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BACKGROUND: Synaptotagmin 11 (SYT11) plays a pivotal role in neuronal vesicular trafficking and exocytosis. However, no independent prognostic studies have focused on various cancers. In this study, we aimed to summarize the clinical significance and molecular landscape of SYT11 in various tumor types. METHODS: Using several available public databases, we investigated abnormal SYT11 expression in different tumor types and its potential clinical association with prognosis, methylation profiling, immune infiltration, gene enrichment analysis, and protein-protein interaction analysis, and identified common pathways. RESULTS: TCGA and Genotype-Tissue Expression (GTEx) showed that SYT11 was widely expressed across tumor and corresponding normal tissues. Survival analysis showed that SYT11 expression correlated with the prognosis of seven cancer types. Additionally, SYT11 mRNA expression was not affected by promoter methylation, but regulated by certain miRNAs and associated with cancer patient prognosis. In vitro experiments further verified a negative correlation between the expression of SYT11 and miR-19a-3p in human colorectal, lung, and renal cancer cell lines. Moreover, aberrant SYT11 expression was significantly associated with immune infiltration. Pathway enrichment analysis revealed that the biological and molecular processes of SYT11 were related to clathrin-mediated endocytosis, Rho GTPase signaling, and cell motility-related functions. CONCLUSIONS: Our results provide a clear understanding of the role of SYT11 in various cancer types and suggest that SYT11 may be of prognostic and clinical significance.
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MicroRNAs , Neoplasias , Sinaptotagminas , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias/genética , Neoplasias/metabolismo , Prognóstico , Sinaptotagminas/genética , Sinaptotagminas/metabolismoRESUMO
LDL lipoprotein receptor-related protein 11 (LRP11) plays a role in several tumors. However, their roles in hepatocellular carcinoma remain unclear. The present study aimed to explore the expression profile and prognostic value of LRP11 in liver hepatocellular carcinoma (LIHC) patients using various cancer databases and bioinformatic tools. In bioinformatics analysis, The Cancer Genome Atlas datasets showed increased LRP11 expression in tumor tissues compared to that in non-tumor tissues in various cancers. Moreover, patients with high expression LRP11 correlated with poor prognosis and clinical features. The LRP11 expression positively correlated with the infiltration of immune cells such as macrophages, neutrophils, and myeloid-derived suppressor cells and a combination of high LRP11 expression and high immune infiltrates was associated with the worst survival in LIHC tumors. Our results also indicated that LRP11 expression was closely associated with immune-modulate function, such as antigen presentation. In DNA methylation profiling, hypomethylation of LRP11 is widely observed in tumors and has prognostic value in LIHC patients. Functional enrichment analysis revealed that LIHC-specific LRP11 interacting genes are involved in protein binding, intracellular processing, and G-protein-related signaling pathways. Analyses of drug sensitivity and immune checkpoint inhibitor predict a number of drugs that could potentially be used to target LRP11. In addition, in vitro experiments verified the promoting effect of LRP11 on the migration, invasion, and colony formation capacity of hepatocellular carcinoma cells. Collectively, our results aided a better understanding of the clinical significance of LRP11 in gene expression, functional interactions, and epigenetic regulation in LIHC and suggested that it may be a useful prognostic biomarker for LIHC patients.
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Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the 5-year relative overall survival (OS) rate is less than 20%. Since there are no specific symptoms, most patients with HCC are diagnosed in an advanced stage with poor prognosis. Therefore, identifying novel prognostic biomarkers to improve the survival of patients with HCC is urgently needed. In the present study, we attempted to identify SAMD13 (Sterile Alpha Motif Domain-Containing Protein 13) as a novel biomarker associated with the prognosis of HCC using various bioinformatics tools. SAMD13 was found to be highly expressed pan-cancer; however, the SAMD13 expression was significantly correlated with the worst prognosis in HCC. Clinicopathological analysis revealed that SAMD13 upregulation was significantly associated with advanced HCC stage and high-grade tumor type. Simultaneously, high SAMD13 expression resulted in association with various immune markers in the immune cell subsets by TIMER databases and efficacy of immunotherapy. Methylation analysis showed SAMD13 was remarkably associated with prognosis. Furthermore, a six-hub gene signature associated with poor prognosis was correlated with the cell cycle, transcription, and epigenetic regulation and this analysis may support the connection between SAMD13 expression and drug-resistance. Our study illustrated the characteristics of SAMD13 role in patients with HCC using various bioinformatics tools and highlights its potential role as a therapeutic target and promising biomarker for prognosis in HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Prognóstico , Epigênese Genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
Sargassum horneri (S. horneri) is a brown seaweed that contains a fucose-rich sulfated polysaccharide called fucoidan and is known to possess beneficial bioactivities, such as anti-inflammatory, antiviral, antioxidative, and antitumoral effects. This study aimed to determine the anti-inflammatory effects of AB_SH (hydrothermal extracts from S. horneri) and its bioactive compound (fucoidan) against tumor necrosis factor alpha (TNF-α)-induced inflammation in human retinal pigment epithelial (RPE) cells. AB_SH did not exhibit any cytotoxicity, and it decreased the mRNA expression of interleukin (IL)-6 and IL-8 and the production of the cytokines IL-6 and TNF-α. It also suppressed the expression levels of phosphorylated nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs), including c-Jun amino-terminal kinases (JNK), p38 protein kinases (p38), and extracellular signal-regulated kinase (ERK) proteins, suggesting that AB_SH inhibits activation of the NF-kB/MAPK signaling pathway. Since fucoidan was identified in the composition analysis of AB_SH, it was additionally shown to be required for its anti-inflammatory effects in TNF-α-stimulated human RPE cells. In line with the AB_SH results, fucoidan reduced the mRNA levels of IL-6, IL-1ß, and IL-8 and production of the cytokines IL-6, TNF-α, and IL-8 through the downregulation of the NF-kB/MAPK signaling pathway in a dose-dependent manner. Collectively, the ability of AB_SH from S. horneri hydrothermal extracts to reduce inflammation indicates that it may be a good functional ingredient for managing ocular disorders.
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Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) pathway is a powerful tool to combat tumor growth and progression; however, drug resistance frequently emerges. We identify CD5L (CD5 antigen-like precursor) as an important gene upregulated in response to antiangiogenic therapy leading to the emergence of adaptive resistance. By using both an RNA-aptamer and a monoclonal antibody targeting CD5L, we are able to abate the pro-angiogenic effects of CD5L overexpression in both in vitro and in vivo settings. In addition, we find that increased expression of vascular CD5L in cancer patients is associated with bevacizumab resistance and worse overall survival. These findings implicate CD5L as an important factor in adaptive resistance to antiangiogenic therapy and suggest that modalities to target CD5L have potentially important clinical utility.
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Neoplasias , Fator A de Crescimento do Endotélio Vascular , Humanos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Anticorpos Monoclonais/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Proteínas Reguladoras de Apoptose , Receptores DepuradoresRESUMO
Owing to increasing air pollution due to industrial development, fine dust has been associated with threatening public health. In particular, ultrafine urban particulate matter (uf-UP, PM 0.1) can easily enter our bodies, causing inflammation-related diseases. Therefore, in the present study, we evaluated the effects of hydrothermal extracts of Sargassum horneri and its bioactive compound, loliolide, on uf-UP-induced inflammation as a potential treatment strategy for retinal disorders. Human retinal pigment epithelial cells (ARPE-19) stimulated with TNF-α or uf-UPs were treated with S. horneri extract and loliolide. S. horneri extracts exhibited anti-inflammatory effects on uf-UP-induced inflammation without cell toxicity through downregulating the mRNA expression of MCP-1, IL-8, IL-6, and TNF-α. UPLC-QTOF/MS analysis confirmed that the hydrothermal extract of S. horneri contained loliolide, which has anti-inflammatory effects. Loliolide effectively reduced the mRNA expression and production of proinflammatory chemokines (IL-8) and cytokines (IL-1ß and IL-6) by downregulating the MAPK/NF-ĸB signaling pathway on TNF-α-stimulated inflammatory ARPE-19 cells. These effects were further confirmed in inflammatory ARPE-19 cells after stimulation with uf-UPs. Collectively, these results suggested the application of S. horneri as a functional ingredient for treating ocular disorders caused by particular matters.
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Benzofuranos , Material Particulado , Sargassum , Humanos , Material Particulado/toxicidade , Interleucina-6 , Interleucina-8 , Fator de Necrose Tumoral alfa , Inflamação/tratamento farmacológico , Anti-Inflamatórios/farmacologia , RNA MensageiroRESUMO
Atopic dermatitis (AD) is a chronic inflammatory skin disease that results from eczema, itching, disrupted barrier function and aberrant cutaneous immune responses. The aim of the present study was to assess the efficacy of kushenol F as an effective treatment for AD via the suppression of thymic stromal lymphopoietin (TSLP) production. The results of the present study demonstrated that the clinical symptoms of AD were less severe and there was reduced ear thickening and scratching behavior in kushenol F-treated Dermatophagoides farinae extract (DFE)/1-chloro-2,4-dinitrochlorobenzene (DNCB)-induced AD mice. Histopathological analysis demonstrated that kushenol F decreased the DFE/DNCB-induced infiltration of eosinophil and mast cells and TSLP protein expression levels. Furthermore, kushenol F-treated mice exhibited significantly lower concentrations of serum histamine, IgE and IgG2a compared with the DFE/DNCB-induced control mice. Kushenol F also significantly decreased phosphorylated NF-κB and IKK levels and the mRNA expression levels of IL-1ß and IL-6 in cytokine combination-induced human keratinocytes. The results of the present study suggested that kushenol F may be a potential therapeutic candidate for the treatment of AD via reducing TSLP levels.
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Cytokine release syndrome (CRS) is a systemic inflammatory response resulting in overexpression of cytokines in serum and tissues, which leads to multiple-organ failure. Due to rapid aggravation of symptoms, timely intervention is paramount; however, current therapies are limited in their capacity to address CRS. Here, we find that the intravenous injection of highly purified detonation-synthesized nanodiamonds (DND) can act as a therapeutic agent for treating CRS by adsorbing inflammatory cytokines. Highly purified DNDs successfully inactivated various key cytokines in plasma from CRS patients with pneumonia, septic shock, and coronavirus disease 2019 pandemic (COVID-19). The intravenous injection of the DND samples in a mouse sepsis model by cecal ligation and puncture significantly improved survival rates and prevented tissue damage by reducing the circulating inflammatory cytokines. The results of this study suggest that the clinical application of highly purified DND can provide survival benefits for CRS patients by adsorbing inflammatory cytokines.
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In recent years, there has been considerable interest in the use of cell-free supernatant of probiotics culture for nutritional and functional applications. In this study, we investigated the effect of the cell-free supernatant from Lactobacillus gasseri BNR17 (CFS) on anti-melanogenesis and reducing oxidative stress in B16-F10 murine melanoma cells and HaCaT human keratinocytes. Treatment with CFS significantly inhibited the production of extracellular and intracellular melanin without cytotoxicity during melanogenesis induced by the α-MSH in B16-F10 cells. The CFS dramatically reduced tyrosinase activity and the melanogenesis-related gene expression. Further, it showed antioxidative effects in a dose-dependent manner in DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) assays and significantly increased the mRNA levels of HO-1 and CAT in HaCaT cells. Furthermore, the CFS increased HO-1 and anti-oxidative-related gene expression during H2O2-induced oxidative stress in HaCaT cells. Together, this study suggests that the CFS reduces hyperpigmentation and inhibits oxidative stress, and thus can be used as a potential skincare product in the future.
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Clinical and preclinical studies have reported that Lactobacillus gasseri BNR17, a probiotic bacterial strain isolated from human breast milk, reduces body weight and white adipose tissue volume. In order to further explore the actions of L. gasseri BNR17, we investigated the anti-menopausal effects of L. gasseri BNR17 in an ovariectomized (OVX) rat model. The serum alanine aminotransferase levels of the rats in the OVX-BNR17 group were lower than those of the rats in the OVX-vehicle only (OVX-Veh) group. Upon administration of L. gasseri BNR17 after ovariectomy, calcitonin and Serotonin 2A levels increased significantly, whereas serum osteocalcin levels showed a decreasing tendency. Compared to the rats in the OVX-Veh group, those in the OVX-BNR17 group showed lower urine deoxypyridinoline levels, lower pain sensitivity, and improved vaginal cornification. Furthermore, L. gasseri BNR17 administration increased bone mineral density in the rats with OVX-induced femoral bone loss. These results suggest that L. gasseri BNR17 administration could alleviate menopausal symptoms, indicating that this bacterium could be a good functional probiotic for managing the health of older women.
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Lactobacillus gasseri , Ovariectomia/efeitos adversos , Pós-Menopausa/efeitos dos fármacos , Probióticos/farmacologia , Animais , Biomarcadores/sangue , Biomarcadores/urina , Densidade Óssea/efeitos dos fármacos , Feminino , Pós-Menopausa/sangue , Pós-Menopausa/urina , Probióticos/administração & dosagem , Ratos , Vagina/efeitos dos fármacos , Vagina/patologiaRESUMO
Cancer cachexia is a highly debilitating condition characterized by weight loss and muscle wasting that contributes significantly to the morbidity and mortality of pancreatic cancer. The factors that induce cachexia in pancreatic cancer are largely unknown. We previously showed that pancreatic adenocarcinoma upregulated factor (PAUF) secreted by pancreatic cancer cells is responsible for tumor growth and metastasis. Here, we analyzed the relation between pancreatic cancer-derived PAUF and cancer cachexia in mice and its clinical significance. Body weight loss and muscle weight loss were significantly higher in mice with Panc-1/PAUF tumors than in those with Panc-1/Mock tumors. Direct administration of rPAUF to muscle recapitulated tumor-induced atrophy, and a PAUF-neutralizing antibody abrogated tumor-induced muscle wasting in Panc-1/PAUF tumor-bearing mice. C2C12 myotubes treated with rPAUF exhibited rapid inactivation of Akt-Foxo3a signaling, resulting in Atrogin1/MAFbx upregulation, myosin heavy chain loss, and muscle atrophy. The neutrophil-to-lymphocyte ratio and body weight loss were significantly higher in pancreatic cancer patients with high PAUF expression than in those with low PAUF expression. Analysis of different pancreatic cancer datasets showed that PAUF expression was significantly higher in the pancreatic cancer group than in the nontumor group. Analysis of The Cancer Genome Atlas data found associations between high PAUF expression or a high DNA copy number and poor overall survival. Our data identified tumor-secreted circulating PAUF as a key factor of cachexia, causing muscle wasting in mice. Neutralizing PAUF may be a useful therapeutic strategy for the treatment of pancreatic cancer-induced cachexia.
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Adenocarcinoma/complicações , Biomarcadores Tumorais/metabolismo , Caquexia/patologia , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Atrofia Muscular/patologia , Neoplasias Pancreáticas/complicações , Animais , Apoptose , Biomarcadores Tumorais/genética , Caquexia/etiologia , Caquexia/metabolismo , Proliferação de Células , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Prognóstico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In patients with advanced-stage cancer, cancer-associated anorexia affects treatment success and patient survival. However, the underlying mechanism is poorly understood. Here, we show that Dilp8, a Drosophila homologue of mammalian insulin-like 3 peptide (INSL3), is secreted from tumour tissues and induces anorexia through the Lgr3 receptor in the brain. Activated Dilp8-Lgr3 signalling upregulated anorexigenic nucleobinding 1 (NUCB1) and downregulated orexigenic short neuropeptide F (sNPF) and NPF expression in the brain. In the cancer condition, the protein expression of Lgr3 and NUCB1 was significantly upregulated in neurons expressing sNPF and NPF. INSL3 levels were increased in tumour-implanted mice and INSL3-treated mouse hypothalamic cells showed Nucb2 upregulation and Npy downregulation. Food consumption was significantly reduced in intracerebrospinal INSL3-injected mice. In patients with pancreatic cancer, higher serum INSL3 levels increased anorexia. These results indicate that tumour-derived Dilp8/INSL3 induces cancer anorexia by regulating feeding hormones through the Lgr3/Lgr8 receptor in Drosophila and mammals.
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Anorexia/metabolismo , Encéfalo/metabolismo , Proteínas de Drosophila/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias/metabolismo , Neuropeptídeos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sequência de Aminoácidos , Animais , Anorexia/etiologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Neoplasias Oculares/patologia , Comportamento Alimentar , Humanos , Hipotálamo/metabolismo , Insulina/sangue , Insulina/química , Insulina/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos Endogâmicos C57BL , Neoplasias/complicações , Neurônios/metabolismo , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/complicações , Proteínas/química , Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de SinaisRESUMO
This study was conducted to identify the composition and diversity of the microbiome in tissues of pancreatic cancer and to determine its role. First, extracellular vesicles (EVs) were obtained from the paired tumor and normal tissues, and 16s rRNA gene sequencing was performed. We identified the microbiomes, compared the diversity between groups, and found that Tepidimonas was more abundant in tumors. Second, larger tumors resulted in lower levels of Leuconostoc and Sutterella, and increased lymph node metastasis resulted in higher levels of Comamonas and Turicibacter in tumor tissues. Moreover, in the case of tumor recurrence, the levels of Streptococcus and Akkermansia were decreased in tumor tissues. Finally, with the supernatant of Tepidimonasfonticaldi, proliferation and migration of cells increased, and epithelial-mesenchymal transition and the Tricarboxylic Acid (TCA) cycle-related metabolites were enhanced. The composition and diversity of EV-derived microbiomes are important for providing novel insights into theragnostic approaches in pancreatic cancer.
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BACKGROUND: Intracellular lipid accumulation is associated with various diseases, particularly cancer. Mitochondrial dysfunction is considered as a cause of lipid accumulation; however, the related underlying mechanism remains unclear. FINDINGS: We found that Von Hippel-Lindau (VHL)-deficiency led to lipid accumulation and mitochondrial dysfunction in renal cell carcinoma cells. Moreover, VHL downregulated ATP-citrate lyase (ACLY), a key enzyme in de novo lipid synthesis, at the transcriptional level, which inhibited intracellular lipid accumulation in human renal carcinoma tissues. We identified PPARγ as the transcription factor regulating ACLY expression by binding to the cis-regulatory site PPRE on its promoter. VHL directly interacted with and promoted ubiquitination of PPARγ, leading to its degradation both in vitro and in vivo, resulting in the downregulation of ACLY. Furthermore, adenovirus-mediated VHL overexpression substantially ameliorated hepatic steatosis induced by a high-fat diet in db/db mice. Importantly, low VHL expression was associated with high ACLY expression and poor prognosis in human liver carcinoma in a dataset in The Cancer Genome Atlas. CONCLUSIONS: VHL plays role in cellular lipid metabolism via regulating mitochondria and targeting PPARγ, a transcription factor for ACLY independent of hypoxia-inducible factor 1α. A novel VHL-PPARγ-ACLY axis and its implication in fatty liver disease and cancer were uncovered.
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ATP Citrato (pro-S)-Liase/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Neoplasias/metabolismo , PPAR gama/metabolismo , Ubiquitinação , Proteína Supressora de Tumor Von Hippel-Lindau/fisiologia , Animais , Linhagem Celular Tumoral , Progressão da Doença , Fígado Gorduroso/metabolismo , Humanos , Camundongos , Complexo de Endopeptidases do Proteassoma/fisiologia , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
Progranulin (PGRN) is a cysteine-rich secreted protein expressed in endothelial cells, immune cells, neurons, and adipocytes. It was first identified for its growth factor-like properties, being implicated in tissue remodeling, development, inflammation, and protein homeostasis. However, these findings are controversial, and the role of PGRN in liver disease remains unknown. In the current study, we examined the effect of PGRN in two different models of chronic liver disease, methionine-choline-deficient diet (MCD)-induced non-alcoholic steatohepatitis (NASH) and carbon tetrachloride (CCl4)-induced liver fibrosis. To induce long-term expression of PGRN, PGRN-expressing adenovirus was delivered via injection into the tibialis anterior. In the CCl4-induced fibrosis model, PGRN showed protective effects against hepatic injury, inflammation, and fibrosis via inhibition of nuclear transcription factor kappa B (NF-κB) phosphorylation. PGRN also decreased lipid accumulation and inhibited pro-inflammatory cytokine production and fibrosis in the MCD-induced NASH model. In vitro treatment of primary macrophages and Raw 264.7 cells with conditioned media from hepatocytes pre-treated with PGRN prior to stimulation with tumor necrosis factor (TNF)-α or palmitate decreased their expression of pro-inflammatory genes. Furthermore, PGRN suppressed inflammatory and fibrotic gene expression in a cell culture model of hepatocyte injury and primary stellate cell activation. These observations increase our understanding of the role of PGRN in liver injury and suggest PGRN delivery as a potential therapeutic strategy in chronic inflammatory liver disease.
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Inflamação/genética , Cirrose Hepática/genética , Hepatopatia Gordurosa não Alcoólica/genética , Progranulinas/genética , Animais , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/genética , Células Estreladas do Fígado/imunologia , Células Estreladas do Fígado/patologia , Hepatócitos/imunologia , Hepatócitos/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Fígado/imunologia , Fígado/patologia , Cirrose Hepática/patologia , Camundongos , NF-kappa B/genética , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/patologia , Progranulinas/imunologia , Células RAW 264.7RESUMO
Yes-associated protein (YAP)-1 is highly upregulated in pancreatic cancer and associated with tumor progression. However, little is known about the role of YAP1 and related genes in pancreatic cancer. Here, we identified target genes regulated by YAP1 and explored their role in pancreatic cancer progression and the related clinical implications. Analysis of different pancreatic cancer databases showed that Neuromedin U (NMU) expression was positively correlated with YAP1 expression in the tumor group. The Cancer Genome Atlas data indicated that high YAP1 and NMU expression levels were associated with poor mean and overall survival. YAP1 overexpression induced NMU expression and transcription and promoted cell motility in vitro and tumor metastasis in vivo via upregulation of epithelial-mesenchymal transition (EMT), whereas specific inhibition of NMU in cells stably expressing YAP1 had the opposite effect in vitro and in vivo. To define this functional association, we identified a transcriptional enhanced associate domain (TEAD) binding site in the NMU promoter and demonstrated that YAP1-TEAD binding upstream of the NMU gene regulated its transcription. These results indicate that the identified positive correlation between YAP1 and NMU is a potential novel drug target and biomarker in metastatic pancreatic cancer.
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Arazyme, a metalloprotease from the spider Nephila clavata, exerts hepatoprotective activity in CCL4-induced acute hepatic injury. This study investigated the hepatoprotective effects in high-fat diet (HFD)-induced non-alcoholic fatty liver disease-like C57BL/6J mice. The mice were randomly divided into four groups (n = 10/group): the normal diet group, the HFD group, the arazyme group (HFD with 0.025% arazyme), and the milk thistle (MT) group (HFD with 0.1% MT). Dietary supplementation of arazyme for 13 weeks significantly lowered plasma triglyceride (TG) and non-esterified fatty acid levels. Suppression of HFD-induced hepatic steatosis in the arazyme group was caused by the reduced hepatic TG and total cholesterol (TC) contents. Arazyme supplementation decreased hepatic lipogenesis-related gene expression, sterol regulatory element-binding transcription protein 1 (Srebf1), fatty acid synthase (Fas), acetyl-CoA carboxylase 1 (Acc1), stearoyl-CoA desaturase-1 (Scd1), Scd2, glycerol-3-phosphate acyltransferase (Gpam), diacylglycerol O-acyltransferase 1 (Dgat1), and Dgat2. Arazyme directly reduced palmitic acid (PA)-induced TG accumulation in HepG2 cells. Arazyme suppressed macrophage infiltration and tumor necrosis factor α (Tnfa), interleukin-1ß (Il1b), and chemokine-ligand-2 (Ccl2) expression in the liver, and inhibited secretion of TNFα and expression of inflammatory mediators, Tnfa, Il1b, Ccl2, Ccl3, Ccl4, and Ccl5, in PA-induced RAW264.7 cells. Arazyme effectively protected hepatic steatosis and steatohepatitis by inhibiting SREBP-1-mediated lipid accumulation and macrophage-mediated inflammation.
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Metaloproteases/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Biomarcadores/sangue , Peso Corporal , Dieta Hiperlipídica , Modelos Animais de Doenças , Regulação da Expressão Gênica , Teste de Tolerância a Glucose , Células Hep G2 , Humanos , Inflamação/patologia , Lipogênese/genética , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Tamanho do Órgão , Ácido Palmítico , Células RAW 264.7RESUMO
Natural killer (NK) cells are primary immune cells that target cancer cells and can be used as a therapeutic agent against pancreatic cancer. Despite the usefulness of NK cells, NK-cell therapy is limited by tumor cell inhibition of NK-cell homing to tumor sites, thereby preventing a sustained antitumor immune response. One approach to successful cancer immunotherapy is to increase trafficking of NK cells to tumor tissues. Here, we developed an antibody-based NK-cell-homing protein, named NK-cell-recruiting protein-conjugated antibody (NRP-body). The effect of NRP-body on infiltration of NK cells into primary and metastatic pancreatic cancer was evaluated in vitro and in murine pancreatic ductal adenocarcinoma models. The NRP-body increased NK-cell infiltration of tumors along a CXCL16 gradient (CXCL16 is cleaved from the NRP-body by furin expressed on the surface of pancreatic cancer cells). CXCL16 induced NK-cell infiltration by activating RhoA via the ERK signaling cascade. Administration of the NRP-body to pancreatic cancer model mice increased tumor tissue infiltration of transferred NK cells and reduced the tumor burden compared with that in controls. Overall survival of NRP-body-treated mice (even the metastasis models) was higher than that of mice receiving NK cells alone. In conclusion, increasing NK-cell infiltration into tumor tissues improved response to this cancer immunotherapy. The combination of an NRP-body with NK-cell therapy might be useful for treating pancreatic cancer.
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Anticorpos Monoclonais/farmacologia , Imunoterapia Adotiva , Células Matadoras Naturais/imunologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia , Animais , Linhagem Celular Tumoral , Quimiotaxia/efeitos dos fármacos , Quimiotaxia/imunologia , Terapia Combinada , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Imunoconjugados/farmacologia , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/metabolismo , Camundongos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Reactive oxygen species (ROS) contribute to the development of non-alcoholic fatty liver disease. ROS generation by infiltrating macrophages involves multiple mechanisms, including Toll-like receptor 4 (TLR4)-mediated NADPH oxidase (NOX) activation. Here, we show that palmitate-stimulated CD11b+F4/80low hepatic infiltrating macrophages, but not CD11b+F4/80high Kupffer cells, generate ROS via dynamin-mediated endocytosis of TLR4 and NOX2, independently from MyD88 and TRIF. We demonstrate that differently from LPS-mediated dimerization of the TLR4-MD2 complex, palmitate binds a monomeric TLR4-MD2 complex that triggers endocytosis, ROS generation and increases pro-interleukin-1ß expression in macrophages. Palmitate-induced ROS generation in human CD68lowCD14high macrophages is strongly suppressed by inhibition of dynamin. Furthermore, Nox2-deficient mice are protected against high-fat diet-induced hepatic steatosis and insulin resistance. Therefore, endocytosis of TLR4 and NOX2 into macrophages might be a novel therapeutic target for non-alcoholic fatty liver disease.
Assuntos
Endocitose , Inflamação/metabolismo , Fígado/metabolismo , Antígeno 96 de Linfócito/metabolismo , Macrófagos/metabolismo , NADPH Oxidase 2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Antígeno CD11b/imunologia , Dieta Hiperlipídica , Ativação Enzimática , Humanos , Imunofenotipagem , Fígado/citologia , Fígado/enzimologia , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 2/genética , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/terapia , Ácido Palmítico/metabolismo , Ácido Palmítico/farmacologia , Células RAW 264.7RESUMO
Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and ranges from isolated steatosis to NASH. To determine whether circulating fatty acids could serve as diagnostic markers of NAFLD severity and whether specific fatty acids could contribute to the pathogenesis of NASH, we analyzed two independent NAFLD patient cohorts and used the methionine- and choline-deficient diet (MCD) NASH mouse model. We identified six fatty acids that could serve as non-invasive markers of NASH in patients with NAFLD. Serum levels of 15:0, 17:0 and 16:1n7t negatively correlated with NAFLD activity scores and hepatocyte ballooning scores, while 18:1n7c serum levels strongly correlated with fibrosis stage and liver inflammation. Serum levels of 15:0 and 17:0 also negatively correlated with fasting glucose and AST, while 16:1n7c and 18:1n7c levels positively correlated with AST and ferritin, respectively. Inclusion of demographic and clinical parameters improved the performance of the fatty acid panels in detecting NASH in NAFLD patients. The panel [15:0, 16:1n7t, 18:1n7c, 22:5n3, age, ferritin and APRI] predicted intermediate or advanced fibrosis in NAFLD patients, with 82% sensitivity at 90% specificity [AUROC = 0.92]. 15:0 and 18:1n7c were further selected for functional studies in vivo. Mice treated with 15:0-supplemented MCD diet showed reduced AST levels and hepatic infiltration of ceroid-laden macrophages compared to MCD-treated mice, suggesting that 15:0 deficiency contributes to liver injury in NASH. In contrast, 18:1n7c-supplemented MCD diet didn't affect liver pathology. In conclusion, 15:0 may serve as a promising biomarker or therapeutic target in NASH, opening avenues for the integration of diagnosis and treatment.