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Water splitting is a promising technique for clean hydrogen production. To improve the sluggish hydrogen evolution reaction (HER) and oxygen evolution reaction (OER), the development of efficient bifunctional electrocatalysts for both HER and OER is urgent to approach the scale-up applications of water splitting. Nowadays transition metal oxides (TMOs) are considered as the promising electrocatalysts due to their low cost, structural flexibility and stability, however, their electrocatalytic activities are eager to be improved. Here, we synthesized waxberry-like hydrophilic Co-doped ZnFe2O4 electrocatalysts as bifunctional electrocatalysts for water splitting. Due to the enhanced active sites by electronic structure tuning and modified super-hydrophilic characteristics, the spinel ZFO-Co0.5 electrocatalyst exhibits excellent catalytic activities for both OER and HER. It exhibits a remarkable low OER overpotential of 220 mV at a current density of 10 mA cm-2 and a Tafel slope of 28.2 mV dec-1. Meanwhile, it achieves a low overpotential of 73 mV at a current density of 10 mA cm-2 with the Tafel slope of 87 mV dec-1 for HER. In addition, for water electrolysis device, the electrocatalytic performance of ZFO-Co0.5||ZFO-Co0.5 surpasses that of commercial IrO2||Pt/C. Our work reveals that the hydrophilic morphology regulation combined with metallic doping strategy is a facile and effective approach to synthesize spinel TMOs as excellent bifunctional electrocatalyst for water splitting.
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BACKGROUND: Many medical graduate students lack a thorough understanding of decision curve analysis (DCA), a valuable tool in clinical research for evaluating diagnostic models. METHODS: This article elucidates the concept and process of DCA through the lens of clinical research practices, exemplified by its application in diagnosing liver cancer using serum alpha-fetoprotein levels and radiomics indices. It covers the calculation of probability thresholds, computation of net benefits for each threshold, construction of decision curves, and comparison of decision curves from different models to identify the one offering the highest net benefit. RESULTS: The paper provides a detailed explanation of DCA, including the creation and comparison of decision curves, and discusses the relationship and differences between decision curves and receiver operating characteristic curves. It highlights the superiority of decision curves in supporting clinical decision-making processes. CONCLUSION: By clarifying the concept of DCA and highlighting its benefits in clinical decisionmaking, this article has improved researchers' comprehension of how DCA is applied and interpreted, thereby enhancing the quality of research in the medical field.
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Técnicas de Apoyo para la Decisión , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/diagnóstico , Toma de Decisiones Clínicas , Curva ROC , alfa-Fetoproteínas/análisis , alfa-Fetoproteínas/metabolismo , Investigación BiomédicaRESUMEN
BACKGROUND: Chronic inflammation and fibrosis are characteristics of silicosis, and the inflammatory mediators involved in silicosis have not been fully elucidated. Recently, macrophage-derived exosomes have been reported to be inflammatory modulators, but their role in silicosis has not been explored. The purpose of the present study was to investigate the role of macrophage-derived exosomal high mobility group box 3 (HMGB3) in silica-induced pulmonary inflammation. METHODS: The induction of the inflammatory response and the recruitment of monocytes/macrophages were evaluated by immunofluorescence, flow cytometry and transwell assays. The expression of inflammatory cytokines was examined by RT-PCR and ELISA, and the signalling pathways involved were examined by western blot analysis. RESULTS: HMGB3 expression was increased in exosomes derived from silica-exposed macrophages. Exosomal HMGB3 significantly upregulated the expression of inflammatory cytokines, activated the STAT3/MAPK (ERK1/2 and p38)/NF-κB pathways in monocytes/macrophages, and promoted the migration of these cells by CCR2. CONCLUSIONS: Exosomal HMGB3 is a proinflammatory modulator of silica-induced inflammation that promotes the inflammatory response and recruitment of monocytes/macrophages by regulating the activation of the STAT3/MAPK/NF-κB/CCR2 pathways.
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Neumonía , Silicosis , Humanos , Dióxido de Silicio/toxicidad , Dióxido de Silicio/metabolismo , FN-kappa B/metabolismo , Macrófagos/metabolismo , Inflamación/inducido químicamente , Inflamación/metabolismo , Neumonía/inducido químicamente , Neumonía/metabolismo , Citocinas/genética , Citocinas/metabolismoRESUMEN
Developing efficient water-splitting electrocatalysts to accelerate the slow oxygen evolution reaction (OER) kinetics is urgently desired for hydrogen production. Herein, ultralow phosphorus (P)-doped NiFe LDH (NiFePx LDH) with mild compressive strain is synthesized as an efficient OER electrocatalyst. Remarkably, NiFePx LDH with the phosphorus mass ratio of 0.32 wt.% and compressive strain ratio of 2.53% (denoted as NiFeP0.32 LDH) exhibits extraordinary OER activity with an overpotential as low as 210 mV, which is superior to that of commercial IrO2 and other reported P-based OER electrocatalysts. Both experimental performance and density function theory (DFT) calculation demonstrate that the doping of P atoms can generate covalent FeâP coordination bonds and lattice distortion, thus resulting in the consequent depletion of electrons around the Fe active center and the downward shift of the d-band center, which can lead to a weaker adsorption ability of *O intermediate to improve the catalytic performance of NiFeP0.32 LDH for OER. This work provides novel insights into the distinctive coordinated configuration of P in NiFePx LDH, which can result in superior catalytic performance for OER.
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High-mobility group AT-hook 2 (HMGA2) is rearranged in various types of mesenchymal tumors, particularly lipomas. HMGA2 is also co-amplified with mouse double minute 2 (MDM2) in well-differentiated liposarcoma/dedifferentiated liposarcoma (WDLPS/DDLPS). We report a case of relapsed DDLPS with a novel in-frame fusion between HMGA2 and KITLG, which encodes the ligand for KIT kinase, a critical protein involved in gametogenesis, hematopoiesis, and melanogenesis. The HMGA2 breakpoint is in intron 3, a commonly observed location for HMGA2 rearrangements, while the KITLG breakpoint is in intron 2, leading to a fusion protein that contains almost the entire coding sequence of KITLG. By immunohistochemical staining, tumor cells expressed KIT and showed phosphorylated MAPK, a major KIT downstream target. We suggest an oncogenic mechanism that involves the overexpression of KITLG caused by its rearrangement with HMGA2, leading to the constitutive activation of KIT kinase. While MDM2 amplification was observed in both the primary tumor and the relapsed tumor, the HMGA2::KITLG was only present in the relapsed tumor, indicating the role of HMGA2::KITLG in disease progression.
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Lipoma , Liposarcoma , Neoplasias de los Tejidos Conjuntivo y Blando , Humanos , Animales , Ratones , Liposarcoma/genética , Liposarcoma/patología , Lipoma/genética , Lipoma/patología , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Amplificación de GenesAsunto(s)
Hemangioendotelioma Epitelioide , Hemangioendotelioma , Hemangioma , Humanos , Proteínas de Unión al Calcio , Familia de Proteínas EGF , Hemangioendotelioma/diagnóstico , Hemangioendotelioma/genética , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Factores de TranscripciónRESUMEN
The polymeric immunoglobulin receptor (PIGR), an exosome-associated glycoprotein, plays an important role in the occurrence and development of different tumors. This study aimed to investigate whether PIGR is essential for colorectal cancer (CRC). Comprehensive bioinformatics analysis and immunohistochemistry (IHC) revealed that expression of PIGR was significantly decreased in CRC patients. Upregulated PIGR displayed favorable prognostic values in CRC patients. Several algorithms, such as TISIDB and TIMER, were used to evaluate the roles of PIGR expression in the regulation of immune response in CRC. Moreover, GSEA enrichment analysis indicated the underlying role of PIGR in the regulation of fatty acid metabolism in CRC. Taken together, our findings might provide a new potential prognostic and immune-associated biomarker for CRC and supply a new destination for PIGR-related immunotherapy in clinical treatment.
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Silicosis is one of the most serious occupational diseases with the main feature of inflammatory cell infiltration, fibroblasts activation, and large deposition of extracellular matrix in the lung. Increasing evidence indicates that macrophage-derived exosomes may play an important role in the development of silicosis by transferring their loaded microRNAs (miRNAs). Hence we carried out high-throughput sequencing to identify the expression of exosomal miRNA from macrophages exposed to silica or not in the previous study. Then we verified that miR-7219-3p was significantly up-regulated in macrophages and their exosomes after silica-exposure, as well as in the silicotic mice model by qRT-PCR, subsequent experiments confirmed that the increase of miR-7219-3p facilitated fibroblast to myofibroblast trans-differentiation (FMT), as well as cell proliferation and migration. Spouty1 (SPRY1), which served as a negative modulator of the Ras/ERK/MAPK signaling pathway, was verified as the target gene of miR-7219-3p, the knockdown or over-expression of SPRY1 apparently promoted or inhibited FMT via the Ras/ERK/MAPK signaling pathway. Furthermore, the inhibition of exosomal miR-7219-3p partially suppressed FMT and silica-induced pulmonary fibrosis in vitro and in vivo. In brief, our results demonstrated that exosomal miR-7219-3p played an important role in FMT and might be a novel therapeutic target of silicosis.
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Exosomas , MicroARNs , Silicosis , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Transdiferenciación Celular , Exosomas/genética , Fibroblastos/metabolismo , Macrófagos/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Dióxido de Silicio/metabolismo , Dióxido de Silicio/toxicidad , Silicosis/genéticaRESUMEN
Nano-hydroxylapatite (nano-HAP)/polycaprolactone (PCL) composite scaffold is proved to possess great potential for bone tissue engineering application since the biocompatibility of PCL and the osteoinduction ability of nano-HAP. However, the interfacial bonding between nano-HAP and PCL is weak by reason of the difference in thermodynamic properties. Herein, nano-HAP was modified by polydopamine (PDA) and then added to the PCL matrix to enhance their interface bonding in bone scaffold manufactured by selective laser sintering (SLS). The results indicated that PDA acted as an interfacial molecular bridge between PCL and nano-HAP. On one hand, the amino groups of PDA formed hydrogen bonding with the hydroxyl groups of nano-HAP, and on the other hand, the catechol groups of PDA formed hydrogen bonding with the ester groups of PCL. Compared with the HAP/PCL scaffolds, the tensile and compressive strength of the P-HAP/PCL scaffolds loading 12â¯wt% P-HAP were increased by 10% and 16%, respectively. Meanwhile, the scaffold possessed great bioactivity and cytocompatibility that could accelerate the formation of apatite layers and promote the cell adhesion, proliferation and differentiation.
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Durapatita , Andamios del Tejido , Durapatita/farmacología , Indoles , Poliésteres/farmacología , Polímeros , Ingeniería de Tejidos/métodosRESUMEN
Fibrosis is a persistent inflammatory response that causes scarring and tissue sclerosis by stimulating myofibroblasts to create significant quantities of extracellular matrix protein deposits in the tissue. Oxidative stress has also been linked to the development of fibrosis in several studies. The nuclear erythroid 2-related factor 2 (NRF2) transcription factor controls the expression of several detoxification and antioxidant genes. By binding to antioxidant response elements, NRF2 is activated by oxidative or electrophilic stress and promotes its target genes, resulting in a protective effect on cells. NRF2 is essential for cell survival under oxidative stress conditions. This review describes Kelch-like epichlorohydrin-associated protein 1 (KEAP1)/NRF2 signaling mechanisms and presents recent research advances regarding NRF2 and its involvement in primary fibrotic lesions such as pulmonary fibrosis, hepatic fibrosis, myocardial fibrosis, and renal fibrosis. The related antioxidant substances and drugs are described, along with the mechanisms by which KEAP1/NRF2 regulation positively affects the therapeutic response. Finally, the therapeutic prospects and potential value of NRF2 in fibrosis are summarized. Further studies on NRF2 may provide novel therapeutic approaches for fibrosis.
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Pseudomyogenic hemangioendothelioma (PHE) is a rare angiogenic tumor. Histologically, the morphological characteristics of neoplastic vessels and endothelial differentiation are not obvious, and it is easy to be confused with epithelioid sarcoma, epithelioid hemangioendothelioma and myogenic tumor. PHE usually occurs in arms and legs in young people and has a significant male predominance. The tumor has a predilection for the distal extremities and its typical manifestation is multiple center invasion of a single limb, which can involve all layers of skin and subcutaneous tissues,and is often accompanied by abvious pain. Histologically, PHE is characterized by infiltrative growth of tumor. Most tumor lesions are composed of sheets and loose fascicles of plump spindle or epithelioid cells within a background of variably prominent inflammatory infiltration, which was commonly composed of neutrophils. Some cells may resemble rhabdomyoblasts, and nuclear atypia and mitosis were rare. The tumor cells generally expressed positive cytokeratin (CK), ETS-related gene (ERG), Friend leukemia virus integration 1 (FLI1) and integrase interactor 1(INI1). In some cases, the tumor cells expressed CD31. A case of a young woman was reported in this paper, who presented with a subcutaneous mass with severe pain and was chronologically misdiagnosed with herpes zoster, low-grade malignant fibrous histiocytoma and epithelioid hemangioendothelioma. In this study, the clinical and pathological features, differential diagnosis and the latest progress in therapy of PHE were analyzed based on relevant literature.
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Hemangioendotelioma Epitelioide , Hemangioma , Histiocitoma Fibroso Maligno , Lesiones Precancerosas , Adolescente , Adulto , Biomarcadores de Tumor , Niño , Diagnóstico Diferencial , Errores Diagnósticos , Femenino , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/patología , Histiocitoma Fibroso Maligno/diagnóstico , Humanos , Masculino , Dolor , Lesiones Precancerosas/diagnósticoRESUMEN
Sarcoma or sarcomatoid malignancies are a set of mesenchymal-origin malignancies with vast heterogeneity in clinical and molecular characteristics. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase oncoprotein expressed by several tumors, including sarcomas. Crizotinib is an effective ALK inhibitor. In this review paper, we summarized findings from the literature regarding the use of crizotinib for the treatment of sarcoma and sarcomatoid malignancies harboring ALK fusions with definitive partners (with the given gene(s) name) from the years 2010 to 2021.One hundred and four articles were retrieved and after exclusion, 28 studies containing 33 patients were finally selected. All 33 patients were treated with crizotinib. Among the 33 cases, 19 were adult patients, 11 were pediatric patients, and 3 cases did not have data on age and/or gender. Most cases had a primary abdominal lesion (16/30), followed by thoracic (10/30), trunk (3/30), retroperitoneal (1/30), and one case of right medial thigh (case 7). Stage IV disease was reported in 76.7% (23/30) of patients. The objective response rate and disease control rate was 86.7% (26/30) and 96.7% (29/30), respectively, which were assessed on average of 8 weeks after crizotinib initiation. Rapid improvement of symptoms was observed within one to two weeks in some cases including patients with extensive diseases or poor performance. There was no difference in crizotinib response between pediatrics and adult cases. Crizotinib is effective; however, surgery remains the mainstay of therapy, with newer evidence showing concurrent crizotinib with surgery conferring long-term overall survival. However, we should still be cognizant of the heterogeneous landscape of crizotinib efficacy and its associated fatal adverse events.
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PURPOSE: To explore the molecular profiles of transcriptional enhanced associate domain (TEAD) family in ovarian serous carcinoma (OSC). METHODS: In this study, we use bioinformatics methods including GEPIA, GE-mini, Oncomine 3.0, Kaplan-Meier plotter, cBioPortal, WebGestalt, TIMER2.0 and DiseaseMeth2.0, and in vitro experimental RT-PCR to assess the expression profiles and prognostic significance of TEAD family in OSC. RESULTS: According to the bioinformatics analysis, TEAD family was abnormally expressed in OSC. In terms of prognosis, Kaplan-Meier plotter indicated that OSC patients with high level of TEAD4 showed poor overall survival (OS), progression-free survival (PFS) and post progression survival (PPS). TEAD family also had significantly diagnostic values for OSC patients. Tumor Immune Estimation Resource (TIMER) algorithm indicated that TEAD family was significantly associated with different types of infiltrating immune cells, including B cells, macrophages, dendritic cells, neutrophils, CD8+ T cells and CD4+ T cells. Gene set enrichment analysis of TEAD family-associated coexpression genes was further explored. In in vitro experiments, the RT-PCR results showed the upregulated TEAD2/4 in OSC tissues and cells (A2780 and TOV112D). Moreover, decreased expression of TEAD2 could induce the ferroptosis through increasing the ROS accumulation. CONCLUSION: Thus, TEAD family correlated with the diagnosis, prognosis and immune infiltration in OSC. These results could provide comprehensive understanding of TEAD family in the diagnosis and prognosis of OSC patients.
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Atrial fibrillation (AF), a common arrhythmia that usually occurs in patients with heart disease, is one of the leading causes for mortality and disability worldwide. Current drug therapy for AF patients lacks sufficient efficacy and has side effects. Radiofrequency ablation is more effective than traditional drug therapy, but this invasive procedure is associated with potential risks and postoperative recurrence, limiting the clinical benefits for AF patients. Therefore, it is necessary to expand our understanding about the underlying molecular mechanism of AF and to explore the new therapeutic strategies. Long noncoding RNA (lncRNA) is a set of noncoding RNA longer than 200 nucleotides. Growing evidence indicates that lncRNA is involved in numerous pathophysiological processes of AF, such as structural remodeling, electrical remodeling, renin-angiotensin system, abnormal calcium regulation, etc. In addition, lncRNA involved in structural remodeling and electrical remodeling has the potential to be a novel target for the diagnosis and treatment of AF, and lncRNA involved in autonomic nerve remodeling may bring new enlightenment for the prognosis and recurrence of AF.
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Fibrilación Atrial , Remodelación Atrial , ARN Largo no Codificante , Fibrilación Atrial/genética , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Recurrencia , Sistema Renina-AngiotensinaRESUMEN
BACKGROUND: Uncontrollable inflammation is a critical feature of gram-negative bacterial pneumonia-induced acute respiratory distress syndrome (ARDS). Both neutrophils and alveolar macrophages participate in inflammation, but how their interaction augments inflammation and triggers ARDS is unclear. The authors hypothesize that neutrophil extracellular traps (NETs), which are formed during neutrophil NETosis, partly cause alveolar macrophage pyroptosis and worsen the severity of ARDS. METHODS: The authors first analysed whether NETs and caspase-1 are involved in clinical cases of ARDS. Then, the authors employed a lipopolysaccharide (LPS)-induced ARDS model to investigate whether targeting NETs or alveolar macrophages is protective. The AIM2 sensor can bind to DNA to promote AIM2 inflammasome activation, so the authors studied whether degradation of NET DNA or silencing of the AIM2 gene could protect alveolar macrophages from pyroptosis in vitro. RESULTS: Analysis of aspirate supernatants from ARDS patients showed that NET and caspase-1 levels were correlated with the severity of ARDS and that the levels of NETs and caspase-1 were higher in nonsurvivors than in survivors. In vivo, the NET level and proportion of pyroptotic alveolar macrophages in bronchoalveolar lavage fluid (BALF) were obviously higher in LPS-challenged mice than in control mice 24 h after injury. Administration of DNase I (a NET DNA-degrading agent) and BB-Cl-amidine (a NET formation inhibitor) alleviated alveolar macrophage pyroptosis, and Ac-YVAD-cmk (a pyroptosis inhibitor) attenuated NET levels in BALF and neutrophil infiltration in alveoli. All treatments markedly attenuated the severity of ARDS. Notably, LPS causes NETs to induce alveolar macrophage pyroptosis, and degradation of NET DNA or silencing of the AIM2 gene protected against alveolar macrophage pyroptosis. CONCLUSION: These findings shed light on the proinflammatory role of NETs in mediating the neutrophil-alveolar macrophage interaction, which influences the progression of ARDS.
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BACKGROUND: Breast cancer (BRCA) is the most common tumor in women, and lipid metabolism involvement has been demonstrated in its tumorigenesis and development. However, the role of lipid metabolism-associated genes (LMAGs) in the immune microenvironment and prognosis of BRCA remains unclear. METHODS: A total of 1076 patients with BRCA were extracted from The Cancer Genome Atlas database and randomly assigned to the training cohort (n = 760) or validation cohort (n = 316). Kaplan-Meier analysis was used to assess differences in survival. Consensus clustering was performed to categorize the patients with BRCA into subtypes. Using multivariate Cox regression analysis, an LMAG-based prognostic risk model was constructed from the training cohort and validated using the validation cohort. The immune microenvironment was evaluated using the ESTIMATE and tumor immune estimation resource algorithms, CIBERSORT, and single sample gene set enrichment analyses. RESULTS: Consensus clustering classified the patients with BRCA into two subgroups with significantly different overall survival rates and immune microenvironments. Better prognosis was associated with high immune infiltration. The prognostic risk model, based on four LMAGs (MED10, PLA2G2D, CYP4F11, and GPS2), successfully stratified the patients into high- and low-risk groups in both the training and validation sets. High risk scores predicted poor prognosis and indicated low immune status. Subgroup analysis suggested that the risk model was an independent predictor of prognosis in BRCA. CONCLUSION: This study demonstrated, for the first time, that LMAG expression plays a crucial role in BRCA. The LMAG-based risk model successfully predicted the prognosis and indicated the immune microenvironment of patients with BRCA. Our study may provide inspiration for further research on BRCA pathomechanisms.
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Idiopathic pulmonary fibrosis (IPF) is a worldwide disease characterized by the chronic and irreversible decline of lung function. Currently, there is no drug to successfully treat the disease except for lung transplantation. Numerous studies have been devoted to the study of the fibrotic process of IPF and findings showed that transforming growth factorß1 (TGFß1) plays a central role in the development of IPF. TGFß1 promotes the fibrotic process of IPF through various signaling pathways, including the Smad, MAPK, and ERK signaling pathways. There are intersections between these signaling pathways, which provide new targets for researchers to study new drugs. In addition, TGFß1 can affect the fibrosis process of IPF by affecting oxidative stress, epigenetics and other aspects. Most of the processes involved in TGFß1 promote IPF, but TGFß1 can also inhibit it. This review discusses the role of TGFß1 in IPF.
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Fibrosis Pulmonar Idiopática/patología , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Humanos , Fibrosis Pulmonar Idiopática/terapia , Sistema de Señalización de MAP Quinasas , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
Macrophages play a key role in silicosis, and exosomes are potent mediators of intercellular communication. This suggests that macrophage-derived exosomes have a potential contribution to the pathogenesis of silicosis. To investigate whether macrophage-derived exosomes promote or inhibit lung fibrosis, in vitro, silica-exposed macrophage-derived exosomes (SiO2 -Exos) were collected and cocultured with fibroblasts. The expression of collagen I and α-SMA was evaluated. Furthermore, the endoplasmic reticulum (ER) stress markers BIP, XBP1s and P-eIF2α were assessed after treatment with or without the ER stress inhibitor 4-PBA. In vivo, mice were pre-treated with the exosome secretion inhibitor GW4869 prior to silica exposure. After sacrifice, lung tissues were histologically examined, and the expression of proinflammatory cytokines (TNF-α, IL-1ß and IL-6) in bronchoalveolar lavage fluid (BALF) was measured. The results showed that the expression of collagen I and α-SMA was up-regulated after treatment with SiO2 -Exos, accompanied by increased expression of BIP, XBP1s and P-eIF2α. Pre-treatment with 4-PBA reversed this effect. More importantly, an in vivo study demonstrated that pre-treatment with GW4869 decreased lung fibrosis and the expression of TNF-α, IL-1ß and IL-6 in BALF. These results suggested that SiO2 -Exos are profibrogenic and that the facilitating effect is dependent on ER stress.
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Estrés del Retículo Endoplásmico , Exosomas/fisiología , Fibroblastos/patología , Macrófagos/fisiología , Fibrosis Pulmonar/patología , Dióxido de Silicio/toxicidad , Silicosis/patología , Animales , Comunicación Celular , Citocinas , Fibroblastos/metabolismo , Macrófagos/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/metabolismo , Transducción de Señal , Silicosis/etiología , Silicosis/metabolismoRESUMEN
OBJECTIVE: Glucose-dependent insulinotropic polypeptide receptor (GIPR) has been identified as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). Therefore, we developed the anti-GIPR antagonistic monoclonal antibody (mAb) alone and in combination with DPP-4 inhibitor as potential therapeutic strategy for treating obesity and dyslipidemia based on this genetic evidence. METHODS: Fully neutralized GIPR activity of GIPR-monoclonal antibody (mAb) was assessed by regulating the in vitro production of cAMP in the mouse GIPR stably expressing cells. Chronic efficacies of GIPR-mAb alone and in combination with DPP-4 inhibitor Sitagliptin in diabetic or DIO mice were both investigated. Multiple metabolic parameters including body weight, glucose level, fat mass, lipid metabolism-related indicators as well as H&E staining and immunohistochemical analysis were performed. Role of GIPR in pancreatic cells on regulating fat metabolism was explored in GIPR ß-cell knockout mouse model. RESULTS: Chronic treatment of GIPR-mAb improved body weight control, glucose metabolism, and was associated with reduced fat mass, enhanced pancreatic function and exchange ratio of the resting respiratory in diabetic mice. In addition, further study of anti-GIPR mAb combined with Sitagliptin in DIO mice demonstrated significantly improved weight loss compare to the both monomer treatment. Furthermore, we demonstrated important role of GIPR in ß-cell in regulating the fat mass and response to antagonistic GIPR-mAb in a conditional GIPR-knockout mouse. CONCLUSION: Chronic treatment with anti-GIPR mAb alone and combined with DPP-4 inhibitor provide preclinical therapeutic approaches to treat obesity.
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Anticuerpos Monoclonales/farmacología , Dipeptidil Peptidasa 4/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Dislipidemias/tratamiento farmacológico , Enfermedades Renales/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Receptores de la Hormona Gastrointestinal/antagonistas & inhibidores , Animales , Peso Corporal , Dieta Alta en Grasa/efectos adversos , Quimioterapia Combinada , Dislipidemias/etiología , Dislipidemias/patología , Enfermedades Renales/etiología , Enfermedades Renales/patología , Masculino , Ratones , Ratones Noqueados , Ratones Obesos , Obesidad/etiología , Obesidad/patología , Receptores de la Hormona Gastrointestinal/inmunología , Receptores de la Hormona Gastrointestinal/fisiología , Pérdida de PesoRESUMEN
AIMS: To explore the protective efficacies and potent mechanism of amygdalin on high glucose-cultured renal cell HBZY-1 in vitro and streptozotocin (STZ)-induced diabetic nephropathy (DN) rat in vivo. MAIN METHODS: The cellar proliferation and generation of ROS in high-glucose cultured HBZY-1 cell were assessed by MTT and DCFH-DA assay, respectively. The fasting blood glucose levels, renal function and inflammation indexes as well as oxidative stress markers in STZ-induced diabetic rats were all measured. The histologic renal section was stained with Mason and periodic acid-Schiff (PAS) method. Immunohistochemistry and western blotting methods were applied to assess expression levels of extracellular matrix (ECM), epithelial-mesenchymal transition (EMT)-related as well as TGF-ß1/Smad signaling pathway-related proteins. KEY FINDINGS: Firstly, amygdalin significantly suppressed the excessive cell proliferation and ROS generation in HBZY-1 cells cultured with high glucose. The hyperglycemia, 24 h-UP excretion, BUN and Scr of DN rats were significantly attenuated after the chronic treatment of amygdalin. Moreover, MDA, SOD, IFN-γ and IL-12 levels in kidney tissues were all effectively reduced. Besides, amygdalin can suppress the ECM accumulation and EMT transformation by inhibiting Smad/TGF-ß pathway to alleviate the renal fibrosis in renal tissues of DN model rats. SIGNIFICANCE: Amygdalin ameliorates excessive oxidative stress, inflammation and renal tissue fibrosis of DN mainly by suppressing TGF-ß1/Smad signaling pathway and regulating the key enzymes of ECM degradation.