RESUMO
Dictamni Cortex, the dried root bark of Dictamnus dasycarpus, has many chemical constituents, such as alkaloids, limonoids, flavonoids, sesquiterpenoids, glycosides, and steroids.It has the effects of anti-inflammation, anti-fungi, anti-arteriosclerosis, stopping bleeding, anti-cancer, neuroprotection, and antioxidation.The chemical constituents of Dictamni Cortex are the important material basis for its medicinal effects.This paper reviewed the chemical constituents and pharmacological activities of Dictamni Cortex and analyzed the research trend and present research progress on this medicinal, with a view to its further development and utilization.
Assuntos
Alcaloides , Dictamnus , Medicamentos de Ervas Chinesas , Limoninas , Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Medicamentos de Ervas Chinesas/farmacologiaRESUMO
In this work, by combining the superiority of polyoxometalates (POMs) and catalytic single-metal site Co of metalloporphyrin, a series of mixed-valence POM-based metal-organic frameworks (MOFs) composites is synthesized by a post-modification method. The electron-transfer property of POM@PCN-222(Co) composite is significantly enhanced owing to the directional electron-transfer from POM to single-metal site Co in PCN-222(Co). In particular, H-POM@PCN-222(Co) gives a high Faradaic efficiency of 96.2% for electroreduction of CO2 into CO and good stability over 10 h. DFT calculations confirm that the directional electron transfer, which accelerates the multi-electron transfer from the electrode to active single-metal site Co, enriches the electron density of the Co center, and ultimately reduces the energy of the rate-determining step, thus increasing the catalytic activity of CO2 reduction reaction (CO2 RR). This work therefore suggests some new insight for the design of efficient electrocatalysts for CO2 RR.
RESUMO
Gut microbiota and bacterial translocation have been implicated as significant contributors to mucosal immune responses and tolerance; alteration of microbial molecules, termed pathogen-associated molecular patterns (PAMP) and bacterial translocation are associated with immune pathology. However, the mechanisms by which dysregulated gut microbiota promotes autoimmunity is unclear. We have taken advantage of a well-characterized murine model of primary biliary cholangitis, dnTGFßRII mice, and an additional unique construct, toll-like receptor 2 (TLR2)-deficient dnTGFßRII mice coined dnTGFßRIITLR2-/- mice to investigate the influences of gut microbiota on autoimmune cholangitis. Firstly, we report that dnTGFßRII mice manifest altered composition of gut microbiota and that alteration of this gut microbiota by administration of antibiotics significantly alleviates T-cell-mediated infiltration and bile duct damage. Second, toll-like receptor 2 (TLR2)-deficient dnTGFßRII mice demonstrate significant exacerbation of autoimmune cholangitis when their epithelial barrier integrity was disrupted. Further, TLR2-deficiency mediates downregulated expression of tight junction-associated protein ZO-1 leading to increased gut permeability and bacterial translocation from gut to liver; use of antibiotics reduces microbiota translocation to liver and also decreases biliary pathology. In conclusion, our data demonstrates the important role of gut microbiota and bacterial translocation in the pathogenesis of murine autoimmune cholangitis.
Assuntos
Doenças Autoimunes/microbiologia , Translocação Bacteriana/imunologia , Ductos Biliares/imunologia , Cirrose Hepática Biliar/imunologia , Receptor do Fator de Crescimento Transformador beta Tipo II/imunologia , Receptor 2 Toll-Like/imunologia , Ampicilina/farmacologia , Animais , Antibacterianos/farmacologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Translocação Bacteriana/efeitos dos fármacos , Ductos Biliares/efeitos dos fármacos , Ductos Biliares/microbiologia , Ductos Biliares/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/microbiologia , Colo/patologia , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Regulação da Expressão Gênica , Imunidade nas Mucosas/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/microbiologia , Fígado/patologia , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/microbiologia , Cirrose Hepática Biliar/patologia , Metronidazol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neomicina/farmacologia , Receptor do Fator de Crescimento Transformador beta Tipo II/deficiência , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Transdução de Sinais , Receptor 2 Toll-Like/deficiência , Receptor 2 Toll-Like/genética , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/imunologiaRESUMO
CXC Chemokine Receptor 3 (CXCR3) is functionally pleiotropic and not only plays an important role in chemotaxis, but also participates in T cell differentiation and may play a critical role in inducing and maintaining immune tolerance. These observations are particularly critical for autoimmune cholangitis in which CXCR3 positive T cells are found around the portal areas of both humans and mouse models of primary biliary cholangitis (PBC). Herein, we investigated the role of CXCR3 in the pathogenesis of autoimmune cholangitis. We have taken advantage of a unique CXCR3 knockout dnTGFßRII mouse to focus on the role of CXCR3, both by direct observation of its influence on the natural course of disease, as well as through adoptive transfer studies into Rag-/- mice. We report herein that not only do CXCR3 deficient mice develop an exacerbation of autoimmune cholangitis associated with an expanded effector memory T cell number, but also selective adoptive transfer of CXCR3 deficient CD8+ T cells induces autoimmune cholangitis. In addition, gene microarray analysis of CXCR3 deficient CD8+ T cells reveal an intense pro-inflammatory profile. Our data suggests that the altered gene profiles induced by CXCR3 deficiency promotes autoimmune cholangitis through pathogenic CD8+ T cells. These data have significance for human PBC and other autoimmune liver diseases in which therapeutic intervention might be directed to chemokines and/or their receptors.
Assuntos
Autoimunidade/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/imunologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Receptores CXCR3/deficiência , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Memória Imunológica , Ligantes , Cirrose Hepática Biliar/metabolismo , Cirrose Hepática Biliar/patologia , Camundongos , Camundongos Knockout , Receptores CXCR3/metabolismoRESUMO
Squalene synthase of Alisma orientale catalyzes farnesyl diphosphate (FPP) to form squalene, which is the key regulatory enzyme of the carbon source flow to protostane triterpenes biosynthesis. For further research on the function and expression of AoSS gene, the open reading frame (ORF) of squalene synthase gene (accession no. JX866770) from A. orientale was subcloned into a prokaryotic expression vector pCzn1 and induced the expression of AoSS gene in Escherichia coli BL21(Roseta). The fusion protein was mainly in the form of inclusion bodies and purified to obtain high purity protein. By verifying its functionality through vitro enzymatic reaction, the results showed that the catalytic protein had the catalytic activity of FPP into squalene. In order to research the expression of AoSS in A. orientale, the purified protein was used to immunized rabbits to prepare polyclonal antibody which was then purified, the titer of the antibody was greater than 1â¶51 200 by ELISA detection, and displayed good specificity by Western blotting. The prepared antibody was used for immunoassay of AoSS in different organs of A. orientale, and the results showed that the AoSS expression level was the highest in tubers, followed by leaves, and lowest in root. Successful construction of prokaryotic expression vector, validation of gene functions and establishment of rapid immunoassay lay the foundation for further researches on the function and regulation of AoSS gene, and also provide scientific basis on the application of the protostane triterpenes of A. orientale in the field of synthetic biology.
Assuntos
Alisma/enzimologia , Farnesil-Difosfato Farnesiltransferase/metabolismo , Sequência de Aminoácidos , Animais , Clonagem Molecular , Farnesil-Difosfato Farnesiltransferase/genética , Folhas de Planta/química , Raízes de Plantas/química , Tubérculos/química , Coelhos , Proteínas Recombinantes de Fusão/biossíntese , EsqualenoRESUMO
OBJECTIVES: Ranunculus L. genus contains 413 species, and it is the biggest genus in the family Ranunculaceae Juss. This review is to provide botanical characteristics, traditional uses, phytochemistry, pharmacology, toxicity, and pharmaceutical preparations of the genus Ranunculus. KEY FINDINGS: The genus Ranunculus contains flavonoids, organic acids, coumarins, lactones, glycosides, sterols, polysaccharides, and trace elements. These chemical constituents complement the pharmacological actions and work together to exert anti-inflammatory, anticancer, antitubercular, antibacterial, antimalarial, etc. Those traditional Chinese medicine characteristics, like clearing away heat and detoxification, make this genus significant in ethnic medicine. The progress in research and the development of various pharmaceutical preparations made it appear in epidemiological and clinical studies. SUMMARY: The genus Ranunculus has attracted the attention of experts and scholars in many fields due to its unique advantages. However, there are many species that are not scientifically investigated. The toxicity issues are also a huge concern. Fortunately, the toxicity can be overcome via special processes like drying or heating and by choosing a safe extraction solvent, such as water thus ensuring the safety of medication. Pharmaceutical preparations containing the plants from Ranunculus have gratifying clinical value, but they are not promoted sufficiently. Therefore, further research should be carried out to promote the genus for its health benefits to humans.
Assuntos
Ranunculus , Ranunculus/química , Humanos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/toxicidade , Compostos Fitoquímicos/isolamento & purificação , Animais , Medicina Tradicional Chinesa/métodos , Ásia , Fitoterapia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/toxicidade , Extratos Vegetais/farmacologia , Extratos Vegetais/toxicidade , Extratos Vegetais/química , EtnofarmacologiaRESUMO
BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common malignant endocrine tumour, and its incidence and prevalence are increasing considerably. Cellular heterogeneity in the tumour microenvironment is important for PTC prognosis. Spatial transcriptomics is a powerful technique for cellular heterogeneity study. METHODS: In conjunction with a clinical pathologist identification method, spatial transcriptomics was employed to characterise the spatial location and RNA profiles of PTC-associated cells within the tissue sections. The spatial RNA-clinical signature genes for each cell type were extracted and applied to outlining the distribution regions of specific cells on the entire section. The cellular heterogeneity of each cell type was further revealed by ContourPlot analysis, monocle analysis, trajectory analysis, ligand-receptor analysis and Gene Ontology enrichment analysis. RESULTS: The spatial distribution region of tumour cells, typical and atypical follicular cells (FCs and AFCs) and immune cells were accurately and comprehensively identified in all five PTC tissue sections. AFCs were identified as a transitional state between FCs and tumour cells, exhibiting a higher resemblance to the latter. Three tumour foci were shared among all patients out of the 13 observed. Notably, tumour foci No. 2 displayed elevated expression levels of genes associated with lower relapse-free survival in PTC patients. We discovered key ligand-receptor interactions, including LAMB3-ITGA2, FN1-ITGA3 and FN1-SDC4, involved in the transition of PTC cells from FCs to AFCs and eventually to tumour cells. High expression of these patterns correlated with reduced relapse-free survival. In the tumour immune microenvironment, reduced interaction between myeloid-derived TGFB1 and TGFBR1 in tumour focus No. 2 contributed to tumourigenesis and increased heterogeneity. The spatial RNA-clinical analysis method developed here revealed prognosis-associated cellular heterogeneity in the PTC microenvironment. CONCLUSIONS: The occurrence of tumour foci No. 2 and three enhanced ligand-receptor interactions in the AFC area/tumour foci reduced the relapse-free survival of PTC patients, potentially leading to improved prognostic strategies and targeted therapies for PTC patients.
Assuntos
Neoplasias da Glândula Tireoide , Humanos , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Ligantes , Microambiente Tumoral/genética , Recidiva Local de Neoplasia , Perfilação da Expressão Gênica , Prognóstico , RNARESUMO
Background: Thyroid tissue has a special immune microenvironment that is not well characterized. Whether immune cells have a prognostic value in the recurrence of papillary thyroid cancer (PTC) needs further investigation. Methods: Multinodular non-toxic goiter (MNG) was taken as normal tissue for the difficulty in obtaining completely normal thyroid tissue (normal thyroid function, no thyroiditis, and no nodules). We compared the composition of mononuclear cells (MNCs) in peripheral blood and thyroid tissues from MNG and PTC patients by high-dimensional flow cytometry profiling and verified the results by multiplex immunohistochemistry. The recurrence rates of PTC patients with different CD8+T cell subset signatures were compared using TCGA database. Results: We observed that the immune cell composition of MNG was different from that in peripheral blood. Thyroid tissue contains higher percentages of T cells and NK cells. Moreover, the percentages of memory T cells and Treg cells were higher in thyroid than in peripheral blood and increased in PTC tumors. We further focused on the antitumoral CD8+T cells and found that the expression patterns of PD-1, CD39, and CD103 on CD8+T cells were different between MNG and PTC. Importantly, we found higher percentages of PD-1+CD39+CD103+CD8+T and PD-1+CD39+CD103-CD8+T cells in PTC tumor tissues from recurrent patients than non-recurrent patients. By analyzing PTC data from TCGA database, we found that the expression patterns of these molecules were associated with different pathologic types and genders among PTC patients. Moreover, patients with PD-1hiCD39loCD103hiCD8hi, PD-1hiCD39hiCD103loCD8hi, and PD-1loCD39hiCD103hiCD8hi expression patterns have a higher 10-year recurrence-free survival. Conclusion: The immune microenvironment in MNG tissue is distinct from that in peripheral blood and paratumor tissue. More memory CD8+T cells were detected in PTC, and expression patterns of PD-1, CD39, and CD103 on CD8+T cells were significantly different in physiology and gender and associated with the recurrence rate of PTC. These observations indicate that CD8+T cell signatures may be useful prognostic markers for PTC recurrence.
Assuntos
Receptor de Morte Celular Programada 1 , Neoplasias da Glândula Tireoide , Humanos , Feminino , Masculino , Câncer Papilífero da Tireoide/metabolismo , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T CD8-Positivos , Linfócitos T Reguladores , Neoplasias da Glândula Tireoide/patologia , Microambiente TumoralRESUMO
OBJECTIVE: To investigate the relationship between fetal chromosomal karyotype and early spontaneous abortion, and the effect of the environmental factors on spontaneous abortion. METHODS: Choronic villi from 252 cases of missed abortion were sampled as patient group and 50 normal pregnancies as control group. Chorionic villi were cultured and karyotype analysis was performed by G-banding. Clinical information was collected. RESULTS: The rate of chorion chromosome abnormality in the patient group was 58.09%, significantly higher than that in the control group (4.17%) (P<0.01). Among the 140 cases of karyotype abnormalities, 81 were trisomy, 29 were monosomy X and 17 were polyploidy, accounting for 57.86%, 20.71% and 12.14% of total abnormalities, respectively. Long time and low dose radiation exposure of the pregnant female seemed to be related with spontaneous abortion(P<0.01). CONCLUSION: Chorion chromosome abnormality is a major reason of early spontaneous abortion and karyotype analysis of chorionic villus is of clinical importance. For pregnant women, long-term exposure to computers and television seems a risk factor for missed abortion.
Assuntos
Aborto Retido/genética , Aberrações Cromossômicas , Adolescente , Adulto , Estudos de Casos e Controles , Vilosidades Coriônicas/metabolismo , Feminino , Humanos , Cariotipagem , Pessoa de Meia-Idade , Gravidez , Fatores de Risco , Adulto JovemRESUMO
The data demonstrated that a transgenic murine model of primary biliary cholangitis (PBC), expressing dominant negative TGF-ß receptor â ¡ (dnTGFßRâ ¡) under the CD4 promoter, showed similarity to PBC patients that is female-dominant. Female dnTGFßRII mice developed more severe lymphocytic infiltration in the liver and had higher levels of inflammatory cytokines, including IFN-γ and TNF-α, than the male mice. Interestingly, elimination of testosterone through gonadectomy in male dnTGFßRII mice did not influence disease severity, supporting that testosterone is an unessential factor in sustaining liver immune homeostasis. Meanwhile, it was observed that treating dnTGFßRII mice with oral antibiotics markedly reduced the differences in the levels of lymphocytic infiltration and cytokines between males and females, suggesting that the commensal gut microbiome plays a role in determining the observed sexual differences in dnTGFßRII mice. Furthermore, the diversity of gut microbiota composition and their metabolic functions in the male and female groups through metagenomic sequencing analysis were identified. The results revealed a testosterone-independent and commensal gut microbiota-mediated female bias in PBC.
Assuntos
Microbioma Gastrointestinal/fisiologia , Cirrose Hepática Biliar , Caracteres Sexuais , Animais , Doenças Autoimunes , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor do Fator de Crescimento Transformador beta Tipo II/genéticaRESUMO
Macrophages are plastic cells that can switch among different states according to bioenergetic or biosynthetic requirements. Our previous work demonstrated that the transcription factor Forkhead Box Protein 1 (FoxO1) plays a pivotal role in regulating the function of macrophages, but the underlying mechanisms are still unclear. Here we identify FoxO1 as a regulator of macrophage function through metabolic reprogramming. Transcriptomic and proteomic analyses showed that the deficiency of FoxO1 results in an alternatively activated (M2) phenotype of macrophages, with lower expression of inflammatory response- and migration-associated genes. Using the high content screening and analysis technology, we found that deletion of FoxO1 in macrophages slows their migration rate and impairs their function to limit tumor cell growth in vitro. Next, we demonstrated that glycolysis is inhibited in FoxO1-deficient macrophages, which leads to the observed functional changes and the reduced tumor suppression capability. This prospective study shows that FoxO1 serves as a bridge between metabolism and macrophage function.
Assuntos
Biologia Celular/normas , Reprogramação Celular/imunologia , Proteína Forkhead Box O1/metabolismo , Macrófagos/metabolismo , Proteômica/métodos , HumanosRESUMO
OBJECTIVE: To evaluate the clinical value of multiplex ligation-dependent probe amplification (MLPA) technique used in karyotype analysis of chorionic villi from missed abortion. METHODS: Feb 2008 to Oct 2008, 91 patients with missed abortion diagnosed by hormonal measurement, type B ultrasound and physical exam matched with 20 normal pregnant women undergoing artificial abortion were enrolled in this study. Chorionic villi was obtained by suction dilation and curettage in aseptic condition, then those villi was cultured and analyzed by traditional cytogenetic karyotyping method, in the mean time, the DNA extracted from villi was detected by MLPA. The results of chromosomal G-banding of chorionic villi were compared between two methods. RESULTS: The diagnostic concordance of MLPA and traditional karyotyping was observed in 92% (84/91) cases, there were 84 cases in the case group with diagnostic concordance by traditional karyotyping and MLPA except 7 cases of euploidy could not be detected by MLPA. The 84 cases included 40 normal karyotype, 29 trisomy of euchromosome, 1 double trisomy of euchromosome, 10 monosomy X, 1 monosomy X combined with trisomy of euchromosome, 2 chimaera of X chromosome, 1 structural abnormity of euchromosome. Among 7 cases with discordance diagnosis, 2 cases with trisomy and 5 cases with tetrasomy of euchromosome were identified in traditional karyotyping, however, they were all diagnosed with normal disomy by MLPA. Of 20 villi from normal pregnancy, two methods got the consistent results. CONCLUSION: The MLPA was rapid and efficacy method used for analyzing aneuploids in chorionic villi.
Assuntos
Aborto Retido/genética , Amostra da Vilosidade Coriônica/métodos , Aberrações Cromossômicas , Cariotipagem , Técnicas de Amplificação de Ácido Nucleico/métodos , Adulto , Citogenética , Feminino , Humanos , Gravidez , Diagnóstico Pré-Natal/métodos , Sensibilidade e Especificidade , Trissomia/genética , Adulto JovemRESUMO
Macrophages are a critical component in host immune responses against tumor. In this work we investigated the role of forkhead box O1 (FoxO1) in the transcriptional regulation in macrophages, which affects the anti-tumor functions of tumor-associated macrophages (TAMs). First, we showed that TAMs expressed reduced levels of FoxO1, which was associated with their protumoral M2 polarization state. The suppression of FoxO1 expression in TAM was induced by the hypoxic condition in the tumor microenviroment. Next, we confirmed that FoxO1 positively regulates MHC-II genes by binding to the promoter region of Ciita gene, the master activator of multiple MHC-II genes. Loss of FoxO1 in TAMs resulted in reduced MHC-II expression. Furthermore, we used FoxO1 conditional knockout mice to show that FoxO1 deficiency in myeloid cells exacerbates tumor growth. These results demonstrate that the protumoral property of TAMs is induced by the hypoxia-triggered FoxO1 deficiency, which could be a potential target of novel anti-tumor therapies.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/fisiologia , Genes MHC da Classe II , Macrófagos/patologia , Melanoma/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Proteína Forkhead Box O1/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia/fisiopatologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Macrófagos/metabolismo , Melanoma/genética , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Prognóstico , Regiões Promotoras Genéticas , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Transativadores/genética , Transativadores/metabolismo , Células Tumorais CultivadasRESUMO
CXC chemokine receptor 3 (CXCR3), a receptor for the C-X-C motif chemokines (CXCL) CXCL9, CXCL10, and CXCL11, which not only plays a role in chemotaxis but also regulates differentiation and development of memory and effector T cell populations. Herein, we explored the function of CXCR3 in the modulation of different organ-specific autoimmune diseases in interleukin (IL)-2 receptor deficiency (CD25-/-) mice, a murine model for both cholangitis and colitis. We observed higher levels of CXCL9 and CXCL10 in the liver and colon and higher expression of CXCR3 on T cells of the CD25-/- mice compared with control animals. Deletion of CXCR3 resulted in enhanced liver inflammation but alleviated colitis. These changes in liver and colon pathology after CXCR3 deletion were associated with increased numbers of hepatic CD4+ and CD8+ T cells, in particular effector memory CD8+ T cells, as well as decreased T cells in mesenteric lymph nodes and colon lamina propria. In addition, increased interferon-γ response and decreased IL-17A response was observed in both liver and colon after CXCR3 deletion. CXCR3 modulated the functions of T cells involved in different autoimmune diseases, whereas the consequence of such modulation was organ-specific regarding to their effects on disease severity. Our findings emphasize the importance of extra caution in immunotherapy for organ-specific autoimmune diseases, as therapeutic interventions aiming at a target such as CXCR3 for certain disease could result in adverse effects in an unrelated organ.
Assuntos
Doenças Autoimunes/etiologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Colangite/etiologia , Colite/etiologia , Receptores CXCR3/metabolismo , Animais , Doenças Autoimunes/metabolismo , Biomarcadores , Colangite/metabolismo , Colangite/patologia , Colite/metabolismo , Colite/patologia , Colo/metabolismo , Modelos Animais de Doenças , Deleção de Genes , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Mediadores da Inflamação/metabolismo , Ligantes , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Knockout , Receptores CXCR3/genéticaRESUMO
Sorafenib is a kinase inhibitor approved for the treatment of primary kidney cancer, advanced primary liver cancer, and radioactive iodine resistant advanced thyroid carcinoma. However, sorafenib usually causes serious side effects, which limit its antitumor effect. Nanoparticle based drug delivery systems have been widely used to enhance the therapeutic effects and reduce the side effects of this drug by the enhanced permeability and retention (EPR) effect. Herein, to improve the therapeutic effect of sorafenib, we developed poly(ethylene glycol)-b-poly(lactic acid-co-glycolic acid) (PEG-PLGA) based nanoparticles by a dialysis method for sorafenib encapsulation. After intravenous injection of the sorafenib loaded nanoparticles (NPsorafenib), the tumor growth of mice bearing B16-F10, MC38 and LLC tumor was significantly inhibited. Meanwhile, the dose of sorafenib was reduced to one ninth and the side effects on the hematopoietic system and immune system were abrogated. More importantly, the tumor growth inhibition effect of NPsorafenib was dramatically reduced in B16-F10 bearing Rag1-/- mice which are adaptive immune cell defective, indicating that the antitumor effects of NPsorafenib are dependent on the adaptive immune cells. These results emphasize the indispensable role of the adaptive immune system in nano-drug mediated antitumor effects and the adaptive immune system should be considered as an important factor for clinical applications.
Assuntos
Antineoplásicos/administração & dosagem , Imunidade Celular/efeitos dos fármacos , Nanopartículas/química , Neoplasias Experimentais/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Proteínas de Homeodomínio/metabolismo , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/farmacocinética , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Poliésteres/química , Polietilenoglicóis/química , SorafenibeRESUMO
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the destruction of interlobular biliary ductules, which progressively leads to cholestasis, hepatic fibrosis, cirrhosis, and eventually liver failure. Several mouse models have been used to clarify the pathogenesis of PBC and are generally considered reflective of an autoimmune cholangitis. Most models focus on issues of molecular mimicry between the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial autoantigen of PBC and xenobiotic cross reactive chemicals. None have focused on the classic models of breaking tolerance, namely immunization with self-tissue. Here, we report a novel mouse model of autoimmune cholangitis via immunization with syngeneic bile duct protein (BDP). Our results demonstrate that syngeneic bile duct antigens efficiently break immune tolerance of recipient mice, capturing several key features of PBC, including liver-specific inflammation focused on portal tract areas, increased number and activation state of CD4 and CD8 T cells in the liver and spleen. Furthermore, the germinal center (GC) responses in the spleen were more enhanced in our mouse model. Finally, these mice were 100% positive for anti-mitochondrial antibodies (AMAs). In conclusion, we developed a novel mouse model of PBC that may help to elucidate the detailed mechanism of this complex disease.
Assuntos
Autoantígenos , Doenças Autoimunes , Ductos Biliares , Colangite , Imunização , Animais , Autoantígenos/imunologia , Autoantígenos/toxicidade , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Ductos Biliares/imunologia , Ductos Biliares/patologia , Colangite/induzido quimicamente , Colangite/imunologia , Colangite/patologia , Modelos Animais de Doenças , Feminino , CamundongosRESUMO
Molecular mechanisms that modulate liver regeneration are of critical importance for a number of hepatic disorders. Kupffer cells and natural killer (NK) cells are two cell subsets indispensable for liver regeneration. We have focused on these two populations and, in particular, the interplay between them. Importantly, we demonstrate that deletion of the myeloid phosphatase and tensin homolog on chromosome 10 (PTEN) leading to an M2-like polarization of Kupffer cells, which results in decreased activation of NK cells. In addition, PTEN-deficient Kupffer cells secrete additional factors that facilitate the proliferation of hepatocytes. In conclusion, PTEN is critical for inhibiting M2-like polarization of Kupffer cells after partial hepatectomy, resulting in NK cell activation and thus the inhibition of liver regeneration. Furthermore, PTEN reduces growth factor secretion by Kupffer cells. Our results suggest that targeting PTEN on Kupffer cells may be useful in altering liver regeneration in patients undergoing liver resection.
Assuntos
Regeneração Hepática , Células Mieloides/metabolismo , PTEN Fosfo-Hidrolase/deficiência , Animais , Polaridade Celular , Hepatectomia , Hepatócitos/metabolismo , Células Matadoras Naturais/metabolismo , Células de Kupffer , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitógenos/metabolismo , Modelos Biológicos , PTEN Fosfo-Hidrolase/metabolismoRESUMO
The functions of macrophages that lead to effective host responses are critical for protection against Staphylococcus aureus. Deep tissue-invading S. aureus initially countered by macrophages trigger macrophage accumulation and induce inflammatory responses through surface receptors, especially toll-like receptor 2 (TLR2). Here, we found that macrophages formed sporadic aggregates in the liver during infection. Within those aggregates, macrophages co-localized with T cells and were indispensable for their infiltration. In addition, we have focused on the mechanisms underlying the polarization of macrophages in Forkhead box transcription factor O1 (FoxO1) conditional knockout Lys Cre/+ FoxO1 fl/fl mice following S. aureus infection and report herein that macrophage M1-M2 polarization via TLR2 is intrinsically regulated by FoxO1. Indeed, for effective FoxO1 activity, stimulation of TLR2 is essential. However, following S. aureus challenge, there was a decrease in macrophage FoxO1, with increased phosphorylation of FoxO1 because of TLR2-mediated activation of PI3K/Akt and c-Raf/MEK/ERK pathway. Following infection in Lys Cre/+ FoxO1 fl/fl mice, mice became more susceptible to S. aureus with reduced macrophage aggregation in the liver and attenuated Th1 and Th17 responses. FoxO1 abrogation reduced M1 pro-inflammatory responses triggered by S. aureus and enhanced M2 polarization in macrophages. In contrast, overexpression of FoxO1 in macrophages increased pro-inflammatory mediators and functional surface molecule expression. In conclusion, macrophage FoxO1 is critical to promote M1 polarization and maintain a competent T cell immune response against S. aureus infection in the liver. FoxO1 regulates macrophage M1-M2 polarization downstream of TLR2 dynamically through phosphorylation.
Assuntos
Proteína Forkhead Box O1/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/metabolismo , Staphylococcus aureus/imunologia , Animais , Biomarcadores , Modelos Animais de Doenças , Proteína Forkhead Box O1/genética , Humanos , Imunomodulação , Imunofenotipagem , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Camundongos , Camundongos Knockout , Transdução de Sinais , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Receptor 2 Toll-Like/metabolismoRESUMO
BACKGROUND: The purpose of this study was to explore diabetes-related distress and depression and their influence on treatment adherence in Chinese patients with type 2 diabetes. METHODS: We surveyed 200 type 2 diabetic patients from two public hospitals using the Diabetes Distress Scale (DDS), Zung Self-rating Depression Scale, and Revised Treatment Adherence in Diabetes Questionnaire (RADQ). A multiple regression model was used to explore the relationship between diabetes distress, depression, and treatment adherence. RESULTS: In the 200 eligible patients, the incidence of depression and diabetes distress was approximately 24% and 64%, respectively. The mean score on the RADQ was 23.0 ± 6.0. Multiple regression analysis showed that DDS scores (ß = 5.34, P = 0.000), age (ß = 0.15, P = 0.014), and family history (ß = 3.2, P = 0.016) had a positive correlation with depression. DDS scores (ß = -2.30, P = 0.000) and treatment methods (ß = -0.93, P = 0.012) were risk factors for poor treatment adherence, whereas age (ß = 0.089, P = 0.000) and cohabitation (ß = 0.93, P = 0.012) increased treatment adherence. The independent-samples t- test showed that depression also affected treatment adherence (t = 2.53, P < 0.05). CONCLUSION: These findings suggest that the DDS is a predictor of depression and that diabetes distress plays a more important part than depression in treatment adherence. Screening for diabetes distress may be useful for primary prevention of psychologic problems; however, some form of specialized psychologic intervention should be incorporated to promote patient adherence with treatment.