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2.
Zhonghua Yan Ke Za Zhi ; 60(6): 518-527, 2024 Jun 11.
Artículo en Chino | MEDLINE | ID: mdl-38825951

RESUMEN

Objective: To explore the differences in metabolites and metabolic pathways in the aqueous humor between patients with presenile cataracts and senile cataracts. Methods: This metabolomic study was conducted at Tianjin Medical University Eye Hospital from August 2020 to September 2022. Eight patients with presenile cataracts (8 eyes) and 8 patients with senile cataracts (9 eyes) were included. Data were collected, including age, gender, preoperative uncorrected visual acuity, intraocular pressure, lens dysfunction index, and axial length. Aqueous humor and anterior capsule tissue samples were obtained during cataract surgery. Metabolites in the aqueous humor were detected using Liquid Chromatography-Mass Spectrometry in a non-targeted approach. The principal component analysis, differential analysis, clustering analysis, and correlation analysis were performed to identify differentially expressed metabolites. These metabolites were ranked based on the fold change (FC). The receiver operating characteristic (ROC) curve analysis and metabolic enrichment analysis were used to identify differential pathways and potential biomarkers for presenile cataracts. Immunohistochemistry was conducted on anterior capsule tissues, and pyruvate levels were measured by colorimetry to validate metabolomic results. Results: Patients with presenile cataracts included 7 males and 1 female, with a mean age of (37.50±4.90) years. Patients with senile cataracts were 7 males and 1 female, with a mean age of (73.44±5.22) years. Except for age, there were no significant differences in baseline data (P>0.05). A total of 347 differential metabolites were identified, 10 of which were potential biomarkers for presenile cataract according to the ROC curve analysis (all P<0.05), including propoxycaine (log2FC=7.26), 2-methyl-2, 3, 4, 5-tetrahydro-1, 5-benzodiazepine-4-ketone (log2FC=6.35), l-pyroglutamic acid (log2FC=-1.72), leanly-proline (log2FC=-0.77), and choline (log2FC=-0.56) in the positive ion mode, and N-phenylacetyl glutamine (log2FC=-1.84), pyruvate (log2FC=1.07), ascorbic acid (log2FC=0.92), pseudouracil nucleoside (log2FC=-0.68), and palmitic acid (log2FC=-0.51) in the negative ion mode. The metabolic enrichment analysis identified 72 differential pathways (32 cationic and 40 anionic), with significant differences in glutathione metabolism, cysteine and methionine metabolism, glycolysis or gluconeogenesis, pyruvate metabolism, and the citric acid cycle (P<0.05). The experimental validation showed reduced lactate dehydrogenase and increased pyruvate levels in patients with presenile cataracts (P<0.05). Conclusions: Pyruvate and nine other metabolites may serve as potential biomarkers for presenile cataracts. Pathways involving glutathione metabolism, cysteine and methionine metabolism, glycolysis or gluconeogenesis, pyruvate metabolism, and the citric acid cycle are notably dysregulated in patients with presenile cataracts.


Asunto(s)
Humor Acuoso , Catarata , Metabolómica , Humanos , Catarata/metabolismo , Humor Acuoso/metabolismo , Metabolómica/métodos , Biomarcadores/metabolismo , Masculino , Femenino
3.
J Vis Exp ; (207)2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38829108

RESUMEN

Many sex-specific biomarkers have been recently revealed in Alzheimer's disease (AD); however, cerebral glial cells were rarely reported. This study analyzed 220,095 single-nuclei transcriptomes from the frontal cortex of thirty-three AD individuals in the GEO database. Sex-specific Differentially Expressed Genes (DEGs) were identified in glial cells, including 243 in astrocytes, 1,154 in microglia, and 572 in oligodendrocytes. Gene Ontology (GO) functional annotation analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed functional concentration in synaptic, neural, and hormone-related pathways. Protein-protein interaction network (PPI) identified MT3, CALM2, DLG2, KCND2, PAKACB, CAMK2D, and NLGN4Y in astrocytes, TREM2, FOS, APOE, APP, and NLGN4Y in microglia, and GRIN2A, ITPR2, GNAS, and NLGN4Y in oligodendrocytes as key genes. NLGN4Y was the only gene shared by the three glia and was identified as the biomarker for the gender specificity of AD. Gene-transcription factor (TF)-miRNA coregulatory network identified key regulators for NLGN4Y and its target TCMs. Ecklonia kurome Okam (Kunbu) and Herba Ephedrae (Mahuang) were identified, and the effects of the active ingredients on AD were displayed. Finally, enrichment analysis of Kunbu and Mahuang suggested that they might act as therapeutic candidates for gender specificity of AD.


Asunto(s)
Enfermedad de Alzheimer , Neuroglía , Transcriptoma , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Humanos , Transcriptoma/genética , Femenino , Neuroglía/metabolismo , Masculino , Biomarcadores/metabolismo , Biomarcadores/análisis
4.
J Craniofac Surg ; 35(4): 1292-1297, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38829148

RESUMEN

BACKGROUND: Acute myocardial infarction (AMI) risk correlates with C-reactive protein (CRP) levels, suggesting systemic inflammation is present well before AMI. Studying different types of periodontal disease (PD), extremely common in individuals at risk for AMI, has been one important research topic. According to recent research, AMI and PD interact via the systemic production of certain proinflammatory and anti-inflammatory cytokines, small signal molecules, and enzymes that control the onset and development of both disorders' chronic inflammatory reactions. This study uses machine learning to identify the interactome hub biomarker genes in acute myocardial infarction and periodontitis. METHODS: GSE208194 and GSE222883 were chosen for our research after a thorough search using keywords related to the study's goal from the gene expression omnibus (GEO) datasets. DEGs were identified from the GEOR tool, and the hub gene was identified using Cytoscape-cytohubba. Using expression values, Random Forest, Adaptive Boosting, and Naive Bayes, widgets-generated transcriptomics data, were labelled, and divided into 80/20 training and testing data with cross-validation. ROC curve, confusion matrix, and AUC were determined. In addition, Functional Enrichment Analysis of Differentially Expressed Gene analysis was performed. RESULTS: Random Forest, AdaBoost, and Naive Bayes models with 99%, 100%, and 75% AUC, respectively. Compared to RF, AdaBoost, and NB classification models, AdaBoost had the highest AUC. Categorization algorithms may be better predictors than important biomarkers. CONCLUSIONS: Machine learning model predicts hub and non-hub genes from genomic datasets with periodontitis and acute myocardial infarction.


Asunto(s)
Aprendizaje Automático , Infarto del Miocardio , Periodontitis , Humanos , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Periodontitis/genética , Periodontitis/metabolismo , Biomarcadores/metabolismo , Perfilación de la Expresión Génica , Teorema de Bayes , Transcriptoma/genética
5.
Clin Exp Dent Res ; 10(3): e883, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38853451

RESUMEN

OBJECTIVE: The objective of this study was to investigate the effectiveness of testing for active matrix metalloproteinase-8 (aMMP-8) by a quantitative point-of-care (PoC), chairside lateral flow immunotest and azurocidin, in the peri-implant sulcular fluid (PISF), as biomarkers for the presence or absence of peri-implant diseases. BACKGROUND: Current research indicates that proinflammatory cytokines and extracellular matrix-degrading enzymes may be of value to diagnose and predict peri-implant disease initiation and progression, but more data are needed. METHODS: Eighty patients with implants were recruited. PISF samples were collected and quantitatively analyzed for aMMP-8 (chairside) and azurocidin with ELISA. Radiographic assessments and clinical indices (probing depth, probing attachment level, bleeding on probing, and plaque) were recorded after sampling. Kruskal-Wallis test and pairwise post hoc Dunn-Bonferroni test were used to relate aMMP-8 levels and azurocidin levels to clinical parameters. The diagnostic ability of aMMP-8 (ng/mL) and azurocidin was analyzed by receiver operator curve analysis. Area under the curve (AUC) was calculated and the Spearman's rho, and the coefficient of determination (R2) were used to calculate the correlations between aMMP-8, azurocidin, and periodontal parameters. RESULTS: Statistically significant differences were observed for aMMP-8 levels but not for azurocidin between healthy implants, implants with mucositis, and those with peri-implantitis (13.65 ± 7.18, 32.33 ± 21.20, and 73.07 ± 43.93 ng/mL, respectively), (Kruskall-Wallis test p < .05). The aMMP-8 test with a threshold of 20 ng/mL has a sensitivity of 71.7% and a specificity of 77.8% to identify peri-implantitis and healthy implants, respectively. AUC was found to be 0.814, and the accuracy of the method reaches 73.8%. Above a cutoff value of 33.7 ng/mL of aMMP-8, the accuracy of the test to detect peri-implantitis reaches 77.5% in relation to 62.5% of BoP from the same site. CONCLUSION: Taken collectively, present data indicate that the aMMP-8 PoC lateral flow immunotest can be a beneficial, adjunctive diagnostic quantitative tool for real-time screening for peri-implant diseases.


Asunto(s)
Biomarcadores , Implantes Dentales , Líquido del Surco Gingival , Metaloproteinasa 8 de la Matriz , Periimplantitis , Humanos , Metaloproteinasa 8 de la Matriz/análisis , Metaloproteinasa 8 de la Matriz/metabolismo , Biomarcadores/análisis , Biomarcadores/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Periimplantitis/diagnóstico , Periimplantitis/metabolismo , Anciano , Implantes Dentales/efectos adversos , Líquido del Surco Gingival/química , Líquido del Surco Gingival/metabolismo , Adulto , Ensayo de Inmunoadsorción Enzimática/métodos , Índice Periodontal , Curva ROC , Proteínas Sanguíneas , Péptidos Catiónicos Antimicrobianos
6.
Brief Bioinform ; 25(4)2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38856169

RESUMEN

Transcriptomic analysis across species is increasingly used to reveal conserved gene regulations which implicate crucial regulators. Cross-species analysis of single-cell RNA sequencing (scRNA-seq) data provides new opportunities to identify the cellular and molecular conservations, especially for cell types and cell type-specific gene regulations. However, few methods have been developed to analyze cross-species scRNA-seq data to uncover both molecular and cellular conservations. Here, we built a tool called CACIMAR, which can perform cross-species analysis of cell identities, markers, regulations, and interactions using scRNA-seq profiles. Based on the weighted sum models of the conserved features, we developed different conservation scores to measure the conservation of cell types, regulatory networks, and intercellular interactions. Using publicly available scRNA-seq data on retinal regeneration in mice, zebrafish, and chick, we demonstrated four main functions of CACIMAR. First, CACIMAR allows to identify conserved cell types even in evolutionarily distant species. Second, the tool facilitates the identification of evolutionarily conserved or species-specific marker genes. Third, CACIMAR enables the identification of conserved intracellular regulations, including cell type-specific regulatory subnetworks and regulators. Lastly, CACIMAR provides a unique feature for identifying conserved intercellular interactions. Overall, CACIMAR facilitates the identification of evolutionarily conserved cell types, marker genes, intracellular regulations, and intercellular interactions, providing insights into the cellular and molecular mechanisms of species evolution.


Asunto(s)
Análisis de Secuencia de ARN , Análisis de la Célula Individual , Pez Cebra , Animales , Análisis de la Célula Individual/métodos , Ratones , Pez Cebra/genética , Análisis de Secuencia de ARN/métodos , Especificidad de la Especie , Programas Informáticos , Redes Reguladoras de Genes , Perfilación de la Expresión Génica/métodos , Pollos , Biomarcadores/metabolismo , Biología Computacional/métodos , Regulación de la Expresión Génica
7.
PLoS One ; 19(6): e0304261, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38870197

RESUMEN

PURPOSE: Patients with Retinitis Pigmentosa (RP) commonly experience sleep-related issues and are susceptible to stress. Moreover, variatiaons in their vision are often linked to anxiety, stress and drowsiness, indicating that stress and sleep deprivation lead to a decline in vision, and vision improves when both are mitigated. The objective of this study was to investigate the utility of salivary biomarkers as biochemical indicators of anxiety and sleep deprivation in RP patients. METHODS: Seventy-eight RP patients and 34 healthy controls were included in this observational study. Anxiety and sleep-quality questionnaires, a complete ophthalmological exam for severity grading and, the collection of salivary samples from participants were assessed for participants. The activity of biomarkers was estimated by ELISA, and statistical analysis was performed to determine associations between the parameters. Associations between underlying psychological factors, grade of disease severity, and biomarkers activity were also examined. RESULTS: Fifty-two (67%) of patients had a severe RP, and 26 (33%) had a mild-moderate grade. Fifty-eight (58,9%) patients reported severe levels of anxiety and 18 (23.,1%) a high level. Forty-six (59%) patients obtained pathological values in sleep-quality questionaries and 43 (55.1%) in sleepiness. Patients with RP exhibited significant differences in testosterone, cortisol, sTNFαRII, sIgA and melatonin as compared to controls and patients with a mild-moderate and advanced stage of disease showed greater differences. In covariate analysis, patients with a severe anxiety level also showed greater differences in mean salivary cortisol, sTNFαRII and melatonin and male patients showed lower IgA levels than female. CONCLUSIONS: The present findings suggest that salivary biomarkers could be suitable non-invasive biochemical markers for the objective assessment of sleep deprivation and anxiety in RP patients. Further research is needed to characterize the effects of untreated negative psychological states and sleep deprivation on increased variability of vision and disease progression, if any.


Asunto(s)
Biomarcadores , Retinitis Pigmentosa , Saliva , Privación de Sueño , Humanos , Masculino , Femenino , Saliva/química , Saliva/metabolismo , Biomarcadores/metabolismo , Biomarcadores/análisis , Retinitis Pigmentosa/metabolismo , Adulto , Persona de Mediana Edad , Privación de Sueño/metabolismo , Estrés Psicológico/metabolismo , Ansiedad/metabolismo , Estudios de Casos y Controles , Hidrocortisona/análisis , Hidrocortisona/metabolismo
8.
Sci Rep ; 14(1): 13619, 2024 06 13.
Artículo en Inglés | MEDLINE | ID: mdl-38871989

RESUMEN

The slow-developing neurological disorder Alzheimer's disease (AD) has no recognized etiology. A bioinformatics investigation verified copper metabolism indicators for AD development. GEO contributed AD-related datasets GSE1297 and GSE5281. Differential expression analysis and WGCNA confirmed biomarker candidate genes. Each immune cell type in AD and control samples was scored using single sample gene set enrichment analysis. Receiver Operating Characteristic (ROC) analysis, short Time-series Expression Miner (STEM) grouping, and expression analysis between control and AD samples discovered copper metabolism indicators that impacted AD progression. We test clinical samples and cellular function to ensure study correctness. Biomarker-targeting miRNAs and lncRNAs were predicted by starBase. Trust website anticipated biomarker-targeting transcription factors. In the end, Cytoscape constructed the TF/miRNA-mRNA and lncRNA-miRNA networks. The DGIdb database predicted biomarker-targeted drugs. We identified 57 differentially expressed copper metabolism-related genes (DE-CMRGs). Next, fourteen copper metabolism indicators impacting AD progression were identified: CCK, ATP6V1E1, SYT1, LDHA, PAM, HPRT1, SCG5, ATP6V1D, GOT1, NFKBIA, SPHK1, MITF, BRCA1, and CD38. A TF/miRNA-mRNA regulation network was then established with two miRNAs (hsa-miR-34a-5p and 34c-5p), six TFs (NFKB1, RELA, MYC, HIF1A, JUN, and SP1), and four biomarkers. The DGIdb database contained 171 drugs targeting ten copper metabolism-relevant biomarkers (BRCA1, MITF, NFKBIA, CD38, CCK2, HPRT1, SPHK1, LDHA, SCG5, and SYT1). Copper metabolism biomarkers CCK, ATP6V1E1, SYT1, LDHA, PAM, HPRT1, SCG5, ATP6V1D, GOT1, NFKBIA, SPHK1, MITF, BRCA1, and CD38 alter AD progression, laying the groundwork for disease pathophysiology and novel AD diagnostic and treatment.


Asunto(s)
Enfermedad de Alzheimer , Biomarcadores , Cobre , Factor de Transcripción Asociado a Microftalmía , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Cobre/metabolismo , Biomarcadores/metabolismo , Factor de Transcripción Asociado a Microftalmía/metabolismo , Factor de Transcripción Asociado a Microftalmía/genética , Redes Reguladoras de Genes , Biología Computacional/métodos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Perfilación de la Expresión Génica
9.
Respir Res ; 25(1): 241, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38872139

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is a chronic disease of unknown etiology that lacks a specific treatment. In IPF, macrophages play a key regulatory role as a major component of the lung immune system, especially during inflammation and fibrosis. However, our understanding of the cellular heterogeneity and molecular characterization of macrophages in IPF, as well as their relevance in the clinical setting, is relatively limited. In this study, we analyzed in-depth single-cell transcriptome sequencing (scRNA-seq) data from lung tissues of IPF patients, identified macrophage subpopulations in IPF, and probed their molecular characteristics and biological functions. hdWGCNA identified co-expressed gene modules of a subpopulation of IPF-associated macrophages (IPF-MΦ), and probed the IPF-MΦ by a machine-learning approach. hdWGCNA identified a subpopulation of IPF-associated macrophage subpopulations and probed the IPF-MΦ signature gene (IRMG) for its prognostic value, and a prediction model was developed on this basis. In addition, IPF-MΦ was obtained after recluster analysis of macrophages in IPF lung tissues. Coexpressed gene modules of IPF-MΦ were identified by hdWGCNA. Then, a machine learning approach was utilized to reveal the characteristic genes of IPF-MΦ, and a prediction model was built on this basis. In addition, we discovered a type of macrophage unique to IPF lung tissue named ATP5-MΦ. Its characteristic gene encodes a subunit of the mitochondrial ATP synthase complex, which is closely related to oxidative phosphorylation and proton transmembrane transport, suggesting that ATP5-MΦ may have higher ATP synthesis capacity in IPF lung tissue. This study provides new insights into the pathogenesis of IPF and provides a basis for evaluating disease prognosis and predictive medicine in IPF patients.


Asunto(s)
Biomarcadores , Fibrosis Pulmonar Idiopática , Aprendizaje Automático , Macrófagos , Análisis de la Célula Individual , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/patología , Humanos , Análisis de la Célula Individual/métodos , Macrófagos/metabolismo , Biomarcadores/metabolismo , Masculino , Femenino , Pulmón/metabolismo , Pulmón/patología
10.
Inhal Toxicol ; 36(4): 261-274, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38836331

RESUMEN

OBJECTIVE: Our work is focused on tungsten, considered as an emerging contaminant. Its environmental dispersion is partly due to mining and military activities. Exposure scenario can also be occupational, in areas such as the hard metal industry and specific nuclear facilities. Our study investigated the cerebral effects induced by the inhalation of tungsten particles. METHODS: Inhalation exposure campaigns were carried out at two different concentrations (5 and 80 mg/m3) in single and repeated modes (4 consecutive days) in adult rats within a nose-only inhalation chamber. Processes involved in brain toxicity were investigated 24 h after exposure. RESULTS AND DISCUSSION: Site-specific effects in terms of neuroanatomy and concentration-dependent changes in specific cellular actors were observed. Results obtained in the olfactory bulb suggest a potential early effect on the survival of microglial cells. Depending on the mode of exposure, these cells showed a decrease in density accompanied by an increase in an apoptotic marker. An abnormal phenotype of the nuclei of mature neurons, suggesting neuronal suffering, was also observed in the frontal cortex, and can be linked to the involvement of oxidative stress. The differential effects observed according to exposure patterns could involve two components: local (brain-specific) and/or systemic. Indeed, tungsten, in addition to being found in the lungs and kidneys, was present in the brain of animals exposed to the high concentration. CONCLUSION: Our data question the perceived innocuity of tungsten relative to other metals and raise hypotheses regarding possible adaptive or neurotoxic mechanisms that could ultimately alter neuronal integrity.


Asunto(s)
Encéfalo , Exposición por Inhalación , Ratas Wistar , Tungsteno , Animales , Tungsteno/toxicidad , Masculino , Exposición por Inhalación/efectos adversos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ratas , Biomarcadores/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/metabolismo , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos
11.
Cell Mol Biol (Noisy-le-grand) ; 70(6): 114-121, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38836671

RESUMEN

Key features of Alzheimer's disease include neuronal loss, accumulation of beta-amyloid plaques, and formation of neurofibrillary tangles. These changes are due in part to abnormal protein metabolism, particularly the accumulation of amyloid beta. Mitochondria are the energy production centers within cells and are also the main source of oxidative stress. In AD, mitochondrial function is impaired, leading to increased oxidative stress and the production of more reactive oxidative substances, further damaging cells. Mitophagy is an important mechanism for maintaining mitochondrial health, helping to clear damaged mitochondria, prevent the spread of oxidative stress, and reduce abnormal protein aggregation. To this end, this article conducts an integrated analysis based on DNA methylation and transcriptome data of AD. After taking the intersection of the genes where the differential methylation sites are located and the differential genes, machine learning methods were used to build an AD diagnostic model. This article screened five diagnostic genes ATG12, CSNK2A2, CSNK2B, MFN1 and PGAM5 and conducted experimental verification. The diagnostic genes discovered and the diagnostic model constructed in this article can provide reference for the development of clinical diagnostic models for AD.


Asunto(s)
Enfermedad de Alzheimer , Autofagia , Metilación de ADN , Mitocondrias , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Humanos , Mitocondrias/genética , Mitocondrias/metabolismo , Autofagia/genética , Metilación de ADN/genética , Biomarcadores/metabolismo , Mitofagia/genética , Transcriptoma/genética , Aprendizaje Automático , Multiómica
12.
Sci Transl Med ; 16(750): eadh0185, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38838133

RESUMEN

Sepsis, the dysregulated host response to infection causing life-threatening organ dysfunction, is a global health challenge requiring better understanding of pathophysiology and new therapeutic approaches. Here, we applied high-throughput tandem mass spectrometry to delineate the plasma proteome for sepsis and comparator groups (noninfected critical illness, postoperative inflammation, and healthy volunteers) involving 2612 samples (from 1611 patients) and 4553 liquid chromatography-mass spectrometry analyses acquired through a single batch of continuous measurements, with a throughput of 100 samples per day. We show how this scale of data can delineate proteins, pathways, and coexpression modules in sepsis and be integrated with paired leukocyte transcriptomic data (837 samples from n = 649 patients). We mapped the plasma proteomic landscape of the host response in sepsis, including changes over time, and identified features relating to etiology, clinical phenotypes (including organ failures), and severity. This work reveals subphenotypes informative for sepsis response state, disease processes, and outcome; identifies potential biomarkers; and advances opportunities for a precision medicine approach to sepsis.


Asunto(s)
Proteoma , Sepsis , Humanos , Sepsis/sangre , Proteoma/metabolismo , Biomarcadores/sangre , Biomarcadores/metabolismo , Proteómica/métodos , Masculino , Proteínas Sanguíneas/metabolismo , Proteínas Sanguíneas/análisis , Femenino , Persona de Mediana Edad , Espectrometría de Masas en Tándem/métodos
13.
Ren Fail ; 46(2): 2359638, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38832484

RESUMEN

Emerging data have revealed that damage to tubular epithelial cell is a driving force in the progression of diabetic kidney disease (DKD). However, the specific mechanisms by which lipotoxicity contributes to the injury of these cells, thereby influencing the development of DKD, are yet to be fully understood. Here, we analyzed the GSE 30529 microarray datasets of human tubulointerstitial tissue samples from the Gene Expression Omnibus database (GEO). Concurrently, we conducted RNA-sequencing on palmitic acid (PA)-treated human renal proximal tubule epithelial cells (HK2 cells). After normalization, the differentially expressed genes (DEGs) were screened by R software and gene ontology (GO) enrichment analysis was conducted, and lysosomal-associated protein transmembrane 5 (LAPTM5) was finally selected. Our findings indicate that the expression of LAPTM5 was obviously increased in DKD patients, and the correlation between LAPTM5, and other clinical parameters of DKD was analyzed using the Spearman correlation analysis. The potential of LAPTM5 as a prognostic biomarker for DKD was further consolidated through receiver operating characteristic (ROC) analysis. To further verify the function of LAPTM5, we established mouse or in vitro systems mimicking DKD. The results showed that a consistent upregulation of LAPTM5, which was also found to be linked with inflammatory mediators within the context of DKD. Additionally, LAPTM5 silencing significantly downregulated mRNA expression of inflammatory factors in PA-treated HK2 cells. These results indicate that LAPTM5 is a potential biomarker and therapeutic treatment target for DKD. This discovery paves the way for future research and development of targeted interventions aimed at mitigating the progression of this prevalent condition.


Asunto(s)
Biología Computacional , Nefropatías Diabéticas , Proteínas de la Membrana , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/patología , Humanos , Animales , Ratones , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Línea Celular , Ácido Palmítico/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Regulación hacia Arriba , Biomarcadores/metabolismo
14.
Sci Rep ; 14(1): 13044, 2024 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-38844441

RESUMEN

High intraocular pressure (IOP) is one of the early complications after pars plana vitrectomy (PPV), which may cause glaucoma and poor visual prognosis secondary to surgery. Proliferative vitreoretinopathy (PVR) is one of the complications of retinal detachment (RD) and is the main reason for the poor prognosis, which is related to different kinds of cytokines. It's essential for the basic mechanism to analyze the relative aqueous humor cytokine profiles with IOP after PPV for RD. In this study, we have collected the aqueous humor of 16 patients and qualified 27 cytokines using Luminex and compared biomarkers with the high IOP group and the normal group. As a result, the concentrations of VEGF, IL-6, FGF2, and G-CSF upregulated significantly (P < 0.05), while VEGFR2 downregulated significantly (P < 0.05) in the high IOP group. IL-6 was positively correlated with high IOP (r = 0.561, P = 0.041). Meanwhile, the concentrations of IL-6 (r = 0.543, P = 0.03), IL-5 (r = 0.576, P = 0.019), IL-15 (r = 0.614, P = 0.011), IL-4 (r = 0.517, P = 0.04), ICAM-1 (r = 0.611, P = 0.012), and G-CSF (r = 0.636, P = 0.008) were significantly associated with preoperative PVR classification, and the aqueous humor levels of IL-4 (r = 0.567, P = 0.022), HGF (r = 0.701, P = 0.005), and MCP-1 (r = 0.565, P = 0.035) are significant relative to laser points. Hence, cytokines might potentially be the therapeutic target of high IOP after PPV.


Asunto(s)
Humor Acuoso , Citocinas , Presión Intraocular , Desprendimiento de Retina , Vitrectomía , Humanos , Desprendimiento de Retina/cirugía , Desprendimiento de Retina/metabolismo , Humor Acuoso/metabolismo , Femenino , Masculino , Citocinas/metabolismo , Presión Intraocular/fisiología , Persona de Mediana Edad , Vitrectomía/efectos adversos , Anciano , Adulto , Biomarcadores/metabolismo , Vitreorretinopatía Proliferativa/metabolismo , Vitreorretinopatía Proliferativa/etiología
15.
BMC Pulm Med ; 24(1): 271, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38844923

RESUMEN

BACKGROUND: This study leverages a two-sample Mendelian Randomization (MR) approach to explore the causal relationships between 1,400 metabolites and pulmonary fibrosis, using genetic variation as instrumental variables. By adhering to stringent criteria for instrumental variable selection, the research aims to uncover metabolic pathways that may influence the risk and progression of pulmonary fibrosis, providing insights into potential therapeutic targets. METHODS: Utilizing data from the OpenGWAS project, which includes a significant European cohort, and metabolite GWAS data from the Canadian Longitudinal Aging Study (CLSA), the study employs advanced statistical methods. These include inverse variance weighting (IVW), weighted median estimations, and comprehensive sensitivity analyses conducted using the R software environment to ensure the robustness of the causal inferences. RESULTS: The study identified 62 metabolites with significant causal relationships with pulmonary fibrosis, highlighting both risk-enhancing and protective metabolic factors. This extensive list of metabolites presents a broad spectrum of potential therapeutic targets and biomarkers for early detection, underscoring the metabolic complexity underlying pulmonary fibrosis. CONCLUSIONS: The findings from this MR study significantly advance our understanding of the metabolic underpinnings of pulmonary fibrosis, suggesting that alterations in specific metabolites could influence the risk and progression of the disease. These insights pave the way for the development of novel diagnostic and therapeutic strategies, emphasizing the potential of metabolic modulation in managing pulmonary fibrosis.


Asunto(s)
Análisis de la Aleatorización Mendeliana , Metabolómica , Fibrosis Pulmonar , Humanos , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo , Canadá/epidemiología , Estudio de Asociación del Genoma Completo , Biomarcadores/metabolismo , Biomarcadores/sangre , Progresión de la Enfermedad , Estudios Longitudinales , Masculino , Polimorfismo de Nucleótido Simple , Femenino
16.
Medicine (Baltimore) ; 103(23): e38484, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38847679

RESUMEN

The correlation between hematopoietic cell-specific lyn substrate 1 (HCLS1) expression levels and heart failure (HF) remains unclear. HF datasets GSE192886 and GSE196656 profiles were generated from GPL24676 and GPL20301 platforms in gene expression omnibus (GEO) database and differentially expressed genes (DEGs) were obtained, which was followed by weighted gene co-expression network analysis, protein-protein interaction (PPI) networks, functional enrichment analysis and comparative toxicogenomics database (CTD) analysis. Heatmaps of gene expression levels were plotted. TargetScan was used to screen miRNAs regulating central DEGs. A total of 500 DEGs were found and mainly concentrated in leukocyte activation, protein phosphorylation, and protein complexes involved in cell adhesion, PI3K Akt signaling pathway, Notch signaling pathway, and right ventricular cardiomyopathy. PPI network identified 15 core genes (HCLS1, FERMT3, CD53, CD34, ITGAL, EP300, LYN, VAV1, ITGAX, LEP, ITGB1, IGF1, MMP9, SMAD2, RAC2). Heatmap shows that 4 genes (EP300, CD53, HCLS1, LYN) are highly expressed in HF tissue samples. We found that 4 genes (EP300, CD53, HCLS1, LYN) were associated with heart diseases, cardiovascular diseases, edema, rheumatoid arthritis, necrosis, and inflammation. HCLS1 is highly expressed in HF and maybe its target.


Asunto(s)
Biomarcadores , Insuficiencia Cardíaca , Humanos , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Biomarcadores/metabolismo , Mapas de Interacción de Proteínas/genética , MicroARNs/metabolismo , MicroARNs/genética , Perfilación de la Expresión Génica
17.
Transl Neurodegener ; 13(1): 29, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38831349

RESUMEN

TDP-43 proteinopathies are a heterogeneous group of neurodegenerative disorders that share the presence of aberrant, misfolded and mislocalized deposits of the protein TDP-43, as in the case of amyotrophic lateral sclerosis and some, but not all, pathological variants of frontotemporal dementia. In recent years, many other diseases have been reported to have primary or secondary TDP-43 proteinopathy, such as Alzheimer's disease, Huntington's disease or the recently described limbic-predominant age-related TDP-43 encephalopathy, highlighting the need for new and accurate methods for the early detection of TDP-43 proteinopathy to help on the stratification of patients with overlapping clinical diagnosis. Currently, TDP-43 proteinopathy remains a post-mortem pathologic diagnosis. Although the main aim is to determine the pathologic TDP-43 proteinopathy in the central nervous system (CNS), the ubiquitous expression of TDP-43 in biofluids and cells outside the CNS facilitates the use of other accessible target tissues that might reflect the potential TDP-43 alterations in the brain. In this review, we describe the main developments in the early detection of TDP-43 proteinopathies, and their potential implications on diagnosis and future treatments.


Asunto(s)
Biomarcadores , Proteínas de Unión al ADN , Proteinopatías TDP-43 , Humanos , Proteinopatías TDP-43/diagnóstico , Proteinopatías TDP-43/metabolismo , Proteinopatías TDP-43/genética , Biomarcadores/análisis , Biomarcadores/metabolismo , Proteínas de Unión al ADN/metabolismo , Encéfalo/metabolismo , Encéfalo/patología
18.
PLoS One ; 19(6): e0299764, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38837947

RESUMEN

BACKGROUND: Increased blood-brain barrier permeability (BBBp) has been hypothesized as a feature of aging that may lead to the development of Alzheimer's disease (AD). We sought to identify the brain regions most vulnerable to greater BBBp during aging and examine their regional relationship with neuroimaging biomarkers of AD. METHODS: We studied 31 cognitively normal older adults (OA) and 10 young adults (YA) from the Berkeley Aging Cohort Study (BACS). Both OA and YA received dynamic contrast-enhanced MRI (DCE-MRI) to quantify Ktrans values, as a measure of BBBp, in 37 brain regions across the cortex. The OA also received Pittsburgh compound B (PiB)-PET to create distribution volume ratios (DVR) images and flortaucipir (FTP)- PET to create partial volume corrected standardized uptake volume ratios (SUVR) images. Repeated measures ANOVA assessed the brain regions where OA showed greater BBBp than YA. In OA, Ktrans values were compared based on sex, Aß positivity status, and APOE4 carrier status within a composite region across the areas susceptible to aging. We used linear models and sparse canonical correlation analysis (SCCA) to examine the relationship between Ktrans and AD biomarkers. RESULTS: OA showed greater BBBp than YA predominately in the temporal lobe, with some involvement of parietal, occipital and frontal lobes. Within an averaged ROI of affected regions, there was no difference in Ktrans values based on sex or Aß positivity, but OA who were APOE4 carriers had significantly higher Ktrans values. There was no direct relationship between averaged Ktrans and global Aß pathology, but there was a trend for an Ab status by tau interaction on Ktrans in this region. SCCA showed increased Ktrans was associated with increased PiB DVR, mainly in temporal and parietal brain regions. There was not a significant relationship between Ktrans and FTP SUVR. DISCUSSION: Our findings indicate that the BBB shows regional vulnerability during normal aging that overlaps considerably with the pattern of AD pathology. Greater BBBp in brain regions affected in aging is related to APOE genotype and may also be related to the pathological accumulation of Aß.


Asunto(s)
Envejecimiento , Enfermedad de Alzheimer , Biomarcadores , Barrera Hematoencefálica , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Masculino , Femenino , Barrera Hematoencefálica/metabolismo , Anciano , Biomarcadores/metabolismo , Envejecimiento/metabolismo , Anciano de 80 o más Años , Adulto , Cognición , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Adulto Joven , Persona de Mediana Edad , Estudios de Cohortes
19.
Sci Rep ; 14(1): 12981, 2024 06 05.
Artículo en Inglés | MEDLINE | ID: mdl-38839916

RESUMEN

Micro RNAs (miRNAs, miRs) and relevant networks might exert crucial functions during differential host cell infection by the different Leishmania species. Thus, a bioinformatic analysis of microarray datasets was developed to identify pivotal shared biomarkers and miRNA-based regulatory networks for Leishmaniasis. A transcriptomic analysis by employing a comprehensive set of gene expression profiling microarrays was conducted to identify the key genes and miRNAs relevant for Leishmania spp. infections. Accordingly, the gene expression profiles of healthy human controls were compared with those of individuals infected with Leishmania mexicana, L. major, L. donovani, and L. braziliensis. The enrichment analysis for datasets was conducted by utilizing EnrichR database, and Protein-Protein Interaction (PPI) network to identify the hub genes. The prognostic value of hub genes was assessed by using receiver operating characteristic (ROC) curves. Finally, the miRNAs that interact with the hub genes were identified using miRTarBase, miRWalk, TargetScan, and miRNet. Differentially expressed genes were identified between the groups compared in this study. These genes were significantly enriched in inflammatory responses, cytokine-mediated signaling pathways and granulocyte and neutrophil chemotaxis responses. The identification of hub genes of recruited datasets suggested that TNF, SOCS3, JUN, TNFAIP3, and CXCL9 may serve as potential infection biomarkers and could deserve value as prognostic biomarkers for leishmaniasis. Additionally, inferred data from miRWalk revealed a significant degree of interaction of a number of miRNAs (hsa-miR-8085, hsa-miR-4673, hsa-miR-4743-3p, hsa-miR-892c-3p, hsa-miR-4644, hsa-miR-671-5p, hsa-miR-7106-5p, hsa-miR-4267, hsa-miR-5196-5p, and hsa-miR-4252) with the majority of the hub genes, suggesting such miRNAs play a crucial role afterwards parasite infection. The hub genes and hub miRNAs identified in this study could be potentially suggested as therapeutic targets or biomarkers for the management of leishmaniasis.


Asunto(s)
Biomarcadores , Biología Computacional , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Leishmaniasis , MicroARNs , Mapas de Interacción de Proteínas , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Leishmaniasis/genética , Leishmaniasis/parasitología , Biología Computacional/métodos , Biomarcadores/metabolismo , Perfilación de la Expresión Génica/métodos , Mapas de Interacción de Proteínas/genética , Transcriptoma , Leishmania/genética
20.
Acta Neuropathol Commun ; 12(1): 85, 2024 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-38822433

RESUMEN

Here, we test whether early visual and OCT rod energy-linked biomarkers indicating pathophysiology in nicotinamide nucleotide transhydrogenase (Nnt)-null 5xFAD mice also occur in Nnt-intact 5xFAD mice and whether these biomarkers can be pharmacologically treated. Four-month-old wild-type or 5xFAD C57BL/6 substrains with either a null (B6J) Nnt or intact Nnt gene (B6NTac) and 5xFAD B6J mice treated for one month with either R-carvedilol + vehicle or only vehicle (0.01% DMSO) were studied. The contrast sensitivity (CS), external limiting membrane-retinal pigment epithelium (ELM-RPE) thickness (a proxy for low pH-triggered water removal), profile shape of the hyperreflective band just posterior to the ELM (i.e., the mitochondrial configuration within photoreceptors per aspect ratio [MCP/AR]), and retinal laminar thickness were measured. Both wild-type substrains showed similar visual performance indices and dark-evoked ELM-RPE contraction. The lack of a light-dark change in B6NTac MCP/AR, unlike in B6J mice, is consistent with relatively greater mitochondrial efficiency. 5xFAD B6J mice, but not 5xFAD B6NTac mice, showed lower-than-WT CS. Light-adapted 5xFAD substrains both showed abnormal ELM-RPE contraction and greater-than-WT MCP/AR contraction. The inner retina and superior outer retina were thinner. Treating 5xFAD B6J mice with R-carvedilol + DMSO or DMSO alone corrected CS and ELM-RPE contraction but not supernormal MCP/AR contraction or laminar thinning. These results provide biomarker evidence for prodromal photoreceptor mitochondrial dysfunction/oxidative stress/oxidative damage, which is unrelated to visual performance, as well as the presence of the Nnt gene. This pathophysiology is druggable in 5xFAD mice.


Asunto(s)
Dimetilsulfóxido , Ratones Endogámicos C57BL , Animales , Ratones , Dimetilsulfóxido/farmacología , Biomarcadores/metabolismo , Ratones Transgénicos , Tomografía de Coherencia Óptica , Células Fotorreceptoras Retinianas Bastones/efectos de los fármacos , Sensibilidad de Contraste/efectos de los fármacos , Sensibilidad de Contraste/fisiología , Modelos Animales de Enfermedad , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/patología , Epitelio Pigmentado de la Retina/metabolismo , Visión Ocular/efectos de los fármacos , Visión Ocular/fisiología
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