RESUMO
Myeloid cells are vital components of the immune system and have pivotal functions in orchestrating immune responses. Understanding their functions within the tumor microenvironment and their interactions with tumor-infiltrating lymphocytes presents formidable challenges across diverse cancer types, particularly with regards to cancer immunotherapies. Here, we explore tumor-infiltrating myeloid cells (TIMs) by conducting a pan-cancer analysis using single-cell transcriptomics across eight distinct cancer types, encompassing a total of 192 tumor samples from 129 patients. By examining gene expression patterns and transcriptional activities of TIMs in different cancer types, we discern notable alterations in abundance of TIMs and kinetic behaviors prior to and following immunotherapy. We also identify specific cell-cell interaction targets in immunotherapy; unique and shared regulatory profiles critical for treatment response; and TIMs associated with survival outcomes. Overall, our study illuminates the heterogeneity of TIMs and improves our understanding of tissue-specific and cancer-specific myeloid subsets within the context of tumor immunotherapies.
Assuntos
Inibidores de Checkpoint Imunológico , Imunoterapia , Células Mieloides , Neoplasias , Análise de Célula Única , Microambiente Tumoral , Humanos , Células Mieloides/imunologia , Células Mieloides/metabolismo , Análise de Célula Única/métodos , Neoplasias/imunologia , Neoplasias/genética , Neoplasias/terapia , Neoplasias/patologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Regulação Neoplásica da Expressão Gênica , Transcriptoma , Perfilação da Expressão GênicaRESUMO
OBJECTIVE: The aim of this study was to investigate the molecular mechanism by which the transcription factor ETS1 regulates N-myc downstream regulatory gene 1 (NDRG1) to provide a new theoretical basis for the study of oral squamous cell carcinoma (OSCC). METHODS: In this study, eight human OSCC and paraneoplastic samples were collected. The expressions of NDRG1, ETS1, and Ki67 were detected by immunohistochemistry; apoptosis was detected by tdt-mediated dUTP notched end labeling; cell migration and invasion were detected by Transwell; quantitative real-time PCR was performed to detect the expression of NDRG1; RNA-binding protein immunoprecipitation (RIP) assays detected NDRG1 expression; immunofluorescence assays detected ETS1 expression. RESULTS: NDRG1 and ETS1 expression was significantly upregulated in cancer tissues and CAL-27 and SCC-6 cells. Knockdown of NDRG1 and ETS1 inhibited cell proliferation, migration, invasion, cloning, and EMT while promoting apoptosis and inhibited tumor development; ETS1 positively regulated NDRG1 expression; Finally, overexpression of NDRG1 in vivo and in vitro reversed the effect of ETS1 knockdown on CAL-27 and SCC-6 cells. CONCLUSIONS: ETS1 positively regulates the expression of NDRG1 and promotes OSCC. Therefore, ETS1 may serve as a new target for the clinical diagnosis and treatment of OSCC.
RESUMO
BACKGROUND: This study aims to screen and identify the biological functions and prognostic value of CXC chemokines in ovarian cancer (OC) through bioinformatics and molecular biology methods, and to provide data support for the selection of biomarkers and prognostic analysis of OC. METHODS: In this study, GEO, ONCOMINE, GEPIA, cBioPortal, GeneMANIA, Metascape, STRING, TRRUST, and TIMER databases were used to study CXC chemokines. Angiogenesis and T cell killing assay were used to detect the effect of CXCL10 on tumor cell immunity and angiogenesis. Real-time quantitative PCR (qRT-PCR), immunoblotting, and ectopic tumor formation experiments were used to verify the effect of CXCL10 on ovarian cancer tumors. RESULTS: We found that CXCL1, CXCL10, CXCL11, CXCL13, and CXCL14 were significantly upregulated in OC samples compared with normal tissues. Our data showed that there was a relationship between the expression of CXC chemokines and the infiltration of six types of immune cells significant correlation. In vitro assay confirmed that overexpression of CXCL10 could enhance the killing effect of T cells and inhibit angiogenesis. Further in vivo assay had shown that CXCL10 could affect the progression of ovarian cancer by increasing the expression of cytotoxic T cells and inhibiting angiogenesis. CONCLUSION: In conclusion, we hope that our data will provide new insights into the development of immunotherapy and the selection of prognostic markers for patients with OC.
Assuntos
Detecção Precoce de Câncer , Neoplasias Ovarianas , Carcinoma Epitelial do Ovário , Quimiocina CXCL10 , Quimiocinas CXC/genética , Feminino , Humanos , Prognóstico , Microambiente TumoralRESUMO
Major depressive disorder (MDD) is a common, chronic, recurrent disease. The existing drugs are ineffective for approximately half of patients, so the development of antidepressant drugs with novel mechanisms is urgent. Cumulative evidence has shown neuro-inflammation plays a key role in the etiology of major depressive disorder. Clinical studies implicated that bile acids, an important component of gut-brain axis, inhibit neuro-inflammation and mediate the pathophysiology of the MDD. Here, we found that ganoderic acid A (GAA) modulated bile acid receptor FXR (farnesoid X receptor), inhibited brain inflammatory activity, and showed antidepressant effects in the chronic social defeat stress depression model, tail suspension, forced swimming, and sucrose preference tests. GAA directly inhibited the activity of the NLRP3 inflammasome, and activated the phosphorylation and expression of the AMPA receptor by modulating FXR in the prefrontal cortex of mice. If we knocked out FXR or injected the FXR-specific inhibitor z-gugglesterone (GS), the antidepressant effects induced by GAA were completely abolished. These results suggest that GAA modulates the bile acid receptor FXR and subsequently regulates neuroimmune and antidepressant behaviors. GAA and its receptor FXR have potential as targets for the treatment of MDD.
Assuntos
Antidepressivos/uso terapêutico , Depressão/metabolismo , Ácidos Heptanoicos/uso terapêutico , Lanosterol/análogos & derivados , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores Citoplasmáticos e Nucleares/deficiência , Sinapses/metabolismo , Animais , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Depressão/psicologia , Ácidos Heptanoicos/farmacologia , Lanosterol/farmacologia , Lanosterol/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Receptores Citoplasmáticos e Nucleares/genética , Derrota Social , Sinapses/efeitos dos fármacos , Sinapses/genéticaRESUMO
Major depressive disorder (MDD) is a prevalent, chronic, and recurrent disease. At least one-third of patients have treatment-resistant depression; therefore, there is an urgent need for novel drug development. Cumulative studies have suggested an inflammatory mechanism for the pathophysiology of MDD. Ganoderma lucidum polysaccharides (GLP) is an anti-inflammatory and immunomodulatory agent. Here, we found that an injection of GLP led to a rapid and robust antidepressant effect after 60 min in the tail suspension test. This antidepressant effect remained after 5 days of treatment with GLP in the forced swim test. Unlike psychostimulants, GLP did not show a hyperactive effect in the open field test. After 60 min or 5 days of treatment, GLP exhibited an antidepressant effect in a chronic social defeat stress (CSDS) depression animal model. Moreover, after 5 days of treatment, GLP attenuated the expression of the proinflammatory cytokines IL-1ß and TNF-α, enhanced the expression of the anti-inflammatory cytokine IL-10 and the neurotrophic factor BDNF, and inhibited the activation of microglia and proliferation of astrocytes in the hippocampus of CSDS mice. In addition, after 5 days of treatment, GLP significantly enhanced GluA1 S845 phosphorylation as well as GluA1 and GluA2 expression levels in the hippocampus of CSDS mice. To determine whether the antidepressant effect was mediated by Dectin-1, we found that GLP treatment enhanced Dectin-1 expression in the hippocampus in CSDS mice, and the Dectin-1-specific inhibitor laminarin almost completely blocked the antidepressant effect of GLP. This study identified GLP, an agonist of Dectin-1, as a novel and rapid antidepressant with clinical potential and multiple beneficial mechanisms, particularly in regulating the neuroimmune system and, subsequently, AMPA receptor function.
Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Imunidade Inata/efeitos dos fármacos , Lectinas Tipo C/metabolismo , Reishi , Derrota Social , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Depressão/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismoRESUMO
Multiple sclerosis (MS), as an inflammatory demyelinating disorder of central nervous system, is the leading cause of non-traumatic neurologic disability in young adults. The pathogenesis of MS remains unknown, however, a dysregulation of glia-neuroimmune signaling plays a key role during progressive disease stage. Most of the existing drugs are aimed at the immune system, but there is no approved drug by promoting remyelination after demyelination so far. There is a great interest in identifying novel agents for treating MS bytargeting to switch the immune imbalance from pro-inflammation and apoptosis to anti-inflammation and regeneration during remyelination phase. Here, we reported that ganoderic acid A (GAA) significantly enhanced the remyelination and rescued motor deficiency in two animal models of MS, including cuprizone-induced demyelination and myelin oligodendrocyte glycoprotein (MOG) 35-55-induced experimental autoimmune encephalomyelitis model. In these two independent MS animal models, GAA modulated neuroimmune to enhance the anti-inflammatory and regeneration markers IL-4 and BDNF, inhibited inflammatory markers IL-1ß and IL-6, followed by down-regulation of microglia activation and astrocyte proliferation. Pharmacological and genetic ablation of farnesoid-X-receptor (FXR) abolished GAA-induced remyelination and restoration of motor deficiency in MS mice. Thus, GAA is a novel and potential therapeutic agent that can rescue MS neuroimmune imbalance and remyelination through an FXR receptor-dependent mechanism. Clinical investigation on the therapeutic effect of GAA in improving remyelination of the MS patients to rescue the motor function is warranted.
Assuntos
Anti-Inflamatórios/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Lanosterol/análogos & derivados , Esclerose Múltipla/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Regeneração/fisiologia , Remielinização/fisiologia , Animais , Anti-Inflamatórios/farmacologia , Feminino , Ácidos Heptanoicos/farmacologia , Lanosterol/farmacologia , Lanosterol/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Regeneração/efeitos dos fármacos , Remielinização/efeitos dos fármacosRESUMO
Molecular abnormalities within the Glucocorticoid Receptor (GR) stress signaling pathway involved in dysfunction of mitochondria and confer vulnerability to stress-related psychiatric disorders. Bcl-2 associated athanogene (Bag-1) is a target for the actions of mood stabilizers. Bag-1 interacts with GR, thereby regulating glucocorticoid function. In this study, we investigate the potential role of Bag-1 in regulating GR translocation into mitochondria. Corticosterone (CORT) treatment significantly enhanced Bag-1/GR complex formation and GR mitochondrial translocation in cultured rat cortical neurons after treatment for 30 min and 24 hr. By contrast, after stimulation with CORT for 3 days, localization of the Bag-1/GR complex and mitochondrial GR were reduced. Similar results were obtained in mice, in which administrated CORT in drinking water for 21 days significantly impaired the GR levels in the mitochondria, while Bag-1 over-expression rescued this reduction. Furthermore, chronic CORT exposure led to anhedonia-like and depression-like behaviors in the sucrose-consumption test and forced swimming test, and these behaviors were rescued by Bag-1 over-expression. These results suggest that Bag-1 mediates GR trafficking to mitochondria and regulates affective resilience in response to a CORT increase and provide potential insight into the mechanisms by which Bag-1 and GR could contribute to the physiology and pathogenesis of psychiatric disorders in response to the change of stress hormone.
Assuntos
Afeto/efeitos dos fármacos , Corticosterona/farmacologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Mitocôndrias/metabolismo , Receptores de Glucocorticoides/metabolismo , Resiliência Psicológica/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Anedonia , Animais , Depressão/psicologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Neurônios/efeitos dos fármacos , Gravidez , Cultura Primária de Células , Transporte Proteico , Ratos , Ratos Sprague-Dawley , Estimulação Química , Natação/psicologiaRESUMO
Regulating synaptic formation and transmission is critical for the physiology and pathology of psychiatric disorders. The adenosine A2A receptor subtype has attracted widespread attention as a key regulator of neuropsychiatric activity, neuroprotection and injury. In this study, we systematically investigated the regulatory effects of a novel A2A receptor agonist, PSB-0777, on the expression of synaptic proteins and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPA receptors) at the cellular level in a time- and dose-dependent manner. After 30 min of high-dose PSB-0777 stimulation, the expression of Synapsin-1 (Syn-1), postsynaptic density protein 95 (PSD95), and AMPA receptors and the number of synapses were rapidly and significantly increased in rat primary cortical neurons compared with the control. Sustained elevation was found in the low and medium-dose groups after 24 h and 3 d of treatment. In contrast, after stimulation with PSB-0777 for 3 consecutive days, the expression of Syn-1 was decreased, and PSD95, AMPA receptors and the number of synapses were no longer increased in the high-dose group. Our study focuses on the detailed and systematic regulation of synaptic proteins and AMPA receptors by an A2A receptor agonist, PSB-0777, which may result in both beneficial and detrimental effects on neurotransmission and neuroprotection and may contribute to the pathophysiology of psychiatric disorders related to A2A receptors. These experimental data may contribute to understanding of the mechanisms for neuroprotective and therapeutic effect of A2A receptor agonists.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Furanos/farmacologia , Fármacos Neuroprotetores/farmacologia , Receptor A2A de Adenosina/fisiologia , Receptores de AMPA/genética , Animais , Células Cultivadas , Córtex Cerebral/metabolismo , Proteína 4 Homóloga a Disks-Large/genética , Relação Dose-Resposta a Droga , Feminino , Ratos , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Sinapsinas/genética , Transmissão Sináptica/efeitos dos fármacosRESUMO
OBJECTIVE: Prolylcarboxypeptidase (PRCP) is a negative regulator of the pressor actions of the renin-angiotensin-aldosterone system. It is also involved in the kallikrein-kinin system. This gene has an important role in blood pressure (BP) regulation. METHODS: A case-control study was performed for 615 Yi participants (303 cases and 312 controls) from a remote mountainous area in Yunnan Province of China. For the PRCP gene, 11 tag single-nucleotide polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The PRCP gene rs12290550 was associated with the occurrence of essential hypertension (EH) and BP traits. Logistic regression analysis indicated that the rs12290550 T allele was significantly linked to the risk of EH (odds ratio (OR) = 1.85, 95% confidence interval (CI) 1.44-2.39, p = 0.2 × 10-5). Under Bonferroni correction, the H7 TAGCACTAACA haplotype containing the risk allele rs12290550 T increased the risk of EH (OR = 4.53, 95% CI 2.29-8.93, p = 0.2×10-5). CONCLUSIONS: The findings of this study demonstrate the strong association of the PRCP gene with EH. rs12290550 may be a useful genetic predictor of EH in the Yi minority.
Assuntos
Carboxipeptidases/genética , Hipertensão Essencial/epidemiologia , Hipertensão Essencial/genética , Polimorfismo Genético/genética , Adulto , Alelos , Pressão Sanguínea/genética , Estudos de Casos e Controles , China/epidemiologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Grupos Minoritários , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Multiple sclerosis (MS) is an inflammatory demyelination disease characterized by autoimmune damage to the central nervous system. In this disease, failure of remyelination could cause persistent disability. Cordycepin, also known as 3'-deoxyadenosine, exerts anti-inflammatory, anti-oxidic, anti-apoptotic and neuroprotective effects. The cuprizone (CPZ) model has been widely used to study MS as it mimics some characteristics of demyelination disease. To determine whether cordycepin promotes remyelination and functional recovery after CPZ-induced demyelination, we administered cordycepin to the CPZ-induced demyelination mice. Cordycepin reversed CPZ-induced loss of body weight and rescued motor dysfunction in the model mice. Cordycepin effectively promoted remyelination and enhanced MBP expression in the corpus callosum. Cordycepin also inhibited the CPZ-induced increase in the number of Iba1-positive microglia, GFAP-positive astrocytes and Olig2-positive oligodendroglial precursor cells in the corpus callosum and cerebral cortex. Pro-inflammatory cytokine expression (IL-1ß and IL-6) was inhibited while anti-inflammatory cytokine IL-4 and neurotrophic factor BDNF release was elevated in the corpus callosum and hippocampus after cordycepin treatment. In addition, we also found that cordycepin ameliorated CPZ-induced body weight loss, motor dysfunction, demyelination, glial cells activation and pro-inflammatory cytokine expression in the corpus callosum and hippocampus. Our results suggest that cordycepin may represent a useful therapeutic agent in demyelination-related diseases via suppression of neuroinflammation.
Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças Desmielinizantes/tratamento farmacológico , Desoxiadenosinas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Remielinização/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Astrócitos/efeitos dos fármacos , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/imunologia , Cuprizona , Citocinas/imunologia , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/imunologia , Desoxiadenosinas/farmacologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologiaRESUMO
RATIONALE: Converging evidence suggests that neuroimmunity plays an important role in the pathophysiology of anxiety. Interleukin (IL)-4 is a key cytokine regulating neuroimmune functions in the central nervous system. More efficient anxiolytics with neuro-immune mechanisms are urgently needed. OBJECTIVE: To determine whether 3'-deoxyadenosine (3'-dA) exerts an anxiolytic effect and to examine the role of IL-4 in the anxiolytic effect of 3'-dA in mice. METHODS: We investigated the effects of 3'-dA on anxiety-like behaviors using elevated plus maze (EPM) or light-dark box (LDB) tests after 45 min or 5 days of treatment. Expression of IL-4, IL-10, IL-1ß, TNF-α, and IL-6 in the prefrontal cortex (PFC) was detected by Western blot and/or double immunostaining. Intracerebroventricular injection of RIL-4Rα (an IL-4-specific inhibitor) and intraperitoneal injection of 3'-dA or imipramine were co-administered, followed by EPM test. RESULTS: 3'-dA exhibited a stronger and faster anxiolytic effect than imipramine in behavioral tests. Furthermore, 3'-dA enhanced IL-4 expression after 45 min or 5 days, TNF-α and IL-1ß expression decreased significantly after a 5-day treatment with 3'-dA, and IL-10 expression increased after a 5-day treatment with 3'-dA or imipramine in the PFC. IL-4 was expressed in neurons and in some astrocytes and microglia. IL-4 expression showed a strong positive correlation with reduced anxiety behaviors. RIL-4Rα completely blocked the anxiolytic effects induced by 3'-dA and imipramine. CONCLUSIONS: This study identifies a novel and common anxiolytic IL-4 signaling pathway and provides an innovative drug with a novel neuro-immune mechanism for treating anxiety disorder.
Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Desoxiadenosinas/uso terapêutico , Interleucina-4/biossíntese , Transdução de Sinais/efeitos dos fármacos , Animais , Ansiolíticos/farmacologia , Ansiedade/psicologia , Desoxiadenosinas/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Transdução de Sinais/fisiologiaRESUMO
In recent years, protein-protein interactions have become an attractive candidate for identifying biomarkers and drug targets for various diseases. However, WD40 repeat (WDR) domain proteins, some of the most abundant mediators of protein interactions, are largely unexplored. In our study, 57 of 361 known WDR proteins were identified as hub nodes, and a hub (WDR54) with elevated mRNA in colorectal cancer (CRC) was selected for further study. Immunohistochemistry of specimens from 945 patients confirmed the elevated expression of WDR54 in CRC, and we found that patients with WDR54-high tumors typically had a shorter disease-specific survival (DSS) than those with WDR54-low tumors, especially for the subgroup without well-differentiated tumors. Multivariate analysis showed that WDR54-high tumors were an independent risk factor for DSS, with a hazard ratio of 2.981 (95% confidence interval, 1.425-6.234; p = 0.004). Knockdown of WDR54 significantly inhibited the growth and aggressiveness of CRC cells and reduced tumor growth in a xenograft model. Each WDR54 isoform (a, b, and c) was found to reverse the inhibitory effect of WDR54 knockdown; however, only isoform c, which exhibited the highest expression, was increased in CRC cells. Sensitization of WDR54 knockdown to an SHP2 inhibitor was consistently found in CRC cells, and the underlying mechanism involved their common function in regulating AKT and ERK signaling. In conclusion, the present study is the first to investigate the significance of WDR54 in cancer and to conclude that WDR54 serves as an oncogene in CRC and may be a potential prognostic marker and therapeutic target.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Proteínas de Membrana/metabolismo , Regulação para Cima , Animais , Biomarcadores Tumorais/genética , Células CACO-2 , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Proteínas de Membrana/genética , Camundongos , Transplante de Neoplasias , Isoformas de Proteínas/metabolismo , Análise de Sobrevida , Repetições WD40RESUMO
Regulation of neuroinflammation is critical to control the detrimental impact of chronic stress in the central nervous system. Neuroinflammation occurs in response to chronic stress, leading to enhanced neuronal damage in the brain. We investigated the regulatory effects of stress hormone corticosterone on neuroinflammation regulator, as well as amyloid-ß and Beta-secretase 1 related signaling. We demonstrate that corticosterone can both positively and negatively regulate amyloid-ß expression, which may be related to the ratio of neuroinflammation regulator and Beta-secretase 1 signaling in rat primary cortical neurons. Thirty minutes of treatment with 1 µM corticosterone significantly decreased the nuclear translocation of neuroinflammation mediator neuroinflammation regulator (Western Blot: P < 0.05, Immunofluorescence: P < 0.001) and production of Beta-secretase 1 enzyme (P < 0.01), which was accompanied by a reduction in amyloid-ß1-42 levels (P < 0.01). In contrast, 1 µM corticosterone treatment over 3 days increased nuclear neuroinflammation regulator localization (P < 0.001), followed by the upregulation of Beta-secretase 1 (P < 0.01) and amyloid-ß1-42 (P < 0.05) expression. This work is the first to demonstrate that the duration of corticosterone exposure can promote or inhibit amyloid-ß production, and to link this effect with Beta-secretase 1 / neuroinflammation regulator signaling, together with providing valuable insight into the mechanisms of neuroinflammation and neuroprotection.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral/metabolismo , Corticosterona/fisiologia , Inflamação/metabolismo , NF-kappa B/metabolismo , Neurônios/metabolismo , Fragmentos de Peptídeos/metabolismo , Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Peptídeos beta-Amiloides/efeitos dos fármacos , Animais , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Corticosterona/farmacologia , Feminino , NF-kappa B/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/efeitos dos fármacos , Gravidez , Ratos , Regulação para CimaRESUMO
Maitake (Grifola frondosa) is an edible mushroom exhibiting high nutritional value in terms of containing health-beneficial bioactive compounds. Previously, we reported that a protein-bound polysaccharide bioactive component of G. frondosa (PGM) could enhance the expression of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR), which is critical for learning and memory. However, the potential benefits of PGM on learning and memory function have never been investigated. In the current study, we aimed to explore the beneficial effect of PGM on learning and memory function in aluminum chloride (AlCl3)-induced amnesia in mice and to explore the underlying mechanisms. Mice were intraperitoneally administered with AlCl3 (60 mg/kg/d) and PGM (5, 10, or 20 mg/kg/d) for 6 weeks consecutively, and then the Morris water maze (MWM) test was conducted to assess the learning and memory function. Hematoxylin-eosin staining was performed to observe the morphology of neurons in the hippocampal dentate gyrus (DG). The expression of p-Tau (Ser396), Tau, p-GluA1 (S845), GluA1, and brain-derived neurotrophic factor (BDNF) proteins was evaluated with western blot. We found that PGM (5 and 10 mg/kg/d) significantly improved learning and memory function and attenuated histopathological abnormalities in the hippocampal DG region in the AlCl3-treated mice. Furthermore, PGM treatment significantly enhanced the level of AMPAR and BDNF in the hippocampus, while suppressing the tau protein hyperphosphorylation at the Ser396 site. These findings indicated that PGM could significantly attenuate the AlCl3-induced amnesia through the synergistic action of its active component on tau pathology, AMPAR and BDNF signaling pathway.
Assuntos
Amnésia/tratamento farmacológico , Grifola/química , Fármacos Neuroprotetores/administração & dosagem , Polissacarídeos/administração & dosagem , Cloreto de Alumínio/administração & dosagem , Cloreto de Alumínio/toxicidade , Amnésia/induzido quimicamente , Animais , Giro Denteado/patologia , Modelos Animais de Doenças , Histocitoquímica , Injeções Intraperitoneais , Aprendizagem/efeitos dos fármacos , Aprendizagem em Labirinto , Memória/efeitos dos fármacos , Camundongos , Neurônios/patologia , Fármacos Neuroprotetores/isolamento & purificação , Polissacarídeos/isolamento & purificação , Resultado do TratamentoRESUMO
PURPOSE: Emerging evidence suggests that many differentially expressed long non-coding RNAs (lncRNAs) are involved in tumorigenesis. However, the functional roles of these transcripts and the mechanisms responsible for their deregulation in non-small-cell lung cancer (NSCLC) remain elusive. Here, we identified a novel lncRNA (lncRNA 1308), which was significantly upregulated in NSCLC tissues and investigated its biological function and potential molecular mechanism. METHODS: Differences in the lncRNA expression profiles between NSCLC and tumor-adjacent normal tissues were assessed by lncRNA expression microarray analysis. The microRNA in vivo precipitation (miRIP) method was used to identify the targeting microRNAs (miRNAs) on lncRNA 1308, and luciferase reporter assays were performed. Loss-of-function studies were used to explore the effect of lncRNA 1308 on lung carcinogenesis in NSCLC cells. RESULTS: The novel lncRNA 1308 was upregulated in NSCLC tissues and cell lines. By using biotin-labeled lncRNA 1308 for miRIP in NSCLC cells and dual-luciferase reporter assays, the results suggested that miRNA-124 was associated with lncRNA 1308. Furthermore, the expression of a disintegrin and a metalloproteinase 15 (ADAM 15) was downregulated in NSCLC cells when silencing of lncRNA 1308, the target of oncogenic miR-124, inhibits NSCLC cell proliferation and invasion. Conversely, the expression of ADAM 15 was significantly increased, when inhibiting the expression of miR-124, and alleviated cell invasion inhibition. CONCLUSION: The results suggested that lncRNA 1308 may function as a competing endogenous RNA (ceRNA) for miR-124 to regulate cell invasion through the miR-124/ADAM 15 signaling pathway, indicating that lncRNA 1308 plays an important role in the disease progression of NSCLC.
RESUMO
BACKGROUND/AIMS: GCNT3 is a member of N-acetylglucosaminyltransferase family involved with mucin biosynthesis. GCNT3 aberrant expression is known to promote the progression of several human cancers. However, its role in tumorigenesis and the progression of non-small cell lung cancer (NSCLC) has not been well-characterized. Our study investigated the functional mechanisms of GCNT3 regulated by microRNAs (miRNAs) in NSCLC. METHODS: The differential expression of mRNAs in NSCLC tissues and matched adjacent non-cancerous lung tissues from patients in Xuanwei, Yunnan province, China, was screened via mRNA microarray. The expression of GCNT3 and its correlation with NSCLC progression was measured in 92 paired tumor tissues and adjacent normal tissues. The functions of GCNT3 in NSCLC cells and its underlying mechanisms were measured using siRNA and GCNT3-expression vectors. The miRNA immunoprecipitation (miRIP) method was used to identify the miRNAs targeting GCNT3. The protein were measured using western blot assay, and the mRNAs were measured by quantitative real-time PCR (qRT-PCR) assay. Cell proliferation was measured using Cell Counting Kit-8 (CCK-8) and a colony forming assays; cell migration and invasion assays were performed using 24-well Transwell chambers with 8-µm pores filter, and analyses of the cell cycle and apoptosis were performed via flow cytometric analysis. The dual luciferase reporter assay was performed to confirm whether GCNT3 gene was a direct target of miR-302b-3p. RESULTS: GCNT3 was found to be highly expressed in both NSCLC tissues and cell lines, and higher expression correlated significantly with advanced tumor-node-metastasis (TNM) stage, positive lymph node metastasis, and poor overall survival. Knockdown of GCNT3 inhibited the proliferation, migration and invasion ability of NSCLC cells, while overexpression facilitated these activities. Further mechanistic experiments using miRIP and dual luciferase reporter assays revealed that GCNT3 was a direct target of miR-302b-3p. Low expression of miR-302b-3p was found in NSCLC cells and negatively correlated with GCNT3 levels, while miR-302b-3p overexpression inhibited the proliferation, migration and invasion of NSCLC cells. Co-transfection with miR-302b-3p and the expression vector of GCNT3 abrogated the effects of mir-302b-3p, confirming that miR-302b-3p inhibited NSCLC progression by targeting GCNT3. Western blotting revealed that E-cadherin, N-cadherin, vimentin, p-Erk and cyclin D1 were downstream molecules of miR-302b-3p/GCNT3 pathway. CONCLUSION: miR-302b-3p/GCNT3 axis regulated cell proliferation, migration, and invasion by activating the Erk signaling pathway and epithelial-mesenchymal transition (EMT), which was identified as a potential therapeutic target for NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , Regiões 3' não Traduzidas , Antagomirs/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Ciclina D1/genética , Ciclina D1/metabolismo , Regulação para Baixo , Transição Epitelial-Mesenquimal , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , N-Acetilglucosaminiltransferases/antagonistas & inibidores , N-Acetilglucosaminiltransferases/genética , Interferência de RNA , RNA Interferente Pequeno/metabolismoRESUMO
Taraxasterol has potent anti-inflammatory and anti-tumor activity. However, the effect and potential mechanisms of Taraxasterol on the growth of human liver cancer have not been clarified. Histidine triad nucleotide-binding protein 1 (Hint1) is a tumor suppressor and its downregulated expression is associated with the development of cancer. Here, we report that Taraxasterol treatment significantly suppressed cell proliferation and induced cell cycle arrest at G0/G1 phase and apoptosis in liver cancer cells, but not in non-tumor hepatocytes. Furthermore, Taraxasterol upregulated Hint1 and Bax, but downregulated Bcl2 and cyclin D1 expression, accompanied by promoting the demethylation in the Hint1 promoter region in liver cancer cells. The effects of Taraxasterol were abrogated by Hint1 silencing and partially mitigated by Bax silencing, Bcl2 or cyclin D1 over-expression in HepG2 cells. Moreover, oral administration with Taraxasterol did not affect body weight, urinary protein levels, and the heart, liver, and kidney morphology in BALB/c mice but effectively inhibited the growth of implanted SK-Hep1 tumor in vivo. Collectively, we demonstrate that Taraxasterol inhibits the growth of liver cancer at least partially by enhancing Hint1 expression to regulate Bax, Bcl2, and cyclin D1 expression. Taraxasterol may be a drug candidate for the treatment of human liver cancer. KEY MESSAGES: Taraxasterol inhibits growth and induces apoptosis in human liver cancer cells. Taraxasterol enhances Hint1 expression by promoting demethylation in Hint1 promoter. Taraxasterol increases Hint1 levels to regulate Bax, Bcl2, and cyclinD1 expression. The effects of Taraxasterol are abrogated by Hint1 silencing in liver cancer cells. Taraxasterol inhibits the growth of subcutaneously implanted liver cancers in mice.
Assuntos
Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/genética , Proteínas do Tecido Nervoso/genética , Esteróis/farmacologia , Triterpenos/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina D1/genética , Ciclina D1/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE To assess the association of single nucleotide polymorphisms (SNPs) of the T-cadherin (CDH13) gene with metabolic syndrome (MS) among ethnic Han Chinese.METHODS Genotypes of 6 SNPs(rs11646213, rs12596316, rs3865188, rs12444338, rs12051272, and rs7195409) of the CDH13 gene among 453 patients with MS and 526 controls were determined with a TaqMan method, and their association with MS was assessed. RESULTS For 5 SNPs (rs11646213, rs3865188, rs12444338, rs12051272, and rs7195409), no difference was found in allelic and genotypic frequencies of the CDH13 gene between the two groups. Comparing with rs12596316 (AA+GG) genotype, rs12596316 AG genotype has significantly increased the risk of MS(P = 0.01,OR = 1.38,95%CI: 1.07-1.78), though no association was found between particular alleles of the rs12596316 with MS.There was no difference in the frequencies of rs11646213-rs12596316-rs3865188-rs12444338-rs12051272 haplotype between the two groups(P > 0.05). CONCLUSION No association was found between the five SNPs (rs11646213, rs3865188, rs12444338, rs12051272 and rs7195409) of the CDH13 gene with the MS, while the rs12596316AG genotype of the CDH13 gene is associated with the susceptibility to MS among ethnic Han Chinese.
Assuntos
Caderinas/genética , Predisposição Genética para Doença/genética , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único , Alelos , Povo Asiático/genética , China , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Haplótipos , Humanos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/etnologia , Fatores de RiscoRESUMO
Dysregulated long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play key roles in the development of human cancers. The lncRNA plasmacytoma variant translocation 1 (PVT1) is reported to be an oncogene in a variety of cancers. However, the roles of PVT1-5 and its related miRNAs in lung cancer are poorly understood. In this study, we found that PVT1-5 expression was significantly increased in lung cancer tissues and cell lines. By using biotin-labeled lncRNA-PVT1-5 probe for miRNA in vivo precipitation (miRIP) in lung cancer cells and dual-luciferase reporterassays, we identified that miR-126 was associated with lncRNA-PVT1-5. Furthermore, knockdown of lncRNA-PVT1-5 in cells could down-regulate the expression of SLC7A5, the target of oncogenic miR-126, resulting in the cell proliferation. Conversely, inhibiting the expression of miR-126 markedly increased the expression of SLC7A5 and alleviated cell proliferation inhibition. Thus, our results indicated that lncRNA-PVT1-5 may function as a competing endogenous RNA (ceRNA) for miR-126 to promote cell proliferation by regulating the miR-126/SLC7A5 pathway, suggesting that lncRNA-PVT1-5 plays a crucial role in lung cancer progression and lncRNA-PVT1-5/miR-126/SLC7A5 regulatory network may shed light on tumorigenesis in lung cancer.