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1.
Nat Commun ; 12(1): 1460, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674584

RESUMO

Mitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1ß in vitro. Accordingly, HIF-1α and IL-1ß are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2-/- mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.


Assuntos
Arginase/metabolismo , Interleucina-10/metabolismo , Macrófagos/metabolismo , Mitocôndrias/metabolismo , Animais , Arginase/genética , Regulação para Baixo , Feminino , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout/genética , Mitocôndrias/enzimologia , Succinato Desidrogenase/metabolismo
2.
Nat Commun ; 12(1): 301, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436596

RESUMO

Macrophages are innate immune cells that contribute to fighting infections, tissue repair, and maintaining tissue homeostasis. To enable such functional diversity, macrophages resolve potentially conflicting cues in the microenvironment via mechanisms that are unclear. Here, we use single-cell RNA sequencing to explore how individual macrophages respond when co-stimulated with inflammatory stimuli LPS and IFN-γ and the resolving cytokine IL-4. These co-stimulated macrophages display a distinct global transcriptional program. However, variable negative cross-regulation between some LPS + IFN-γ-specific and IL-4-specific genes results in cell-to-cell heterogeneity in transcription. Interestingly, negative cross-regulation leads to mutually exclusive expression of the T-cell-polarizing cytokine genes Il6 and Il12b versus the IL-4-associated factors Arg1 and Chil3 in single co-stimulated macrophages, and single-cell secretion measurements show that these specialized functions are maintained for at least 48 h. This study suggests that increasing functional diversity in the population is one strategy macrophages use to respond to conflicting environmental cues.


Assuntos
Polaridade Celular , Macrófagos/citologia , Animais , Arginase/metabolismo , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Interferon gama/farmacologia , Interleucina-12/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Aprendizado de Máquina , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Redes Neurais de Computação , Razão de Chances , Análise de Célula Única , Fatores de Transcrição/metabolismo , Transcrição Genética/efeitos dos fármacos
3.
Exp Parasitol ; 222: 108063, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33412170

RESUMO

Leishmaniasis is one of the most neglected tropical infectious diseases in the world. The emergence of drug resistance and toxicity and the high cost of the available drugs with a lack of new anti-leishmanial drugs highlight the need to search for newer therapies with anti-leishmanial activities. Due to the mesenchymal stem cell (MSC) immunomodulatory capacity, they have been applied in a wide variety of disorders. In this study, the potential effects of adipose-derived MSC (AD-MSCs) therapy and its combination with glucantime were evaluated in a murine model of cutaneous leishmaniasis induced by L. major. The results showed that AD-MSCs improved wound healing and decreased parasite burden. The real-time PCR results obtained from mice treated with AD-MSCs showed that IL-12 and TNF-α genes were upregulated. IL-10, arginase, and FOXP3 genes were downregulated whereas no differences in expression of the IL-4 gene were found. Overall, it seems that AD-MSCs therapy enhances Th1 immune response in L. major infected BALB/c mice. Unexpectedly, our results showed that the association of glucantime to AD-MSCs treatments did not lead to an increment in the anti-leishmanial activity.


Assuntos
Leishmania major , Leishmaniose Cutânea/terapia , Células-Tronco Mesenquimais/imunologia , Análise de Variância , Animais , Arginase/genética , Arginase/metabolismo , Regulação para Baixo , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Células Th1/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
4.
PLoS One ; 15(4): e0227734, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298302

RESUMO

Both conventional and regulatory CD4+ T-cells rely on costimulatory signals mediated by cell surface receptors including CD28 for full activation. We showed previously that stimulation of CD4+ Foxp3+ regulatory T-cells by superagonistic anti-CD28 monoclonal antibodies (mAb) improves myocardial healing after experimental myocardial infarction (MI). However, the effect of ligand binding blocking anti-CD28 monoclonal antibodies has not yet been tested in this context. We hypothesize that ligand blocking anti-CD28 mAb treatment might favorably impact on healing after MI by limiting the activation of conventional CD4+ T-cells. Therefore, we studied the therapeutic effect of the recently characterized mAb E18 which blocks ligand binding to CD28 in a mouse permanent coronary ligation model. E18 or an irrelevant control mAb was applied once on day two after myocardial infarction to wildtype mice. Echocardiography was performed on day 7 after MI. E18 treatment improved the survival and reduced the incidence of left ventricular ruptures after experimental myocardial infarction. Accordingly, although we found no difference in infarct size, there was significantly less left ventricular dilation after E18 treatment in surviving animals as determined by echocardiography at day 7 after MI. In sham operated control mice neither antibody had an impact on body weight, survival, and echocardiographic parameters. Mechanistically, compared to control immunoglobulin, E18 treatment reduced the number of CD4+ T-cells and monocytes/macrophages within the infarct and periinfarct zone on day 5. This was accompanied by an upregulation of arginase which is a marker for alternatively differentiated macrophages. The data indicate that CD28-dependent costimulation of CD4+ T-cells impairs myocardial healing and anti-CD28 antibody treatment constitutes a potentially clinically translatable approach to improve the outcome early after MI.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos CD28/antagonistas & inibidores , Linfócitos T CD4-Positivos/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Animais , Anticorpos Monoclonais/uso terapêutico , Arginase/imunologia , Arginase/metabolismo , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Humanos , Ligantes , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Miocárdio/imunologia , Miocárdio/patologia
5.
Parasite Immunol ; 42(7): e12722, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32294247

RESUMO

Leishmaniasis is a neglected infectious disease with clinical presentations ranging from asymptomatic or mild symptoms to chronic infection and eventual death. The mechanisms of disease susceptibility and pathology have been extensively studied, but there are no steadfast rules regarding leishmaniasis. A Th1 response is usually associated with infection control, while a predominant Th2 response is detrimental to the patient. In this scenario, the enzymes arginase and inducible nitric oxide synthase represent two possible pathways of immune response. While the former contributes to parasite replication, the latter is crucial for its control. In the present review, we collected study results that associate arginase expression in patients and in experimental models with disease susceptibility/chronicity and show some proposed mechanisms that explain the role of arginase in maintaining Leishmania infection, including polyamine and thiol synthesis, tissue-resident macrophage (TRM) proliferation and activation and T-cell suppression and exhaustion.


Assuntos
Arginase/metabolismo , Leishmania/imunologia , Leishmaniose/imunologia , Macrófagos/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunidade Inata/imunologia , Leishmaniose/parasitologia , Neutrófilos/imunologia , Células Th1/imunologia , Células Th2/imunologia
6.
Am J Physiol Heart Circ Physiol ; 318(6): H1447-H1460, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32330087

RESUMO

Macrophages play a pivotal role in tissue repair following myocardial infarction (MI). In response to injury, they exist along a spectrum of activation states tightly regulated by their microenvironment. Cardiosphere-derived cells (CDCs) have been shown to mediate cardioprotection via modulation of the macrophage response. Our study was designed to gain mechanistic insight into the role of CDC-derived extracellular vesicles (EVs) in modulating macrophage phenotypes and operant signaling pathways to better understand their potential contribution to immunomodulatory cardioprotection. We found that CDC-derived EVs alter the functional phenotype of macrophages, modifying levels of phagocytosis and efferocytosis without changing viability or proliferation. Interestingly, extracellular vesicles differentially regulate several M1/M2 genes dependent on macrophage activation before EV treatment but consistently upregulate arginase 1 regardless of macrophage origin or polarization state. CDC-derived EVs polarize M1 macrophages to a proangiogenic phenotype dependent on arginase 1 upregulation and independent of VEGF-A. In addition, EV-dependent arginase 1 upregulation downregulates nitric oxide (NO) secretion in activated macrophages. These data suggest a novel urea-cycle-dependent mechanism in macrophages that promotes angiogenesis and provides additional mechanistic insight into the potential contribution of CDC-derived extracellular vesicles in immunomodulatory cardioprotection.NEW & NOTEWORTHY We hypothesized that in the window of therapeutic extracellular vesicle (EV) administration, inflammatory M1 macrophages are likely the primary target of cardiosphere-derived cell (CDC)-derived EVs. The effect of CDC-EVs on this population, however, is currently unknown. In this study, we demonstrate that CDC-derived EVs polarize M1 macrophages to a proangiogenic phenotype dependent on arginase 1 upregulation. These results provide insight into an immunomodulatory mechanism of CDC-EVs in a more physiologically relevant model of post-myocardial infarction (post-MI) macrophage polarization.


Assuntos
Arginase/metabolismo , Vesículas Extracelulares/metabolismo , Macrófagos/metabolismo , Animais , Proliferação de Células/fisiologia , Sobrevivência Celular , Humanos , Camundongos , Fagocitose/fisiologia , Fenótipo
7.
Medicine (Baltimore) ; 99(9): e19159, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32118719

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Pathologic distinction between HCC and intrahepatic cholangiocarcinoma (ICC) and metastatic adenocarcinoma can be challenging and sometimes requires immunohistochemical panels. Recently, arginase-1 (ARG-1) has been introduced for differentiation of these tumors. METHODS: We will search Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure through August 1, 2019, comprehensive collection studies about the diagnostic value of ARG-1 for HCC. Two reviewers will screen literature according to the inclusion and exclusion criteria, extract data, and assess the quality of included studies. Review Manager 5.3 and STATA 15.0 will be used to conduct the meta-analysis. RESULTS: The review will provide a high-quality synthesis of current evidence of the diagnostic value of liver cancer. The results will be published in a peer-reviewed journal. CONCLUSION: We hope that the results of this study will provide significant evidence to assess the value of ARG-1 in differential diagnosis of HCC, ICC, and metastatic carcinoma of liver.


Assuntos
Arginase/metabolismo , Carcinoma Hepatocelular/diagnóstico , Colangiocarcinoma/diagnóstico , Neoplasias Hepáticas/diagnóstico , Carcinoma Hepatocelular/metabolismo , Colangiocarcinoma/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Revisões Sistemáticas como Assunto
8.
Parasit Vectors ; 13(1): 49, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029006

RESUMO

BACKGROUND: Cystic echinococcosis is a chronic disease caused by infection with the larvae of Echinococcus granulosus. The parasite's ability to establish persistent infection is partly due to its evolving immune evasion strategies. One strategy may involve the protective effect of arginase, which impedes the control of pathogens or tumors, whereas it remains largely unknown during E. granulosus infection. Here, we analyzed whether arginase was produced in peritoneal cells and assessed its role in immunosuppression in mice infected with protoscoleces of E. granulosus. METHODS: BALB/c mice injected with protoscoleces of E. granulosus were used to evaluate the expression of arginase (ARG) in mRNA and protein levels. The profiles of ARG-1 expression in peritoneal cells and CD3ζ expression in T cells from spleens were assessed at different time points (3, 6, 9 and 12 months post-infection) by flow cytometry. In vitro, peritoneal cells were co-cultured with purified T cells in a transwell system, and the levels of CD3ζ re-expression were compared by flow cytometry. Meanwhile, the changes of L-arginine and its related metabolites in serum were tested. RESULTS: Compared to the control group, the peritoneal cells from infected mice showed higher levels of ARG-1 mRNA and protein, unchanged ARG-2 and iNOS. Enhanced ARG-1 expression was present in SSClowCD11b+F4/80+, CD11b+CD11c+, CD11b+Gr-1+Ly-6C+Ly-6G-, CD11b+Gr-1+Ly-6C-Ly-6G+, CD11b+Gr-1+ and CD11b+Ly-6G+ cells. The proportion of cells and the proportion of ARG-1 expression in corresponding cells exhibited a rising trend along with the extension of infection time, except for fluctuations in SSClowCD11b+F4/80+ and CD11b+CD11c+ cells at 12 months post-infection, whereas the expression of CD3ζ chain in CD4+ and CD8+ T cells showed a descending trend. Purified T cells showed declined re-expression of CD3ζ when co-cultured with peritoneal cells from infected mice, and CD3ζ was regenerated by supplement of L-arginine or arginase inhibitor BEC, rather than NOS inhibitor L-NMMA or catalase. Meanwhile, the concentrations of L-arginine, L-citrulline and NO decreased, and those of L-ornithine and urea increased in serum post-infection. CONCLUSIONS: Our findings demonstrated that ARG-1 expression is enhanced in multiple myeloid cells from peritoneum and promotes immune evasion of E. granulosus in mice by inhibiting the expression of T cell receptor CD3ζ chain and antagonism against iNOS.


Assuntos
Arginase/imunologia , Echinococcus granulosus/imunologia , Evasão da Resposta Imune/fisiologia , Animais , Arginase/metabolismo , Equinococose/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Células Mieloides/imunologia , Óxido Nítrico Sintase Tipo II/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Linfócitos T/imunologia
9.
In Vitro Cell Dev Biol Anim ; 56(2): 154-164, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31898012

RESUMO

Cigarette smoke exposure is one of the main etiologies for chronic obstructive pulmonary disease. Moreover, cigarette smoke participates in disease progression by inducing abnormal macrophage polarization; however, the effects of cigarette smoke on M1/M2 macrophage polarization have not been established. The aim of the current study was to determine the effects of cigarette smoke extract (CSE) on M1/M2 macrophage polarization in alveolar and peritoneal macrophages (AM and PM, respectively) at different concentrations and exposure times. Rat AM and PM were cultured with CSE at different concentrations. CCK-8 was used as an indicator of cell viability, and mRNA expression of M1 (iNOS, TNF-α, and IL-1ß) and M2 markers (arg-1, CD206, and TGF-ß1) were measured at 3, 6, 9, 12, and 24 h using qPCR. Expressions of CD86 and CD206 proteins at 12 h were determined using flow cytometry, and the iNOS/arg-1 ratio was used to determine the polarization dominance of M1 and M2. M2 subtypes were detected at 12 h using qPCR and flow cytometry. CSE increased the expression of iNOS, TNF-α, and IL-1ß mRNA, and the proportion of CD86-positive cells in AM and PM promoted M1 polarization, and M1 polarization was continuously enhanced as exposure time and concentration increased. CSE reduced the expression of arg-1, CD206, and TGF-ß1 mRNA and the proportion of CD206-positive cells in AM and PM and inhibited M2 polarization. At 9-24 h of CSE exposure, the expression of arg-1 in AM and PM gradually increased, showing tendency towards activation of M2 polarization. Besides, CSE might induce M2b and M2d polarization at 12 h. After 12 h of CSE exposure, transformation from M1 to M2 polarization dominance was shown in AM; however, M1 polarization was continuously enhanced in PM within 24 h of CSE exposure. CSE promoted M1 polarization in macrophages, exhibiting dynamic regulatory effects on M2 polarization, first as a suppressor and then as a promoter. The polarization change induced by CSE on AM was more sensitive than PM.


Assuntos
Polaridade Celular , Fumar Cigarros/efeitos adversos , Macrófagos Alveolares/patologia , Macrófagos Peritoneais/patologia , Animais , Antígenos CD/metabolismo , Arginase/metabolismo , Polaridade Celular/genética , Forma Celular/genética , Sobrevivência Celular/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Macrófagos Alveolares/metabolismo , Macrófagos Peritoneais/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Fatores de Tempo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
Proc Natl Acad Sci U S A ; 117(6): 3083-3092, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31980528

RESUMO

Inflammatory bowel disease (IBD) comprises chronic relapsing disorders of the gastrointestinal tract characterized pathologically by intestinal inflammation and epithelial injury. Here, we uncover a function of extracellular matrix protein 1 (ECM1) in promoting the pathogenesis of human and mouse IBD. ECM1 was highly expressed in macrophages, particularly tissue-infiltrated macrophages under inflammatory conditions, and ECM1 expression was significantly induced during IBD progression. The macrophage-specific knockout of ECM1 resulted in increased arginase 1 (ARG1) expression and impaired polarization into the M1 macrophage phenotype after lipopolysaccharide (LPS) treatment. A mechanistic study showed that ECM1 can regulate M1 macrophage polarization through the granulocyte-macrophage colony-stimulating factor/STAT5 signaling pathway. Pathological changes in mice with dextran sodium sulfate-induced IBD were alleviated by the specific knockout of the ECM1 gene in macrophages. Taken together, our findings show that ECM1 has an important function in promoting M1 macrophage polarization, which is critical for controlling inflammation and tissue repair in the intestine.


Assuntos
Proteínas da Matriz Extracelular/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Ativação de Macrófagos/fisiologia , Macrófagos/metabolismo , Animais , Arginase/metabolismo , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Doenças Inflamatórias Intestinais/patologia , Intestinos/patologia , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais
11.
JCI Insight ; 5(2)2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-31996482

RESUMO

Inducible nitric oxide synthase (iNOS) and arginase-2 (ARG2) share a common substrate, arginine. Higher expression of iNOS and exhaled NO are linked to airway inflammation in patients. iNOS deletion in animal models suggests that eosinophilic inflammation is regulated by arginine metabolism. Moreover, ARG2 is a regulator of Th2 response, as shown by the development of severe eosinophilic inflammation in ARG2-/- mice. However, potential synergistic roles of iNOS and ARG2 in asthma have not been explored. Here, we hypothesized that arginine metabolic fate via iNOS and ARG2 may govern airway inflammation. In an asthma cohort, ARG2 variant genotypes were associated with arginase activity. ARG2 variants with lower arginase activity, combined with levels of exhaled NO, identified a severe asthma phenotype. Airway inflammation was present in WT, ARG2-/-, iNOS-/-, and ARG2-/-/iNOS-/- mice but was greatest in ARG2-/-. Eosinophilic and neutrophilic infiltration in the ARG2-/- mice was abrogated in ARG2-/-/iNOS-/- animals. Similarly, angiogenic airway remodeling was greatest in ARG2-/- mice. Cytokines driving inflammation and remodeling were highest in lungs of asthmatic ARG2-/- mice and lowest in the iNOS-/-. ARG2 metabolism of arginine suppresses inflammation, while iNOS metabolism promotes airway inflammation, supporting a central role for arginine metabolic control of inflammation.


Assuntos
Arginase/metabolismo , Arginina/metabolismo , Inflamação/metabolismo , Pulmão/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Adulto , Animais , Arginase/genética , Asma/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Genótipo , Humanos , Inflamação/imunologia , Inflamação/patologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Polimorfismo de Nucleotídeo Único
12.
PLoS Negl Trop Dis ; 14(1): e0007843, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31929528

RESUMO

BACKGROUND: Neglected parasitic diseases (NTDs) like cutaneous leishmaniasis (CL) have caused high mortality and morbidity rate in developing countries. This disease is considered as one of the six major tropical diseases, and has a great importance in HIV infected individuals as an opportunistic infection in those areas that both infections are endemic. This study evaluated the therapeutic effects of the Urtica dioica L (U. dioica) aqueous extract as an anti-leishmanial herbal drug in-vitro and in-vivo, and in addition to that, evaluated two vital immune system cytokines including gamma interferon (IFN-γ) and interleukin-4 (IL-4) plus nitric oxide (NO) and arginase activity against Leishmania major (L. major) infected mice. METHODOLOGY/PRINCIPAL FINDINGS: In-vitro anti-leishmanial activity of U. dioica aqueous extract was determined using MTT method and also Parasite Rescue Transformation Assay. Also, the footpad lesion size and parasite load in BALB/c mice infected with L. major were quantified for in-vivo assessment. Furthermore, for evaluating the immune responses, the levels of IFN-γ, IL-4, NO and arginase were measured in the BALB/c mice. These results indicated that U. dioica extract significantly reduced the L. major promastigotes viability. According to the in-vitro cytotoxicity assay of the extract on Leishmania parasites (CC50) and infected macrophages (EC50), the extract had no toxicity to the macrophages, however it efficiently killed the L. major amastigotes. In addition, the lesion size, parasite load, IL-4, and ARG were decreased in the treated infected mice, however IFN-γ and NO were significantly increased. CONCLUSIONS/SIGNIFICANCE: This study established satisfactory results in Leishmania parasite clearing both in-vivo and in-vitro. Therefore, U. dioica extract can be considered as an effective and harmless herbal compound for killing the parasite without toxicity to the host macrophages. Furthermore, it also can treat the CL by switching the mouse immune response towards a cell-mediated response (Th1); hence, it may be identified as a perfect therapeutic herbal drug for CL treatment.


Assuntos
Leishmania major/efeitos dos fármacos , Extratos Vegetais/farmacologia , Urtica dioica/química , Animais , Antiprotozoários/farmacologia , Arginase/metabolismo , Linhagem Celular , Interferon gama/metabolismo , Interleucina-4/metabolismo , Leishmaniose Cutânea/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Carga Parasitária , Extratos Vegetais/toxicidade , Urtica dioica/toxicidade
13.
Cell ; 180(1): 64-78.e16, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31923400

RESUMO

Enteric-associated neurons (EANs) are closely associated with immune cells and continuously monitor and modulate homeostatic intestinal functions, including motility and nutrient sensing. Bidirectional interactions between neuronal and immune cells are altered during disease processes such as neurodegeneration or irritable bowel syndrome. We investigated the effects of infection-induced inflammation on intrinsic EANs (iEANs) and the role of intestinal muscularis macrophages (MMs) in this context. Using murine models of enteric infections, we observed long-term gastrointestinal symptoms, including reduced motility and loss of excitatory iEANs, which was mediated by a Nlrp6- and Casp11-dependent mechanism, depended on infection history, and could be reversed by manipulation of the microbiota. MMs responded to luminal infection by upregulating a neuroprotective program via ß2-adrenergic receptor (ß2-AR) signaling and mediated neuronal protection through an arginase 1-polyamine axis. Our results identify a mechanism of neuronal death post-infection and point to a role for tissue-resident MMs in limiting neuronal damage.


Assuntos
Mucosa Intestinal/imunologia , Macrófagos/imunologia , Receptores Adrenérgicos beta 2/metabolismo , Adrenérgicos , Animais , Arginase/metabolismo , Caspases Iniciadoras/imunologia , Caspases Iniciadoras/metabolismo , Sistema Nervoso Entérico/imunologia , Sistema Nervoso Entérico/metabolismo , Feminino , Gastroenteropatias , Microbioma Gastrointestinal , Infecções , Inflamação/imunologia , Mucosa Intestinal/metabolismo , Intestino Delgado/imunologia , Intestinos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microbiota , Neurônios/fisiologia , Receptores Adrenérgicos beta 2/imunologia , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Transdução de Sinais
14.
Eur J Immunol ; 50(2): 220-233, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31777959

RESUMO

The role of complement system in heart diseases is controversial. Besides, the mechanisms by which complement components participate in cardiac remodeling (CR) and heart failure during uremia are unclear. In this study, 5/6 nephrectomy was performed to adult mice to establish the uremic model and CR deteriorated over the course of uremia. Although complement pathways were not further activated over the course of the disease, soluble complement factor B (CFB) was upregulated at post-nephrectomy day 90 (PNx90) compared with PNx30. Further, CFB notably deteriorated CR in uremic mice but this effect was reversed by depletion of macrophages with liposomal clodronate. In vivo and in vitro CFB upregulated arginase 1 (ARG1) expression, increased ARG1 enzymatic activity, and stimulated the syntheses of ornithine, leading to polyamine overproduction in macrophages. Putrescine, an important polyamine, promoted cardiac fibroblast proliferation and collagen production, resulting in progressive CR. In vivo the inhibition of ARG1 activity with Nω -hydroxyl-l-arginine remarkably improved the general survival rates, inhibited the infiltration of cardiac fibroblasts, and alleviated progression of CR in uremic mice. Taken together, the CFB-ARG1-putrescine axis is related to progression of CR and ARG1 hyperactivity in macrophages may provide a novel therapeutic target against the heart injury in uremia.


Assuntos
Arginase/metabolismo , Fator B do Complemento/metabolismo , Uremia/metabolismo , Remodelação Ventricular/fisiologia , Animais , Arginina/metabolismo , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Ornitina/metabolismo , Poliaminas/metabolismo , Transdução de Sinais/fisiologia
15.
Immunol Cell Biol ; 98(2): 152-164, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31845380

RESUMO

Depending on the microenvironment conditions, macrophages display phenotypic and functional heterogeneity. This study characterized the programmed cell death-ligand 2 (PD-L2)-expressing macrophage-like cells drained from surgical wound zones, and investigated their influence on helper T (Th) cell responses. Although all CD14+ myeloid cells possessed macrophage-like features, CD206+ and CD163+ cells constituted a specific subpopulation with high PD-L2 expression. There was a modest correlation between the PD-L2 levels on CD206+ macrophages and the amount of interferon (IFN)-γ in the drainage fluid. The adhesion-independent macrophages simultaneously presented both classically-activated M1 and alternatively-activated M2 characteristics. CD206+ and PD-L2+ cells were identified with high granularity and size, expressed arginase-1 and costimulatory molecules, had enhanced phagocytic activity and produced reactive oxygen species. The genes associated with macrophage differentiation (MERTK, AXL and TYRO3) were also upregulated. These cells provided costimulation to Th cells; yet, when PD-L2 was blocked, T-cell proliferation and IFNγ production were enhanced. Under defined conditions devoid of activation stimuli and matrix adhesion, ex vivo-generated monocyte-derived macrophages displayed limited capacity to stimulate T cells. Upon exposure to IFNγ, they significantly upregulated programmed death 1 ligands, especially PD-L2. These cells did not completely abrogate T-cell differentiation; however, PD-L2 checkpoint blockade restored Th1 proliferation and secretion of interleukin-2, tumor necrosis factor-α and IFNγ. In conclusion, upregulation of PD-L2 on the wound zone macrophages may constitute a negative feedback loop that restrains the Th1 effector responses and avoids exacerbation of inflammation during tissue healing.


Assuntos
Diferenciação Celular/imunologia , Inflamação/metabolismo , Macrófagos/metabolismo , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Células Th1/imunologia , Cicatrização/fisiologia , Adulto , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Arginase/metabolismo , Antígeno B7-H1/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Interferon gama/farmacologia , Interleucina-2/metabolismo , Lectinas Tipo C/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Lectinas de Ligação a Manose/metabolismo , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Superfície Celular/metabolismo , Células Th1/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Cicatrização/efeitos dos fármacos , c-Mer Tirosina Quinase/genética , c-Mer Tirosina Quinase/metabolismo
16.
J Inorg Biochem ; 202: 110812, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31731096

RESUMO

Ureohydrolases form a conserved family of enzymes with a strict requirement for divalent metal ions for catalytic activity. They catalyze the hydrolysis of the guanidino group and produce urea. In their active sites six highly conserved amino acid residues form a binding pocket for two catalytically essential metal ions that are needed to activate a water molecule to initiate the hydrolysis of the guanidino group in a nucleophilic attack. Focus in this review is on two members of the ureohydrolase family, the Mn2+-dependent arginase and agmatinase, which play important roles in functions related to replication and cell survival. We will focus in particular on Mn2+ binding interactions, and on how this metal ion contributes to the reaction catalyzed by these enzymes. We also include the agmatinase-like protein (ALP) because it is functionally closely related to agmatinase, also requires at least one Mn2+ ion for catalytic activity, but may possess an active site that differs significantly from all other known ureohydrolases.


Assuntos
Arginase , Manganês , Ureo-Hidrolases , Arginase/química , Arginase/metabolismo , Catálise , Manganês/química , Manganês/metabolismo , Ureo-Hidrolases/química , Ureo-Hidrolases/metabolismo
17.
Andrologia ; 52(2): e13464, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31721281

RESUMO

This study was made to investigate the effects of intramuscular administrations of dexamethasone on seminal plasma nitric oxide levels and arginase activity, and some spermatological parameters in rams. Ten Akkaraman rams weighing 50-60 kg and 2 years old were used as material in this study. The study was performed during the breeding season (September-November) for rams. The semen was collected by artificial vagina at 1st, 4th, 24th, 48th, 72nd and 96th hours for control group before dexamethasone administration. For treatment group, 0.25 mg/kg dexamethasone was administered and semen was collected at the time points described for control group. Spermatological characteristics of semen samples (semen volume, pH, sperm motility, density and abnormal sperm rate), seminal plasma arginase enzyme activities and nitric oxide levels were determined. It was determined that the administration of dexamethasone was detected to decrease seminal plasma arginase activity (p < .05 and .01) and nitric oxide level (p < .05), semen volume (p < .05 and .01), mass activity (p < .05 and .01), sperm density (p < .05) and sperm motility (p < .05 and .01), and to increase abnormal sperm rate (p < .05 and .01). In conclusion, dexamethasone is not recommended to be used during the breeding season as it damages the sperm quality of the rams.


Assuntos
Arginase/metabolismo , Dexametasona/efeitos adversos , Glucocorticoides/efeitos adversos , Óxido Nítrico/metabolismo , Sêmen/efeitos dos fármacos , Animais , Masculino , Sêmen/enzimologia , Ovinos
18.
Reprod Domest Anim ; 55(2): 162-169, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31808580

RESUMO

The effects of vitamin E and vitamin E-selenium combination on seminal plasma arginase activity and nitric oxide level and some spermatological properties in rams were investigated in this study. For control group, animals were injected intramuscularly with physiological saline. For vitamin E group, rams were injected intramuscularly with 300 mg/ram vitamin E. For vitamin E + selenium group, animals were injected intramuscularly with 5 ml/ram vitamin E + selenium. The semen was collected by artificial vagina at 1st, 4th, 24th, 48th and 72nd hr after administration in each group. Significant decreases in seminal plasma arginase activity (at 1st, 24th and 48th hr), nitric oxide level (at 72nd hr) and abnormal sperm rate (at 1st, 24th and 72nd hr), and significant increases in semen volume (at 24th hr), semen mass activity (at 24th and 48th hr), sperm motility (at 24th, 48th and 72nd hr) and concentration (at 1st hr) were observed in vitamin E group compared with control group. Similarly, significant increase in semen volume (at 1st, 24th and 48th hr), mass activity, (at 48th hr), motility (at 48th and 72nd hr) and concentration (at 4th, 24th and 48th hr), and significant decrements in abnormal sperm rate (at 1st, 24th, 48th and 72nd hr), seminal plasma nitric oxide level (at 1st, 4th, 24th and 48th hr) and semen pH (at 24th and 48th hr) were detected in vitamin E + selenium group in comparison to the control group. As a result, it is suggested that vitamin E and/or vitamin E + selenium applications may improve reproductive performance.


Assuntos
Selênio/administração & dosagem , Carneiro Doméstico/fisiologia , Vitamina E/administração & dosagem , Animais , Arginase/metabolismo , Masculino , Óxido Nítrico/metabolismo , Sêmen/química , Sêmen/efeitos dos fármacos , Sêmen/enzimologia , Análise do Sêmen/veterinária , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/anormalidades , Espermatozoides/efeitos dos fármacos
19.
Brain Dev ; 42(2): 231-235, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31604595

RESUMO

An adult female patient was diagnosed with arginase 1 deficiency (ARG1-D) at 4 years of age, and had been managed with protein restriction combined with sodium benzoate therapy. Though the treatment was successful in ameliorating hyperammonemia, hyperargininemia persisted. After being under control with a strict restriction of dietary protein, severe fall of serum albumin levels appeared and her condition became strikingly worsened. However, after sodium phenylbutyrate (NaPB) therapy was initiated, the clinical condition and metabolic stability was greatly improved. Current management of ARG1-D is aimed at lowering plasma arginine levels. The nitrogen scavengers, such as NaPB can excrete the waste nitrogen not through the urea cycle but via the alternative pathway. The removal of nitrogen via alternative pathway lowers the flux of arginine in the urea cycle. Thereby, the clinical complications due to insufficient amount of protein intake can be prevented. Thus, NaPB therapy can be expected as a useful therapeutic option, particularly in patients with ARG1-D.


Assuntos
Arginase/genética , Hiperargininemia/tratamento farmacológico , Fenilbutiratos/uso terapêutico , Adulto , Arginase/metabolismo , Arginina/metabolismo , Feminino , Humanos , Hiperamonemia/sangue , Hiperargininemia/sangue , Hiperargininemia/genética , Fenilbutiratos/metabolismo
20.
Br J Nutr ; 123(2): 135-148, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31647043

RESUMO

Oral arginine supplements are popular mainly for their presumed vasodilatory benefit. Arginine is a substrate for at least four enzymes including nitric oxide synthase (NOS) and arginase, but the impact of oral supplements on its different metabolic pathways is not clear. Deficiencies of arginine-metabolising enzymes are associated with conditions such as hyperammonaemia, endothelial dysfunction, central nervous system and muscle dysfunction, which complicate the use of oral arginine supplements. We examined the effect of l-arginine (l-Arg) and d-arginine (d-Arg), each at 500 mg/kg per d in drinking water administered for 4 weeks to separate groups of 9-week-old male Sprague-Dawley rats. We quantified the expression of enzymes and plasma, urine and organ levels of various metabolites of arginine. l-Arg significantly decreased cationic transporter-1 expression in the liver and the ileum and increased endothelial NOS expression in the aorta and the kidney and plasma nitrite levels, but did not affect the mean arterial pressure. l-Arg also decreased the expression of arginase II in the ileum, arginine:glycine amidinotransferase in the liver and the kidney and glyoxalase I in the liver, ileum and brain, but increased the expression of arginine decarboxylase and polyamines levels in the liver. d-Arg, the supposedly inert isomer, also unexpectedly affected the expression of some enzymes and metabolites. In conclusion, both l- and d-Arg significantly affected enzymes and metabolites in several pathways that use arginine as a substrate and further studies with different doses and treatment durations are planned to establish their safety or adverse effects to guide their use as oral supplements.


Assuntos
Arginina/administração & dosagem , Arginina/metabolismo , Suplementos Nutricionais , Administração Oral , Animais , Arginase/efeitos dos fármacos , Arginase/metabolismo , Arginina/farmacologia , Transportador 1 de Aminoácidos Catiônicos/efeitos dos fármacos , Transportador 1 de Aminoácidos Catiônicos/metabolismo , Creatina/efeitos dos fármacos , Creatina/metabolismo , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Nitratos/sangue , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/efeitos dos fármacos , Óxido Nítrico Sintase/metabolismo , Nitritos/sangue , Ratos , Ratos Sprague-Dawley
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