RESUMO
Tight junctions (TJs) are cell-cell interactions that localize at the most apical portion of epithelial/endothelial cells. One of the predominant functions of TJs is to regulate material transport through paracellular pathway, which serves as a selective barrier. In recent years, the expression and function of TJs in salivary glands has attracted great interest. The characteristics of multiple salivary gland TJ proteins have been identified. During salivation, the activation of muscarinic acetylcholine receptor and transient receptor potential vanilloid subtype 1, as well as other stimuli, promote the opening of acinar TJs by inducing internalization of TJs, thereby contributing to increased paracellular permeability. Besides, endothelial TJs are also redistributed with leakage of blood vessels in cholinergic-stimulated submandibular glands. Furthermore, under pathological conditions, such as Sjögren's syndrome, diabetes mellitus, immunoglobulin G4-related sialadenitis, and autotransplantation, the integrity and barrier function of TJ complex are impaired and may contribute to hyposalivation. Moreover, in submandibular glands of Sjögren's syndrome mouse model and patients, the endothelial barrier is disrupted and involved in hyposecretion and lymphocytic infiltration. These findings enrich our understanding of the secretory mechanisms that link the importance of epithelial and endothelial TJ functions to salivation under both physiological and pathophysiological conditions.
Assuntos
Sialorreia , Síndrome de Sjogren , Camundongos , Animais , Humanos , Junções Íntimas/metabolismo , Junções Íntimas/patologia , Síndrome de Sjogren/patologia , Células Endoteliais , Glândulas Salivares/patologia , Saliva/metabolismo , Glândula Submandibular/metabolismoRESUMO
Like many complex human diseases, esophageal squamous cell carcinoma (ESCC) is known to cluster in families. Familial ESCC cases often show early onset and worse prognosis than the sporadic cases. However, the molecular genetic basis underlying the development of familial ESCC is mostly unknown. We reported that SLC22A3 is significantly down-regulated in nontumor esophageal tissues from patients with familial ESCC compared with tissues from patients with sporadic ESCCs. A-to-I RNA editing of the SLC22A3 gene results in its reduced expression in the nontumor esophageal tissues of familial ESCCs and is significantly correlated with lymph node metastasis. The RNA-editing enzyme ADAR2, a familial ESCC susceptibility gene identified by our post hoc genome-wide association study, is positively correlated with the editing level of SLC22A3 Moreover, functional studies showed that SLC22A3 is a metastasis suppressor in ESCC, and deregulation of SLC22A3 facilitates cell invasion and filopodia formation by reducing its direct association with α-actinin-4 (ACTN4), leading to the increased actin-binding activity of ACTN4 in normal esophageal cells. Collectively, we now show that A-to-I RNA editing of SLC22A3 contributes to the early development and progression of familial esophageal cancer in high-risk individuals.
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Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Edição de RNA , Actinina/metabolismo , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Adulto , Idoso , Animais , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/secundário , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Regulação para Baixo , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/secundário , Carcinoma de Células Escamosas do Esôfago , Esôfago/citologia , Esôfago/metabolismo , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Humanos , Metástase Linfática/genética , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Proteínas de Transporte de Cátions Orgânicos/deficiência , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de RiscoRESUMO
Reprogramming of intracellular metabolism is common in liver cancer cells. Understanding the mechanisms of cell metabolic reprogramming may present a new basis for liver cancer treatment. In our previous study, we reported that a novel oncogene eukaryotic translation initiation factor 5A2 (EIF5A2) promotes tumorigenesis under hypoxic condition. Here, we aim to investigate the role of EIF5A2 in cell metabolic reprogramming during hepatocellular carcinoma (HCC) development. In this study, we reported that the messenger RNA (mRNA) level of EIF5A2 was upregulated in 59 of 105 (56.2%) HCC clinical samples (P = 0.015), and EIF5A2 overexpression was significantly associated with shorter survival time of patients with HCC (P = 0.021). Ectopic expression of EIF5A2 in HCC cell lines significantly promoted cell growth and accelerated glucose utilization and lipogenesis rates. The high rates of glucose uptake and lactate secretion conferred by EIF5A2 revealed an abnormal activity of aerobic glycolysis in HCC cells. Several key enzymes involved in glycolysis including glucose transporter type 1 and 2, hexokinase 2, phosphofructokinase liver type, glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase M2 isoform, phosphoglycerate mutase 1 and lactate dehydrogenase A were upregulated by overexpression of EIF5A2. Moreover, EIF5A2 showed positive correlations with FASN and ACSS2, two key enzymes involved in the fatty acid de novo biosynthetic pathway, at both protein and mRNA levels in HCC. These results indicated that EIF5A2 may regulate fatty acid de novo biosynthesis by increasing the uptake of acetate. In conclusion, our findings demonstrate that EIF5A2 has a critical role in HCC cell metabolic reprogramming and may serve as a prominent novel therapeutic target for liver cancer treatment.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Glucose/metabolismo , Lipogênese , Neoplasias Hepáticas/metabolismo , Redes e Vias Metabólicas , Fatores de Iniciação de Peptídeos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Reprogramação Celular , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Glicólise , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Fatores de Iniciação de Peptídeos/genética , Prognóstico , Proteínas de Ligação a RNA/genética , Taxa de Sobrevida , Fator de Iniciação de Tradução Eucariótico 5ARESUMO
BACKGROUND: Surgical site infection (SSI) is the third most frequent type of nosocomial infections. Triclosan-coated sutures are often used to reduce the risk of SSI, but studies examining this have given conflicting results. Therefore, this meta-analysis was performed to assess the efficacy of triclosan-coated sutures for reducing risk of SSI in adults. METHODS: PubMed, EMBASE, Google Scholar, and ClinicalTrials.gov were searched to identify randomized clinical trials evaluating triclosan-coated sutures for preventing SSI on patients 18 y or older. RESULTS: Thirteen randomized clinical trials involving 5256 participants were included. Triclosan-coated sutures were associated with lower risk of SSI than uncoated sutures across all surgeries (risk ratio [RR] 0.76, 95% confidence interval [CI] 0.65-0.88, P < 0.001). Similar proportions of patients experienced wound dehiscence with either type of suture (RR 0.97, 95% CI 0.49-1.89, P = 0.92). Subgroup analysis showed lower risk of SSI with triclosan-coated sutures in abdominal surgeries (RR 0.70, 95% CI 0.50-0.99, P = 0.04) and group with prophylactic antibiotic (RR 0.79, 95% CI 0.63-0.99, P = 0.04). However, such risk reduction was not observed in cardiac surgeries, breast surgeries, or group without prophylactic antibiotic. CONCLUSIONS: Triclosan-coated sutures can decrease the incidence of SSI in abdominal surgeries and might not interfere with wound healing process. Nevertheless, further studies are needed to examine whether triclosan-coated sutures are effective at preventing SSI in non-abdominal surgeries and to further study the interaction of antibiotic prophylaxis with triclosan-coated sutures.
Assuntos
Anti-Infecciosos Locais/administração & dosagem , Deiscência da Ferida Operatória/prevenção & controle , Infecção da Ferida Cirúrgica/prevenção & controle , Suturas , Triclosan/administração & dosagem , Adulto , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Suturas/economiaRESUMO
Adult T cell leukemia and lymphoma (ATL) is a highly aggressive form of hematological malignancy and is caused by chronic infection of human T cell leukemia virus type 1 (HTLV-1). The viral genome encodes an oncogenic protein, Tax, which plays a key role in transactivating viral gene transcription and in deregulating cellular oncogenic signaling to promote survival, proliferation and transformation of virally infected T cells. Hence, Tax is a desirable therapeutic target, particularly at early stage of HTLV-1-mediated oncogenesis. We here show that niclosamide, an anti-helminthic molecule, induced apoptosis of HTLV-1-transformed T cells. Niclosamide facilitated degradation of the Tax protein in proteasome. Consistent with niclosamide-mediated Tax degradation, this compound inhibited activities of MAPK/ERK1/2 and IκB kinases. In addition, niclosamide downregulated Stat3 and pro-survival Bcl-2 family members such as Mcl-1 and repressed the viral gene transcription of HTLV-1 through induction of Tax degradation. Since Tax, Stat3 and Mcl-1 are crucial molecules for promoting survival and growth of HTLV-1-transformed T cells, our findings demonstrate a novel mechanism of niclosamide in inducing Tax degradation and downregulating various cellular pro-survival molecules, thereby promoting apoptosis of HTLV-1-associated leukemia cells.
Assuntos
Antinematódeos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Produtos do Gene tax/antagonistas & inibidores , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Niclosamida/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Apoptose , Linhagem Celular Transformada , Produtos do Gene tax/genética , Produtos do Gene tax/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Humanos , Quinase I-kappa B/antagonistas & inibidores , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Linfócitos TRESUMO
Alterations in gene expression after chemotherapy may potentially help to identify mediators that induce suppression or regeneration in bone marrow. This paper reports our observation that the expression of the chemokine monokine induced by IFN-γ (Mig) and its receptor CXCR3 was significantly activated in mice after treatment with the chemotherapeutic agent 5-fluorouracil (5-FU). The neutralization of antibodies against the activated Mig increased the survival rate and accelerated BM recovery after chemotherapy. In addition, elevation of Mig plasma levels after 5-FU treatment corresponded with increased mortality. The cell cycle-inhibiting effect of the prophylactic administration of Mig protected hematopoietic progenitor cells (HPCs) from 1-ß-d-arabinofuranosylcytosine in spleen colony assays and enhanced the irradiated recipients' survival. In CXCR3(-/-) mice, Mig did not propagate BM suppression, indicating that the suppressive effect of Mig is dependent on CXCR3. On the one hand, Mig stimulated p70 S6K and Erk1/2 pathways in mesenchymal stroma cells, inhibiting mesenchymal stroma cell-dependent HPC expansion. Moreover, Mig suppressed the STAT5 pathway in HPCs, inhibiting leukocyte differentiation. Our results strongly suggest that Mig contributes to the acute lethal toxicity arising from 5-FU administration. Neutralization of Mig may offer new strategies to alleviate BM toxicity with potentially dramatic implications for chemotherapy.
Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Células da Medula Óssea/efeitos dos fármacos , Quimiocina CXCL9/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/mortalidade , Tolerância Imunológica/efeitos dos fármacos , Animais , Anticorpos/farmacologia , Células da Medula Óssea/patologia , Células Cultivadas , Quimiocina CXCL9/antagonistas & inibidores , Quimiocina CXCL9/imunologia , Quimiocina CXCL9/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Fluoruracila/efeitos adversos , Fluoruracila/farmacologia , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Tolerância Imunológica/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise em Microsséries , Ratos , Ratos Wistar , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
Rosuvastatin (RSV) is widely used to treat hyperlipidemia and hypercholesterolemia and is recommended for the primary and secondary prevention of cardiovascular diseases (CVD). In this study, we aimed to explore its action and mechanism in lung adenocarcinoma (LUAD) therapy. Lewis and CMT64 cell-based murine subcutaneous LUAD models were employed to explore the effects of RSV monotherapy combined with cisplatin and gemcitabine. Human lung fibroblasts and human LUAD cell lines were used to assess the effects of RSV on normal and LUAD cells. Bioinformatics and RNA interference were used to observe the contribution of cyclin A2 (CCNA2) knockdown to RSV inhibition and to improve chemosensitivity in LUAD. RSV significantly suppressed grafted tumor growth in a murine subcutaneous LUAD model and exhibited synergistic anti-tumor activity with cisplatin and gemcitabine. In vitro and in vivo experiments demonstrated that RSV impaired the proliferation and migration of cancer cells while showing little inhibition of normal lung cells. RNA interference and CCK8 detection preliminarily indicated that RSV inhibited tumor growth and enhanced the chemosensitivity to cisplatin and gemcitabine by downregulating CCNA2. RSV suppressed LUAD progression and enhanced chemosensitivity to cisplatin and gemcitabine by downregulating CCNA2, which should be prior consideration for the treatment of LUAD, especially for patients co-diagnosed with hyperlipidemia and hypercholesterolemia.
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Background: Although low-level laser therapy (LLLT) is a widely used noninvasive treatment because of photobiomodulation effects, its application for xerostomia remained uncertain. Tight junctions (TJs), mainly composed of claudins, occludin, and ZO family members, are crucial structures that determine material transport through paracellular pathway in salivary gland epithelial cells. This work aimed to investigate whether LLLT affected salivary secretion through epithelial TJs. Methods: Transepithelial electrical resistance (TER) measurement and paracellular permeability assay were applied to evaluate paracellular permeability in submandibular gland (SMG)-C6 cells after irradiation with 540 nm green light. Immunofluorescence and western blot were used to detect the expression of TJ proteins. Quantitative phosphoproteomics were performed to explore possible intracellular signals. Results: We found that irradiation with 540 nm green light significantly decreased TER values while increased paracellular transport in SMG-C6 cells. 540 nm green light-induced redistribution of claudin-1, -3, and -4, but not occludin or ZO-1. Moreover, above phenomena were abolished by preincubation with capsazepine, an antagonist of transient receptor potential vanilloid subtype 1. Notably, irradiation with 540 nm green light on the skin covering the whole submandibular gland regions promoted salivary secretion and attenuated lymphocytic infiltration in 21-week-old non-obese diabetic mice (n = 5 per group), a xerostomia animal model for Sjögren's syndrome. Through in-depth bioinformatics analysis and expression verification, ERK1/2 and EphA2 served as potential canonical and noncanonical signals underlying 540 nm green light. Conclusions: Our findings uncovered the novel therapeutic effects of 540 nm green light on xerostomia through regulation on the expression and distribution of TJs.
Assuntos
Terapia com Luz de Baixa Intensidade , Animais , Camundongos , Glândula Submandibular/efeitos da radiação , Glândula Submandibular/metabolismo , Saliva/metabolismo , Xerostomia/etiologia , Junções Íntimas/efeitos da radiação , Junções Íntimas/metabolismo , Ratos , Luz VerdeRESUMO
In 2023, Baishideng Publishing Group (Baishideng) routinely published 47 open-access journals, including 46 English-language journals and 1 Chinese-language journal. Our successes were accomplished through the collective dedicated efforts of Baishideng staffs, Editorial Board Members, and Peer Reviewers. Among these 47 Baishideng journals, 7 are included in the Science Citation Index Expanded (SCIE) and 6 in the Emerging Sources Citation Index (ESCI). With the support of Baishideng authors, company staffs, Editorial Board Members, and Peer Reviewers, the publication work of 2023 is about to be successfully completed. This editorial summarizes the 2023 activities and accomplishments of the 13 SCIE- and ESCI-indexed Baishideng journals, outlines the Baishideng publishing policy changes and additions made this year, and highlights the unique advantages of Baishideng journals.
Assuntos
Publicações Periódicas como Assunto , Editoração , Humanos , IdiomaRESUMO
Human T cell leukemia virus type 1 and type 2 (HTLV-1 and -2) are two closely related retroviruses with the former causing adult T cell leukemia. HTLV-2 infection is prevalent among intravenous drug users, and the viral genome encodes the viral transactivator Tax, which is highly homologous to the transforming protein Tax from HTLV-1. However, the link between HTLV-2 infection and leukemia has not been established. In the present study, we evaluated the activity of HTLV-2 Tax in promoting aberrant proliferation of human CD4 T lymphocytes. Tax2 efficiently immortalized CD4(+) memory T lymphocytes with a CD3/TCRαß/CD4/CD25/CD45RO/CD69 immunophenotype, promoted constitutive activation of PI3K/Akt, IκB kinase/NF-κB, mitogen-activated protein kinase, and STAT3, and it also increased the level of Mcl-1. Disruption of these oncogenic pathways led to growth retardation and apoptotic cell death of the Tax2-established T cell lines. We further found that Tax2 induced autophagy by interacting with the autophagy molecule complex containing Beclin1 and PI3K class III to form the LC3(+) autophagosome. Tax2-mediated autophagy promoted survival and proliferation of the immortalized T cells. The present study demonstrated the oncogenic properties of Tax2 in human T cells and also implicated Tax2 in serving as a molecular tool to generate distinct T cell subtype lines.
Assuntos
Autofagia , Linfócitos T CD4-Positivos/metabolismo , Transformação Celular Viral , Produtos do Gene tax/metabolismo , Vírus Linfotrópico T Tipo 2 Humano/metabolismo , Memória Imunológica , Antígenos CD/genética , Antígenos CD/metabolismo , Linfócitos T CD4-Positivos/patologia , Linhagem Celular , Proliferação de Células , Sobrevivência Celular/genética , Ativação Enzimática/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Produtos do Gene tax/genética , Infecções por HTLV-II/genética , Infecções por HTLV-II/metabolismo , Infecções por HTLV-II/patologia , Vírus Linfotrópico T Tipo 2 Humano/genética , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Leucemia de Células T/genética , Leucemia de Células T/metabolismo , Leucemia de Células T/patologia , Leucemia de Células T/virologia , Proteína de Sequência 1 de Leucemia de Células Mieloides , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismoRESUMO
Monocyte-to-M0/M1 macrophage differentiation with unclear molecular mechanisms is a pivotal cellular event in many cardiovascular diseases including atherosclerosis. Long non-coding RNAs (lncRNAs) are a group of protein expression regulators; however, the roles of monocyte-lncRNAs in macrophage differentiation and its related vascular diseases are still unclear. The study aims to investigate whether the novel leukocyte-specific lncRNA Morrbid could regulate macrophage differentiation and atherogenesis. We identified that Morrbid was increased in monocytes and arterial walls from atherosclerotic mouse and from patients with atherosclerosis. In cultured monocytes, Morrbid expression was markedly increased during monocyte to M0 macrophage differentiation with an additional increase during M0 macrophage-to-M1 macrophage differentiation. The differentiation stimuli-induced monocyte-macrophage differentiation and the macrophage activity were inhibited by Morrbid knockdown. Moreover, overexpression of Morrbid alone was sufficient to elicit the monocyte-macrophage differentiation. The role of Morrbid in monocyte-macrophage differentiation was also identified in vivo in atherosclerotic mice and was verified in Morrbid knockout mice. We identified that PI3-kinase/Akt was involved in the up-regulation of Morrbid expression, whereas s100a10 was involved in Morrbid-mediated effect on macrophage differentiation. To provide a proof of concept of Morrbid in pathogenesis of monocyte/macrophage-related vascular disease, we applied an acute atherosclerosis model in mice. The results revealed that overexpression of Morrbid enhanced but monocyte/macrophage-specific Morrbid knockout inhibited the monocytes/macrophages recruitment and atherosclerotic lesion formation in mice. The results suggest that Morrbid is a novel biomarker and a modulator of monocyte-macrophage phenotypes, which is involved in atherogenesis.
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To investigate the effectiveness of EDL-291, a 6,7-dimethoxy-1-[4-(4-methoxypyridin-3-yl)benzyl]-1,2,3,4-tetrahydroisoquinoline dihydrochloride compound, in inhibiting the survival of glioblastoma in vitro and in vivo. Dose-response curves were generated to determine the EC50 in rat and human glioblastoma cell lines by treatment with different dilutions of EDL-291. To evaluate the architecture of the glioblastoma cells after treatment with EDL-291, the rat and human glioblastoma cells were stained with Mito Tracker Green FM. To determine whether autophagy was induced in EDL-291-treated glioblastoma cells, both rat and human glioblastoma cell lines were stained with acridine orange and light chain-3 immunoblots were performed. The efficacy of EDL-291 was monitored in vivo using a rat glioblastoma model. Rat glioblastoma cells were transplanted into an intracranial rat model, followed by infusions of saline, a low dose of EDL-291 (20 mg/kg for the first half hour, followed by 40 mg/kg EDL-291 in saline for 4 h), or a high dose of EDL-291 (60 mg/kg for the first half hour, followed by 90 mg/kg EDL-291 for 4 h). EDL-291 inhibits glioblastoma in vitro by destroying the mitochondria as shown with Mito Tracker Green FM. Acridine orange staining and light chain-3 immunoblots suggest that autophagy is induced when glioblastoma cells are treated with EDL-291. In vivo, a low dosage of EDL-291 is sufficient and effective in reducing glioblastoma tumor size. EDL-291 selectively induces cell death in rat and human glioblastoma cell lines by the induction of autophagy. EDL-291 exhibits antiglioblastoma effects both in vitro and in vivo.
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Antineoplásicos/farmacologia , Glioblastoma/tratamento farmacológico , Isoquinolinas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Autofagia/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glioblastoma/patologia , Humanos , Isoquinolinas/química , Isoquinolinas/uso terapêutico , Masculino , Microscopia Confocal , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Background and aims Reg4 is a recently discovered member of the regenerating gene family with distinctive expression profiles in primary cancers. To date, the physiological function of Reg4 is poorly understood. Previously, the authors found that Reg4 was markedly upregulated during acute pancreatitis (AP). The aim of this study was to investigate the role of Reg4 in experimental pancreatitis. Methods AP was induced in C57BL/6 mice by administration of either l-arginine or caerulein, and Reg4 expression was assessed by immunofluorescence, reverse transcriptase (RT)-PCR and western blot analyses. Recombinant human Reg4 protein (rReg4), heat-inactivated Reg4, neutralising antibody and vehicle were also administered to mice by subcutaneous injection. The severity of AP was determined by measuring amylase and lipase activities in the serum and histological grading. The effect of rReg4 on cell death was examined and epidermal growth factor receptor (EGFR), p-EGFR, Akt, p-Akt, Bcl-2 and Bcl-xL expression were assessed by western blot analysis of isolated murine acinar cells treated with l-arginine. Results Reg4 mRNA and protein were markedly upregulated during arginine-induced pancreatitis. Reg4 was widely expressed in residual acinar cells around the islets and regenerating metaplastic epithelium. rReg4 could protect against arginine-induced necrosis of acinar cells both in vivo and in vitro. This protective effect was also confirmed in the caerulein-induced murine model of AP. It was shown that arginine induced expression of Bcl-2 and Bcl-xL, while rReg4 upregulated Bcl-2 and Bcl-xL expression by activating the EGFR/Akt pathway. The upregulation of Bcl-xL correlated inversely with cell necrosis in isolated pancreatic acinar cells. Conclusions The data suggest that Reg4 may protect against acinar cell necrosis in experimental pancreatitis by enhancing the expression of Bcl-2 and Bcl-xL via activation of the EGFR/Akt signalling pathway.
Assuntos
Pancreatite Necrosante Aguda/prevenção & controle , Proteínas Recombinantes/uso terapêutico , Animais , Arginina/farmacologia , Morte Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Receptores ErbB/metabolismo , Lectinas Tipo C/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Pâncreas/patologia , Pancreatite Necrosante Aguda/induzido quimicamente , Pancreatite Necrosante Aguda/metabolismo , Pancreatite Necrosante Aguda/patologia , Proteínas Associadas a Pancreatite , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Recombinantes/farmacologia , Regulação para Cima/efeitos dos fármacos , Proteína bcl-X/biossínteseRESUMO
This paper explores cycles in innovative outcomes corresponding with the timing of political turnover. Using data on local government officials and firm level innovation activities in China, firm innovation is found to be negatively associated with a turnover of local political leaders. We examine several potential explanations and find evidence supporting the premise that political turnover reduces firms' incentives to innovate until the uncertainty is resolved. This paper also indicates that local political turnover significantly inhibits firms' research and development investment, government subsidies, and expansion decisions, leading to less innovative outcomes. Moreover, reductions in innovation are greater in cities with higher levels of government expenditure or intellectual property rights trials, or in smaller firms or non-state-owned enterprises during the rotation of local government leaders.
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OBJECTIVE: IgG4-related sialadenitis (IgG4-RS) is a chronic fibroinflammatory disease characterized by glandular fibrosis and hyposalivation. This study was undertaken to explore the role of cellular senescence in the pathogenesis of IgG4-RS-related fibrosis. METHODS: The expression of senescence markers and proinflammatory cytokines in the submandibular glands (SMGs) of IgG4-RS patients (n = 18) and controls (n = 14) was determined by proteomics, real-time polymerase chain reaction, Western blotting, and immunohistochemistry. After interleukin-4 (IL-4) treatment, high-throughput RNA sequencing was performed to identify the differentially expressed genes in SMG-C6 cells. A glandular fibrosis model was established by the intraglandular injection of IL-4 into mouse SMGs (n = 8 per group). RESULTS: Salivary acinar and ductal epithelial cells underwent senescence in IgG4-RS patients, as indicated by the elevated activity of senescence-associated ß-galactosidase, lipofuscin accumulation, enhanced expression of senescence markers (p53 and p16INK4A ), and up-regulation of senescence-associated secretory phenotype factors. Moreover, there was a significant increase in IL-4 levels in SMGs from IgG4-RS patients (P < 0.01), which positively correlated with p16INK4A expression and the fibrosis score. Incubation with IL-4 exacerbated salivary epithelial cell senescence by increasing the expression of p16INK4A through the reactive oxygen species (ROS)/p38 MAPK pathway. Supernatant collected from IL-4-induced senescent SMG-C6 cells enhanced fibroblast activation and matrix protein production (P < 0.05). Furthermore, injecting mice with IL-4 promoted fibrosis and senescence phenotypes in SMGs in vivo. CONCLUSION: The cellular senescence induced by IL-4 through the ROS/p38 MAPK-p16INK4A pathway promotes fibrogenesis in IgG4-RS. Our data suggest that cellular senescence could serve as a novel therapeutic target for treating IgG4-RS.
Assuntos
Interleucina-4 , Sialadenite , Animais , Senescência Celular , Inibidor p16 de Quinase Dependente de Ciclina , Células Epiteliais/metabolismo , Fibrose , Humanos , Imunoglobulina G/metabolismo , Camundongos , Espécies Reativas de Oxigênio , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
OBJECTIVE: To compare the behavioral effects of psychoactive drugs between two strains of mice. METHODS: The Kunming (KM) and ICR mice were injected intraperitoneally with caffeine (3, 10, 30, 100 mg/kg), ephedrine (3, 10, 30, 100 mg/kg), diazepam (1, 3,1 0 mg/kg) and chloral hydrate (10, 30, 100 mg/kg), respectively. Ten min after injection, the locomotor activity in the open field was recorded for 2 h. The total distance, the distance ratio to total distance and the time in central region were analyzed for each drugs. Thirty min after injection, the latent time in the passive avoidance test was measured in a shuttle box. RESULTS: Caffeine and diazepam prolonged the latent time, and ephedrine and chloral hydrate decreased the latent time, but there were no differences between the two strains. The two strains of mice exhibited significant differences in the total distance after injection of ephedrine 10 mg/kg, diazepam 3 mg/kg and chloral hydrate 100 mg/kg. Compared to KM mice, ICR mice exhibited an increase in the distance ratio and the time in central region after injection of ephedrine 10-100 mg/kg, but a decrease after diazepam 3-10 mg/kg. CONCLUSION: KM and ICR mice show no differences in latent time, but significant differences in the total distance, the distance ratio and the time in central region in the locomotor activity. Therefore, selection of mouse strains is important in the study of psychoactive drugs.
Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Atividade Motora/efeitos dos fármacos , Animais , Cafeína/farmacologia , Hidrato de Cloral/farmacologia , Diazepam/farmacologia , Relação Dose-Resposta a Droga , Efedrina/farmacologia , Camundongos , Camundongos Endogâmicos ICRRESUMO
Hierarchical structures with sophisticated patterns allow the emergence of challenging properties. However, the highly cooperative and specific interactions needed for assembly spanning different length scales are typically lacking in inorganic nanoparticles (NPs). Here we show that size can be a common structural driving force for controlling hierarchical assembly of inorganic NPs into anisotropic superstructures. It involves first the self-limiting assembly of small CdS NPs into large supraparticles and their subsequent spontaneous organization into chains and tubules hundreds of nanometers long. Our quantitative calculations based on DLVO theory reveals an intrinsic size effect relating to the dimension change of assembly units in accordance with a negative cooperativity. It is shown that the size increase in building blocks creates an effective kinetic barrier contrast at different attachment sites due to the increase of interparticle electrostatic repulsion, switching the assembly from thermodynamically preferred 3D to kinetically favored 1D pathway. The size-encoded hierarchical assembly is accompanied by the ligand-controlled Oswald ripening process, which is responsible for the variation of hierarchical patterns from chains to tubules. The general principle in governing multistage inorganic NP ordering represents an important guideline toward the complex mesoscale structures that may surpass traditional materials in both design and functionality.
Assuntos
Nanopartículas , Anisotropia , Eletricidade EstáticaRESUMO
Nondestructive instrumental identification of the green tea quality instead of professional human panel tests is highly desired for industrial application recently. The special flavor is a key quality-trait that influence consumer preference. However, flavonoids, as well as sensory-associated compounds, which play a critical role in the quality-traits profile of green tea samples have been poorly investigated. In this study, we were proposing an objective and accurate near infrared spectroscopy (NIRS) profile to support quality control within the entire green tea sensory evaluation chain, the complexity of green tea samples' sensory analysis was performed by two complementary methods: the standard calculation and the novel NIRS roadmap coupled with chemometrics. The green tea samples' physical quality, gustatory index, and nutritional index were measured respectively, which taking into consideration the gustatory evaluation of green tea for five commercially representative overall quality ("very bad", "bad", "regular", "good" and "excellent"). Our findings highlight the underexplored role of NIRS in chemical-to-sensory relationships and its widespread importance and utility in green tea quality improvement. Collectively, the comprehensive characterization of sensory-associated attribution allowed the identification of a wide array of spectrometric features, mostly related to moisture, soluble solids (SS), tea polyphenol (TPP), epigallocatechin gallate (EGCG), epicatechin (EC) and tea polysaccharide (TPS), which can be used as putative biomarkers to rapidly evaluate the green tea flavor variations related to rank differences. Otherwise, the NIRS' data were split into the calibration (n = 80) and prediction (n = 40) set independently, which showed high correlation coefficient with Rp-values of 0.9024, 0.9020 in physical and total cup quality, respectively. In this research, we demonstrated that NIRS was an easily-generated strategy and able to close the loop to feedback into the process for advanced process control. However, the established models should be improved by more green tea samples from different regions.
Assuntos
Catequina , Chá , Calibragem , Catequina/análise , Flavonoides , Humanos , Polifenóis , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
Acute liver failure (ALF) is a life-threatening disease that has proven difficult to cure. In Western countries, acetaminophen (APAP) poisoning is the most common cause of ALF. However, the mode of cell death in APAP-induced ALF cases is controversial. Previous studies have shown that administration of anti-interleukin-1 (anti-IL-1) antibody attenuated APAP-induced liver injury, and that administration of anti-IL-1 receptor antagonist (anti-IL-1Ra) antibody exacerbated organ injury. These results prompted us to investigate the roles of IL-1Ra in APAP-induced ALF mice. Our results show that administration of recombinant human IL-1Ra (rhIL-1Ra) could significantly improve the survival rate of mice with ALF induced by APAP. Furthermore, we found that rhIL-1Ras could dramatically inhibit the activities of alanine aminotransferase and aspartate aminotransferase in serum, reduce the death of hepatocytes and accelerate the proliferation of hepatocytes. In addition, we show that hepatocellular apoptosis rather than necrosis was the major cause of ALF-induced animal death, and that the anti-apoptosis role of rhIL-1Ra was mediated by reducing the release of cytochrome c from the mitochondria, and the activities of caspase-3, caspase-8 and caspase-9 in the liver tissue. In conclusion, these data indicate that rhIL-1Ra is a promising candidate for the treatment of APAP-induced ALF in mice through the reduction of hepatocellular apoptosis.
Assuntos
Acetaminofen/intoxicação , Analgésicos não Narcóticos/intoxicação , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Falência Hepática Aguda/patologia , Acetaminofen/metabolismo , Alanina Transaminase/sangue , Alanina Transaminase/metabolismo , Analgésicos não Narcóticos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/metabolismo , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Grupo dos Citocromos c/metabolismo , Hepatócitos/metabolismo , Humanos , Proteína Antagonista do Receptor de Interleucina 1/genética , Fígado/metabolismo , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necrose/metabolismo , Proteínas Recombinantes/metabolismo , Taxa de SobrevidaRESUMO
Regenerating gene (Reg) IV is a newly discovered member of the regenerating gene family belonging to the calcium (C-type) dependent lectin superfamily. Reg IV is highly expressed in the gastrointestinal tract and markedly up-regulated in colon adenocarcinoma, pancreatic cancer, gastric adenocarcinoma, and inflammatory bowel disease. However, the physiological and pathological functions of Reg IV are largely unknown, partly due to the limited access of the bioactive protein. We report here the first expression and purification of Reg IV proteins using a prokaryotic system. Human Reg IV was expressed in Escherichia coli as an insoluble protein which was identified in the fraction of inclusion body after ultrasonication of the bacteria. After the protein aggregate was solubilized by guanidine-HCl, it was refolded by sucrose and arginine-assisted procedures and purified using cation-exchange chromatography. The protein identity and purity of the final preparation were confirmed by analysis of the protein mass and immune specificity in SDS-PAGE, Western blotting, and HPLC assay. The biological activity of the protein was determined by the HCT116 and HT29 cell proliferation assays. The highly purified bioactive human Reg IV should aid in further characterization of its physiological and pathological functions.