RESUMO
Remarkable progress has occurred over the past two decades in identifying microbiomes affecting the human body in numerous ways. The microbiome is linked to gastrointestinal (GI) tract cancer. The purpose of this study was to determine if there is a common microbiome among GI tract cancers and how the microbiome affects the disease. To ensure ethnic consistency, Korean patients with GI tract cancer were selected. Fusobacterium nucleatum is an enriched bacteria in all cancer tissues. F. nucleatum is a Gram-negative obligate anaerobe that promotes colorectal cancer. Through Gene Set Enrichment Analysis (GSEA) and Differentially Expressed Genes (DEG) analyses, the upregulation of the G2M checkpoint pathway was identified in the F. nucleatum-high group. Cell viability and G2M checkpoint pathway genes were examined in MC 38 cells treated with F. nucleatum. F. nucleatum upregulated the expression of G2M checkpoint pathway genes and the cell proliferation of MC 38 cells. F. nucleatum facilitated cancer's use of G2M checkpoint pathways and F. nucleatum could be a therapeutic target in Korean GI tract cancer.
RESUMO
Disruption of the skin microbial balance can exacerbate certain skin diseases and affect prognosis and treatment. Changes in the distribution and prevalence of certain microbial species on the skin, such as Staphylococcus aureus (SA), can impact the development of severe atopic dermatitis (AD) or psoriasis (Pso). A dysfunctional skin barrier develops in AD and Pso due to SA colonization, resulting in keratinization and chronic or progressive chronic inflammation. Disruption of the skin barrier following SA colonization can elevate the production of T helper 2 (Th2)-derived cytokines, which can cause an imbalance in Th1, Th2, and Th17 cells. This study examined the ability of potential therapeutic skin microbiomes, such as Cutibacterium avidum R-CH3 and Staphylococcus hominis R9, to inhibit SA biofilm formation and restore skin barrier function-related genes through the activation of the aryl hydrocarbon receptor (AhR) and the nuclear factor erythroid-2-related factor 2 (Nrf2) downstream target. We observed that IL-4/IL-13-induced downregulation of FLG, LOR, and IVL induced by SA colonization could be reversed by dual AhR/Nrf2 activation. Further, OVOL1 expression may be modulated by functional microbiomes via dual AhR/Nrf2 activation. Our results suggest that our potential therapeutic skin microbiomes can prevent SA-derived Th2-biased skin barrier disruption via IL-13 and IL-4-dependent FLG deregulation, STAT3 activation, and AhR-mediated STAT6 expression.
Assuntos
Microbiota , Psoríase , Receptores de Hidrocarboneto Arílico , Staphylococcus aureus , Humanos , Imunidade , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Proteínas de Filamentos Intermediários/genética , Queratinócitos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Psoríase/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Pele/metabolismo , Pele/microbiologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/metabolismoRESUMO
The skin supports a diverse microbiome whose imbalance is related to skin inflammation and diseases. Exposure to fine particulate matter (PM2.5), a major air pollutant, can adversely affect the skin microbiota equilibrium. In this study, the effect and mechanism of PM2.5 exposure in HaCaT keratinocytes were investigated. PM2.5 stimulated the aryl hydrocarbon receptor (AhR) to produce reactive oxygen species (ROS) in HaCaT cells, leading to mitochondrial dysfunction and intrinsic mitochondrial apoptosis. We observed that the culture medium derived from a particular skin microbe, Staphylococcus epidermidis WF2R11, remarkably reduced oxidative stress in HaCaT cells caused by PM2.5-mediated activation of the AhR pathway. Staphylococcus epidermidis WF2R11 also exhibited inhibition of ROS-induced inflammatory cytokine secretion. Herein, we demonstrated that S. epidermidis WF2R11 could act as a suppressor of AhRs, affect cell proliferation, and inhibit apoptosis. Our results highlight the importance of the clinical application of skin microbiome interventions in the treatment of inflammatory skin diseases.
Assuntos
Receptores de Hidrocarboneto Arílico , Staphylococcus epidermidis , Células HaCaT , Humanos , Queratinócitos , Material Particulado/metabolismo , Material Particulado/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismoRESUMO
The identification of predictive biomarkers or models is necessary for the selection of patients who might benefit the most from immunotherapy. Seven histological features (signet ring cell [SRC], fibrous stroma, myxoid stroma, tumor-infiltrating lymphocytes [TILs], necrosis, tertiary lymphoid follicles, and ulceration) detected in surgically resected tissues (N = 44) were used to train a model. The presence of SRC became an optimal decision parameter for pathology alone (AUC = 0.78). Analysis of differentially expressed genes (DEGs) for the prediction of genomic markers showed that C-X-C motif chemokine ligand 11 (CXCL11) was high in responders (P < 0.001). Immunohistochemistry (IHC) was performed to verify its potential as a biomarker. IHC revealed that the expression of CXCL11 was associated with responsiveness (P = 0.003). The response prediction model was trained by integrating the results of the analysis of pathological factors and RNA sequencing (RNA-seq). When trained with the C5.0 decision tree model, the categorical level of the expression of CXCL11, a single variable, was shown to be the best model (AUC = 0.812). The AUC of the model trained with the random forest was 0.944. Survival analysis revealed that the C5.0-trained model (log-rank P = 0.01 for progression-free survival [PFS]; log-rank P = 0.012 for overall survival [OS]) and the random forest-trained model (log-rank P < 0.001 for PFS; log-rank P = 0.001 for OS) predicted prognosis more accurately than the PD-L1 test (log-rank P = 0.031 for PFS; log-rank P = 0.107 for OS).
Assuntos
Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Terapia de Alvo Molecular , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Bases de Dados Genéticas , Gerenciamento Clínico , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Curva ROC , Reprodutibilidade dos Testes , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/etiologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
Recently, several capsular stroke models have been reported with different targets of destruction. This study was performed to establish an accurate internal capsule (IC) target for capsular stroke modeling in rats. We injected adeno-associated virus serotype 5 (AAV)-CaMKII-EYFP into forelimb motor cortex and AAV-CaMKII-mCherry into hindlimb motor cortex (n = 9) to anterogradely trace the pyramidal fibers and map their somatotopic distribution in the IC. On the basis of the neural tracing results, we created photothrombotic infarct lesions in rat forelimb and hindlimb motor fiber (FMF and HMF) areas of the IC (n = 29) and assessed motor behavior using a forelimb-use asymmetry test, a foot-fault test, and a single-pellet reaching test. We found that the FMFs and HMFs were primarily distributed in the inferior portion of the posterior limb of the IC, with the FMFs located largely ventral to the HMFs but with an area of partial overlap. Photothrombotic lesions in the FMF area resulted in persistent motor deficits. In contrast, lesions in the HMF area did not result in persistent motor deficits. These results indicate that identification of the somatotopic distribution of pyramidal fibers is critical for accurate targeting in animal capsular stroke models: only infarcts in the FMF area resulted in long-lasting motor deficits.