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Airborne electromagnetic (AEM) surveys using airborne mobile platforms enable rapid and efficient exploration of areas where groundwork is difficult. They have been widely used in fields such as shallow resource exploration and environmental engineering. Three-dimensional AEM inversion is the main technique used in fine structural interpretation. However, most current methods focus on separate component data inversions, which limit the kinds of structures that can be recovered in the inversion results. To address this issue, a method for the robust 3D joint inversion of multicomponent frequency-domain AEM data was developed in this study. First, a finite element method based on unstructured tetrahedral grids was used to solve the forward problem of frequency-domain AEM data for both isotropic and anisotropic media. During inversion, a limited-memory quasi-Newton (L-BFGS) method was used to reduce the memory requirements and enable the joint inversion of large-scale multicomponent AEM data. The effectiveness of our algorithm was demonstrated using synthetic models for both isotropic and anisotropic cases, with 5% Gaussian noise added to the modeling data to simulate the measured data for separate and joint inversions. The results of the synthetic models show that joint inversion has advantages over separate inversion in that it enables the recovery of finer underground structures and provides a novel approach for the fine interpretation of frequency-domain AEM data.
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BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (iCCA) is closely correlated with hepatic progenitor cell (HPC) expansion and liver fibrosis. Brahma-related gene 1 (Brg1), an enzymatic subunit of the switch/sucrose nonfermentable complex that is critical in stem cell maintenance and tumor promotion, is prominently up-regulated in both HPCs and iCCA; however, its role in this correlation remains undefined. APPROACH AND RESULTS: A retrospective cohort study indicated that high Brg1 expression suggests poor prognosis in patients with iCCA. In chronically injured livers induced by a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet or bile duct ligation surgery, HPCs were dramatically activated, as indicated by their enhanced expression of Brg1 and a subset of stem cell markers; however, Brg1 ablation in HPCs strongly suppressed HPC expansion and liver fibrosis. Furthermore, in a chemically induced iCCA model, inhibition of Brg1 by a specific inhibitor or inducible gene ablation markedly improved histology and suppressed iCCA growth. Mechanistically, in addition to transcriptionally promoting both Wnt receptor genes and target genes, Brg1 was found to bind to the ß-catenin/transcription factor 4 transcription complex, suggesting a possible approach for regulation of Wnt/ß-catenin signaling. CONCLUSIONS: We have demonstrated the function of Brg1 in promoting HPC expansion, liver cirrhosis, and, ultimately, iCCA development in chronically injured livers, which is largely dependent on Wnt/ß-catenin signaling. Our data suggest that therapies targeting Brg1-expressing HPCs are promising for the treatment of liver cirrhosis and iCCA.
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Neoplasias de los Conductos Biliares/genética , Colangiocarcinoma/genética , ADN Helicasas/genética , Cirrosis Hepática/genética , Recurrencia Local de Neoplasia/epidemiología , Proteínas Nucleares/genética , Factores de Transcripción/genética , Adulto , Anciano , Animales , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/uso terapéutico , Neoplasias de los Conductos Biliares/inducido químicamente , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/terapia , Conductos Biliares Intrahepáticos/patología , Conductos Biliares Intrahepáticos/cirugía , Colangiocarcinoma/inducido químicamente , Colangiocarcinoma/mortalidad , Colangiocarcinoma/terapia , ADN Helicasas/antagonistas & inhibidores , ADN Helicasas/metabolismo , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Hígado/patología , Hígado/cirugía , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/patología , Cirrosis Hepática/prevención & control , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/genética , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Pronóstico , Piridinas/farmacología , Piridinas/uso terapéutico , Estudios Retrospectivos , Células Madre/metabolismo , Células Madre/patología , Tioacetamida/administración & dosificación , Tioacetamida/toxicidad , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Regulación hacia Arriba , Vía de Señalización Wnt/genéticaRESUMEN
Liver cancer and other malignant tumor cells rely on the glycolytic pathway to obtain energy (i.e. the Warburg effect); however, the underlying mechanism is unclear. Mitochondria are sites of oxidative phosphorylation and adenosine triphosphate (ATP) production. The 13 constituent respiratory chain proteins encoded by the mitochondrial genome (namely, mtDNA) play essential roles. We found that in human hepatocellular carcinoma (HCC) tissues, 11 out of the 13 mtDNA-encoded genes exhibited decreased mRNA levels and 5 genes displayed decreased protein levels, including the cytochrome B (mt-CYB) and cytochrome C oxidase II (mt-CO2) genes. Mitochondrial gene sequencing revealed abnormalities in the levels of a large number of mitochondrial miRNAs (mitomiRs). MicroRNA-181a-5p (mir-181a-5p), which potentially targets genes encoding mt-CYB and mt-CO2 protein, was screened out from 549 downregulated mitomiRs via bioinformatic analysis. After overexpression of mitomiR-181a-5p, mt-CYB and mt-CO2 levels were reduced in HCC cells, and the mitochondrial membrane potential (MMP) maintained by the electron transport chain (ETC) was decreased. Furthermore, the expression of hexokinase 2 (HK2) and glucose transporter type 1 (GLUT1) was upregulated, accompanied by elevated glucose, lactic acid release, and activity of lactate dehydrogenase (LDH). In vivo experiments confirmed that constitutive mitomiR-181a-5p expression caused reprogramming of glucose metabolism and promoted tumor growth and early lung metastasis in liver cancer. In summary, the present study reveals the important role of mitomiRs in glucose metabolism reprogramming in liver cancer, which is of considerable value in exploring new therapeutic targets for HCC.
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Complejo IV de Transporte de Electrones/genética , Transporte de Electrón/genética , Neoplasias Hepáticas/genética , MicroARNs/genética , Proliferación Celular/genética , Reprogramación Celular/genética , Citocromos b/genética , ADN Mitocondrial/genética , Glucosa/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/patología , Potencial de la Membrana Mitocondrial/genética , Redes y Vías Metabólicas/genética , Mitocondrias/genética , Mitocondrias/metabolismo , Fosforilación OxidativaRESUMEN
BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant primary tumor in the liver, and the rates of incidence and mortality are rapidly increasing globally. Histone deacetylase 8 (HDAC8) is a transcriptional regulator and is associated with tumorigenesis of several tumor types. This study aimed to evaluate the correlation between HDAC8 expression and clinicopathological parameters in ICC patients. METHODS: ICC tissues and corresponding nonmalignant bile duct tissues were obtained from 60 patients. HDAC8 and Ki-67 expression were evaluated by immunohistochemistry staining. HDAC8 expression and the clinicopathological features and prognosis of the patients were analyzed. The mRNA level of HDAC8 in ICC was further analyzed using data from The Cancer Genome Atlas (TCGA). RESULTS: The expression of HDAC8 were lower in ICC tissues (39/60, 65%) than in the corresponding nonmalignant bile duct tissues (54/60, 90%) (Pâ¯=â¯0.001). Low HDAC8 expression in ICC was significantly associated with lymph node metastases (47.6% vs. 17.9%, Pâ¯=â¯0.015). In addition, the positive cells rate of HDAC8 was statistically and negatively correlated with the Ki-67 index in ICC lesions (r = -0.7660, P < 0.001). Importantly, the overall survival rate and recurrence-free survival rate in ICC patients with low HDAC8 expression were lower than those with high HDAC8 expression (Pâ¯=â¯0.008 and Pâ¯=â¯0.011, respectively). CONCLUSIONS: Decreased HDAC8 expression in ICC is related to poor prognosis, and HDAC8 may be an independent prognostic indicator of ICC patients after curative resection.
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Neoplasias de los Conductos Biliares/metabolismo , Conductos Biliares Intrahepáticos/metabolismo , Colangiocarcinoma/metabolismo , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/genética , Colangiocarcinoma/secundario , Supervivencia sin Enfermedad , Femenino , Humanos , Antígeno Ki-67/metabolismo , Metástasis Linfática , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Tasa de SupervivenciaRESUMEN
Acute liver failure (ALF) is associated with high mortality, and a poor understanding of the underlying pathophysiology has resulted in a lack of effective treatments so far. Here, using an amatoxin-induced rhesus monkey model of ALF, we panoramically revealed the cellular and molecular events that lead to the development of ALF. The challenged monkeys with toxins underwent a typical course of ALF including severe hepatic injury, systemic inflammation and eventual death. Adaptive immune was not noticeably disturbed throughout the progress of ALF. A systematic examination of serum factors and cytokines revealed that IL-6 increase was the most rapid and drastic. Interestingly, we found that IL-6 was mainly produced by circulating monocytes. Furthermore, ablation of monocyte-derived IL-6 in mice decreased liver injury and systemic inflammation following chemical injection. Our findings reveal a critical role of circulating monocytes in initiating and accelerating ALF, indicating a potential therapeutic target in clinical treatment for ALF.
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Amanitinas/toxicidad , Encefalopatía Hepática/inmunología , Interleucina-6/inmunología , Lipopolisacáridos/toxicidad , Fallo Hepático Agudo/inmunología , Monocitos/inmunología , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Citocinas/genética , Citocinas/inmunología , Progresión de la Enfermedad , Expresión Génica , Encefalopatía Hepática/inducido químicamente , Encefalopatía Hepática/genética , Encefalopatía Hepática/patología , Interleucina-6/deficiencia , Interleucina-6/genética , L-Lactato Deshidrogenasa/sangre , Fallo Hepático Agudo/inducido químicamente , Fallo Hepático Agudo/genética , Fallo Hepático Agudo/patología , Pruebas de Función Hepática , Macaca mulatta , Ratones , Monocitos/patologíaRESUMEN
BACKGROUND: The stimulatory G protein a subunit (Gsα) plays important roles in diverse cell processes including tumorigenesis. Activating mutations in Gsα gene (GNAS) have been reported to be associated with poor prognosis in various human carcinomas. Furthermore, Gsα signaling is crucial in promoting liver regeneration by interacting with growth factor signaling, indicating that Gsα might play a promoting role in cancer development. However, little is known about the correlation between Gsα levels and clinicopathological parameters in intrahepatic cholangiocarcinoma (ICC). METHODS: We performed immunoblotting to examine the expression levels of Gsα and Ki67 proteins in tumor tissues and the corresponding adjacent tissues. A total of 74 pair of specimens resected from 74 ICC patients were examined. The association between Gsα levels and clinicopathological findings and prognosis of the patients was evaluated. RESULTS: Western blotting demonstrated that the expression of Gsα was significantly higher in ICC tissues compared with that in their corresponding adjacent tissues. Gsα protein was highly expressed in about half of ICC tissues (48.6%, 36/74) while only 28.4% (21/74) of tumor adjacent tissues showed Gsα high expression (P=0.011). High Gsα expression in ICC was significantly associated with the numbers of tumor nodules (P=0.037) and lymph node metastases (P=0.010). Moreover, the level of Gsα was significantly and positively correlated with Ki67 expression (P<0.001). In addition, the recurrence-free survival rate and overall survival rate in the Gsα high group were significantly lower than those in the Gsα low group (P=0.004 and P=0.005, respectively). CONCLUSIONS: High Gsα expression is correlated with poor prognosis in ICC patients. Gsα might serve as a potential prognostic indicator of ICC.
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Neoplasias de los Conductos Biliares/química , Biomarcadores de Tumor/análisis , Colangiocarcinoma/química , Cromograninas/análisis , Subunidades alfa de la Proteína de Unión al GTP Gs/análisis , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/cirugía , Western Blotting , Colangiocarcinoma/mortalidad , Colangiocarcinoma/secundario , Colangiocarcinoma/cirugía , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Antígeno Ki-67/análisis , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
Dengue fever, as a mosquito-borne viral disease widely spread in tropical and subtropical regions, remarkably threatens public health, while the mechanism involved in host-DENV interaction has not been fully elucidated. Firstly, we analyzed the expression levels of long non-coding RNAs (lncRNAs) in THP-1 cells after DENV-3 infection and Antibody- Dependent Enhancement of viral infection (ADE-VI) by RNA-Seq. Secondly, through the RT-qPCR to confirm those differentially expressed (DE) lncRNAs. Then, we also analyzed the competitive endogenous RNA (CeRNA) regulatory network of DE lncRNAs. Finally, we predicted the encode ability of DE lncRNAs. It was found that on the X and Y chromosomes, the expression levels of lncRNAs in THP-1 cells after ADE-VI were significantly different from those in the negative control and the DENV-3 infection groups. There were 71 DE lncRNAs after DENV-3 infection, including 42 up-regulated and 29 down-regulated lncRNAs. A total of 70 DE lncRNAs after ADE-VI were detected, including 38 up-regulated and 32 down- regulated lncRNAs. After ADE-VI and DENV-3 infection, there were 35 DE lncRNAs, including 11 up-regulated and 24 down-regulated lncRNAs. The analysis of the CeRNA regulatory network of DE lncRNAs revealed that, TRIM29, STC2, and IGFBP5 were correlated with the ADE-VI. Additionally, it was found that lncRNAs not only participated in the CeRNA regulatory network, but also maybe encoded small peptides. Our findings provided clues for further investigation into the lncRNAs associated antiviral mechanism of ADE-VI and DENV-3 infection.
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Virus del Dengue , Dengue , ARN Largo no Codificante , Virosis , Animales , Anticuerpos Antivirales/metabolismo , Acrecentamiento Dependiente de Anticuerpo , Proteínas de Unión al ADN , Dengue/genética , Humanos , ARN Largo no Codificante/genética , Factores de TranscripciónRESUMEN
Semaphorin 4D (Sema4D) is highly expressed in various cancers and leukemia. It is involved in the development of acute leukemia. A high level of soluble Sema4D is also present in the plasma of acute leukemia patients. However, it remains unknown whether Sema4D is associated with the clinical characteristics of acute leukemia. In this study, Sema4D expression was examined in peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) of patients with acute leukemia, and it was highly expressed in the PBMCs of B-acute lymphoblastic leukemia (ALL), T-ALL, and acute myeloid leukemia (AML) patients and in the BMMCs of B-ALL and AML patients but not in the BMMCs of T-ALL patients. Sema4D expression was higher in the PBMCs of T-ALL patients than in the PBMCs of B-ALL or AML patients. In addition, Sema4D expression in BMMCs was reduced in B-ALL patients during the chemotherapy process. It was lower in remission patients than in newly diagnosed and patients without remission. In acute leukemia, soluble Sema4D level in serum is positively correlated with Sema4D expression in PBMCs, leukocyte number, and peripheral blast number. Those results suggest that the levels of Sema4D and its soluble form are associated with acute leukemia development and may be regarded as a potential biomarker in pediatric acute leukemia.
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Antígenos CD , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Enfermedad Aguda , Antígenos CD/genética , Niño , Humanos , Leucemia Mieloide Aguda/genética , Leucocitos Mononucleares/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , SemaforinasRESUMEN
BACKGROUND & AIMS: N6-methyladenosine (m6A), the most prevalent and dynamic posttranscriptional methylation modification of mammalian mRNA, is involved in various biological processes, but its role in liver regeneration has not been characterized. METHODS: We first conducted transcriptome-wide m6A mRNA sequencing and characterized the expression pattern of m6A in regenerating mouse liver. Next, we generated hepatocyte-specific Mettl3- or Mettl14-deficient mice and investigated their role in liver regeneration. A series of biochemical experiments in vitro and in vivo was further performed to investigate potential mechanisms. RESULTS: We identified an overwhelming proportion of m6A-modified genes with initially up-regulated and subsequently down-regulated m6A levels as liver regeneration progressed. Loss of Mettl14 but not of Mettl3 resulted in markedly disrupted liver regeneration, and Mettl14-ablated hepatocytes were arrested in the G1 phase of the cell cycle. Most strikingly, the Mettl14-ablated regenerating liver exhibited extensive parenchymal necrosis. mRNA transcripts, such as Hsp90b1, Erp29, Stt3a, P4hb, and Lman1, encoding proteins involved in polypeptide processing and the endoplasmic reticulum (ER) stress response, were m6A-hypomethylated, and their mRNA and protein levels were subsequently decreased, resulting in unresolved ER stress, hepatocyte death, and inhibited proliferation. CONCLUSIONS: We demonstrate the essential role of Mettl14 in facilitating liver regeneration by modulating polypeptide-processing proteins in the ER in an m6A-dependent manner.
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Adenosina/análogos & derivados , Retículo Endoplásmico/metabolismo , Homeostasis , Regeneración Hepática , Metiltransferasas/metabolismo , Adenosina/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Proliferación Celular/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/genética , Eliminación de Gen , Hepatectomía , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Hepatocitos/ultraestructura , Homeostasis/efectos de los fármacos , Homeostasis/genética , Hígado/metabolismo , Hígado/cirugía , Regeneración Hepática/efectos de los fármacos , Regeneración Hepática/genética , Masculino , Metiltransferasas/deficiencia , Ratones Noqueados , Necrosis , Especificidad de Órganos/efectos de los fármacos , Especificidad de Órganos/genética , Péptidos/genética , Péptidos/metabolismo , Estabilidad del ARN/efectos de los fármacos , Estabilidad del ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ácido Tauroquenodesoxicólico/farmacología , Transcriptoma/genéticaRESUMEN
Rationale: Congenital biliary atresia (BA) is a destructive obliterative cholangiopathy of neonates that affects both intrahepatic and extrahepatic bile ducts. However, the cause of BA is largely unknown. Methods: We explored the cell junctions and polarity complexes in early biopsy BA livers by immunofluorescence staining and western blot. Cdc42, as a key cell junction and polarity regulator, was found dramatically decreased in BA livers. Therefore, in order to investigate the role of Cdc42 in BA development, we constructed liver-specific and tamoxifen induced cholangiocyte-specific Cdc42 deleted transgenic mice. We further evaluated the role of bile acid in aggravating biliary damage in Cdc42 insufficient mouse liver. Results: We found a dramatic defect in the assembly of cell junctions and polarity complexes in both cholangiocytes and hepatocytes in BA livers. This defect was characterized by the disordered location of cell junction proteins, including ZO1, ß-catenin, E-cadherin and claudin-3. Cdc42 and its active form, Cdc42-GTP, which serves as a small Rho GTPase to orchestrate the assembly of polarity complexes with Par6/Par3/αPKC, were substantially reduced in BA livers. Selective Cdc42 deficiency in fetal mouse cholangiocytes resulted in histological changes similar to those found in human BA livers, including obstruction in both the intra- and extrahepatic bile ducts, epithelial atrophy, and the disruption of cell junction and polarity complexes. A reduction in bile acids notably improved the histology and serological indices in Cdc42-mutant mice. Conclusion: Our results illustrate that BA is closely correlated with the impaired assembly of cell junction and polarity complexes in liver cells, which is likely caused by Cdc42 insufficiency and aggravated by bile acid corrosion.
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Atresia Biliar , Enfermedades Genéticas Congénitas , Uniones Intercelulares , Hígado/metabolismo , Proteína de Unión al GTP cdc42/deficiencia , Animales , Atresia Biliar/genética , Atresia Biliar/metabolismo , Atresia Biliar/patología , Femenino , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/metabolismo , Enfermedades Genéticas Congénitas/patología , Humanos , Lactante , Uniones Intercelulares/genética , Uniones Intercelulares/metabolismo , Uniones Intercelulares/patología , Hígado/patología , Masculino , Ratones , Ratones Noqueados , Proteína de Unión al GTP cdc42/metabolismoRESUMEN
Numb, a stem cell fate determinant, acts as a tumor suppressor and is closely related to a wide variety of malignancies. Intrahepatic cholangiocarcinoma (iCCA) originates from hepatic progenitors (HPCs); however, the role of Numb in HPC malignant transformation and iCCA development is still unclear. A retrospective cohort study indicated that Numb was frequently decreased in tumor tissues and suggests poor prognosis in iCCA patients. Consistently, in a chemically induced iCCA mouse model, Numb was downregulated in tumor cells compared to normal cholangiocytes. In diet-induced chronic liver injury mouse models, Numb ablation significantly promoted histological impairment, HPC expansion, and tumorigenesis. Similarly, Numb silencing in cultured iCCA cells enhanced cell spheroid growth, invasion, metastasis, and the expression of stem cell markers. Mechanistically, Numb was found to bind to the Notch intracellular domain (NICD), and Numb ablation promoted Notch signaling; this effect was reversed when Notch signaling was blocked by γ-secretase inhibitor treatment. Our results suggested that loss of Numb plays an important role in promoting HPC expansion, HPC malignant transformation, and, ultimately, iCCA development in chronically injured livers. Therapies targeting suppressed Numb are promising for the treatment of iCCA.
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Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/patología , Hígado/patología , Proteínas de la Membrana/deficiencia , Proteínas del Tejido Nervioso/deficiencia , Receptores Notch/metabolismo , Transducción de Señal , Células Madre/metabolismo , Animales , Neoplasias de los Conductos Biliares/genética , Peso Corporal , Carcinogénesis/genética , Carcinogénesis/patología , Proliferación Celular , Colangiocarcinoma/genética , Regulación hacia Abajo/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Antígeno Ki-67/metabolismo , Cirrosis Hepática/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Metástasis de la Neoplasia , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Tamaño de los Órganos , Pronóstico , Dominios Proteicos , Receptores Notch/química , Factor de Transcripción HES-1/metabolismoRESUMEN
BACKGROUND: Using a toxin-induced nonhuman primate model of acute liver failure (ALF), we previously reported that peripheral infusion of human umbilical cord mesenchymal stem cells (hUC-MSCs) strongly suppresses the activation of circulating monocytes and interleukin-6 (IL-6) production, thereby disrupting the development of a cytokine storm and improving the prognosis of monkeys. MSCs are considered to play a therapeutic role under different stresses by adaptively producing specific factors, prompting us to investigate the factors that hUC-MSCs produce in response to high serum levels of IL-6, which plays a critical role in initiating and accelerating ALF. METHODS: We stimulated hUC-MSCs with IL-6, and the hUC-MSC-derived exosomes were deeply sequenced. The miRNAs in the exosomes that have potential to suppress IL-6-associated signaling pathway were screened, and the role of one of the most possible miRNAs was tested in the mouse model of inflammatory liver injury. RESULT: We determined that miR-455-3p, which is secreted through exosomes and potentially targets PI3K signaling, was highly produced by hUC-MSCs with IL-6 stimulation. The miR-455-3p-enriched exosomes could inhibit the activation and cytokine production of macrophages challenged with lipopolysaccharide (LPS) both in vivo and in vitro. In a chemical liver injury mouse model, enforced expression of miR-455-3p could attenuate macrophage infiltration and local liver damage and reduce the serum levels of inflammatory factors, thereby improving liver histology and systemic disorder. CONCLUSIONS: miR-455-3p-enriched exosomes derived from hUC-MSCs are a promising therapy for acute inflammatory liver injury.
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Enfermedad Hepática Inducida por Sustancias y Drogas/terapia , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Exosomas/metabolismo , Exosomas/trasplante , Células Madre Mesenquimatosas/metabolismo , MicroARNs/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Interleucina-6/farmacología , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Cordón Umbilical/citologíaRESUMEN
BACKGROUND: Escherichia coli strains are the most commonly isolated bacteria in hospitals. The normally harmless commensal E. coli can become a highly adapted pathogen, capable of causing various diseases both in healthy and immunocompromised individuals, by acquiring a combination of mobile genetic elements. Our aim was to characterize E. coli strains from a hospital in western China to determine their virulence and antimicrobial resistance potential. METHODS: A total of 97 E. coli clinical isolates were collected from the First Affiliated Hospital of Chengdu Medical College from 2015 to 2016. Microbiological methods, PCR, and antimicrobial susceptibility tests were used in this study. RESULTS: The frequency of occurrence of the virulence genes fimC, irp2, fimH, fyuA, lpfA, hlyA, sat, and cnf1 in the E. coli isolates was 93.81, 92.78, 91.75, 84.54, 41.24, 32.99, 28.86, and 7.22%, respectively. Ninety-five (97.9%) isolates carried two or more different virulence genes. Of these, 44 (45.4%) isolates simultaneously harbored five virulence genes, 24 (24.7%) isolates harbored four virulence genes, and 17 (17.5%) isolates harbored six virulence genes. In addition, all E. coli isolates were multidrug resistant and had a high degree of antimicrobial resistance. CONCLUSION: These results indicate a high frequency of occurrence and heterogeneity of virulence gene profiles among clinical multidrug resistant E. coli isolates. Therefore, appropriate surveillance and control measures are essential to prevent the further spread of these isolates in hospitals.
RESUMEN
Histone deacetylase 3 (HDAC3) plays pivotal roles in cell cycle regulation and is often aberrantly expressed in various cancers including hepatocellular carcinoma (HCC), but little is known about its role in liver regeneration and liver cancer cells proliferation. Using an inducible hepatocyte-selective HDAC3 knockout mouse, we find that lack of HDAC3 dramatically impaired liver regeneration and blocked hepatocyte proliferation in the G1 phase entry. HDAC3 inactivation robustly disrupted the signal transducer and activator of transcription 3 (STAT3) cascade. HDAC3 silencing impaired the ac-STAT3-to-p-STAT3 transition in the cytoplasm, leading to the subsequent breakdown of STAT3 signaling. Furthermore, overexpressed HDAC3 was further associated with increased tumor growth and a poor prognosis in HCC patients. Inhibition of HDAC3 expression reduced liver cancer cells growth and inhibited xenograft tumor growth. Our results suggest that HDAC3 is an important regulator of STAT3-dependent cell proliferation in liver regeneration and cancer. These findings provide novel insights into the HDAC3-STAT3 pathway in liver pathophysiological processes.