RESUMEN
BACKGROUND AND AIMS: Hepatitis B virus (HBV)-associated liver cirrhosis (LC), a common condition with high incidence and mortality rates, is often associated with diabetes mellitus (DM). However, the molecular mechanisms underlying impaired glucose regulation during HBV-associated LC remain unclear. METHODS: Data from 63 patients with LC and 62 patients with LC-associated DM were analysed. Co-culture of NK cells and islet ß cell lines were used to study the glucose regulation mechanism. A mouse model of LC was used to verify the effect of S100A8/A9 on the glucose regulation. RESULTS: Higher levels of interferon (IFN)-γ derived from natural killer (NK) cells and lower levels of insulin emerged in the peripheral blood of patients with both LC and DM compared with those from patients with LC only. IFN-γ derived from NK cells facilitated ß cell necroptosis and impaired insulin production. Furthermore, S100A8/A9 elevation in patients with both LC and DM was found to upregulate IFN-γ production in NK cells. Consistently, in the mouse model for LC, mice treated with carbon tetrachloride (CCL4) and S100A8/A9 exhibited increased blood glucose, impaired insulin production, increased IFN-γ, and increased ß cells necroptosis compared with those treated with CCL4. Mechanistically, S100A8/A9 activated the p38 MAPK pathway to increase IFN-γ production in NK cells. These effects were diminished after blocking RAGE. CONCLUSION: Together, the data indicate that IFN-γ produced by NK cells induces ß cell necroptosis via the S100A8/A9-RAGE-p38 MAPK axis in patients with LC and DM. Reduced levels of S100A8/A9, NK cells, and IFN-γ could be valuable for the treatment of LC with DM. Accumulation of S100A8/A9 in patients with LC may indicate the emergence of DM.
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Calgranulina A , Calgranulina B , Virus de la Hepatitis B , Células Secretoras de Insulina , Interferón gamma , Células Asesinas Naturales , Cirrosis Hepática , Necroptosis , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Humanos , Animales , Interferón gamma/metabolismo , Calgranulina B/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/virología , Cirrosis Hepática/inmunología , Ratones , Masculino , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Células Secretoras de Insulina/virología , Calgranulina A/metabolismo , Ratones Endogámicos C57BL , Femenino , Persona de Mediana Edad , Hepatitis B/complicaciones , Hepatitis B/patología , Hepatitis B/metabolismo , Modelos Animales de Enfermedad , Tetracloruro de CarbonoRESUMEN
OBJECTIVES: To investigate the role of calprotectin S100 A8/A9 complex in evaluating the condition of children with severe Mycoplasma pneumoniae pneumonia (SMPP). METHODS: A prospective study was conducted among 136 children with Mycoplasma pneumoniae pneumonia (MPP) and 30 healthy controls. According to the severity of the condition, the children with MPP were divided into mild subgroup (40 children) and SMPP subgroup (96 children). The levels of S100 A8/A9 complex and related inflammatory factors were compared between the MPP group and the healthy control group, as well as between the two subgroups of MPP. The role of S100 A8/A9 in assessing the severity of MPP was explored. RESULTS: The MPP group had a significantly higher level of S100 A8/A9 than the healthy control group, with a significantly greater increase in the SMPP subgroup (P<0.05). The multivariate logistic regression analysis showed that the increases in serum C reactive protein (CRP) and S100A8/A9 were closely associated with SMPP (P<0.05). The receiver operating characteristic (ROC) curve analysis showed that the combined measurement of serum S100 A8/A9 and CRP had an area under the ROC curve of 0.904 in predicting SMPP, which was significantly higher than the AUC of S100 A8/A9 or CRP alone (P<0.05), with a specificity of 0.718 and a sensitivity of 0.952. CONCLUSIONS: S100 A8/A9 is closely associated with the severity of MPP, and the combination of S100 A8/A9 with CRP is more advantageous for assessing the severity of MPP in children.
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Calgranulina A , Calgranulina B , Neumonía por Mycoplasma , Humanos , Neumonía por Mycoplasma/sangre , Neumonía por Mycoplasma/diagnóstico , Masculino , Femenino , Calgranulina A/sangre , Calgranulina B/sangre , Preescolar , Niño , Estudios Prospectivos , Modelos Logísticos , Índice de Severidad de la Enfermedad , Proteína C-Reactiva/análisis , Complejo de Antígeno L1 de Leucocito/sangre , Complejo de Antígeno L1 de Leucocito/análisis , LactanteRESUMEN
Acne vulgaris, rosacea, and hidradenitis suppurativa are enduring inflammatory skin conditions that frequently manifest with akin clinical attributes, posing a considerable challenge for their distinctive diagnosis. While these conditions do exhibit certain resemblances, they also demonstrate distinct underlying pathophysiological mechanisms and treatment modalities. Delving into both the molecular parallels and disparities among these three disorders can yield invaluable insights for refined diagnostics, effective management, and targeted therapeutic interventions. In this report, we present a comparative analysis of transcriptomic data across these three diseases, elucidating differentially expressed genes and enriched pathways specific to each ailment, as well as those shared among them. Specifically, we identified multiple zinc-binding proteins (SERPINA1, S100A7, S100A8, S100A9 and KRT16) as consistently highly upregulated genes across all three diseases. Our hypothesis suggests that these proteins could bind and sequester zinc, potentially leading to localized zinc deficiency and heightened inflammation. We identified high-dose dietary zinc as a promising therapeutic approach and confirmed its effectiveness through validation in an acne mouse model.
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Acné Vulgar , Perfilación de la Expresión Génica , Hidradenitis Supurativa , Rosácea , Zinc , Acné Vulgar/tratamiento farmacológico , Acné Vulgar/genética , Zinc/uso terapéutico , Zinc/metabolismo , Rosácea/tratamiento farmacológico , Rosácea/genética , Hidradenitis Supurativa/tratamiento farmacológico , Hidradenitis Supurativa/genética , Animales , Ratones , Humanos , Proteína A7 de Unión a Calcio de la Familia S100/metabolismo , Proteína A7 de Unión a Calcio de la Familia S100/genética , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Transcriptoma , Proteínas S100/genética , Proteínas S100/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Modelos Animales de Enfermedad , Regulación hacia ArribaRESUMEN
Herein, we aimed to identify blood biomarkers that compensate for the poor specificity of D-dimer in the diagnosis of deep vein thrombosis (DVT). S100A8 was identified by conducting protein microarray analysis of blood samples from patients with and without DVT. We used ELISA to detect S100A8, VCAM-1, and ICAM-1 expression levels in human blood and evaluated their correlations. Additionally, we employed human recombinant protein S100A8 to induce human umbilical vein endothelial cells and examined the role of the TLR4/MAPK/VCAM-1 and ICAM-1 signaling axes in the pathogenic mechanism of S100A8. Simultaneously, we constructed a rat model of thrombosis induced by inferior vena cava stenosis and detected levels of S100A8, VCAM-1, and ICAM-1 in the blood of DVT rats using ELISA. The associations of thrombus tissue, neutrophils, and CD68-positive cells with S100A8 and p38MAPK, TLR4, and VCAM-1 expression levels in vein walls were explored. The results revealed that blood S100A8 was significantly upregulated during the acute phase of DVT and activated p38MAPK expression by combining with TLR4 to enhance the expression and secretion of VCAM-1 and ICAM-1, thereby affecting the occurrence and development of DVT. Therefore, S100A8 could be a potential biomarker for early diagnosis and screening of DVT.
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Biomarcadores , Calgranulina A , Molécula 1 de Adhesión Intercelular , Molécula 1 de Adhesión Celular Vascular , Trombosis de la Vena , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/metabolismo , Trombosis de la Vena/sangre , Humanos , Calgranulina A/sangre , Calgranulina A/metabolismo , Biomarcadores/sangre , Animales , Molécula 1 de Adhesión Celular Vascular/metabolismo , Molécula 1 de Adhesión Celular Vascular/sangre , Molécula 1 de Adhesión Intercelular/sangre , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Ratas , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Persona de Mediana Edad , Femenino , Receptor Toll-Like 4/metabolismo , Transducción de Señal , Modelos Animales de Enfermedad , Adulto , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoAsunto(s)
Actinas , Neoplasias de la Mama , Calgranulina A , Calgranulina B , Movimiento Celular , Transición Epitelial-Mesenquimal , Humanos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Femenino , Actinas/metabolismo , Calgranulina B/metabolismo , Calgranulina B/genética , Calgranulina A/metabolismo , Calgranulina A/genética , Línea Celular Tumoral , Invasividad Neoplásica , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Receptor para Productos Finales de Glicación Avanzada/genética , PolimerizacionRESUMEN
Neutrophils play important roles in inflammatory airway diseases. In this study, we assessed whether apolipoprotein A-I modifies neutrophil heterogeneity as part of the mechanism by which it attenuates acute airway inflammation. Neutrophilic airway inflammation was induced by daily intranasal administration of LPS plus house dust mite (LPS+HDM) to Apoa1-/- and Apoa1+/+ mice for 3 d. Single-cell RNA sequencing was performed on cells recovered from bronchoalveolar lavage fluid on day 4. Unsupervised profiling identified 10 clusters of neutrophils in bronchoalveolar lavage fluid from Apoa1-/- and Apoa1+/+ mice. LPS+HDM-challenged Apoa1-/- mice had an increased proportion of the Neu4 neutrophil cluster that expressed S100a8, S100a9, and Mmp8 and had high maturation, aggregation, and TLR4 binding scores. There was also an increase in the Neu6 cluster of immature neutrophils, whereas neutrophil clusters expressing IFN-stimulated genes were decreased. An unsupervised trajectory analysis showed that Neu4 represented a distinct lineage in Apoa1-/- mice. LPS+HDM-challenged Apoa1-/- mice also had an increased proportion of recruited airspace macrophages, which was associated with a reciprocal reduction in resident airspace macrophages. Increased expression of a common set of proinflammatory genes, S100a8, S100a9, and Lcn2, was present in all neutrophils and airspace macrophages from LPS+HDM-challenged Apoa1-/- mice. These findings show that Apoa1-/- mice have increases in specific neutrophil and macrophage clusters in the lung during acute inflammation mediated by LPS+HDM, as well as enhanced expression of a common set of proinflammatory genes. This suggests that modifications in neutrophil and macrophage heterogeneity contribute to the mechanism by which apolipoprotein A-I attenuates acute airway inflammation.
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Apolipoproteína A-I , Ratones Noqueados , Neutrófilos , Neumonía , Animales , Ratones , Neutrófilos/inmunología , Neumonía/inmunología , Neumonía/genética , Apolipoproteína A-I/genética , Ratones Endogámicos C57BL , Lipopolisacáridos/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Líquido del Lavado Bronquioalveolar/citología , Pulmón/inmunología , Pulmón/patología , Calgranulina A , Calgranulina BRESUMEN
BACKGROUND: Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA). METHODS: Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months. RESULTS: At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25-5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48-9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03-8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02-5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57-5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23-5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46-9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76-7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07-3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10-4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15-8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders. CONCLUSION: Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.
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Abatacept , Antirreumáticos , Artritis Juvenil , Biomarcadores , Humanos , Abatacept/uso terapéutico , Artritis Juvenil/tratamiento farmacológico , Artritis Juvenil/sangre , Masculino , Femenino , Niño , Biomarcadores/sangre , Antirreumáticos/uso terapéutico , Calgranulina B/sangre , Adolescente , Resultado del Tratamiento , Preescolar , Calgranulina A/sangre , Proteína S100A12/sangre , Proteínas S100/sangreRESUMEN
S100a8/a9, largely released by polymorphonuclear neutrophils (PMNs), belongs to the S100 family of calcium-binding proteins and plays a role in a variety of inflammatory diseases. Although S100a8/a9 has been reported to trigger endothelial cell apoptosis, the mechanisms of S100a8/a9-induced endothelial dysfunction during sepsis require in-depth research. We demonstrate that high expression levels of S100a8/a9 suppress Ndufa3 expression in mitochondrial complex I via downregulation of Nrf1 expression. Mitochondrial complex I deficiency contributes to NAD+-dependent Sirt1 suppression, which induces mitochondrial disorders, including excessive fission and blocked mitophagy, and mtDNA released from damaged mitochondria ultimately activates ZBP1-mediated PANoptosis in endothelial cells. Moreover, based on comprehensive scRNA-seq and bulk RNA-seq analyses, S100A8/A9hi neutrophils are closely associated with the circulating endothelial cell count (a useful marker of endothelial damage), and S100A8 is an independent risk factor for poor prognosis in sepsis patients.
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Calgranulina A , Calgranulina B , Mitocondrias , Neutrófilos , Sepsis , Calgranulina A/metabolismo , Calgranulina A/genética , Neutrófilos/metabolismo , Sepsis/patología , Sepsis/metabolismo , Sepsis/genética , Humanos , Calgranulina B/metabolismo , Calgranulina B/genética , Mitocondrias/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Complejo I de Transporte de Electrón/deficiencia , Complejo I de Transporte de Electrón/genética , Células Endoteliales/metabolismo , Células Endoteliales/patología , Animales , Ratones , Masculino , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Mitofagia , Ratones Endogámicos C57BL , ApoptosisRESUMEN
BACKGROUND: S100a8/9 (S100 calcium binding protein a8/9) belongs to the S100 family and has gained a lot of interest as a critical regulator of inflammatory response. Our previous study found that S100a8/9 homolog promoted aortic valve sclerosis in mice with chronic kidney disease. However, the role of S100a8/9 in pressure overload-induced cardiac hypertrophy remains unclear. The present study was to explore the role of S100a8/9 in cardiac hypertrophy. METHODS AND RESULTS: Cardiomyocyte-specific S100a9 loss or gain of function was achieved using an adeno-associated virus system, and the model of cardiac hypertrophy was established by aortic banding-induced pressure overload. The results indicate that S100a8/9 expression was increased in response to pressure overload. S100a9 deficiency alleviated pressure overload-induced hypertrophic response, whereas S100a9 overexpression accelerated cardiac hypertrophy. S100a9-overexpressed mice showed increased FGF23 (fibroblast growth factor 23) expression in the hearts after exposure to pressure overload, which activated calcineurin/NFAT (nuclear factor of activated T cells) signaling in cardiac myocytes and thus promoted hypertrophic response. A specific antibody that blocks FGFR4 (FGF receptor 4) largely abolished the prohypertrophic response of S100a9 in mice. CONCLUSIONS: In conclusion, S100a8/9 promoted the development of cardiac hypertrophy in mice. Targeting S100a8/9 may be a promising therapeutic approach to treat cardiac hypertrophy.
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Calgranulina A , Calgranulina B , Factor-23 de Crecimiento de Fibroblastos , Factores de Transcripción NFATC , Regulación hacia Arriba , Animales , Masculino , Ratones , Calcineurina/metabolismo , Calgranulina A/metabolismo , Calgranulina A/genética , Calgranulina B/metabolismo , Calgranulina B/genética , Cardiomegalia/metabolismo , Cardiomegalia/patología , Modelos Animales de Enfermedad , Factor-23 de Crecimiento de Fibroblastos/metabolismo , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/patología , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Factores de Transcripción NFATC/metabolismo , Factores de Transcripción NFATC/genética , Transducción de SeñalRESUMEN
Chemotherapy remains the first-line treatment for advanced esophageal cancer. However, durable benefits are achieved by only a limited subset of individuals due to the elusive chemoresistance. Here, we utilize patient-derived xenografts (PDXs) from esophageal squamous-cell carcinoma to investigate chemoresistance mechanisms in preclinical settings. We observe that activated cancer-associated fibroblasts (CAFs) are enriched in the tumor microenvironment of PDXs resistant to chemotherapy. Mechanistically, we reveal that cancer-cell-derived S100A8 triggers the intracellular RhoA-ROCK-MLC2-MRTF-A pathway by binding to the CD147 receptor of CAFs, inducing CAF polarization and leading to chemoresistance. Therapeutically, we demonstrate that blocking the S100A8-CD147 pathway can improve chemotherapy efficiency. Prognostically, we found the S100A8 levels in peripheral blood can serve as an indicator of chemotherapy responsiveness. Collectively, our study offers a comprehensive understanding of the molecular mechanisms underlying chemoresistance in esophageal cancer and highlights the potential value of S100A8 in the clinical management of esophageal cancer.
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Calgranulina A , Fibroblastos Asociados al Cáncer , Resistencia a Antineoplásicos , Neoplasias Esofágicas , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Humanos , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/genética , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Calgranulina A/metabolismo , Calgranulina A/genética , Animales , Ratones , Microambiente Tumoral/efectos de los fármacos , Línea Celular Tumoral , Reprogramación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Basigina/metabolismo , Basigina/genética , Proteína de Unión al GTP rhoA/metabolismo , Proteína de Unión al GTP rhoA/genética , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/genética , Ensayos Antitumor por Modelo de Xenoinjerto , FemeninoRESUMEN
Ubiquitin-proteasome system dysfunction triggers α-synuclein aggregation, a hallmark of neurodegenerative diseases, such as Parkinson's disease (PD). However, the crosstalk between deubiquitinating enzyme (DUBs) and α-synuclein pathology remains unclear. In this study, we observed a decrease in the level of ubiquitin-specific protease 14 (USP14), a DUB, in the cerebrospinal fluid (CSF) of PD patients, particularly females. Moreover, CSF USP14 exhibited a dual correlation with α-synuclein in male and female PD patients. To investigate the impact of USP14 deficiency, we crossed USP14 heterozygous mouse (USP14+/-) with transgenic A53T PD mouse (A53T-Tg) or injected adeno-associated virus (AAV) carrying human α-synuclein (AAV-hα-Syn) in USP14+/- mice. We found that Usp14 deficiency improved the behavioral abnormities and pathological α-synuclein deposition in female A53T-Tg or AAV-hα-Syn mice. Additionally, Usp14 inactivation attenuates the pro-inflammatory response in female AAV-hα-Syn mice, whereas Usp14 inactivation demonstrated opposite effects in male AAV-hα-Syn mice. Mechanistically, the heterodimeric protein S100A8/A9 may be the downstream target of Usp14 deficiency in female mouse models of α-synucleinopathies. Furthermore, upregulated S100A8/A9 was responsible for α-synuclein degradation by autophagy and the suppression of the pro-inflammatory response in microglia after Usp14 knockdown. Consequently, our study suggests that USP14 could serve as a novel therapeutic target in PD.
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Calgranulina A , Calgranulina B , Ratones Transgénicos , Enfermedad de Parkinson , Ubiquitina Tiolesterasa , alfa-Sinucleína , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Animales , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/deficiencia , Humanos , Ratones , Femenino , Masculino , Calgranulina B/metabolismo , Calgranulina B/genética , Calgranulina A/metabolismo , Calgranulina A/genética , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
The study of S100A9 in viral infections has seen increased interest since the COVID-19 pandemic. S100A8/A9 levels were found to be correlated with the severity of COVID-19 disease, cytokine storm, and changes in myeloid cell subsets. These data led to the hypothesis that S100A8/A9 proteins might play an active role in COVID-19 pathogenesis. This review explores the structures and functions of S100A8/9 and the current knowledge on the involvement of S100A8/A9 and its constituents in viral infections. The potential roles of S100A9 in SARS-CoV-2 infections are also discussed.
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COVID-19 , Calgranulina A , Calgranulina B , Inflamación , SARS-CoV-2 , Humanos , COVID-19/inmunología , SARS-CoV-2/inmunología , Inflamación/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Virosis/inmunologíaRESUMEN
OBJECTIVES: The aim of this study was to: (1) investigate the expression patterns of antimicrobial peptides (AMPs), specifically psoriasin (S100A7) and calgranulin A and B (S100A8/A9), in patients with oral lichen planus (OLP) compared to healthy individuals; (2) evaluate the oral health-related quality of life (OHrQoL) in OLP patients versus healthy controls; (3) investigate the impact of clinical severity of OLP on OHrQoL; and (4) assess the influence of AMP expression on clinical severity and OHrQoL in OLP patients. MATERIALS AND METHODS: Oral mucosal biopsies (n = 38) were collected from healthy individuals (n = 17) and patients with OLP (n = 21). Levels of AMPs (S100A7, S100A8, S100A9) and pro-inflammatory cytokines interleukin-8 (IL-8) and tumor necrosis factor alpha (TNFα) were assessed by RT-qPCR. AMP protein localization was identified by indirect immunofluorescence analysis. OHrQoL was assessed using the OHIP-G14 questionnaire, and clinical severity was evaluated with the Oral Disease Severity Score (ODSS). Correlations between OLP manifestation, OHrQoL, and AMP expression were evaluated. RESULTS: (1) S100A7 (p < 0.001), IL-8 (p < 0.001), and TNFα (p < 0.001) mRNA levels were significantly upregulated in OLP tissue compared to healthy tissue, while S100A8 (p < 0.001) and S100A9 (p < 0.001) mRNA levels were downregulated. Immunofluorescence staining revealed an enhanced expression of S100A7 and decreased protein expression of S100A9 in OLP tissue. (2) OLP patients (9.58 ± 8.32) reported significantly higher OHIP-G14 scores compared to healthy individuals (0.67 ± 0.87; p < 0.001), particularly in the categories "physical pain" (p < 0.001) and "psychological discomfort" (p = 0.025). (3,4) Clinical severity (25.21 ± 9.77) of OLP correlated positively with OHrQoL (ρ = 0.497) and psoriasin expression (ρ = 0.402). CONCLUSIONS: This study demonstrated differential expression patterns of AMPs in OLP and highlighted the correlation between the clinical manifestation of OLP and OHrQoL. Further research approaches should address the role of psoriasin in the risk of malignant transformation of OLP. CLINICAL RELEVANCE: Psoriasin is a putative biomarker to monitor disease severity including malignant transformation of OLP lesions. OHIP-G14 scores can be useful to monitor OHrQoL in OLP patients.
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Liquen Plano Oral , Proteína A7 de Unión a Calcio de la Familia S100 , Femenino , Humanos , Masculino , Biopsia , Calgranulina A/metabolismo , Estudios de Casos y Controles , Liquen Plano Oral/metabolismo , Calidad de Vida , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteína A7 de Unión a Calcio de la Familia S100/metabolismo , Proteínas S100/metabolismo , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Regulación hacia ArribaRESUMEN
Thromboangiitis obliterans (TAO) is characterized by inflammation and obstruction of small-and medium-sized distal arteries, with limited pharmacotherapies and surgical interventions. The precise pathogenesis of TAO remains elusive. By utilizing the technology of tandem mass tags (TMT) for quantitative proteomics and leveraging bioinformatics tools, a comparative analysis of protein profiles was conducted between normal and TAO rats to identify key proteins driving TAO development. The results unveiled 1385 differentially expressed proteins (DEPs) in the TAO compared with the normal group-comprising 365 proteins with upregulated expression and 1020 proteins with downregulated expression. Function annotation through gene ontology indicated these DEPs mainly involved in cell adhesion, positive regulation of cell migration, and cytosol. The principal signaling pathways involved regulation of the actin cytoskeleton, vascular smooth contraction, and focal adhesion. The roles of these DEPs and associated signaling pathways serve as a fundamental framework for comprehending the mechanisms underpinning the onset and progression of TAO. Furthermore, we conducted a comprehensive evaluation of the effects of S100A8/A9 and its inhibitor, paquinimod, on smooth muscle cells (SMCs) and in TAO rats. We observed that paquinimod reduces SMCs proliferation and migration, promotes phenotype switching and alleviates vascular stenosis in TAO rats. In conclusion, our study revealed that the early activation of S100A8/A9 in the femoral artery is implicated in TAO development, targeting S100A8/A9 signaling may provide a novel approach for TAO prevention and treatment.
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Calgranulina A , Calgranulina B , Proteómica , Tromboangitis Obliterante , Animales , Tromboangitis Obliterante/metabolismo , Tromboangitis Obliterante/patología , Calgranulina A/metabolismo , Calgranulina A/genética , Calgranulina B/metabolismo , Ratas , Masculino , Miocitos del Músculo Liso/metabolismo , Movimiento Celular , Espectrometría de Masas en Tándem , Proliferación Celular/efectos de los fármacos , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
Calcium-binding S100A8 and S100A9 proteins play a significant role in various disorders due to their pro-inflammatory functions. Substantially, they are also relevant in neurodegenerative disorders via the delivery of signals for the immune response. However, at the same time, they can aggregate and accelerate the progression of diseases. Natively, S100A8 and S100A9 exist as homo- and heterodimers, but upon aggregation, they form amyloid-like oligomers, fibrils, or amorphous aggregates. In this study, we aimed to elucidate the aggregation propensities of S100A8, S100A9, and their heterodimer calprotectin by investigating aggregation kinetics, secondary structures, and morphologies of the aggregates. For the first time, we followed the in vitro aggregation of S100A8, which formed spherical aggregates, unlike the fibrillar structures of S100A9 under the same conditions. The aggregates were sensitive to amyloid-specific ThT and ThS dyes and had a secondary structure composed of ß-sheets. Similarly to S100A9, S100A8 protein was stabilized by calcium ions, resulting in aggregation inhibition. Finally, the formation of S100A8 and S100A9 heterodimers stabilized the proteins in the absence of calcium ions and prevented their aggregation.
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Amiloide , Calgranulina A , Calgranulina B , Complejo de Antígeno L1 de Leucocito , Calgranulina B/metabolismo , Calgranulina A/metabolismo , Complejo de Antígeno L1 de Leucocito/metabolismo , Amiloide/metabolismo , Humanos , Agregado de Proteínas/fisiología , Agregado de Proteínas/efectos de los fármacos , Calcio/metabolismo , Estructura Secundaria de ProteínaRESUMEN
The dysfunction of innate immunity components is one of the major drivers for ulcerative colitis (UC), and increasing reports indicate that the gut microbiome serves as an intermediate between genetic mutations and UC development. Here, we find that the IL-17 receptor subunit, CMTM4, is reduced in UC patients and dextran sulfate sodium (DSS)-induced colitis. The deletion of CMTM4 (Cmtm4-/-) in mice leads to a higher susceptibility to DSS-induced colitis than in wild-type, and the gut microbiome significantly changes in composition. The causal role of the gut microbiome is confirmed with a cohousing experiment. We further identify that S100a8/9 is significantly up-regulated in Cmtm4-/- colitis, with the block of its receptor RAGE that reverses the phenotype associated with the CMTM4 deficiency. CMTM4 deficiency rather suppresses S100a8/9 expression in vitro via the IL17 pathway, further supporting that the elevation of S100a8/9 in vivo is most likely a result of microbial dysbiosis. Taken together, the results suggest that CMTM4 is involved in the maintenance of intestinal homeostasis, suppression of S100a8/9, and prevention of colitis development. Our study further shows CMTM4 as a crucial innate immunity component, confirming its important role in UC development and providing insights into potential targets for the development of future therapies.
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Calgranulina A , Calgranulina B , Colitis , Sulfato de Dextran , Disbiosis , Microbioma Gastrointestinal , Proteínas con Dominio MARVEL , Animales , Calgranulina B/genética , Calgranulina B/metabolismo , Disbiosis/microbiología , Disbiosis/genética , Disbiosis/inmunología , Ratones , Humanos , Calgranulina A/genética , Calgranulina A/metabolismo , Proteínas con Dominio MARVEL/genética , Proteínas con Dominio MARVEL/metabolismo , Colitis/genética , Colitis/microbiología , Colitis/inducido químicamente , Colitis/patología , Sulfato de Dextran/toxicidad , Sulfato de Dextran/efectos adversos , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/genética , Colitis Ulcerosa/patología , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/metabolismo , Masculino , Femenino , Ratones Noqueados , Modelos Animales de EnfermedadRESUMEN
Background: Allergic asthma is the most prevalent asthma phenotype and is associated with the disorders of immune cells and glycolysis. Macrophages are the most common type of immune cells in the lungs. Calprotectin (S100A8 and S100A9) are two pro-inflammatory molecules that target the Toll-like receptor 4 (TLR4) and are substantially increased in the serum of patients with severe asthma. This study aimed to determine the effects of S100A8/A9 on macrophage polarization and glycolysis associated with allergic asthma. Methods: To better understand the roles of S100A8 and S100A9 in the pathogenesis of allergic asthma, we used ovalbumin (OVA)-induced MH-S cells, and OVA-sensitized and challenged mouse models (wild-type male BALB/c mice). Enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, flow cytometry, hematoxylin-eosin staining, and western blotting were performed. The glycolysis inhibitor 3-bromopyruvate (3-BP) was used to observe changes in glycolysis in mice. Results: We found knockdown of S100A8 or S100A9 in OVA-induced MH-S cells inhibited inflammatory cytokines, macrophage polarization biomarker expression, and pyroptosis cell proportion, but increased anti-inflammatory cytokine interleukin (IL)-10 mRNA; also, glycolysis was inhibited, as evidenced by decreased lactate and key enzyme expression; especially, knockdown of S100A8 or S100A9 inhibited the activity of TLR4/myeloid differentiation primary response gene 88 (MyD88)/Nuclear factor kappa-B (NF-κB) signaling pathway. Intervention with lipopolysaccharides (LPS) abolished the beneficial effects of S100A8 and S100A9 knockdown. The observation of OVA-sensitized and challenged mice showed that S100A8 or S100A9 knockdown promoted respiratory function, improved lung injury, and inhibited inflammation; knockdown of S100A8 or S100A9 also suppressed macrophage polarization, glycolysis levels, and activation of the TLR4/MyD88/NF-κB signaling pathway in the lung. Conversely, S100A9 overexpression exacerbated lung injury and inflammation, promoting macrophage polarization and glycolysis, which were antagonized by the glycolysis inhibitor 3-BP. Conclusion: S100A8 and S100A9 play critical roles in allergic asthma pathogenesis by promoting macrophage perturbation and glycolysis through the TLR4/MyD88/NF-κB signaling pathway. Inhibition of S100A8 and S100A9 may be a potential therapeutic strategy for allergic asthma.
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Asma , Calgranulina A , Calgranulina B , Modelos Animales de Enfermedad , Glucólisis , Macrófagos , Ratones Endogámicos BALB C , Animales , Masculino , Ratones , Asma/genética , Asma/inmunología , Asma/patología , Calgranulina A/metabolismo , Calgranulina A/genética , Calgranulina B/genética , Calgranulina B/metabolismo , Citocinas/metabolismo , Glucólisis/efectos de los fármacos , Glucólisis/genética , Macrófagos/metabolismo , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , FN-kappa B/metabolismo , Ovalbúmina , Transducción de Señal/genética , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genéticaRESUMEN
Excessive inflammatory responses are the main characteristic of ulcerative colitis (UC). Activation of formyl peptide receptor 1 (FPR1) has been found to promote the proliferation and migration of epithelial cells, but its role and therapeutic potential in UC remain unclear. This study observed an increased expression of FPR1 in a mouse model of colitis. Interestingly, FPR1 deficiency exacerbated UC and increased the secretion of the proinflammatory mediator from immune cells (e.g. macrophages), S100a8, a member of the damage-associated molecular patterns. Notably, the administration of the FPR agonist Cmpd43 ameliorated colon injury in a preclinical mice model of UC, likely via inhibiting phosphorylation of cyclic adenosine monophosphate-response element-binding protein and expression of CCAAT/enhancer-binding protein ß, which in turn suppressed the secretion of S100a8. In conclusion, these findings discovered a novel role of FPR1 in the development of colitis and will facilitate the development of FPR1-based pharmacotherapy to treat UC.
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Proteína beta Potenciadora de Unión a CCAAT , Calgranulina A , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Modelos Animales de Enfermedad , Homeostasis , Mucosa Intestinal , Ratones Noqueados , Receptores de Formil Péptido , Transducción de Señal , Animales , Receptores de Formil Péptido/metabolismo , Receptores de Formil Péptido/genética , Ratones , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Calgranulina A/metabolismo , Calgranulina A/genética , Colitis/metabolismo , Humanos , Ratones Endogámicos C57BL , Colon/metabolismo , Colon/patología , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/tratamiento farmacológicoRESUMEN
Our developed cell division-specific 'centrin' gene deleted Leishmania donovani (LdCen1-/-) the causative parasite of the fatal visceral-leishmaniasis (VL), exhibits a selective growth arrest at the intracellular stage and is anticipated as a live attenuated vaccine candidate against VL. LdCen1-/- immunization in animals has shown increased IFN-γ secreting CD4+ and CD8+ T cells along with protection conferred by a protective proinflammatory immune response. A label-free proteomics approach has been employed to understand the physiology of infection and predict disease interceptors during Leishmania-host interactions. Proteomic modulation after infection of human macrophage cell lines suggested elevated annexin A6, implying involvement in various biological processes such as membrane repair, transport, actin dynamics, cell proliferation, survival, differentiation, and inflammation, thereby potentiating its immunological protective capacity. Additionally, S100A8 and S100A9 proteins, known for maintaining homeostatic balance in regulating the inflammatory response, have been upregulated after infection. The inhibitory clade of serpins, known to inhibit cysteine proteases (CPs), was upregulated in host cells after 48 h of infection. This is reflected in the diminished expression of CPs in the parasites during infection. Such proteome analysis confirms LdCen1-/- efficacy as a vaccine candidate and predicts potential markers in future vaccine development strategies against infectious diseases.
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Leishmania donovani , Macrófagos , Proteoma , Proteínas Protozoarias , Leishmania donovani/inmunología , Leishmania donovani/genética , Humanos , Macrófagos/inmunología , Macrófagos/parasitología , Proteínas Protozoarias/genética , Proteínas Protozoarias/inmunología , Proteínas Protozoarias/metabolismo , Línea Celular , Leishmaniasis Visceral/inmunología , Leishmaniasis Visceral/parasitología , Proteómica , Animales , Calgranulina A/metabolismo , Calgranulina A/genética , Calgranulina A/inmunologíaRESUMEN
Heart failure is the prevalent complication of acute myocardial infarction. We aim to identify a biomarker for heart failure post-acute myocardial infarction. This observational study includes 1062 and 1043 patients with acute myocardial infarction in the discovery and validation cohorts, respectively. The outcomes are in-hospital and long-term heart failure events. S100A8/A9 is screened out through proteomic analysis, and elevated circulating S100A8/A9 is independently associated with heart failure in discovery and validation cohorts. Furthermore, the predictive value of S100A8/A9 is superior to the traditional biomarkers, and the addition of S100A8/A9 improves the risk estimation using traditional risk factors. We finally report causal effect of S100A8/A9 on heart failure in three independent cohorts using Mendelian randomization approach. Here, we show that S100A8/A9 is a predictor and potentially causal medicator for heart failure post-acute myocardial infarction.