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1.
FASEB J ; 35(9): e21834, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403553

RESUMO

Two distinct genetic mutational pathways characterized by either chromosomal instability or high-frequency microsatellite instability (MSI-H) are recognized in the pathogenesis of colorectal cancer (CRC). Recently, it has been shown that patients with primary CRC that displays MSI-H have a significant, stage-independent, multivariate survival advantage. Biological properties of CMS1 (MSI-H type) can affect therapeutic efficiencies of agents used in the treatment of CRC, and therefore become a new predictive factor of the treatment. But, the predictive impact of MSI-H status for adjuvant chemotherapy remains controversial. This study will assess whether there is any unnecessary or inappropriate use of treatment agents recommended for adjuvant therapy of stage 2 and 3 of disease and for palliative or curative treatment of liver metastatic disease in microsatellite instability high group, a molecular subtype of colon cancer. Within this scope, the efficiencies of fluorouracil- and oxaliplatin-based chemotherapeutic agents will be shown on stage 3 microsatellite instability high colon tumor cell lines first, and then a microfluidic model will be created, imitating the metastasis of colon cancer to the liver. In the microfluidic chip model, we will create in liver tissue, where the metastasis of microsatellite instability high colon cancer will be simulated; the effectiveness of chemotherapeutic agents, immunotherapy agents, and targeted agents on tumor cells as well as drug response will be assessed according to cell viability through released biomarkers from the cells. The proposed hypothesis study includes the modeling and treatment of patient-derived post-metastatic liver cancer in microfluidics which has priority at the global and our region and consequently develop personal medication.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Dispositivos Lab-On-A-Chip , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Instabilidade de Microssatélites , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Neoplasias do Colo/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/uso terapêutico , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/secundário , Modelos Biológicos , Metástase Neoplásica/patologia , Especificidade de Órgãos , Oxaliplatina/uso terapêutico
2.
Nature ; 595(7866): 289-294, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34194041

RESUMO

The global decline in malaria has stalled1, emphasizing the need for vaccines that induce durable sterilizing immunity. Here we optimized regimens for chemoprophylaxis vaccination (CVac), for which aseptic, purified, cryopreserved, infectious Plasmodium falciparum sporozoites (PfSPZ) were inoculated under prophylactic cover with pyrimethamine (PYR) (Sanaria PfSPZ-CVac(PYR)) or chloroquine (CQ) (PfSPZ-CVac(CQ))-which kill liver-stage and blood-stage parasites, respectively-and we assessed vaccine efficacy against homologous (that is, the same strain as the vaccine) and heterologous (a different strain) controlled human malaria infection (CHMI) three months after immunization ( https://clinicaltrials.gov/ , NCT02511054 and NCT03083847). We report that a fourfold increase in the dose of PfSPZ-CVac(PYR) from 5.12 × 104 to 2 × 105 PfSPZs transformed a minimal vaccine efficacy (low dose, two out of nine (22.2%) participants protected against homologous CHMI), to a high-level vaccine efficacy with seven out of eight (87.5%) individuals protected against homologous and seven out of nine (77.8%) protected against heterologous CHMI. Increased protection was associated with Vδ2 γδ T cell and antibody responses. At the higher dose, PfSPZ-CVac(CQ) protected six out of six (100%) participants against heterologous CHMI three months after immunization. All homologous (four out of four) and heterologous (eight out of eight) infectivity control participants showed parasitaemia. PfSPZ-CVac(CQ) and PfSPZ-CVac(PYR) induced a durable, sterile vaccine efficacy against a heterologous South American strain of P. falciparum, which has a genome and predicted CD8 T cell immunome that differs more strongly from the African vaccine strain than other analysed African P. falciparum strains.


Assuntos
Anticorpos Neutralizantes/imunologia , Fígado/imunologia , Fígado/parasitologia , Vacinas Antimaláricas/imunologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/imunologia , Vacinas Atenuadas/imunologia , Adulto , Animais , Formação de Anticorpos/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Estágios do Ciclo de Vida/imunologia , Malária/sangue , Malária/imunologia , Malária/parasitologia , Malária/prevenção & controle , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/efeitos adversos , Vacinas Antimaláricas/química , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/crescimento & desenvolvimento , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo , Vacinação/efeitos adversos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/química
3.
J Autoimmun ; 123: 102706, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34293683

RESUMO

Autoimmune phenomena and clinically apparent autoimmune diseases, including autoimmune hepatitis, are increasingly been reported not only after natural infection with the SARS-CoV-2 virus, but also after vaccination against it. We report the case of a 63-year old man without a history of autoimmunity or SARS-CoV-2 natural infection who experienced acute severe autoimmune-like hepatitis seven days after the first dose of the mRNA-1273 SARS-CoV-2 vaccine. Liver histology showed inflammatory portal infiltrate with interface hepatitis, lobular and centrilobular inflammation with centrilobular necrosis, in absence of fibrosis and steatosis. Serum immunoglobulin G was slightly elevated. Autoimmune liver serology showed an indirect immunofluorescence pattern on triple rodent tissue compatible with anti-mitochondrial antibody (AMA), but, unexpectedly, this pattern was not mirrored by positivity for primary biliary cholangitis (PBC)-specific molecular tests, indicating that this antibody is different from classical AMA. Anti-nuclear antibody (ANA) was also positive with a rim-like indirect immunofluorescence pattern on liver and HEp2 cell substrates, similar to PBC-specific ANA; however, anti-gp210 and a large panel of molecular-based assays for nuclear antigens were negative, suggesting a unique ANA in our patient. He carries the HLA DRB1*11:01 allele, which is protective against PBC. Response to prednisone treatment was satisfactory. The clinical significance of these novel specificities needs to be further evaluated in this emerging condition.


Assuntos
Autoanticorpos/imunologia , Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , Cadeias HLA-DRB1/imunologia , Hepatite Autoimune/etiologia , Mitocôndrias/imunologia , SARS-CoV-2/imunologia , Vacinação/efeitos adversos , Animais , Anticorpos Antinucleares/imunologia , Especificidade de Anticorpos , Autoantígenos/imunologia , Linhagem Celular , Técnica Indireta de Fluorescência para Anticorpo , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/imunologia , Hepatite Autoimune/patologia , Humanos , Imunossupressores/uso terapêutico , Fígado/imunologia , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Rosuvastatina Cálcica/efeitos adversos , Rosuvastatina Cálcica/uso terapêutico
4.
Anticancer Res ; 41(7): 3419-3427, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230137

RESUMO

BACKGROUND/AIM: Liver metastases are among the principal mortality causes in cancer patients. Dendritic cell immunotherapies have shown promising results in some tumors by mediating immunological mechanisms that could be involved in liver metastases during primary tumor growth. The present study aimed to evaluate the impact of prophylactic dendritic cell vaccination on the liver of mice with 4T1 mouse breast carcinoma. MATERIALS AND METHODS: Adult female Balb/c mice were submitted or not to vaccination with dendritic cells before the induction of 4T1 tumor lineage. Liver tissues from mice were analyzed by flow cytometry (markers CD3, CD4, CD8, CD25, IL-10, IL-12, IL-17, TNF-α, IFN-γ, T-bet, GATA3, RORγt, and FoxP3) and hematoxylin-eosin. The dendritic cell vaccine was differentiated and matured ex vivo from the bone marrow. RESULTS: Prophylactic vaccination reduced areas of liver metastases (p=0.0049), induced an increase in the percentage of total T and cytotoxic T lymphocytes (p<0.0001), as well as FoxP3+ (p<0.0001). It also increased the levels of cytokines IL-10 and IL-17 in helper T lymphocytes (p<0.0001). CONCLUSION: The prophylactic dendritic cell vaccine changed the cell phenotype in the immune response of liver, and it was able to reduce metastases. Cytotoxic T cells and regulatory T lymphocytes were more present, likewise, the production of IL-10 and IL-7 simultaneously, demonstrating that the vaccine can induce a state of control of pro-inflammatory responses, which can provide a less favorable environment for metastatic tumor growth.


Assuntos
Neoplasias da Mama/imunologia , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Neoplasias Hepáticas/imunologia , Fígado/imunologia , Animais , Biomarcadores Tumorais/imunologia , Medula Óssea/imunologia , Neoplasias da Mama/patologia , Modelos Animais de Doenças , Feminino , Imunidade/imunologia , Imunoterapia/métodos , Fígado/patologia , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Vacinação/métodos
5.
Science ; 373(6550)2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34210853

RESUMO

The mechanisms by which macrophages regulate energy storage remain poorly understood. We identify in a genetic screen a platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF)-family ortholog, Pvf3, that is produced by macrophages and is required for lipid storage in fat-body cells of Drosophila larvae. Genetic and pharmacological experiments indicate that the mouse Pvf3 ortholog PDGFcc, produced by adipose tissue-resident macrophages, controls lipid storage in adipocytes in a leptin receptor- and C-C chemokine receptor type 2-independent manner. PDGFcc production is regulated by diet and acts in a paracrine manner to control lipid storage in adipose tissues of newborn and adult mice. At the organismal level upon PDGFcc blockade, excess lipids are redirected toward thermogenesis in brown fat. These data identify a macrophage-dependent mechanism, conducive to the design of pharmacological interventions, that controls energy storage in metazoans.


Assuntos
Adipócitos/imunologia , Dieta Hiperlipídica , Proteínas de Drosophila/metabolismo , Metabolismo Energético , Linfocinas/metabolismo , Macrófagos/imunologia , Obesidade/imunologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Termogênese , Tecido Adiposo Marrom/imunologia , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster , Feminino , Hemócitos/imunologia , Fígado/imunologia , Linfocinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Crescimento Derivado de Plaquetas/genética , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Front Immunol ; 12: 595150, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262555

RESUMO

As one of the current global health conundrums, COVID-19 pandemic caused a dramatic increase of cases exceeding 79 million and 1.7 million deaths worldwide. Severe presentation of COVID-19 is characterized by cytokine storm and chronic inflammation resulting in multi-organ dysfunction. Currently, it is unclear whether extrapulmonary tissues contribute to the cytokine storm mediated-disease exacerbation. In this study, we applied systems immunology analysis to investigate the immunomodulatory effects of SARS-CoV-2 infection in lung, liver, kidney, and heart tissues and the potential contribution of these tissues to cytokines production. Notably, genes associated with neutrophil-mediated immune response (e.g. CXCL1) were particularly upregulated in lung, whereas genes associated with eosinophil-mediated immune response (e.g. CCL11) were particularly upregulated in heart tissue. In contrast, immune responses mediated by monocytes, dendritic cells, T-cells and B-cells were almost similarly dysregulated in all tissue types. Focused analysis of 14 cytokines classically upregulated in COVID-19 patients revealed that only some of these cytokines are dysregulated in lung tissue, whereas the other cytokines are upregulated in extrapulmonary tissues (e.g. IL6 and IL2RA). Investigations of potential mechanisms by which SARS-CoV-2 modulates the immune response and cytokine production revealed a marked dysregulation of NF-κB signaling particularly CBM complex and the NF-κB inhibitor BCL3. Moreover, overexpression of mucin family genes (e.g. MUC3A, MUC4, MUC5B, MUC16, and MUC17) and HSP90AB1 suggest that the exacerbated inflammation activated pulmonary and extrapulmonary tissues remodeling. In addition, we identified multiple sets of immune response associated genes upregulated in a tissue-specific manner (DCLRE1C, CHI3L1, and PARP14 in lung; APOA4, NFASC, WIPF3, and CD34 in liver; LILRA5, ISG20, S100A12, and HLX in kidney; and ASS1 and PTPN1 in heart). Altogether, these findings suggest that the cytokines storm triggered by SARS-CoV-2 infection is potentially the result of dysregulated cytokine production by inflamed pulmonary and extrapulmonary (e.g. liver, kidney, and heart) tissues.


Assuntos
COVID-19/epidemiologia , COVID-19/imunologia , Rim/imunologia , Fígado/imunologia , Pulmão/imunologia , Miocárdio/imunologia , Pandemias , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Biomarcadores/sangue , COVID-19/sangue , COVID-19/complicações , Estudos de Casos e Controles , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/biossíntese , Humanos , Imunidade/genética , Monócitos/imunologia , Neutrófilos/imunologia , Transcriptoma , Regulação para Cima/genética
8.
Nat Commun ; 12(1): 4355, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272362

RESUMO

Mucosal-associated Invariant T (MAIT) cells are recognized for their antibacterial functions. The protective capacity of MAIT cells has been demonstrated in murine models of local infection, including in the lungs. Here we show that during systemic infection of mice with Francisella tularensis live vaccine strain results in evident MAIT cell expansion in the liver, lungs, kidney and spleen and peripheral blood. The responding MAIT cells manifest a polarised Th1-like MAIT-1 phenotype, including transcription factor and cytokine profile, and confer a critical role in controlling bacterial load. Post resolution of the primary infection, the expanded MAIT cells form stable memory-like MAIT-1 cell populations, suggesting a basis for vaccination. Indeed, a systemic vaccination with synthetic antigen 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil in combination with CpG adjuvant similarly boosts MAIT cells, and results in enhanced protection against both systemic and local infections with different bacteria. Our study highlights the potential utility of targeting MAIT cells to combat a range of bacterial pathogens.


Assuntos
Citocinas/metabolismo , Francisella tularensis/imunologia , Imunidade Inata , Células T Invariantes Associadas à Mucosa/imunologia , Adjuvantes Imunológicos , Animais , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Fígado/imunologia , Pulmão/imunologia , Camundongos , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/imunologia , Células T Invariantes Associadas à Mucosa/metabolismo , Fenótipo , RNA-Seq , Ribitol/análogos & derivados , Ribitol/imunologia , Análise de Célula Única , Baço/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Transcriptoma/genética , Uracila/análogos & derivados , Uracila/imunologia , Vacinas Atenuadas/imunologia
9.
Front Immunol ; 12: 624419, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34140948

RESUMO

Integrin regulation by Rap1 is indispensable for lymphocyte recirculation. In mice having B-cell-specific Rap1a/b double knockouts (DKO), the number of B cells in lymph nodes decreased to approximately 4% of that of control mice, and B cells were present in the spleen and blood. Upon the immunization with NP-CGG, DKO mice demonstrated the defective GC formation in the spleen, and the reduced NP-specific antibody production. In vitro, Rap1 deficiency impaired the movement of activated B cells along the gradients of chemoattractants known to be critical for their localization in the follicles. Furthermore, B-1a cells were almost completely absent in the peritoneal cavity, spleen and blood of adult DKO mice, and the number of B-cell progenitor/precursor (B-p) were reduced in neonatal and fetal livers. However, DKO B-ps normally proliferated, and differentiated into IgM+ cells in the presence of IL-7. CXCL12-dependent migration of B-ps on the VCAM-1 was severely impaired by Rap1 deficiency. Immunostaining study of fetal livers revealed defects in the co-localization of DKO B-ps and IL-7-producing stromal cells. This study proposes that the profound effects of Rap1-deficiency on humoral responses and B-1a cell generation may be due to or in part caused by impairments of the chemoattractant-dependent positioning and the contact with stromal cells.


Assuntos
Linfócitos B/metabolismo , Quimiotaxia de Leucócito , Centro Germinativo/metabolismo , Proteínas rap de Ligação ao GTP/metabolismo , Proteínas rap1 de Ligação ao GTP/metabolismo , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Quimiocina CXCL12/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Centro Germinativo/citologia , Centro Germinativo/efeitos dos fármacos , Centro Germinativo/imunologia , Imunidade Humoral , Imunização , Molécula 1 de Adesão Intercelular/metabolismo , Fígado/imunologia , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Precursoras de Linfócitos B/imunologia , Células Precursoras de Linfócitos B/metabolismo , Baço/imunologia , Baço/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , gama-Globulinas/farmacologia , Proteínas rap de Ligação ao GTP/genética , Proteínas rap1 de Ligação ao GTP/genética
10.
Diabetes ; 70(6): 1303-1316, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34162682

RESUMO

Adiponectin is an adipokine that exerts insulin-sensitizing and anti-inflammatory roles in insulin target tissues including liver. While the insulin-sensitizing function of adiponectin has been extensively investigated, the precise mechanism by which adiponectin alleviates diet-induced hepatic inflammation remains elusive. Here, we report that hepatocyte-specific knockout (KO) of the adaptor protein APPL2 enhanced adiponectin sensitivity and prevented mice from developing high-fat diet-induced inflammation, insulin resistance, and glucose intolerance, although it caused fatty liver. The improved anti-inflammatory and insulin-sensitizing effects in the APPL2 hepatocyte-specific KO mice were largely reversed by knocking out adiponectin. Mechanistically, hepatocyte APPL2 deficiency enhances adiponectin signaling in the liver, which blocks TNF-α-stimulated MCP-1 expression via inhibiting the mTORC1 signaling pathway, leading to reduced macrophage infiltration and thus reduced inflammation in the liver. With results taken together, our study uncovers a mechanism underlying the anti-inflammatory role of adiponectin in the liver and reveals the hepatic APPL2-mTORC1-MCP-1 axis as a potential target for treating overnutrition-induced inflammation in the liver.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Adiponectina/fisiologia , Hepatite/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Movimento Celular/genética , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Regulação para Baixo/genética , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Hepatite/imunologia , Hepatite/metabolismo , Hepatite/patologia , Hepatócitos/metabolismo , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Resistência à Insulina/genética , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Knockout
11.
Fish Shellfish Immunol ; 116: 19-29, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34153428

RESUMO

Streptococcus agalactiae is one of the most important pathogens infecting tilapia worldwide and causes meningoencephalitis, septicemia and high mortalities with considerable losses. Various types of vaccines have been developed against S. agalactiae infection, such as inactivated vaccines, live attenuated vaccines and subunit vaccines. Bacterial ghosts (BGs) are nonliving, empty cell envelopes and have been reported as novel vaccine candidates. Therefore, the main aims of this study were to develop an S. agalactiae ghost vaccine (SAGV) and to evaluate the immune response and protective effect of SAGV against S. agalactiae with two novel adjuvants, Montanide™ ISA 763B VG and Montanide™ GEL02. Nile tilapia, mean weight 50 g, were divided into four groups as follows; 1) fish injected with PBS as control, 2) fish injected with the SAGV alone; 3) fish injected with the SAGV+Montanide™ ISA 763B VG; and 4) fish injected with SAGV+Montanide™ GEL02. Following vaccination, innate immunity parameters including serum lysozyme, myeloperoxidase, catalase, and bactericidal activity were all significantly enhanced. Moreover, specific serum IgM antibodies were induced and reached their highest level 2-8 weeks post vaccination. Importantly, the relative percent survival of tilapia vaccinated against the SAGV formulated with both adjuvants was 80-93%. Furthermore, the transcription of immune-related genes (IgM, TCRß, IL-1ß, IL-8 and TNFα) were up-regulated in tilapia after vaccination, indicating that both cellular and humoral immune responses were induced by these adjuvanted vaccines. In summary, Montanide™ ISA 763B VG and Montanide™ GEL02 can enhance immunoprotection induced by the SAGV vaccine against streptococcosis, demonstrating that both have value as potential adjuvants of fish vaccines.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Ciclídeos/imunologia , Doenças dos Peixes/prevenção & controle , Manitol/análogos & derivados , Manitol/administração & dosagem , Infecções Estreptocócicas/prevenção & controle , Vacinas Estreptocócicas/administração & dosagem , Streptococcus agalactiae/imunologia , Animais , Anticorpos Antibacterianos/sangue , Catalase/sangue , Ciclídeos/sangue , Doenças dos Peixes/sangue , Doenças dos Peixes/imunologia , Proteínas de Peixes/sangue , Fígado/imunologia , Muramidase/sangue , Peroxidase/sangue , Baço/imunologia , Infecções Estreptocócicas/sangue , Infecções Estreptocócicas/imunologia
12.
Medicine (Baltimore) ; 100(25): e26243, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160387

RESUMO

RATIONALE: Eszopiclone, sold under the brand name Lunesta, is a new type of non-benzodiazepine hypnotic. Eszopiclone is a zopiclone dextrorotation, which is classified as a cyclopyrrolone. It functions by binding gamma-aminobutyric acid (GABA) receptors. Compared with benzodiazepines hypnotics, eszopiclone has higher selectivity for certain subunits of the GABA(A) receptor. So far, there are no reports about the elevation of serum enzymes or severe liver injury caused by eszopiclone. Here, we present a case report of acute liver injury following eszopiclone treatment in a patient with chronic hepatitis B virus (HBV). PATIENT CONCERNS: The patient was a 53-year-old female with a 36-year history of positive HBV markers. Due to poor sleep, the patient took trazodone hydrochloride orally for 1 year. After hospital admission for positive hepatitis B pathogenic markers, abdominal distension, fatigue, and aggravation, she was treated with eszopiclone under the guidance of the mental health department. DIAGNOSES: Her transaminase levels increased abnormally after eszopiclone treatment and rapidly decreased after drug withdrawal. This was determined to be an acute liver injury event. liver-protecting treatment was maintained. Considering the patient's anxiety and depression, the patient's family members refused a liver biopsy. OUTCOMES: Transaminase levels decreased rapidly within one week, and the patient continued to take trazodone hydrochloride after discharge. No adverse events occurred in the follow-up period. LESSONS: Sleep disorders are more common in patients with chronic diseases, especially patients with chronic liver disease. Recently, it has become common for patients with hepatitis B and C to use antidepressants along with antiviral treatment. Patients with chronic hepatitis B or C may have a threefold risk of liver dysfunction after receiving antituberculosis treatment.[1,2] A proinflammatory environment induced by actively replicating the hepatitis virus may alter the detoxication process and increase drug toxicity.[3] At this time, the safety of other drugs should be reevaluated. Although hepatitis and liver injury are listed as rare adverse reactions of eszopiclone, this case is the first to report the eszopiclone-involved acute liver injury.


Assuntos
Compostos Azabicíclicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Hepatite B Crônica/complicações , Piperazinas/efeitos adversos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feminino , Vírus da Hepatite B/imunologia , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/imunologia , Testes de Função Hepática , Pessoa de Meia-Idade , Distúrbios do Início e da Manutenção do Sono/etiologia
13.
Nat Commun ; 12(1): 3543, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112803

RESUMO

Metastatic spread of a cancer to secondary sites is a coordinated, non-random process. Cancer cell-secreted vesicles, especially exosomes, have recently been implicated in the guidance of metastatic dissemination, with specific surface composition determining some aspects of organ-specific localization. Nevertheless, whether the tumor microenvironment influences exosome biodistribution has yet to be investigated. Here, we show that microenvironmental cytokines, particularly CCL2, decorate cancer exosomes via binding to surface glycosaminoglycan side chains of proteoglycans, causing exosome accumulation in specific cell subsets and organs. Exosome retention results in changes in the immune landscape within these organs, coupled with a higher metastatic burden. Strikingly, CCL2-decorated exosomes are directed to a subset of cells that express the CCL2 receptor CCR2, demonstrating that exosome-bound cytokines are a crucial determinant of exosome-cell interactions. In addition to the finding that cytokine-conjugated exosomes are detected in the blood of cancer patients, we discovered that healthy subjects derived exosomes are also associated with cytokines. Although displaying a different profile from exosomes isolated from cancer patients, it further indicates that specific combinations of cytokines bound to exosomes could likewise affect other physiological and disease settings.


Assuntos
Neoplasias da Mama/sangue , Quimiocina CCL2/metabolismo , Exossomos/metabolismo , Receptores CCR2/metabolismo , Microambiente Tumoral , Animais , Neoplasias da Mama/patologia , Citocinas/metabolismo , Exossomos/imunologia , Exossomos/patologia , Feminino , Glicosaminoglicanos/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Proteoglicanas/metabolismo , Receptores de Citocinas/metabolismo , Baço/imunologia , Baço/metabolismo , Baço/patologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
14.
Front Immunol ; 12: 535012, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093514

RESUMO

Rejection after organ transplantation is a cause of graft failure. Effectively reducing rejection and inducing tolerance is a challenge in the field of transplantation immunology. The liver, as an immunologically privileged organ, has high rates of spontaneous and operational tolerance after transplantation, allowing it to maintain its normal function for long periods. Although modern immunosuppression regimens have serious toxicity and side effects, it is very risky to discontinue immunosuppression regimens blindly. A more effective treatment to induce immune tolerance is the most sought-after goal in transplant medicine. Tregs have been shown to play a pivotal role in the regulation of immune balance, and infusion of Tregs can also effectively prevent rejection and cure autoimmune diseases without significant side effects. Given the immune characteristics of the liver, the correct use of Tregs can more effectively induce the occurrence of operational tolerance for liver transplants than for other organ transplants. This review mainly summarizes the latest research advances regarding the characteristics of the hepatic immune microenvironment, operational tolerance, Treg generation in vitro, and the application of Tregs in liver transplantation. It is hoped that this review will provide a deeper understanding of Tregs as the most effective treatment to induce and maintain operational tolerance after liver transplantation.


Assuntos
Pesquisa Biomédica/métodos , Tolerância Imunológica/imunologia , Transplante de Fígado/métodos , Linfócitos T Reguladores/imunologia , Imunologia de Transplantes/imunologia , Tolerância ao Transplante/imunologia , Pesquisa Biomédica/tendências , Previsões , Rejeição de Enxerto/imunologia , Humanos , Fígado/imunologia
15.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071550

RESUMO

Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients' lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.


Assuntos
Carcinoma Hepatocelular/terapia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva/métodos , Neoplasias Hepáticas/terapia , Fígado/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Animais , Carcinoma Hepatocelular/imunologia , Humanos , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/imunologia , Recidiva Local de Neoplasia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
16.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34071962

RESUMO

Alcoholic liver disease (ALD) is a globally prevalent chronic liver disease caused by chronic or binge consumption of alcohol. The liver is the major organ that metabolizes alcohol; therefore, it is particularly sensitive to alcohol intake. Metabolites and byproducts generated during alcohol metabolism cause liver damage, leading to ALD via several mechanisms, such as impairing lipid metabolism, intensifying inflammatory reactions, and inducing fibrosis. Despite the severity of ALD, the development of novel treatments has been hampered by the lack of animal models that fully mimic human ALD. To overcome the current limitations of ALD studies and therapy development, it is necessary to understand the molecular mechanisms underlying alcohol-induced liver injury. Hence, to provide insights into the progression of ALD, this review examines previous studies conducted on alcohol metabolism in the liver. There is a particular focus on the occurrence of ALD caused by hepatotoxicity originating from alcohol metabolism.


Assuntos
Etanol/metabolismo , Inativação Metabólica , Fígado/metabolismo , Animais , Suscetibilidade a Doenças , Hepatócitos/metabolismo , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunomodulação , Metabolismo dos Lipídeos , Fígado/imunologia , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Redes e Vias Metabólicas , Oxirredução , Espécies Reativas de Oxigênio , Sensibilidade e Especificidade
17.
J Vet Sci ; 22(3): e34, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34056875

RESUMO

Anti-lipopolysaccharide (LPS) antibody administration has the potential benefits of neutralizing and consequently controlling rumen-derived LPS during subacute ruminal acidosis. Four Holstein bulls were used in this crossover study with a 2-week wash-out period. Anti-LPS antibody (0 or 4 g) was administered once daily for 14 days. Significantly lower ruminal LPS and higher 1-h mean ruminal pH were identified in the 4 g group. However, blood metabolites, acute-phase proteins, cytokines, and hepatic transcriptomes were not different between the two groups. Therefore, anti-LPS antibody administration mitigated ruminal LPS release and pH depression without accompanying responses in acute-phase inflammation or hepatic transcriptomic expression.


Assuntos
Acidose/veterinária , Reação de Fase Aguda/imunologia , Doenças dos Bovinos/imunologia , Fermentação/efeitos dos fármacos , Imunoglobulinas/administração & dosagem , Lipopolissacarídeos/metabolismo , Rúmen/efeitos dos fármacos , Acidose/imunologia , Acidose/metabolismo , Animais , Bovinos , Doenças dos Bovinos/metabolismo , Fígado/imunologia , Fígado/metabolismo , Masculino , Rúmen/metabolismo , Transcriptoma
18.
Nat Med ; 27(6): 1043-1054, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34017133

RESUMO

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions that underlie the development of life-threatening cirrhosis, liver failure and liver cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single-cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH. We identified a significant pathology-associated increase in hepatic conventional dendritic cells (cDCs) and further defined their source as NASH-induced boost in cycling of cDC progenitors in the bone marrow. Analysis of blood and liver from patients on the NAFLD/NASH spectrum showed that type 1 cDCs (cDC1) were more abundant and activated in disease. Sequencing of physically interacting cDC-T cell pairs from liver-draining lymph nodes revealed that cDCs in NASH promote inflammatory T cell reprogramming, previously associated with NASH worsening. Finally, depletion of cDC1 in XCR1DTA mice or using anti-XCL1-blocking antibody attenuated liver pathology in NASH mouse models. Overall, our study provides a comprehensive characterization of cDC biology in NASH and identifies XCR1+ cDC1 as an important driver of liver pathology.


Assuntos
Células Dendríticas/imunologia , Fígado Gorduroso/imunologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Receptores de Quimiocinas/genética , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Reprogramação Celular/genética , Reprogramação Celular/imunologia , Células Dendríticas/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Feminino , Humanos , Fígado/imunologia , Fígado/patologia , Linfonodos/imunologia , Linfonodos/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores de Quimiocinas/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia
19.
Aging (Albany NY) ; 13(9): 12929-12954, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952716

RESUMO

Liver hepatocellular carcinoma (LIHC) remains one of the most common causes of cancer death. Prior research suggested that the PPM1G gene is involved in LIHC. To explore the role of PPM1G in LIHC, we used several online databases. Expression profiling was performed via the Gene Expression Profiling Interactive Analysis (GEPIA), Hepatocellular Carcinoma Database (HCCDB), Oncomine and Human Protein Atlas (HPA) platforms. Mutation profiles were investigated via cBio Cancer Genomics Portal (cBioPortal). Survival analysis was performed via the Kaplan-Meier (KM) plotter and International Cancer Genome Consortium (ICGC) platforms. The biological function of PPM1G was analyzed via the Enrichr database. The influence of PPM1G expression in the tumor immune microenvironment was assessed via Tumor Immune Estimation Resource (TIMER). PPM1G expression was upregulated in various tumors, including LIHC. Overexpression of PPM1G was associated with poor prognosis in LIHC. PPM1G expression might be regulated by promoter methylation, copy number variations (CNVs) and kinases and correlate with immune infiltration. The gene ontology (GO) terms associated with high PPM1G expression were mRNA splicing and the cell cycle. The results suggest that PPM1G is correlated with the prognosis of LIHC patients and associated with the tumor immune microenvironment in LIHC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/mortalidade , Proteína Fosfatase 2C/genética , Microambiente Tumoral/imunologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Variações do Número de Cópias de DNA , Metilação de DNA , Análise Mutacional de DNA , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/imunologia , Redes Reguladoras de Genes/imunologia , Humanos , Estimativa de Kaplan-Meier , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Mutação , Prognóstico , Regiões Promotoras Genéticas/genética , Microambiente Tumoral/genética , Regulação para Cima/imunologia
20.
Int J Biol Macromol ; 183: 1379-1392, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33992651

RESUMO

Gut microbiota and intestinal permeability have been demonstrated to be the key players in the gut-liver cross talk in nonalcoholic fatty liver disease (NAFLD). Lycium barbarum polysaccharides (LBPs), which seem to be a potential prebiotic, and aerobic exercise (AE) have shown protective effects on NAFLD. However, their combined effects on intestinal microecology remain unclear. This study evaluated the effects of LBP, AE, and its combination (LBP + AE) on gut microbiota composition, intestinal barrier, and hepatic inflammation in NAFLD. LBP + AE showed high abundance and diversity of gut microbiota, restored the gut microbiota composition, increased some Bacteroidetes, short chain fatty acids, but decreased Proteobacteria and the ratio of Firmicutes/Bacteroidetes. Simultaneously, LBP, AE, and LBP + AE could restore the colonic and ileum tight junctions by increasing the expression of zonula occludens-1 and occludin. They also downregulated gut-derived lipopolysaccharides (LPSs), hepatic LPS-binding proteins, inflammatory factors, and related indicators of the LPS/TLR4/NF-κB signaling pathway for the liver. Our results implied that LBP could be considered a prebiotic agent, and LBP + AE might be a promising treatment for NAFLD because it could maintain gut microbiota balance, thereby restoring intestinal barrier and exerting hepatic benefits.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/terapia , Condicionamento Físico Animal/métodos , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/microbiologia , Inflamação/terapia , Mucosa Intestinal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/imunologia , Hepatopatia Gordurosa não Alcoólica/microbiologia , Prebióticos
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