RESUMEN

BACKGROUND: The netrin-1/CD146 pathway regulates colorectal cancer (CRC) liver metastasis, angiogenesis, and vascular development. However, few investigations have yet examined the biological function of netrin-1/CD146 complex in CRC. In this work, we investigated the relationship between the netrin-1/CD146 axis and S100 proteins in sentinel lymph node, and revealed a possible new clue for vascular metastasis of CRC. METHODS: The expression levels of netrin-1 and CD146 proteins in CRC, as well as S100A8 and S100A9 proteins in the sentinel lymph nodes were determined by immunohistochemistry. Using GEPIA and UALCAN, we analyzed netrin-1 and CD146 gene expression in CRC, their association with CRC stage, and their expression levels and prognosis in CRC patients. RESULTS: The expression level of netrin-1 in N1a+1b (CRC lymphatic metastasis groups, exculded N1c) was positively increased with N0 (p = 0.012). The level of netrin-1 protein was positively correlated with CD146 protein (p < 0.05). The level of S100A9 protein was positively correlated with CD146 protein (r = 0.492, p = 0.007). Moreover, netrin-1 expression was obviously correlated with S100A9 expression in the N1 stage (r = 0.867, p = 0.000). CD146 level was correlated with S100A9 level in the N2 stage (r = 0.731, p = 0.039). CD146 mRNA expression was higher in normal colorectal tissues than in CRC (p < 0.05). Netrin-1 and CD146 expression were not significantly associated with the tumor stages and prognosis of patients with CRC (p > 0.05). CONCLUSIONS: The netrin-1/CD146 and netrin-1/S100A9 axis in CRC tissues might related with early stage of lymph node metastasis, thus providing potential novel channels for blocking lymphatic metastasis and guiding biomarker discovery in CRC patients.

Asunto(s)

Antígeno CD146 , Calgranulina B , Neoplasias Colorrectales , Metástasis Linfática , Netrina-1 , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Antígeno CD146/genética , Antígeno CD146/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Ganglios Linfáticos/patología , Ganglios Linfáticos/metabolismo , Metástasis Linfática/genética , Metástasis Linfática/patología , Estadificación de Neoplasias , Netrina-1/metabolismo , Netrina-1/genética , Pronóstico

RESUMEN

Hemorrhage, a condition that accompanies most physical trauma cases, remains an important field of study, a field that has been extensively studied in the immunological context for myeloid and lymphoid cells, but not as much for erythroid cells. In this study, we studied the immunological response of murine erythroid cells to acute blood loss using flow cytometry, NanoString immune transcriptome profiling, and BioPlex cytokine secretome profiling. We observed that acute blood loss forces the differentiation of murine erythroid cells in both bone marrow and spleen and that there was an up-regulation of several immune response genes, in particular pathogen-associated molecular pattern sensing gene Clec5a in post-acute blood loss murine bone marrow erythroid cells. We believe that the up-regulation of the Clec5a gene in bone marrow erythroid cells could help bone marrow erythroid cells detect and eliminate pathogens with the help of reactive oxygen species and antimicrobial proteins calprotectin and cathelicidin, the genes of which (S100a8, S100a9, and Camp) dominate the expression in bone marrow erythroid cells of mice.

Asunto(s)

Diferenciación Celular , Quimiocina CCL3 , Células Eritroides , Antígenos Comunes de Leucocito , Animales , Ratones , Células Eritroides/metabolismo , Células Eritroides/citología , Quimiocina CCL3/metabolismo , Quimiocina CCL3/genética , Antígenos Comunes de Leucocito/metabolismo , Lectinas Tipo C/metabolismo , Lectinas Tipo C/genética , Ratones Endogámicos C57BL , Calgranulina A/metabolismo , Calgranulina A/genética , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/citología , Calgranulina B/metabolismo , Calgranulina B/genética , Masculino

RESUMEN

Extracellular vesicles (EVs) act as mediators for intercellular transfer of Aß and tau proteins, promoting the propagation of these pathological misfolded proteins throughout the brain in Alzheimer's disease (AD). Levels of blood exosomal Aß42, total Tau (t-Tau) and phosphorylated Tau (p-Tau) had a high correlation with their concentrations in cerebrospinal fluid (CSF), demonstrating that exosomal biomarkers have equal contribution as those in CSF for the diagnosis of AD. We aimed to comprehensively characterize the proteome of plasma-derived EVs to identify differentially expressed proteins (DEPs) and pathways in AD. Tandem mass tag (TMT) labeled quantitative proteomics was applied to analyze plasma-derived EV proteins in 9 AD patients and 9 healthy controls. 335 proteins were quantified, and 12 DEPs were identified including seven upregulated proteins and five down-regulated proteins. Oligomerized Aß1-42 induced SH-SY5Y cell damage model was built to mimic the pathological changes of AD, and small interfering RNA (siRNA) against S100A8 was used to knock down S100A8 expression. Results displayed S100A8 was down regulated in plasma-derived EVs from AD patients, while enriched in EVs derived from Aß1-42-induced SH-SY5Y cells. Furthermore, Aß1-42-induced SH-SY5Y cells treated with S100A8 siRNA showed decreased Aß levels in cell lysate and EVs, especially in EVs. SIGNIFICANCE: The investigation aimed to comprehensively characterize the proteome of plasma-derived EVs to identify DEPs and potential biomarker of AD. S100A8 was found down regulated in plasma-derived EVs from AD patients using TMT labeled quantitative proteomics. The diagnostic value of S100A8 was also confirmed using receiver operating characteristic curve (ROC) analysis. Furthermore, Aß1-42-induced SH-SY5Y cells treated with S100A8 siRNA showed decreased Aß levels in cell lysate and EVs, especially in EVs. The preliminary findings suggest that suppression of S100A8 expression inhibits Aß aggregation both in cell lysate and EVs from Aß1-42-induced SH-SY5Y cells, and S100A8 more likely regulates Aß aggregation via EVs. Therefore, plasma-derived EV S100A8 might be a potential biomarker of AD. Manipulation of S100A8 expression may be a novel therapeutic strategy in the treatment of AD.

Asunto(s)

Enfermedad de Alzheimer , Biomarcadores , Calgranulina A , Vesículas Extracelulares , Proteómica , Humanos , Enfermedad de Alzheimer/metabolismo , Biomarcadores/metabolismo , Proteómica/métodos , Masculino , Vesículas Extracelulares/metabolismo , Femenino , Anciano , Calgranulina A/metabolismo , Línea Celular Tumoral , Péptidos beta-Amiloides/metabolismo , Persona de Mediana Edad , Proteoma/metabolismo

RESUMEN

Intestinal barrier hemostasis is the key to health. As a resveratrol analogue, pterostilbene (PT) has been reported to prevent dextran sodium sulfate (DSS)-induced intestinal barrier dysfunction mainly associated with the intestinal NF-κB signaling pathway. However, the exact underlying mechanisms are not yet well-defined yet. In this study, we performed RNA-sequencing analysis and unexpectedly found that alarmin S100A8 sensitively responded to DSS-induced intestinal injury. Accordingly, histologic assessments suggested that the high expression of S100A8 was accompanied by increased intestinal infiltration of macrophages, upregulated intestinal epithelial Toll-like receptor 4 (TLR-4), and activated NF-κB signaling pathway. Interestingly, the above phenomena were effectively counteracted upon the addition of PT. Furthermore, by using a coculture system of macrophage THP-1 cells and HT-29 colon cells, we identified macrophage-secreted S100A8 activated intestinal epithelial NF-κB signaling pathway through TLR-4. Taken together, these findings suggested that PT ameliorated DSS-induced intestinal barrier injury through suppression of the macrophage S100A8-intestinal epithelial TLR-4-NF-κB signaling cascade.

Asunto(s)

Calgranulina A , Sulfato de Dextran , Mucosa Intestinal , Ratones Endogámicos C57BL , FN-kappa B , Transducción de Señal , Estilbenos , Receptor Toll-Like 4 , Sulfato de Dextran/efectos adversos , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Animales , Transducción de Señal/efectos de los fármacos , Humanos , Ratones , Calgranulina A/genética , Calgranulina A/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Estilbenos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Masculino , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis/genética

RESUMEN

BACKGROUND: Microglia is the primary source of inflammatory factors during migraine attacks. This study aims to investigate the role of microglia related genes (MRGs) in migraine attacks. METHODS: The RNA sequencing results of migraineurs and the panglaodb database were used to obtain differentially expressed genes (DEGs) in migraine related to microglia. A migraine rat model was established for validating and localizing of the MRGs, and subsequent screening for target genes was conducted. A shRNA was designed to interference the expression of target genes and administered into the trigeminal ganglion (TG) of rats. Pain sensitivity in rats was evaluated via the hot water tail-flick (HWTF) and formalin-induced pain (FIP) experiments. ELISA was used to quantify the levels of inflammatory cytokines and CGRP. WB and immunofluorescence assays were applied to detect the activation of microglia. RESULTS: A total of five DEGs in migraine related to microglia were obtained from RNA sequencing and panglaodb database. Animal experiments showed that these genes expression were heightened in the TG and medulla oblongata (MO) of migraine rats. The gene S100A8 co-localized with microglia in both TG and MO. The HWTF and FIP experiments demonstrated that interference with S100A8 alleviated the sense of pain in migraine rats. Moreover, the levels of TNFα, IL-1ß, IL-6, and CGRP in the TG and MO of rats in the model rats were increased, and the expression of microglia markers IBA-1, M1 polarization markers CD86 and iNOS was upregulated. Significantly, interference with S100A8 reversed these indicators. CONCLUSION: Interference with S100A8 in microglia increased the pain threshold during migraine attacks, and inhibited neuroinflammation and microglia activation.

Asunto(s)

Calgranulina A , Microglía , Trastornos Migrañosos , Enfermedades Neuroinflamatorias , Ratas Sprague-Dawley , Animales , Microglía/metabolismo , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/genética , Ratas , Masculino , Calgranulina A/metabolismo , Calgranulina A/genética , Enfermedades Neuroinflamatorias/metabolismo , Ganglio del Trigémino/metabolismo , Modelos Animales de Enfermedad

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.

Asunto(s)

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 Carbono

RESUMEN

Fatty liver, which is induced by abnormal lipid metabolism, is one of the most common causes of chronic liver disease globally and causes liver fibrosis. During this process, bone marrow-derived mesenchymal stromal cells (BMSCs) and hepatic stellate cells (HSCs) migrate toward the injured liver and participate in fibrogenesis by transdifferentiating into myofibroblasts. S100A8/A9 is a powerful inducer of cell migration and is involved in liver injury. But there are few reports about the effects of S100A8/A9 on BMSC/HSC migration. In the current study, we found that S100A8/A9 expression was increased during fatty liver injury/fibrogenesis. Moreover, S100A8/A9 expression had a positive correlation with fibrosis marker gene expressions in the injured liver. S100A8/A9 was mainly produced by neutrophils in the fibrotic liver. In vitro, neutrophil-secreted S100A8/A9 promoted BMSC/HSC migration via remodeling of microfilaments. Using specific siRNA and inhibitor, we proved that S100A8/A9-induced BMSC/HSC migration is dependent on TLR4/Rho GTPases signaling. Moreover, S100A8/A9 knock-down alleviated liver injury and fibrogenesis in vivo, while injection of S100A9 neutralizing antibody performed similar roles. We proved that S100A8/A9 was involved in liver injury and fibrogenesis via inducing BMSC/HSC migration. Our research reveals a new mechanism underlying BMSC/HSC migration in liver fibrosis and suggests S100A8/A9 as a potential therapeutic target of liver fibrosis. KEY MESSAGES: S100A8/A9 is secreted by neutrophils and increased in fatty liver injury. Neutrophil-secreted S100A8/A9 is a mediator of BMSC/HSC migration in vitro. S100A8/A9-induced BMSC/HSC migration is dependent on TLR4/Rho GTPases signaling. S100A8/A9 blockade alleviates liver injury and fibrogenesis in vivo.

Asunto(s)

Calgranulina A , Calgranulina B , Movimiento Celular , Cirrosis Hepática , Miofibroblastos , Neutrófilos , Receptor Toll-Like 4 , Animales , Masculino , Ratones , Calgranulina A/metabolismo , Calgranulina A/genética , Calgranulina B/metabolismo , Calgranulina B/genética , Hígado Graso/metabolismo , Hígado Graso/patología , Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Células Madre Mesenquimatosas/metabolismo , Ratones Endogámicos C57BL , Miofibroblastos/metabolismo , Neutrófilos/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Humanos

RESUMEN

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is associated with a loss or an imbalance of host-microorganism interactions. However, such interactions at protein levels remain largely unknown. Here, we applied a depletion-assisted metaproteomics approach to obtain in-depth host-microbiome association networks of IBD, where the core host proteins shifted from those maintaining mucosal homeostasis in controls to those involved in inflammation, proteolysis, and intestinal barrier in IBD. Microbial nodes such as short-chain fatty-acid producer-related host-microbial crosstalk were lost or suppressed by inflammatory proteins in IBD. Guided by protein-protein association networks, we employed proteomics and lipidomics to investigate the effects of UC-related core proteins S100A8, S100A9, and cytokines (IL-1ß, IL-6, and TNF-α) on gut bacteria. These proteins suppressed purine nucleotide biosynthesis in stool-derived in vitro communities, which was also reduced in IBD stool samples. Single species study revealed that S100A8, S100A9, and cytokines can synergistically or antagonistically alter gut bacteria intracellular and secreted proteome, with combined S100A8 and S100A9 potently inhibiting beneficial Bifidobacterium adolescentis. Furthermore, these inflammatory proteins only altered the extracellular but not intracellular proteins of Ruminococcus gnavus. Generally, S100A8 induced more significant bacterial proteome changes than S100A9, IL-1ß, IL-6, and TNF-α but gut bacteria degrade significantly more S100A8 than S100A9 in the presence of both proteins. Among the investigated species, distinct lipid alterations were only observed in Bacteroides vulgatus treated with combined S100A8, S100A9, and cytokines. These results provided a valuable resource of inflammatory protein-centric host-microbial molecular interactions.

Asunto(s)

Colitis Ulcerosa , Citocinas , Microbioma Gastrointestinal , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/metabolismo , Humanos , Citocinas/metabolismo , Calgranulina B/metabolismo , Calgranulina A/metabolismo , Proteómica , Heces/microbiología , Ruminococcus/metabolismo , Interacciones Microbiota-Huesped , Clostridiales

RESUMEN

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.

Asunto(s)

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 , Lactante

RESUMEN

Radiation-induced pulmonary fibrosis (RIPF) is a frequently encountered late complication in patients undergoing radiation therapy, presenting a substantial risk to patient mortality and quality of life. The pathogenesis of RIPF remains unclear, and current treatment options are limited in efficacy. High-dose vitamin C has demonstrated potential when used in conjunction with other adjuvant therapies due to potent anticancer properties. However, the potential relationship between high-dose vitamin C and RIPF has not yet been explored in existing literature. In our study, the RIPF model and the LLC tumor model were used as two animal models to explore how high-dose vitamin C can improve RIPF without hampering the antitumour efficacy of radiotherapy. The impact of high-dose vitamin C on RIPF was assessed through various assays, including micro-CT, HE staining, Masson staining, and immunohistochemistry. Our results indicated that administering high-dose vitamin C 2 days before radiation and continuing for a duration of 6 weeks significantly inhibited the progression of RIPF. In order to explore the mechanism by which high-dose vitamin C attenuates RIPF, we utilized RNA-seq analysis of mouse lung tissue in conjunction with publicly available databases. Our findings indicated that high-dose vitamin C inhibits the differentiation of fibroblasts into myofibroblasts by targeting S100A8 and S100A9 derived from neutrophils. Additionally, the combination of high-dose vitamin C and radiation demonstrated enhanced inhibition of tumor growth in a murine LLC tumor model. These results revealed that the combination of radiotherapy and high-dose vitamin C may offer a promising therapeutic approach for the clinical management of thoracic tumors and the prevention of RIPF.

Asunto(s)

Ácido Ascórbico , Calgranulina A , Calgranulina B , Fibrosis Pulmonar , Animales , Ácido Ascórbico/farmacología , Ácido Ascórbico/uso terapéutico , Ácido Ascórbico/administración & dosificación , Ratones , Calgranulina A/metabolismo , Calgranulina A/genética , Fibrosis Pulmonar/prevención & control , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/tratamiento farmacológico , Calgranulina B/metabolismo , Calgranulina B/genética , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Humanos , Masculino

RESUMEN

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.

Asunto(s)

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 Arriba

RESUMEN

Familial Mediterranean fever (FMF) is characterized by inflammatory attacks due to overactivation of pyrin inflammasome. This study aimed to investigate the reliability of S100A8/A9, neopterin, and matrix metalloproteinase 3 (MMP3) at monitoring subclinical inflammation and disease activity, and at differentiating FMF attacks from appendicitis, the most common misdiagnosis among FMF patients. Blood samples (n = 75), comprising from FMF patients during an attack (n = 20), the same FMF patients during the attack-free period (n = 14), patients with appendicitis (n = 24), and healthy volunteers (n = 17) were obtained. Duplicate determinations of S100A8/A9, neopterin, and MMP-3 levels were conducted using the enzyme-linked immunosorbent assay (ELISA). FMF patients with and without attack and patients with appendicitis had significantly elevated S100A8/A9 levels compared to healthy volunteers (P-values: < 0.001, 0.036, 0.002, respectively). Patients with appendicitis and FMF patients with and without attack had significantly increased serum neopterin levels compared to healthy volunteers (P-value: < 0.001). MMP3 levels were significantly higher among patients with appendicitis and FMF patients during attack compared to healthy controls (P-values: < 0.001, 0.001). Serum levels of S100A8/A9, neopterin, and MMP3 were increased significantly during attacks compared to attack-free periods among FMF patients (P-values: 0.03, 0.047, 0.007). S100A8/A9 emerges as a valuable marker for monitoring disease activity. Neopterin and S100A8/A9 might help physicians to monitor subclinical inflammation during the attack-free periods of FMF patients. MMP3 might aid in diagnosing FMF attacks when distinguishing between attack and attack-free periods is challenging.

Asunto(s)

Calgranulina A , Calgranulina B , Fiebre Mediterránea Familiar , Metaloproteinasa 3 de la Matriz , Neopterin , Humanos , Fiebre Mediterránea Familiar/sangre , Fiebre Mediterránea Familiar/diagnóstico , Calgranulina A/sangre , Femenino , Masculino , Metaloproteinasa 3 de la Matriz/sangre , Neopterin/sangre , Adulto , Calgranulina B/sangre , Biomarcadores/sangre , Apendicitis/sangre , Apendicitis/diagnóstico , Adulto Joven , Diagnóstico Diferencial , Persona de Mediana Edad , Adolescente

RESUMEN

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.

Asunto(s)

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/sangre

Asunto(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 , Polimerizacion

RESUMEN

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.

Asunto(s)

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/metabolismo

RESUMEN

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.

Asunto(s)

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 B

RESUMEN

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.

Asunto(s)

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 , Apoptosis

RESUMEN

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.

Asunto(s)

Calgranulina A , Calgranulina B , Ratones Transgénicos , Enfermedad de Parkinson , Ubiquitina Tiolesterasa , alfa-Sinucleína , Animales , Femenino , Humanos , Masculino , Ratones , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Calgranulina A/metabolismo , Calgranulina A/genética , Calgranulina B/metabolismo , Calgranulina B/genética , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/deficiencia

RESUMEN

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.

Asunto(s)

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 Arriba

RESUMEN

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.

Asunto(s)

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 Señal