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House dust mite (HDM) allergens cause inflammatory responses and chronic allergic diseases such as bronchial asthma and atopic dermatitis. Here, we investigate the mechanism by which HDM induces C-C chemokine ligand 20 (CCL20) expression to promote chronic inflammation and airway remodeling in an HDM-induced bronchial asthma mouse model. We showed that HDM increased CCL20 levels via the Akt-ERK1/2-C/EBPß pathway. To investigate the role of CCL20 in chronic airway inflammation and remodeling, we made a mouse model of CCL20-induced bronchial asthma. Treatment of anti-CCL20Ab in this mouse model showed the reduced airway hyper-responsiveness and inflammatory cell infiltration into peribronchial region by neutralizing CCL20. In addition, CCL20 induced the Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation through NLRP3 deubiquitination and transcriptional upregulation in BEAS-2B cells. As expected, anti-CCL20Ab markedly suppressed NLRP3 activation induced by CCL20. Moreover, HDM-induced CCL20 leads to epithelial-mesenchymal transition in the lung epithelium which appears to be an important regulator of airway remodeling in allergic asthma. We also found that anti-CCL20Ab attenuates airway inflammation and remodeling in an HDM-induced mouse model of bronchial asthma. Taken together, our results suggest that HDM-induced CCL20 is required for chronic inflammation that contributes airway remodeling in a mouse model of asthma.
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Asma , Pyroglyphidae , Remodelación de las Vías Aéreas (Respiratorias) , Animales , Asma/metabolismo , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal , Inflamación/complicaciones , Ligandos , Pulmón/metabolismo , Sistema de Señalización de MAP Quinasas , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Microtubule-associated tumor suppressor 1 (MTUS1) is thought to be downregulated in arious human cancers, which suggests its role as a tumor suppressor. This study investigated the clinicopathological significance of MTUS1 expression in lung adenocarcinoma. Tissue microarray blocks consisting of 161 cases were constructed, and immunohistochemical staining was used to assess MTUS1 expression. Correlations of MTUS1 expression and clinicopathological parameters were analyzed. In addition, we used public databases and performed bioinformatics analysis. Low level of MTUS1 was significantly associated with higher clinical stage (p = 0.006), higher tumor stage (p = 0.044), lymph node metastasis (p = 0.01), worse histologic grade (p = 0.007), lymphovascular invasion (p = 0.014), and higher Ki-67 proliferation index (p < 0.001). Patients with low MTUS1 expression also showed shorter disease-free survival (p = 0.002) and cancer-specific survival (p = 0.006). Analysis of data from the Cancer Genome Atlas confirmed that the mRNA expression of MTUS1 in lung adenocarcinoma was significantly lower than that of normal lung tissue (p = 0.02), and patients with decreased MTUS1 expression showed significantly shorter overall survival (p = 0.008). These results suggest that MTUS1 may be a potential biomarker for predicting clinical outcomes in lung adenocarcinoma patients.
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BACKGROUND: Cholecystitis is an important risk factor for gallbladder cancer, but the bile microbiome and its association with gallbladder disease has not been investigated fully. We aimed to analyze the bile microbiome in normal conditions, chronic cholecystitis, and gallbladder cancer, and to identify candidate bacteria that play an important role in gallbladder carcinogenesis. METHODS: We performed metagenome sequencing on bile samples of 10 healthy individuals, 10 patients with chronic cholecystitis, and 5 patients with gallbladder cancer, and compared the clinical, radiological, and pathological characteristics of the participants. RESULTS: No significant bacterial signal was identified in the normal bile. The predominant dysbiotic bacteria in both chronic cholecystitis and gallbladder cancer were those belonging to the Enterobacteriaceae family. Klebsiella increased significantly in the order of normal, chronic cholecystitis, and gallbladder cancer. Patients with chronic cholecystitis and dysbiotic microbiome patterns had larger gallstones and showed marked epithelial atypia, which are considered as precancerous conditions. CONCLUSION: We investigated the bile microbiome in normal, chronic cholecystitis, and gallbladder cancer. We suggest possible roles of Enterobacteriaceae, including Klebsiella, in gallbladder carcinogenesis. Our findings reveal a possible link between a dysbiotic bile microbiome and the development of chronic calculous cholecystitis and gallbladder cancer.
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Bacterias/aislamiento & purificación , Bilis/metabolismo , Bilis/microbiología , Disbiosis/microbiología , Enfermedades de la Vesícula Biliar/microbiología , Neoplasias de la Vesícula Biliar/microbiología , Vesícula Biliar/microbiología , Adulto , Bacterias/clasificación , Estudios de Casos y Controles , Colecistitis/microbiología , Colecistitis/patología , Humanos , Metagenómica , Microbiota , Persona de Mediana Edad , FilogeniaRESUMEN
BACKGROUND: Yin Yang 1 (YY1), the multifunctional transcription factor, has recently been assigned biological properties related to human malignancies. YY1 can facilitate both tumor suppression and tumor growth. The conflicting role of YY1 in human malignancies is not yet fully explained. OBJECTIVE: In this study, we determined the clinicopathologic significance and prognostic role of YY1 in stage III colorectal cancer (CRC). MATERIALS AND METHODS: YY1 expression was evaluated immunohistochemically in tissue microarray from 345 CRCs. YY1 expression was scored by the proportion of tumor cells with nuclear staining into 4 scores (0, none; 1+, ≤10%; 2+, 10 to ≤25%; 3+, >25%). A score of 0 and 1 were considered as loss of expression. RESULTS: Loss of YY1 expression was observed in 49 (14.2%) out of 345 CRCs and was associated with larger tumor size (P = 0.004), tumor deposit (P = 0.008), and higher pathologic tumor (pT) stage (P = 0.004). In stage III group, loss of YY1 expression was associated with larger tumor size (P = 0.027) and tumor deposit (P = 0.011). Kaplan-Meier survival curves revealed no significant difference between patients with YY1 loss and patients with intact YY1 in both cancer-specific survival and recurrence-free survival (P = 0.330 and P = 0.470, respectively). In American Joint Committee on Cancer (AJCC) stage subgroup, loss of YY1 expression was associated with poor recurrence-free survival in AJCC stage III CRC (P = 0.038). CONCLUSION: Loss of YY1 expression was significantly associated with aggressive phenotypes and poor patient outcome in AJCC stage III CRC.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Expresión Génica , Factor de Transcripción YY1/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/clasificación , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Análisis de Matrices TisularesRESUMEN
DNA base editors and prime editing technology enable therapeutic in situ correction of disease-causing alleles. These techniques could have broad applications for ex vivo editing of cells prior to transplantation in a range of diseases, but it is critical that the target population is efficiently modified and engrafts into the host. Chemically derived hepatic progenitors (CdHs) are a multipotent population capable of robust engraftment and hepatocyte differentiation. Here we reprogrammed hepatocytes from a mouse model of hereditary tyrosinemia type 1 (HT1) into expandable CdHs and successfully corrected the disease-causing mutation using both adenine base editors (ABEs) and prime editors (PEs). ABE- and PE-corrected CdHs repopulated the liver with fumarylacetoacetate hydrolase-positive cells and dramatically increased survival of mutant HT1 mice. These results demonstrate the feasibility of precise gene editing in transplantable cell populations for potential treatment of genetic liver disease.
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Adenina , Hepatopatías , Adenina/farmacología , Animales , Edición Génica , Hepatocitos , Hepatopatías/terapia , RatonesRESUMEN
An epoxy-based solder paste (ESP) is a promising alternative to conventional solder pastes to improve the reliability of fine-pitch electrical joining because the epoxy encapsulates the solder joint. However, development of an appropriate epoxy formulation and investigation of its reaction mechanism with solder powder is challenging. In this study, we demonstrate a newly designed ESP consisting of diglycidyl ether of bisphenol F (DGEBF) resin, Sn-3.0 Ag-0.5 Cu (SAC305) solder powder, and L-glutamic acid (Glu), which is a proteinogenic amino acid for biosynthesis of proteins in living systems. The mechanism of the thermochemical reaction was explored and tentatively proposed, which reveals that the products of the reaction between SAC305 and Glu function as catalysts for the etherification of epoxides and alcohols produced by chemical bonding between DGEBF and Glu, consequently leading to highly crosslinked polymeric networks and an enhancement of impact resistance. Our findings provide further insight into the mechanism of the reaction between various formulations comprising an epoxy, amino acid, and solder powder, and their potential use as ESPs for electrical joining.
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BACKGROUND AND AIM: Stem cell treatments using scaffolds for liver disease have been well studied. However, macro-encapsulation of mesenchymal stem cells (MSCs) to minimize or inhibit stem cell homing has not been evaluated. Here, we conducted a proof-of-concept study using MSCs macro-encapsulated in poly lactic-co-glycolic acid in liver disease models. METHODS: Poly lactic-co-glycolic acid semipermeable membranes (surface pore size up to 40 µm) were used as the macro-encapsulation system. Macro-encapsulated pouches were loaded with MSCs and sealed. Each pouch was implanted in the subcutaneous region of the dorsum or interlobular space of the liver. Acute liver injury was induced using thioacetamide intraperitoneal injection thrice a week. For the chronic liver fibrosis model, thioacetamide dose was gradually increased, starting from 100 to 400 mg/kg over 16 weeks (thrice a week). RESULTS: In the acute liver injury model, the treated groups showed decreased liver inflammation and necrosis compared with the control. Hepatic fibrosis decreased in the treated group in the chronic liver fibrosis model compared with that in the control group. Encapsulated MSCs exhibited changed cell morphology and characteristics after implantation, showing increased periodic acid-Schiff staining and CYP2E1 expression. Migration and homing of MSCs into the liver was not observed. Under hypoxic conditions, macro-encapsulated MSCs secreted more growth hormones, including vascular endothelial growth factor, platelet-derived growth factor, angiopoietin-2, and placental growth factor, than monolayered MSCs in vitro. CONCLUSIONS: Macro-encapsulated MSCs attenuate hepatic inflammation and fibrosis by upregulating hypoxia-induced growth hormone secretion in liver disease models.
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Hepatopatías , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Animales , Modelos Animales de Enfermedad , Femenino , Fibrosis , Inflamación/patología , Hígado/patología , Cirrosis Hepática/patología , Cirrosis Hepática/terapia , Hepatopatías/patología , Factor de Crecimiento Placentario , Tioacetamida/toxicidad , Factor A de Crecimiento Endotelial VascularRESUMEN
BACKGROUND/AIM: Dual-specificity protein phosphatase 4 (DUSP4) negatively regulates MAPK signaling and is involved in various cellular processes. We herein evaluated the relationship between DUSP4 expression and clinicopathological characteristics in a large series of gastric cancer samples. MATERIALS AND METHODS: DUSP4 expression was examined by immunohistochemistry in 508 gastric cancer samples. Cases were classified according to the TCGA molecular classification and HER2 amplification. Kaplan-Meier plots were used to predict the relationship between mRNA expression of DUSP4 and survival. RESULTS: Low expression of DUSP4 was significantly correlated with larger tumor size, higher pT category, positive nodal status, higher stage, lymphovascular invasion, perineural invasion, worse overall survival, and worse recurrence-free survival. No correlation was observed between DUSP4 expression and molecular characteristics. Bioinformatics analysis showed that low mRNA expression was associated with a poor prognosis. CONCLUSION: Low expression of DUSP4 is associated with aggressive phenotypes of gastric cancer and a poor prognosis.
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Neoplasias Gástricas , Fosfatasas de Especificidad Dual/genética , Humanos , Inmunohistoquímica , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Fenotipo , Pronóstico , Neoplasias Gástricas/genéticaRESUMEN
BACKGROUND AND AIMS: Fat accumulation results from increased fat absorption and/or defective fat metabolism. Currently, the lipid-sensing nuclear receptor that controls fat utilization in hepatocytes is elusive. Liver X receptor alpha (LXRα) promotes accumulation of lipids through the induction of several lipogenic genes. However, its effect on lipid degradation is open for study. Here, we investigated the inhibitory role of LXRα in autophagy/lipophagy in hepatocytes and the underlying basis. APPROACH AND RESULTS: In LXRα knockout mice fed a high-fat diet, or cell models, LXRα activation suppressed the function of mitochondria by inhibiting autophagy/lipophagy and induced hepatic steatosis. Gene sets associated with "autophagy" were enriched in hepatic transcriptome data. Autophagy flux was markedly augmented in the LXRα knockout mouse liver and primary hepatocytes. Mechanistically, LXRα suppressed autophagy-related 4B cysteine peptidase (ATG4B) and Rab-8B, responsible for autophagosome and -lysosome formation, by inducing let-7a and microRNA (miR)-34a. Chromatin immunoprecipitation assay enabled us to find LXRα as a transcription factor of let-7a and miR-34a. Moreover, 3' untranslated region luciferase assay substantiated the direct inhibitory effects of let-7a and miR-34a on ATG4B and Rab-8B. Consistently, either LXRα activation or the let-7a/miR-34a transfection lowered mitochondrial oxygen consumption rate and mitochondrial transmembrane potential and increased fat levels. In obese animals or nonalcoholic fatty liver disease (NAFLD) patients, let-7a and miR-34a levels were elevated with simultaneous decreases in ATG4B and Rab-8B levels. CONCLUSIONS: LXRα inhibits autophagy in hepatocytes through down-regulating ATG4B and Rab-8B by transcriptionally activating microRNA let-7a-2 and microRNA 34a genes and suppresses mitochondrial biogenesis and fuel consumption. This highlights a function of LXRα that culminates in the progression of liver steatosis and steatohepatitis, and the identified targets may be applied for a therapeutic strategy in the treatment of NAFLD.
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Proteínas Relacionadas con la Autofagia/metabolismo , Autofagia/fisiología , Cisteína Endopeptidasas/metabolismo , Hepatocitos/metabolismo , Receptores X del Hígado/metabolismo , Mitocondrias/fisiología , Proteínas de Unión al GTP rab/metabolismo , Activación Metabólica , Animales , Autofagia/genética , Proteínas Relacionadas con la Autofagia/genética , Cisteína Endopeptidasas/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Regulación hacia Abajo , Hígado Graso/etiología , Hígado Graso/genética , Hígado Graso/metabolismo , Hígado Graso/fisiopatología , Células Hep G2/metabolismo , Células Hep G2/fisiología , Hepatocitos/fisiología , Humanos , Metabolismo de los Lípidos/genética , Metabolismo de los Lípidos/fisiología , Hígado/metabolismo , Hígado/fisiología , Hígado/fisiopatología , Receptores X del Hígado/genética , Receptores X del Hígado/fisiología , Ratones , Ratones Noqueados , MicroARNs/genética , MicroARNs/metabolismo , MicroARNs/fisiología , Mitocondrias/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Biogénesis de Organelos , Consumo de Oxígeno/genética , Consumo de Oxígeno/fisiología , Transcriptoma , Proteínas de Unión al GTP rab/genéticaRESUMEN
AIMS: CD47 is upregulated on the surface of various tumour cells, and it is known to inhibit the phagocytosis of tumour cells by macrophages. Immunotherapy that targets CD47 has demonstrated success in preclinical trials and is now under clinical investigation for both solid and haematological malignancies. However, data regarding CD47 expression in hepatocellular carcinoma (HCC) tissue and its correlation with clinical outcomes in patients with HCC remain limited. Here, we investigated the clinicopathological features associated with CD47 expression in HCC. METHODS: CD47 expression was evaluated by immunohistochemistry in tissue microarray sections containing 166 HCC tissues. CD47 expression was considered positive if 10% or more tumour cells were stained. RESULTS: CD47 expression was observed in 36 (21.7%) of 166 HCC tissues and was significantly associated with frequent large vessel invasion, advanced American Joint Committee on Cancer stage and higher Ki-67 proliferation index. In the survival analyses, CD47 expression was not associated with recurrence-free survival or overall survival in total patients with HCC. However, in patients who received surgical resection without any adjuvant treatment, CD47 expression was associated with shorter recurrence-free survival. CONCLUSIONS: CD47 expression was significantly associated with adverse pathological features and poor clinical outcomes in patients with HCC who did not receive adjuvant treatment.
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Biomarcadores de Tumor/metabolismo , Antígeno CD47/biosíntesis , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
OBJECTIVES/HYPOTHESIS: Ultrasound-guided fine-needle aspiration cytology (US-FNAC) is a well-established procedure performed to establish the diagnosis of Kikuchi-Fujimoto disease (KFD). Ultrasound-guided core needle biopsy (US-CNB) is an alternative diagnostic tool for KFD. However, the efficacy of US-CNB is not well evaluated. This study aimed to evaluate the efficacy of US-CNB and compare it with that of US-FNAC in the diagnosis of KFD. STUDY DESIGN: Retrospective cohort study. METHODS: We analyzed 170 patients who were diagnosed with KFD between January 2009 and May 2019. US-FNAC, US-CNB, and excisional biopsy were performed in 47, 114, and 9 patients, respectively. Diagnostic accuracies of US-FNAC and US-CNB were analyzed and compared. RESULTS: Of the 170 patients, 45 and 125 were men and women, respectively. The mean age was 26.9 ± 9.1 years. The most common symptom was cervical lymphadenopathy, followed by fever, headache, and myalgia. The diagnosis of KFD was established primarily by US-FNAC in 21 (44.7%) of the 47 patients, by US-CNB in 109 (95.6%) of the 114 patients, and by excisional biopsy in all 9 patients. There was no specific major complication related to US-FNAC and US-CNB. CONCLUSION: US-CNB can be considered safe and effective and used as the primary modality for the pathological diagnosis of KFD. LEVEL OF EVIDENCE: 4. Laryngoscope, 131:E1519-E1523, 2021.
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Linfadenitis Necrotizante Histiocítica/diagnóstico , Ganglios Linfáticos/patología , Adolescente , Adulto , Axila , Biopsia con Aguja Gruesa/efectos adversos , Biopsia con Aguja Gruesa/métodos , Biopsia con Aguja Gruesa/estadística & datos numéricos , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/efectos adversos , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/estadística & datos numéricos , Femenino , Ingle , Linfadenitis Necrotizante Histiocítica/patología , Humanos , Masculino , Cuello , Estudios Retrospectivos , Sensibilidad y Especificidad , Adulto JovenRESUMEN
Excessive tumor necrosis factor-α (TNF-α) is associated with the pathogenesis of rheumatoid arthritis (RA). Approximately 90% of patients with RA, who have inadequate response to methotrexate, follow anti-TNF-α therapy as the first-line immuno-treatment. However, ineffective long-term anti-TNF-α antibody cycling for 40% of non-responders to anti-TNF-α antibodies is costly and associated with various side effects, which needs alternative mechanism of action therapies. In the present study, a novel strategy to down-regulate TNF-α level was developed by using an alternative method of suppressing TNF-α converting enzyme (TACE), a transmembrane enzyme involved in cleaving and releasing bioactive soluble TNF-α. TACE suppression can be an effective remedy to block the production of soluble TNF-α, leading to an increased sensitivity to anti-TNF-α non-responders. A disease site-targeted RNA interference system was developed by forming non-viral complex between shRNA against TACE (shTACE) and bone resorption site-specific peptide carrier composed of aspartate repeating and arginine repeating sequences. The shTACE/peptide carrier complex alleviated arthritic symptoms in collagen induced arthritis (CIA) models by demonstrating enhanced anti-inflammatory and anti-osteoclastogenic effects. Similar results were obtained with human primary synovial cells and osteoclast precursor isolated from tissues and synovial fluids of RA patients. Taken together, the shTACE/targeting peptide complex provides a strong potential as an alternative anti-TNF-α therapeutic for RA treatment.
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Artritis Experimental , Artritis Reumatoide , Proteína ADAM17 , Animales , Artritis Reumatoide/tratamiento farmacológico , Humanos , Interferencia de ARN , Inhibidores del Factor de Necrosis Tumoral , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Lung cancer is an aggressive disease and the leading cause of cancer-related deaths worldwide. In the past several decades, the incidence of adenocarcinoma has significantly increased, and accounts for ~40% of all lung cancer cases. In the present study, we investigated the clinicopathologic significance of microRNA-130b (miR-130b) in lung adenocarcinoma and analyzed its cancer-specific functions. RNA was extracted from formalin-fixed paraffin-embedded specimens of 146 lung adenocarcinoma cases, and miR-130b expression was analyzed using quantitative real-time polymerase chain reaction. NCI-H1650 cells were transfected with miR-130b mimic and inhibitor to determine its effects on tumor cell proliferation, migration, and invasion. The expression of miR-130b in lung adenocarcinoma tissues was classified into two groups according to the median value. High expression of miR-130b was associated with higher histological grade, advanced pathologic T stage, lymph node metastasis, and lymphovascular invasion. Moreover, survival analysis showed that high miR-130b expression was significantly associated with unfavorable prognosis. In addition, miR-130b upregulation promoted cell migration and invasion, while its downregulation resulted in decreased cell proliferation, migration, and wound healing in in vitro experiments. In conclusion, these findings suggest that miR-130b promotes tumor progression and serves as a biomarker of poor prognosis for patients with lung adenocarcinoma. Hence, targeting miR-130b may serve as a potential therapeutic strategy for lung cancer.
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Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , MicroARNs/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/mortalidad , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Humanos , Pulmón/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , MicroARNs/genética , Persona de Mediana Edad , Oncogenes/genética , Pronóstico , Transcriptoma/genéticaRESUMEN
The Rv2626c protein of Mycobacterium tuberculosis is a promising vaccine candidate owing to its strong serum antibody response in patients with tuberculosis. However, there is limited information regarding the intracellular response induced by Rv2626c in macrophages. In this study, we demonstrated that Rv2626c interacts with the RING domain of TRAF6 and inhibits lysine (K) 63-linked polyubiquitination of TRAF6 (E3 ubiquitin ligase activity); this results in the suppression of TLR4 inflammatory signaling in macrophages. Furthermore, we showed that the C-terminal 123-131-amino acid Rv2626c motif promotes macrophage recruitment, phagocytosis, M2 macrophage polarization, and subsequent bacterial clearance. We developed rRv2626c-CA, a conjugated peptide containing the C-terminal 123-131-amino acid Rv2626c that targets macrophages, penetrates the cell membrane, and has demonstrated significant therapeutic effects in a mouse model of cecal ligation and puncture-induced sepsis. This multifunctional rRv2626c-CA has considerably improved potency, with an IC50 that is 250-fold (in vitro) or 1,000-fold (in vivo) lower than that of rRv2626c-WT. We provide evidence for new peptide-based drugs with anti-inflammatory and antibacterial properties for the treatment of sepsis.
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Mycobacterium tuberculosis/química , Péptidos/aislamiento & purificación , Péptidos/uso terapéutico , Sepsis/tratamiento farmacológico , Animales , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antibacterianos/uso terapéutico , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/uso terapéutico , Modelos Animales de Enfermedad , Femenino , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Péptidos/químicaRESUMEN
Single-stranded DNA binding protein 2 (SSBP2) is involved in DNA damage response and may induce growth arrest in cancer cells, having a potent tumor suppressor role. SSBP2 is ubiquitously expressed and the loss of its expression has been reported in various tumor types. However, the correlation between SSBP2 expression and colorectal cancer (CRC) prognosis remains unclear. SSBP2 nuclear expression was evaluated immunohistochemically in 48 normal colonic mucosae, 47 adenomas, 391 primary adenocarcinomas, and 131 metastatic carcinoma tissue samples. The clinicopathological factors, overall survival (OS), and recurrence-free survival were evaluated, and associations with the clinicopathological parameters were analyzed in 391 colorectal adenocarcinoma patients. A diffuse nuclear SSBP2 expression was detected in all normal colonic mucosa and adenoma samples. SSBP2 expression loss was observed in 131 (34.3%) primary adenocarcinoma and 100 (76.3%) metastatic carcinoma samples. SSBP2 expression was significantly associated with poor prognostic factors, such as vascular invasion (p = 0.005), high pT category (p = 0.045), and shorter OS (p = 0.038), using univariate survival analysis. Nuclear SSBP2 expression loss was significantly observed in colorectal carcinoma and metastatic carcinoma tissues, being associated with poor prognostic factors. SSBP2 acts as a tumor suppressor and may be used as a CRC prognostic biomarker.
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Dense granule proteins (GRAs) are essential components in Toxoplasma gondii, which are suggested to be promising serodiagnostic markers in toxoplasmosis. In this study, we investigated the function of GRA9 in host response and the associated regulatory mechanism, which were unknown. We found that GRA9 interacts with NLR family pyrin domain containing 3 (NLRP3) involved in inflammation by forming the NLRP3 inflammasome. The C-terminal of GRA9 (GRA9C) is essential for GRA9-NLRP3 interaction by disrupting the NLRP3 inflammasome through blocking the binding of apoptotic speck-containing (ASC)-NLRP3. Notably, Q200 of GRA9C is essential for the interaction of NLRP3 and blocking the conjugation of ASC. Recombinant GRA9C (rGRA9C) showed an anti-inflammatory effect and the elimination of bacteria by converting M1 to M2 macrophages. In vivo, rGRA9C increased the anti-inflammatory and bactericidal effects and subsequent anti-septic activity in CLP- and E. coli- or P. aeruginosa-induced sepsis model mice by increasing M2 polarization. Taken together, our findings defined a role of T. gondii GRA9 associated with NLRP3 in host macrophages, suggesting its potential as a new candidate therapeutic agent for sepsis.
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Inflamasomas/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Proteínas Protozoarias/inmunología , Sepsis/terapia , Toxoplasma/inmunología , Animales , Antígenos de Protozoos/química , Antígenos de Protozoos/inmunología , Proteínas Adaptadoras de Señalización CARD/inmunología , Modelos Animales de Enfermedad , Femenino , Interacciones Huésped-Parásitos/inmunología , Macrófagos/clasificación , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Mitocondrias/inmunología , Proteínas Protozoarias/química , Proteínas Protozoarias/genética , Sepsis/inmunología , Sepsis/prevención & control , Toxoplasma/genética , Toxoplasma/patogenicidadRESUMEN
Sepsis is an aberrant systemic inflammatory response mediated by excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Developing an efficient antioxidant therapy for sepsis via scavenging ROS and RNS remains a big challenge owing to the insufficient activity and sustainability of conventional antioxidants. Herein, biocompatible transition-metal dichalcogenide antioxidants with excellent scavenging activity and sustainability for H2O2, O2â¢-, OHâ¢, and nitric oxide are developed for effective sepsis treatment. WS2, MoSe2, and WSe2 nanosheets exfoliated and functionalized with a biocompatible polymer effectively scavenge mitochondrial and intracellular ROS and RNS in inflammatory cells. Among the nanosheets, WS2 most efficiently suppresses the excessive secretion of inflammatory cytokines along with scavenging ROS and RNS without affecting the expression levels of the anti-inflammatory cytokine and ROS-producing enzymes. The WS2 nanosheets significantly improve the survival rate up to 90% for severely septic mice by reducing systemic inflammation. The pharmacokinetics suggests that the WS2 nanosheets can be excreted from mice 3 days after intravenous injection. This work demonstrates the potential of therapeutic nanosheet antioxidants for effective treatment of ROS and RNS-related diseases.
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Antioxidantes , Sepsis , Animales , Antioxidantes/farmacología , Peróxido de Hidrógeno , Ratones , Nitrógeno , Oxígeno , Especies de Nitrógeno Reactivo , Especies Reactivas de Oxígeno , Sepsis/tratamiento farmacológicoRESUMEN
Single-stranded DNA binding protein 2 (SSBP2) is ubiquitously expressed, with several studies reporting it to be a tumor suppressor. We investigated SSBP2 expression and its clinicopathological significance in gastric cancer. SSBP2 expression was examined by immunohistochemistry in 539 gastric cancer sections. The cases were divided into three subtypes, namely, Epstein-Barr virus-associated (EBV), microsatellite unstable, and others (microsatellite stable and EBV negative), based on the molecular classification of The Cancer Genome Atlas (TCGA). Cases were also divided into two subgroups according to the amplification status of human epidermal growth factor receptor 2 (HER2). Most cases showed SSBP2 positivity, and only 24 (4.5%) cases displayed negative nuclear expression. Loss of nuclear expression correlated significantly with high pT category (P = 0.001), nodal metastasis (P = 0.002), and stage of progression (P = 0.005), with no correlation between molecular characteristics and SSBP2 expression. All HER2 amplification cases displayed positive SSBP2 expression. Negative SSBP2 cases showed significantly shorter recurrence-free survival (RFS) compared to positive SSBP2 cases (P = 0.008). Loss of nuclear expression of SSBP2 was significantly associated with shorter RFS in the microsatellite stable and EBV negative groups (P = 0.002), as well as the HER2 negative group (P = 0.007). However, there were no statistically significant differences in multivariate analyses. Loss of nuclear expression of SSBP2 was a poor prognostic factor, associated with stage of progression and recurrence, and showed no significant difference in molecular characteristics, including TCGA subtype and HER2 status.
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Proteínas de Unión al ADN/metabolismo , Receptor ErbB-2/genética , Neoplasias Gástricas , Adenocarcinoma/patología , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Núcleo Celular/metabolismo , Proteínas de Unión al ADN/genética , Femenino , Expresión Génica , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/clasificación , Neoplasias Gástricas/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Voriconazole, a triazole antifungal agent used to treat serious fungal infections, has a pharmacokinetic characteristic of undergoing hepatic metabolism by the cytochrome P450 system. Few cases of hyperkalemia have been reported, which presented only when the serum voriconazole level was exceptionally elevated by drug-drug interactions. Additionally, azole antifungals may interfere with the biosynthesis of adrenal steroids and therefore can predispose patients to aldosterone deficiency. However, it is unclear whether voriconazole itself can induce hypoaldosteronism or hyperkalemia. Here, we report a case of voriconazole-induced hyperkalemia in a patient administered concurrent medications to treat comorbidities. Voriconazole was orally administered for pulmonary aspergillosis, and three episodes of severe hyperkalemia recurred, which improved with emergency treatment. In the first episode, renin-angiotensin-aldosterone system inhibitors were associated. We found that dronedarone might have increased the voriconazole level in the second episode. At that time, severe hypercalcemia was concurrent, which improved with acute hemodialysis and eliminating dronedarone. Finally, severe hyperkalemia recurred without concurrent medications known to interact with voriconazole. Upon switching from voriconazole to itraconazole, the hyperkalemia was resolved. Drug level monitoring is necessary when voriconazole is used. Genetic susceptibility, such as through CYP2C19 polymorphism, may be investigated for patients with adverse reactions to voriconazole.
RESUMEN
BACKGROUND/AIM: Microtubule-associated tumor suppressor 1 (MTUS1) is a novel tumor suppressor involved in proliferation and migration, and down-regulation of MTUS1 is associated with the poor prognosis of several cancers. We evaluated the clinicopathological significance of MTUS1 expression in renal cell carcinoma (RCC). PATIENTS AND METHODS: We assessed MTUS1 expression by immunohistochemical staining of tissue microarrays from 249 cases of RCC. We analyzed the correlation of MTUS1 expression and clinicopathological characteristics. Additionally, we used public databases and performed bioinformatics analysis. RESULTS: We investigated The Cancer Genome Atlas databases and identified that MTUS1 mRNA expression was significantly lower in RCC tissues than in normal tissues. Loss of MTUS1 expression was correlated with high WHO/ISUP nuclear grade, lymphovascular invasion, renal vein thrombus, and high pT stage in patients with RCC. Although there was no statistically significant correlation between MTUS1 expression and patients' prognosis in our cohort, MTUS1 overexpression was significantly correlated with a favorable prognosis in public data. CONCLUSION: Loss of MTUS1 expression in RCC might be a potential biomarker for predicting clinical outcome.