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Sepsis, a systemic inflammatory response caused by infection, can lead to sepsis-associated encephalopathy (SAE), characterized by brain dysfunction without direct central nervous system infection. The pathogenesis of SAE involves blood-brain barrier disruption, neuroinflammation and neuronal death, with neuroinflammation being the core process. Nogo-A, a neurite growth-inhibitory protein in the central nervous system, is not well understood in sepsis. This study explores Nogo-A's mechanisms in sepsis, focusing on SAE. Using in vivo and in vitro methods, healthy SPF C57BL/6J male mice were divided into Sham, Nogo-A-NC-Model, and Nogo-A-KD-Model groups, with sepsis induced by abdominal ligation and puncture. Morris water maze tests assessed learning and memory, and brain tissues underwent hematoxylin-eosin (HE) staining, Nissl staining, and Western blot analysis. In vitro, Nogo-A gene knockdown models were constructed using BV-2 microglia cells to study inflammation and oxidative stress. Results showed Nogo-A expression affected learning and memory in septic mice, with knockdown reducing neuronal damage. Bioinformatics analysis suggested Nogo-A may activate reactive oxygen species (ROS) to inhibit p-SHP2, activating mitochondrial autophagy and promoting neuronal apoptosis. Western blot results confirmed that Nogo-A affects mitochondrial autophagy and neuronal survival by inhibiting SHP2 and activating ROS. Nogo-A's role in neuroinflammation and neuroprotection was emphasized, revealing its impact on endoplasmic reticulum (ER) stress, mitochondrial autophagy, and NLRP3 inflammasome activation. This study provides a theoretical basis for SAE treatment, suggesting further multi-gene and multi-pathway analyses and validation in clinical samples. Developing gene therapy and drug interventions targeting Nogo-A pathways will offer more effective treatment strategies.
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High-grade serous ovarian cancer (HGSOC) is an aggressive disease known to develop resistance to chemotherapy. We investigated the prognostic significance of tumor cell states and potential mechanisms underlying chemotherapy resistance in HGSOC. Transcriptome deconvolution was performed to address cellular heterogeneity. Kaplan-Meier survival curves were plotted to illustrate the outcomes of patients with varying cellular abundances. The association between gene expression and chemotherapy response was tested. After adjusting for surgery status and grading, several cell states exhibited a significant correlation with patient survival. Cell states can organize into carcinoma ecotypes (CE). CE9 and CE10 were proinflammatory, characterized by higher immunoreactivity, and were associated with favorable survival outcomes. Ratios of cell states and ecotypes had better prognostic abilities than a single cell state or ecotype. A total of 1265 differentially expressed genes were identified between samples with high and low levels of C9 or CE10. These genes were partitioned into three co-expressed modules, which were associated with tumor cells and immune cells. Pogz was identified to be linked with immune cell genes and the chemotherapy response of paclitaxel. Collectively, the survival of HGSOC patients is correlated with specific cell states and ecotypes.
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Cistadenocarcinoma Seroso , Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/tratamiento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/mortalidad , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/inmunología , Pronóstico , Regulación Neoplásica de la Expresión Génica , Persona de Mediana Edad , Clasificación del Tumor , Transcriptoma , Estimación de Kaplan-Meier , Anciano , Resistencia a Antineoplásicos/genéticaRESUMEN
Background: Periostin (POSTN) is a critical extracellular matrix protein in various tumor microenvironments. However, the function of POSTN in thyroid cancer progression remains largely unknown. Methods: Postn and Rag1 knock-out mice and orthotopic mouse models were used to determine the role of POSTN on papillary thyroid tumor progression. Immunofluorescence, cell co-culture, fluorescence in situ hybridization, chromatin immunoprecipitation assay, recombinant protein and inhibitor treatment were performed to explore the underlying mechanisms of POSTN-promoted papillary thyroid tumor growth. Results: POSTN is up-regulated in papillary thyroid tumors and negatively correlates with the overall survival of patients with thyroid cancer. Cancer-associated fibroblast (CAF)-derived POSTN promotes papillary thyroid tumor growth in vivo and in vitro. POSTN deficiency in CAFs significantly impairs CAF-promoted papillary thyroid tumor growth. POSTN promotes papillary thyroid tumor cell proliferation and IL-4 expression through integrin-FAK-STAT3 signaling. In turn, tumor cell-derived IL-4 induces the activation of CAFs and stimulates POSTN expression by activating STAT6. We reveal the crucial role of CAF-derived POSTN and tumor cell-derived IL-4 in driving the development of papillary thyroid tumors through the POSTN-integrin-FAK-STAT3-IL-4 pathway in tumor cells and IL-4-STAT6-POSTN signaling in CAFs. Conclusion: Our findings underscore the significance of POSTN and IL-4 as critical molecular mediators in the dynamic interplay between CAFs and tumor cells, ultimately supporting the growth of papillary thyroid tumors.
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Fibroblastos Asociados al Cáncer , Proliferación Celular , Ratones Noqueados , Periostina , Factor de Transcripción STAT3 , Transducción de Señal , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Animales , Humanos , Ratones , Fibroblastos Asociados al Cáncer/metabolismo , Línea Celular Tumoral , Quinasa 1 de Adhesión Focal/metabolismo , Integrinas/metabolismo , Interleucina-4/metabolismo , Periostina/metabolismo , Factor de Transcripción STAT3/metabolismo , Cáncer Papilar Tiroideo/metabolismo , Cáncer Papilar Tiroideo/patología , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/genética , Microambiente TumoralRESUMEN
BACKGROUND: This study aimed to investigate the underlying mechanisms of matricellular protein periostin (POSTN) on tumour-stroma crosstalk in the liver metastatic microenvironment of colorectal cancer (CRC). METHODS: Postn-knockout mice and hepatic Postn-overexpressing mice were used to investigate the functions of POSTN on the formation of fibrotic microenvironment and the tumour-stroma crosstalk in the liver metastatic microenvironment of CRC. Clinical samples and database were analyzed to show the correlation between POSTN expression and fibrotic features and TGF-ß signalling in metastatic livers of CRC. RESULTS: POSTN deficiency reduced hepatic stellate cell (HSC) activation and liver metastasis, whereas POSTN overexpression in the liver significantly augmented the formation of a fibrotic microenvironment to support the liver metastatic growth of CRC cells in mice. Moreover, HSC-derived POSTN promoted TGF-ß1 expression in CRC cells through the integrin/FAK/ERK/STAT3 pathway; conversely, tumour cell-derived TGF-ß1 induced POSTN expression in HSCs via the Smad pathway. POSTN levels correlated with fibrotic features and TGF-ß signalling in metastatic liver tissues of CRC patients. CONCLUSIONS: POSTN and TGF-ß1 cooperatively contribute to the tumour-stroma crosstalk by forming a supporting fibrotic microenvironment to promote liver metastasis of CRC cells via the POSTN/integrin/FAK/ERK/STAT3/TGF-ß axis in tumour cells and TGF-ß/Smad/POSTN signalling in activated HSCs.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Animales , Humanos , Ratones , Neoplasias Colorrectales/patología , Integrinas/metabolismo , Hígado/metabolismo , Neoplasias Hepáticas/patología , Periostina , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Microambiente TumoralRESUMEN
BACKGROUND: Immune dysregulation is a feature of sepsis. However, a comprehensive analysis of the immune landscapes in septic patients has not been conducted. OBJECTIVES: This study aims to explore the abundance ratios of immune cells in sepsis and investigate their clinical value. METHODS: Sepsis transcriptome data sets were downloaded from the NCBI GEO database. The immunedeconv R package was employed to analyze the abundance of immune cells in sepsis patients and calculate the ratios of different immune cell types. Differential analysis of immune cell ratios was performed using the t test. The Spearman rank correlation coefficient was utilized to find the relationships between immune cell abundance and pathways. The prognostic significance of immune cell ratios for patient survival probability was assessed using the log-rank test. In addition, differential gene expression was performed using the limma package, and gene co-expression analysis was executed using the WGCNA package. RESULTS: We found significant changes in immune cell ratios between sepsis patients and healthy controls. Some of these ratios were associated with 28-day survival. Certain pathways showed significant correlations with immune cell ratios. Notably, six immune cell ratios demonstrated discriminative ability for patients with systemic inflammatory response syndrome (SIRS), bacterial sepsis, and viral sepsis, with an Area Under the Curve (AUC) larger than 0.84. Patients with a high eosinophil/B.cell.memory ratio exhibited poor survival outcomes. A total of 774 differential genes were identified in sepsis patients with a high eosinophil/B.cell.memory ratio compared to those with a low ratio. These genes were organized into seven co-expression modules associated with relevant pathways, including interferon signaling, T-cell receptor signaling, and specific granule pathways. CONCLUSIONS: Immune cell ratios eosinophil/B.cell.memory and NK.cell.activated/NK.cell.resting in sepsis patients can be utilized for disease subtyping, prognosis, and diagnosis. The proposed cell ratios may have higher prognostic values than the neutrophil-to-lymphocyte ratio (NLR).
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Eosinófilos , Sepsis , Humanos , Curva ROC , Sepsis/genética , Sepsis/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica , Pronóstico , Células Asesinas Naturales , Estudios RetrospectivosRESUMEN
Periostin, a multifunctional extracellular protein, plays an important role in inflammatory disorders and tumorigenesis. Our previous work has demonstrated that periostin deficiency inhibits colorectal cancer (CRC) progression. Here, we aim to clarify the role of periostin in the immune microenvironment of CRC. We find that periostin deficiency significantly decreases the infiltration of programmed death receptor 1 (PD-1)+ tumor-associated macrophages (TAMs) in CRC tissues. Periostin promotes the expression of PD-1 on TAMs by integrin-ILK-nuclear factor κB (NF-κB) signaling, and PD-1+ TAMs produce interleukin-6 (IL-6) and interferon γ (IFN-γ) to induce the expression of PD-L1 on colorectal tumor cells. Moreover, combined inhibition of periostin and PD-1 significantly suppresses CRC progression compared with the inhibition of periostin or PD-1 alone. In summary, our results suggest that periostin deficiency reduces the infiltration of PD-1+ TAMs and enhances the efficacy of anti-PD-1 treatment in CRC.
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Neoplasias Colorrectales , Macrófagos Asociados a Tumores , Humanos , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Macrófagos/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Transducción de Señal , Microambiente Tumoral , Macrófagos Asociados a Tumores/metabolismoRESUMEN
BACKGROUND & AIMS: The matricellular protein periostin plays a critical role in liver inflammation, fibrosis, and even carcinoma. Here, the biological function of periostin in alcohol-related liver disease (ALD) was investigated. METHODS: We used wild-type (WT), Postn-null (Postn-/-) mice and Postn-/- mice with periostin recovery to investigate the biological function of periostin in ALD. Proximity-dependent biotin identification analysis identified the protein that interacted with periostin, and coimmunoprecipitation analysis validated the interaction between protein disulfide isomerase (PDI) and periostin. Pharmacological intervention and genetic knockdown of PDI were used to investigate the functional correlation between periostin and PDI in ALD development. RESULTS: Periostin was markedly upregulated in the livers of mice that were fed ethanol. Interestingly, periostin deficiency severely aggravated ALD in mice, whereas the recovery of periostin in the livers of Postn-/- mice significantly ameliorated ALD. Mechanistic studies showed that the upregulation of periostin alleviated ALD by activating autophagy through inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) pathway, which was verified in murine models treated with the mTOR inhibitor rapamycin and the autophagy inhibitor MHY1485. Furthermore, a protein interaction map of periostin was generated by proximity-dependent biotin identification analysis. Interaction profile analysis identified PDI as a key protein that interacted with periostin. Intriguingly, periostin-mediated enhancement of autophagy by inhibiting the mTORC1 pathway in ALD depended on its interaction with PDI. Moreover, alcohol-induced periostin overexpression was regulated by transcription factor EB. CONCLUSIONS: Collectively, these findings clarify a novel biological function and mechanism of periostin in ALD and the periostin-PDI-mTORC1 axis is a critical determinant of ALD.
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Hepatocitos , Hepatopatías Alcohólicas , Ratones , Animales , Hepatocitos/metabolismo , Proteína Disulfuro Isomerasas/genética , Proteína Disulfuro Isomerasas/metabolismo , Biotina/metabolismo , Hepatopatías Alcohólicas/patología , Etanol/toxicidad , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , AutofagiaRESUMEN
AIM: High-grade serous ovarian cancer (HGSOC) is an aggressive disease that is largely resistant to today's immunotherapies. Here, we aimed to investigate the prognostic significance of CTLA4, PD-1, and T-cell activation status in HGSOC. METHODS: Using a publicly accessed microarray dataset including 260 HGSOC samples, we calculated Kaplan-Meier survival curves for overall survival (OS), evaluated associations with multivariate Cox regression models to evaluate the associations, and summarized using a hazard ratio (HR). The correlations between PD-1 gene expression and that of other genes were calculated by Pearson correlation. RESULTS: Multivariate survival analyses showed that high PD-1 expression but not CTLA4 was associated with longer OS (HR = 0.69; 95% confidence interval [CI] = 0.52-0.91; p = 0.01), and that higher T-cell activation score was associated with better outcome (HR = 0.74; 95% confidence interval [CI] = 0.58-0.95; p = 0.02). The top three PD-1 highly correlated genes were SIRPG (r = 0.90, p < 2E-16), FASL (r = 0.89, p < 2E-16), and CD8a (r = 0.87, p < 2E-16). HGSOC patients' OS is positively associated T-cell activation score and PD-1 expression but not CTLA4. CONCLUSION: T cell activation score may serve as a candidate for personalized immunotherapy in HGSOC. The application of anti-PD-1 therapy to HGSOC should be cautious.
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Cistadenocarcinoma Seroso , Neoplasias Ováricas , Carcinoma Epitelial de Ovario , Cistadenocarcinoma Seroso/genética , Femenino , Humanos , Pronóstico , Linfocitos TRESUMEN
Although the anti-inflammatory properties of developmental endothelial locus-1 (DEL-1) are well known, few studies have examined the role of DEL-1 in spinal cord injury (SCI). Here, the protective effect of DEL-1 on SCI was investigated using hypoxia/recovery (H/R) injury of astrocytes and a mouse SCI model. The effects of DEL-1 overexpression/silencing on primary astrocytes were assessed by flow cytometry, immunofluorescence, and western blotting. Female Sprague-Dawley rats were intrathecally injected with recombinant adeno-associated virus (AAV) at T10, and DEL-1 was permanently expressed. Protein levels in the spinal cord, functional testing, and electrophysiology, pathology, and immunofluorescence were all measured after treatment. DEL-1 overexpression significantly increased the expression of SIRT1/SERCA2At the same time, inflammation, endoplasmic reticulum stress, and apoptosis were all significantly inhibited, the motor function of SCI rats was noticeably restored, and the myelin sheath of the injured site was more complete. Furthermore, after DEL-1 silencing SIRT1/SERCA2 expression decreased, while inflammation, endoplasmic reticulum stress, and apoptotic responses increased significantly. DEL-1 treatment, however, did not increase SERCA2 expression after SIRT1 silencing. These findings demonstrate that DEL-1 protects against SCI via SIRT1/SERCA2 signaling, promoting spinal neural recovery.
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Apoptosis/fisiología , Proteínas de Unión al Calcio/metabolismo , Moléculas de Adhesión Celular/metabolismo , Estrés del Retículo Endoplásmico/fisiología , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Sirtuina 1/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Animales , Animales Recién Nacidos , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/fisiologíaRESUMEN
OBJECTIVE: This study aimed to assess the effect of the collagen/silk fibroin scaffolds seeded with human umbilical cord-mesenchymal stem cells on functional recovery after acute complete spinal cord injury. METHODS: The fibroin and collagen were mixed (mass ratio, 3:7), and the composite scaffolds were produced. Forty rats were randomly divided into the Sham group (without spinal cord injury), spinal cord injury group (spinal cord transection without any implantation), collagen/silk fibroin scaffolds group (spinal cord transection with implantation of the collagen/silk fibroin scaffolds), and collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group (spinal cord transection with the implantation of the collagen/silk fibroin scaffolds co-cultured with human umbilical cord-mesenchymal stem cells). Motor evoked potential, Basso-Beattie-Bresnahan scale, modified Bielschowsky's silver staining, and immunofluorescence staining were performed. RESULTS: The BBB scores in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group were significantly higher than those in the spinal cord injury and collagen/silk fibroin scaffolds groups (p<0.05 or p<0.01). The amplitude and latency were markedly improved in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group compared with the spinal cord injury and collagen/silk fibroin scaffolds groups (p<0.05 or p<0.01). Meanwhile, compared to the spinal cord injury and collagen/silk fibroin scaffolds groups, more neurofilament positive nerve fiber ensheathed by myelin basic protein positive structure at the injury site were observed in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group (p<0.01, p<0.05). The results of Bielschowsky's silver staining indicated more nerve fibers was observed at the lesion site in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group compared with the spinal cord injury and collagen/silk fibroin scaffolds groups (p<0.01, p< 0.05). CONCLUSION: The results demonstrated that the transplantation of human umbilical cord-mesenchymal stem cells on a collagen/silk fibroin scaffolds could promote nerve regeneration, and recovery of neurological function after acute spinal cord injury.
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Fibroínas , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Traumatismos de la Médula Espinal , Animales , Colágeno , Humanos , Ratas , Recuperación de la Función , Médula Espinal , Andamios del Tejido , Cordón UmbilicalRESUMEN
BACKGROUND: Severe trauma and burns accompanied by sepsis are associated with high morbidity and mortality. Little is known about the transcriptional similarity between trauma, burns, sepsis, and systemic inflammatory response syndrome (SIRS). Uncovering key genes and molecular networks is critical to understanding the biology of disease. Conventional analysis of gene changes (fold change) analysis is difficult for time-serial data such as post-injury blood transcriptome. METHODS: Weighted gene co-expression network analysis (WGCNA) was applied to the trauma dataset to identify modules and hub genes. Module stability was tested by half sampling. Module preservations of burns, sepsis, and SIRS were calculated using trauma as reference. Module functional enrichment was analyzed in gProfiler server. Candidate drugs were screened using Connectivity Map based on hub genes. The modules were visualized in Cytoscape. RESULTS: Seventeen modules were identified. The modules were robust to the exclusion of half the sample. They were involved in lymphocyte and platelet activation, erythrocyte differentiation, cell cycle, translation, and interferon signaling. In addition, highly connected hub genes were identified in each module, such as GUCY1B1, BCL11B, HMMR, and CEACAM6. High BCL11B (M13) or low CEACAM6 (M27) expression indicates better survival prognosis in sepsis patients regardless of endotype class and age. Network preservation in burns, sepsis, and SIRS showed a general similarity between trauma and burns. M4, M5, M13, M16, M20, and M27 were significantly associated with injury time in trauma and burns. High M13 (T cell activation), low M15 (cell cycle), and low M27 (neutrophil activation) indicate better survival of sepsis patients, regardless of endotype class and age. Moreover, the modules can efficiently separate patients with different diseases. Some modules and hub genes have good prognostic performance in sepsis. Based on the hub genes of each module, six candidate drugs were screened. CONCLUSION: This study first compared the gene co-expression modules in trauma, burns, sepsis, and SIRS. The identified modules are useful for disease prognosis and drug discovery. BCL11B and CEACAM6 may be promising biomarkers for sepsis risk assessment.
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SUMMARY OBJECTIVE: This study aimed to assess the effect of the collagen/silk fibroin scaffolds seeded with human umbilical cord-mesenchymal stem cells on functional recovery after acute complete spinal cord injury. METHODS: The fibroin and collagen were mixed (mass ratio, 3:7), and the composite scaffolds were produced. Forty rats were randomly divided into the Sham group (without spinal cord injury), spinal cord injury group (spinal cord transection without any implantation), collagen/silk fibroin scaffolds group (spinal cord transection with implantation of the collagen/silk fibroin scaffolds), and collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group (spinal cord transection with the implantation of the collagen/silk fibroin scaffolds co-cultured with human umbilical cord-mesenchymal stem cells). Motor evoked potential, Basso-Beattie-Bresnahan scale, modified Bielschowsky's silver staining, and immunofluorescence staining were performed. RESULTS: The BBB scores in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group were significantly higher than those in the spinal cord injury and collagen/silk fibroin scaffolds groups (p<0.05 or p<0.01). The amplitude and latency were markedly improved in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group compared with the spinal cord injury and collagen/silk fibroin scaffolds groups (p<0.05 or p<0.01). Meanwhile, compared to the spinal cord injury and collagen/silk fibroin scaffolds groups, more neurofilament positive nerve fiber ensheathed by myelin basic protein positive structure at the injury site were observed in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group (p<0.01, p<0.05). The results of Bielschowsky's silver staining indicated more nerve fibers was observed at the lesion site in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group compared with the spinal cord injury and collagen/silk fibroin scaffolds groups (p<0.01, p< 0.05). CONCLUSION: The results demonstrated that the transplantation of human umbilical cord-mesenchymal stem cells on a collagen/silk fibroin scaffolds could promote nerve regeneration, and recovery of neurological function after acute spinal cord injury.
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Humanos , Animales , Ratas , Traumatismos de la Médula Espinal , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Fibroínas , Médula Espinal , Cordón Umbilical , Colágeno , Recuperación de la Función , Andamios del TejidoRESUMEN
Periostin is a critical extracellular regulator in the pathogenesis of liver disorders such as hepatosteatosis, non-alcoholic steatohepatitis, inflammation, and fibrosis. Periostin is also involved in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanisms of periostin in hepatic stellate cell (HSC) activation and tumor cell proliferation in the pathogenesis of HCC remain largely unknown. We demonstrate that periostin is markedly upregulated in diethylnitrosamine (DEN)-induced mouse HCC tissues and that periostin knockout impairs DEN-induced HCC development. Periostin is predominantly derived from activated HSCs and periostin deficiency in HSCs impairs HSC activation and inhibits HSC-promoted HCC cell proliferation in vitro and tumor growth in vivo. Mechanistically, periostin promotes HSC activation through the integrin-FAK-STAT3-periostin pathway and augments HCC cell proliferation by activating ERK. There are positive correlations between periostin and HSC activation and cell proliferation in HCC clinical samples. Collectively, our findings demonstrate that HSC-derived periostin promotes HCC development by enhancing HSC activation through an autocrine periostin-integrin-FAK-STAT3-periostin circuit and by augmenting HCC cell proliferation via the ERK pathway in a paracrine manner. Thus, periostin is a multifaceted extracellular regulator in the development of HCC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Carcinoma Hepatocelular/patología , Moléculas de Adhesión Celular/metabolismo , Células Estrelladas Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Animales , Carcinógenos/toxicidad , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/metabolismo , Proliferación Celular , Dietilnitrosamina/toxicidad , Humanos , Neoplasias Hepáticas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/fisiologíaRESUMEN
Periostin (POSTN) is a type of matricellular protein, but its functions in adipose fibrosis remain unclear. Here, we found that POSTN expression is significantly increased in mouse adipose tissue after treatment with lipopolysaccharide (LPS) or a high-fat diet (HFD) and that adipose progenitor cells are the main source of POSTN. In our mouse model of fibrosis, POSTN deletion protected mice from adipose fibrosis, probably through reducing the accumulation of macrophages and promoting adipocyte differentiation of progenitor cells. Taken together, our study demonstrates that POSTN deficiency attenuates adipose tissue fibrosis and improves insulin resistance, providing new insights into the diagnosis and treatment of type II diabetes by targeting adipose tissue fibrosis.
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Tejido Adiposo/patología , Moléculas de Adhesión Celular/deficiencia , Lipopolisacáridos/farmacología , Obesidad/patología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Moléculas de Adhesión Celular/genética , Dieta Alta en Grasa/efectos adversos , Fibrosis , Resistencia a la Insulina , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Due to endogenous neuronal deficiency and glial scar formation, spinal cord injury (SCI) often leads to irreversible neurological loss. Accumulating evidence has shown that a suitable scaffold has important value for promoting nerve regeneration after SCI. Collagen/heparin sulfate scaffold (CHSS) has shown effect for guiding axonal regeneration and decreasing glial scar deposition after SCI. The current research aimed to evaluate the utility of the CHSSs adsorbed with mesenchymal stem cells (MSCs) on nerve regeneration, and functional recovery after acute complete SCI. METHODS: CHSSs were prepared, and evaluated for biocompatibility. The CHSSs adsorbed with MSCs were transplanted into these canines with complete SCI. RESULTS: We observed that MSCs had good biocompatibility with CHSSs. In complete transverse SCI models, the implantation of CHSS co-cultured with MSCs exhibited significant improvement in locomotion, motor evoked potential, magnetic resonance imaging, diffusion tensor imaging, and urodynamic parameters. Meanwhile, nerve fibers were markedly improved in the CHSS adsorbed with MSCs group. Moreover, we observed that the implantation of CHSS combined with MSCs modulated inflammatory cytokine levels. CONCLUSIONS: The results preliminarily demonstrated that the transplantation of MSCs on a CHSS could improve the recovery of motor function after SCI. Thus, implanting the MSCs-laden CHSS is a promising combinatorial therapy for treatment in acute SCI.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Traumatismos de la Médula Espinal , Andamios del Tejido , Animales , Colágeno , Imagen de Difusión Tensora , Perros , Estudios de Factibilidad , Heparina , Trasplante de Células Madre Mesenquimatosas/veterinaria , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/veterinaria , SulfatosRESUMEN
The gene encoding the phage major capsid protein 10A was cloned into the prokaryotic expression vector pET24a, and a 6XHis-tag was fused to the 3'-end of the 10A gene to verify complete expression. The recombinant plasmid was transformed into Escherichia coli (E. coli) BL21 (DE3) cells, and 10A expression was induced by IPTG. SDS-PAGE and Western blot were used to confirm the target protein expression. The T7Select10-3b vector was added to the cultured bacteria expressing 10A at a multiplicity of infection (MOI) ranging from 0.01 to 0.1, and complete lysis of the bacteria was monitored by absorbance changes in the medium. The recombinant phage (reP) was harvested by PEG/NaCl sedimentation and resuspended in PBS. ELISA was performed to verify the presence of the 6XHis-tag on the surface of reP. The 10A-fusion expression vectors (pET10A-flag, pET10A-egfp, and pET10A-pct) were constructed, and fusion proteins were expressed and detected by the same method. The corresponding rePs (reP-Flag, reP-EGFP, and reP-PCT) were prepared by T7Select10-3b infection. After the expression of the peptides/proteins on the reP surfaces was confirmed, reP-Flag and reP-PCT were used to immunize mice to prepare anti-Flag and anti-PCT antibodies. The results showed that rePs prepared using the 10A-fusion vector and T7Select10-3b can be used as antigens to immunize mice and prepare antibodies. This method may be able to meet the rapid antigen preparation requirements for antibody production. Notably, the recombinant phage (reP) described in this study was obtained by the sedimentation method from T7Select10-3b-infected E. coli BL21 (DE3) cells carrying the major capsid protein 10A expression vector or 10A-fusion protein vector.
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Anticuerpos/inmunología , Antígenos , Bacteriófago T7 , Técnicas de Visualización de Superficie Celular , Escherichia coli , Proteínas Recombinantes de Fusión , Animales , Antígenos/biosíntesis , Antígenos/genética , Antígenos/inmunología , Bacteriófago T7/genética , Bacteriófago T7/inmunología , Bacteriófago T7/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Femenino , Ratones , Ratones Endogámicos BALB C , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunologíaRESUMEN
Periostin is a multifunctional extracellular matrix protein involved in various inflammatory diseases and tumor metastasis; however, evidence regarding whether and how periostin actively contributes to inflammation-associated tumorigenesis remains elusive. Here, we demonstrate that periostin deficiency significantly inhibits the occurrence of colorectal cancer in azoxymethane/dextran sulfate sodium-treated mice and in ApcMin/+ mice. Moreover, periostin deficiency attenuates the severity of colitis and reduces the proliferation of tumor cells. Mechanistically, stromal fibroblast-derived periostin activates FAK-Src kinases through integrin-mediated outside-in signaling, which results in the activation of YAP/TAZ and, subsequently, IL-6 expression in tumor cells. Conversely, IL-6 induces periostin expression in fibroblasts by activating STAT3, which ultimately facilitates colorectal tumor development. These findings provide the evidence that periostin promotes colorectal tumorigenesis, and identify periostin- and IL-6-mediated tumor-stroma interaction as a promising target for treating colitis-associated colorectal cancer.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Carcinogénesis/patología , Moléculas de Adhesión Celular/metabolismo , Neoplasias Colorrectales/patología , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Integrinas/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Familia-src Quinasas/metabolismo , Poliposis Adenomatosa del Colon/metabolismo , Animales , Azoximetano , Moléculas de Adhesión Celular/deficiencia , Proliferación Celular , Colitis/complicaciones , Sulfato de Dextran , Humanos , Inflamación/patología , Interleucina-6/metabolismo , Intestinos/patología , Ratones Endogámicos C57BL , Miofibroblastos/patología , Lesiones Precancerosas/patología , Factor de Transcripción STAT3 , Transducción de Señal , Células del Estroma/patología , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAPRESUMEN
MicroRNAs (miRNAs) are a group of small non-coding RNAs that directly bind to the 3'-untranslated-region (3'UTR) of mRNA, thereby blocking gene expression post-transcriptionally. Accumulating evidence prove that microRNA-873 (miR-873) functions as a promoter or suppressor in various cancers, while whether it affects the progression of colorectal cancer (CRC) is yet unknown. Here we found that miR-873 was downregulated in human CRC clinical samples, mouse CRC specimens and cell lines with high metastatic potential. We also demonstrated that low miR-873 expression was closely associated with poor prognosis of CRC. Overexpressing miR-873 suppressed proliferation and metastasis of CRC cells both in vitro and in vivo, while inhibiting miR-873 expression promoted the proliferation, migration and invasion in vitro. Moreover, miR-873 exerted its function by perturbing the ERK-CyclinD1 pathway and the epithelial-mesenchymal transition (EMT) process. Furthermore, we revealed that miR-873 acted as a tumor-suppressive microRNA by directly binding to the 3'UTRs of ELK1 and STRN4 and suppressed their expression. Our study uncovered an inhibitory role of miR-873 in CRC progression and might provide a promising marker for CRC diagnosis and prognosis.
RESUMEN
Extracellular matrix protein periostin is highly expressed in various tumors and plays a critical role in tumor development and progression. Periostin is mainly secreted by stromal cells such as cancer-associated fibroblasts, myofibroblasts, osteoblasts and bone marrow-derived mesenchymal stromal cells. But in some cases, tumor cells, especially cancer stem cells, can also produce periostin. Periostin has been shown to regulate multiple biological behaviors of tumor cells, including proliferation, survival, invasion, angiogenesis, metastasis and chemoresistance. Moreover, an excessive periostin deposition exerts a pivotal role in remodeling various tumor microenvironments, such as cancer stem cell niche, perivascular niche, premetastatic niche, immunosuppressive microenvironment, bone marrow microenvironment and other tumor growth-supportive microenvironments. In this review, we provide an update understanding of the multifaceted functions and mechanisms of periostin in tumor development and progression.
Asunto(s)
Moléculas de Adhesión Celular/fisiología , Neoplasias/patología , Células Madre Neoplásicas , Células del Estroma , Microambiente Tumoral , Humanos , Nicho de Células MadreRESUMEN
Singapore grouper iridovirus (SGIV) is a lethal grouper virus containing 162 predicted ORFs. Previous proteomic studies led to identification of 73 SGIV structural proteins. Here, SDS-assisted tube-gel digestion and DOC-assisted in-solution digestion coupled with LC-ESI-MS/MS were applied to further profile the SGIV structural proteome. We identified a total of 90 SGIV structural proteins including 24 newly reported proteins. Additionally, several PTMs were identified, including 26 N-terminal acetylated proteins, three phosphorylated proteins, and one myristoylated protein. Importantly, 47 of the proteins that were identified are predicted to contain conserved domains. Our work greatly expands the repertoire of the SGIV structural proteome and provides more insight into the biology of SGIV.