-analysis implies that OPN might be a valuable biomarker for a poor prognosis and poor clinicopathological outcomes for patients with NSCLC.


Our findings suggest that osteopontin is an important biomarker for poor prognosis and poor clinicopathological outcome in Non-small cell lung cancer (NSCLC) patients.Increased expression of osteopontin in NSCLC patients is associated not only with poorer survival but also with tumor differentiation, lymph node metastasis, and distant metastasis.This may be due to that osteopontin promotes multiple pathological processes including cancer cell proliferation, invasion, tumor progression, and metastasis in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Prognóstico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Osteopontina/análise , Biomarcadores Tumorais/análise
20.
Immun Inflamm Dis ; 12(2): e1132, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38415922

RESUMO

BACKGROUND: Neuropathic pain (NP) is a chronic pathological pain that affects the quality of life and is a huge medical burden for affected patients. In this study, we aimed to explore the effects of secreted phosphoprotein 1 (SPP1) on NP. METHODS: We established a chronic constriction injury (CCI) rat model, knocked down SPP1 via an intrathecal injection, and/or activated the extracellular signal-regulated kinase (ERK) pathway with insulin-like growth factor 1 (IGF-1) treatment. Pain behaviors, including paw withdrawal threshold (PWT), paw withdrawal latency (PWL), lifting number, and frequency, were assessed. After sacrificing rats, the L4-L5 dorsal root ganglion was collected. Then, SPP1 levels were determined using quantitative polymerase chain reaction (qPCR) and western blot analysis. The levels of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, IL-10, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)-ß were determined using qPCR and enzyme-linked immunosorbent assay. The levels of ERK pathway factors were determined via western blot analysis. RESULTS: We found that CCI decreased PWT and PWL, increased the lifting number and frequency, and upregulated SPP1 levels. The loss of SPP1 reversed these CCI-induced effects. Additionally, CCI upregulated IL-1ß, TNF-α, IL-6, EGF, and VEGF levels, downregulated TGF-ß levels, and activated the ERK pathway, while silencing of SPP1 abrogated these CCI-induced effects. Moreover, IGF-1 treatment reversed the effects of SPP1 loss. CONCLUSIONS: The data indicate that silencing SPP1 attenuates NP via inactivation of the ERK pathway, suggesting that SPP1 may be a promising target for NP treatment.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular , Neuralgia , Humanos , Animais , Ratos , Fator A de Crescimento do Endotélio Vascular , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Epidérmico , Osteopontina , Interleucina-6 , Qualidade de Vida , Neuralgia/etiologia , Interleucina-1beta , Transdução de Sinais , Nervo Isquiático
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