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1.
Int J Nanomedicine ; 14: 5229-5242, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371958

RESUMO

Purpose: Dexamethasone (Dex) has long been used as a potent immunosuppressive agent in the treatment of inflammatory and autoimmune diseases, despite serious side effects. In the present study, Dex and model antigen ovalbumin (OVA) were encapsulated with poly(lactic-co-glycolic acid) to deliver Dex and OVA preferentially to phagocytic cells, reducing systemic side effects of Dex. The OVA-specific immune tolerance-inducing activity of the nanoparticles (NPs) was examined. Methods: Polymeric NPs containing OVA and Dex (NP[OVA+Dex]) were prepared by the water-in-oil-in-water double emulsion solvent evaporation method. The effects of NP[OVA+Dex] on the maturation and function of immature dendritic cells (DCs) were examined in vitro. Furthermore, the OVA-specific immune tolerizing effects of NP[OVA+Dex] were confirmed in mice that were intravenously injected or orally fed with the NPs. Results: Immature DCs treated in vitro with NP[OVA+Dex] did not mature into immunogenic DCs but instead were converted into tolerogenic DCs. Furthermore, profoundly suppressed generation of OVA-specific cytotoxic T cells and production of OVA-specific IgG were observed in mice injected with NP[OVA+Dex], whereas regulatory T cells were concomitantly increased. Feeding of mice with NP[OVA+Dex] also induced OVA-specific immune tolerance. Conclusion: The present study demonstrates that oral feeding as well as intravenous injection of poly(lactic-co-glycolic acid) NPs encapsulating both antigen and Dex is a useful means of inducing antigen-specific immune tolerance, which is crucial for the treatment of autoimmune diseases.


Assuntos
Antígenos/imunologia , Materiais Biocompatíveis/química , Dexametasona/farmacologia , Epitopos/imunologia , Tolerância Imunológica , Nanopartículas/química , Administração Oral , Animais , Apresentação do Antígeno/efeitos dos fármacos , Citocinas/biossíntese , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Imunidade/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Ovalbumina/imunologia , Fagocitose/efeitos dos fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo
2.
J Chem Ecol ; 45(8): 715-724, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31385154

RESUMO

Plants emit a specific blend of volatiles in response to herbivory and these volatiles, which often attract predators and parasitoids function as an indirect plant defense. The impact of plant volatiles in shaping herbivore defenses is unclear. Here, we report that specific plant volatiles induce immune responses in the polyphagous herbivore, Spodoptera litura. We characterized the hemocyte profile and established their functional significance with respect to ontogeny and exposure to specific plant volatiles. Fifth instar larvae showed the highest number and hemocytes diversity. We characterized seven different types of hemocytes, of which granulocytes performed phagocytosis, oenocytoids showed melanization activity, and plasmatocytes along with granulocytes and oenocytoids were found to be involved in encapsulation. Among the six volatiles tested, exposure to (E)-ß-ocimene caused the highest increase in total hemocytes number (THC) followed by linalool and (Z)-3-hexenyl acetate exposure. Although THC did not differ between these three volatile treatments, circulating hemocytes diversity varied significantly. (E)-ß-ocimene exposure showed higher number of plasmatocytes and phenol oxidase activity. The interaction of the parasitic wasp Bracon brevicornis with (E)-ß-ocimene exposed larvae was poor in terms of delayed paralysis and lower egg deposition. In choice assays, the wasp showed clear preference towards control larvae indicating (E)-ß-ocimene treatment renders the host unattractive. Hemocyte profiles post-parasitoid exposure and (E)-ß-ocimene treatment were similar indicating cue-based priming. When challenged with Bacillus thuringiensis, linalool exposure resulted in the highest survival as compared to other volatiles. Our results show that specific HIPVs can modulate cellular immunity of S. litura, revealing a new role for HIPVs in tri-trophic interactions.


Assuntos
Compostos Orgânicos Voláteis/farmacologia , Vespas/fisiologia , Alcenos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Hemócitos/citologia , Hemócitos/efeitos dos fármacos , Hemócitos/metabolismo , Herbivoria , Interações Hospedeiro-Parasita , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/metabolismo , Larva/fisiologia , Monofenol Mono-Oxigenase/metabolismo , Monoterpenos/farmacologia , Oviposição/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Plantas/química , Plantas/metabolismo , Plantas/parasitologia , Compostos Orgânicos Voláteis/química , Vespas/imunologia
3.
Anticancer Res ; 39(8): 4503-4509, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366552

RESUMO

BACKGROUND/AIM: Oral administration of Pantoea agglomerans-derived lipopolysaccharide (LPSp) has been reported to have a preventive effect against various lifestyle-related diseases. Therefore, we examined the preventive effect on high blood pressure, which is a kind of reserve arm for lifestyle-related diseases. MATERIALS AND METHODS: Spontaneous hypertensive rat (SHR) and WKY rat were bred from 6 to 16 weeks of age. SHR were orally administered 100 µg/kg LPSp and 0.1% NaCl, and blood pressure was measured at 6, 10, 13 and 16 weeks. Furthermore, at 16 weeks of age, blood biochemical markers were measured and microbial community composition was analyzed. RESULTS: SHRs developed hypertension with age, which was exacerbated by salt loading. Although there was almost no reduction in blood pressure in SHRs that received LPSp. It was suppressed at 13-16 weeks of age in those with salt loading. CONCLUSION: Oral administration of LPSp showed a preventive effect on salt-loaded hypertension.


Assuntos
Citocinas/genética , Hipertensão/tratamento farmacológico , Lipopolissacarídeos/administração & dosagem , Pantoea/química , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hipertensão/genética , Hipertensão/patologia , Lipopolissacarídeos/química , Masculino , Fagocitose/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Sais/toxicidade
4.
Anticancer Res ; 39(8): 4533-4537, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366556

RESUMO

BACKGROUND/AIM: Serum-derived macrophage activating factor, serum-MAF, is known to increase the phagocytic activity of macrophages by enhancing the engulfment efficiency. To elucidate the mechanisms underlying phagocytic activation, morphological changes were observed and analyzed. MATERIALS AND METHODS: Morphological changes in macrophages were observed and quantitatively analyzed using scanning electron microscope (SEM) and confocal microscope. RESULTS: SEM and confocal microscopy images revealed frill-like structures and active actin accumulations, respectively, in serum-MAF treated macrophages. Actin accumulation was induced within 5 min following serum-MAF treatment. CONCLUSION: Serum-MAF induced a rapid rearrangement of cytoskeletal actin and enhanced phagocytic activity. Findings of the current study may contribute to the development of techniques that facilitate activation of the human immune system, which in turn may be beneficial for cancer immunotherapy.


Assuntos
Actinas/química , Macrófagos/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-maf/farmacologia , Actinas/ultraestrutura , Humanos , Imunoterapia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Microscopia Confocal , Microscopia Eletrônica de Varredura , Proteínas Proto-Oncogênicas c-maf/genética , Células U937 , Proteína de Ligação a Vitamina D/química , Proteína de Ligação a Vitamina D/metabolismo
5.
Environ Pollut ; 252(Pt B): 1764-1771, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31295695

RESUMO

Phagocytosis suppression induced by nanoparticles (NPs) exposure is increasingly reported in marine species. However, the mechanisms underlying this impact remain poorly understood. In order to improve our present understanding of the immunotoxicity of NPs, acute (96 h) TiO2 NP exposure and rescue trials via exogenous supply of Ca2+ were performed in the blood clam, Tegillarca granosa. The results show that the phagocytosis rate, cell viability, and intracellular Ca2+ concentration of haemocytes were significantly suppressed, whereas the intracellular ROS concentration of haemocytes significantly increased upon nTiO2 exposure. Exposure to nTiO2 also led to the significant downregulation of Caspase-3, Caspase-6, apoptosis regulator Bcl-2, Bcl-2-associated X, calmodulin kinase II, and calmodulin kinase kinase II. Furthermore, the toxic impacts of nTiO2 were partially mitigated by the addition of exogenous Ca2+, as indicated by the recovery tendency in almost all the measured parameters. The present study indicates that Ca2+ signaling could be one of the key pathways through which nTiO2 attacks phagocytosis.


Assuntos
Apoptose/efeitos dos fármacos , Arcidae/efeitos dos fármacos , Cálcio/farmacologia , Hemócitos/efeitos dos fármacos , Nanopartículas/toxicidade , Fagocitose/efeitos dos fármacos , Titânio/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Apoptose/genética , Arcidae/fisiologia , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/genética , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Hemócitos/patologia
6.
J Agric Food Chem ; 67(32): 9070-9078, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31343168

RESUMO

In this study, an immunologically active novel microparticulate mushroom ß-glucan (PRA-1p) was prepared using an alkali-soluble glucan PRA-1 by an emulsification and cross-linking method. PRA-1 was a hyperbranched (1→3),(1→6)-ß-d-glucan with a degree of branching of 0.89, isolated from the sclerotia of Polyporus rhinocerus. PRA-1 had a rod-like conformation, while PRA-1p exhibited a monodisperse and homogeneous spherical conformation with a diameter ranging from 0.3 to 2.0 µm in water. PRA-1p significantly induced nitric oxide and reactive oxygen species production as well as morphological changes of murine macrophages (RAW 264.7 cells) and upregulated their phagocytic activity. Furthermore, PRA-1p treatment markedly enhanced the secretion of cytokines, including cutaneous T cell-attracting chemokine 27, granulocyte-colony-stimulating factor, monocyte chemoattractant protein 1, macrophage inflammatory protein 1α, macrophage inflammatory protein 2, regulated on activation, normal T cell expressed and secreted, soluble tumor necrosis factor receptor 1, and tissue inhibitors of metalloproteinases. Activation of RAW 264.7 cells triggered by PRA-1p was associated with activation of inducible nitric oxide synthase, nuclear factor κB, extracellular signal-regulated kinase, and protein kinase B. This work suggests that novel PRA-1p derived from the mushroom sclerotia of P. rhinocerus has potential application as an immunostimulatory agent.


Assuntos
Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polyporus/química , beta-Glucanas/química , beta-Glucanas/farmacologia , Animais , Quimiocina CCL27/genética , Quimiocina CCL27/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fatores Imunológicos/isolamento & purificação , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , NF-kappa B/genética , NF-kappa B/imunologia , Óxido Nítrico/imunologia , Fagocitose/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Polyporus/imunologia , Células RAW 264.7 , Espécies Reativas de Oxigênio/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , beta-Glucanas/isolamento & purificação
7.
AAPS PharmSciTech ; 20(6): 241, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31250260

RESUMO

Particulate drug delivery systems (PDDS) have been broadly explored as platforms for delivery of drugs, enzymes, cells, and vaccines for pharmaceutical applications. Studies suggest that microspheres (MS) can stimulate innate immune cells even without a drug payload; however, less is known regarding how they impact host cells in dealing with the bacillary infection. We examined the role of drug-free inhalable alginate microspheres (A-MS) on phagocytosis efficiency and subsequent immune cell activation in Escherichia coli-infected THP-1-derived macrophages. Alginate particles have been widely investigated as carriers for prolonged delivery of bioactive (i.e., drugs, diagnostics, and vaccines). A-MS were fabricated by industry scalable spray-congealing process using divalent cation-induced gelification. E. coli-infected macrophages (multiplicity of infection (MOI 1:10) were treated with drug-free A-MS, where we found a consistent moderate reduction in bacillary viability. Particles were more efficiently and rapidly phagocytized by infected macrophages as compared with normal macrophage cells. Subsequently, A-MS induced markers of M1 macrophage responses and stimulated the processing and secretion of pro-inflammatory cytokines (IL-6, IL-12). It also notably augmented the generation of reactive oxygen species (ROS) and nitric oxide (NO) in infected cells. Results illustrate that, the blank A-MS (without a drug payload) able to moderately check the growth of intracellular E. coli (without significant cytotoxicity) by modulating the M1 inflammatory response by host cells. This "added value" can be utilized in the design and development of therapeutic system with the additional advantage of immune-modulatory activity, in addition to serving as a drug carrier.


Assuntos
Alginatos/farmacologia , Escherichia coli/imunologia , Imunidade Inata/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Microesferas , Alginatos/química , Animais , Citocinas/metabolismo , Humanos , Macrófagos/imunologia , Óxido Nítrico/metabolismo , Fagocitose/efeitos dos fármacos
8.
J Agric Food Chem ; 67(26): 7485-7495, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31180669

RESUMO

Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium, contaminating in a wide variety of foods and feeds. Mycotoxins, including OTA, could cause immunosuppression in almost all previous studies in vivo. However, the vast majority of results in vitro showed that mycotoxins caused immunostimulation. Why the results of studies in vitro are contrary to studies in vivo is unknown. Our study aims to explore the underlying reason and mechanism of the paradoxical effect. In this study, porcine alveolar macrophage cell line 3D4/21 was chosen as an in vitro model and treated with 1.0 µg/mL OTA for different times. Some indexes, such as expression of inflammatory cytokines, migration, phagocytosis, macrophage polarization, autophagy-related proteins, and Akt1 phosphorylation, were detected. The results showed that pro-inflammatory cytokine expression, migration, and phagocytosis were increased, with macrophage polarization to the M1 phenotype at 24 h of OTA exposure. Surprisedly, anti-inflammatory cytokine expression was increased, cell phagocytosis and migration were decreased, and macrophage polarization was switched from M1 to M2 at 72 h of OTA exposure. Furthermore, we found that long-time exposure of OTA also suppressed autophagy, and the autophagy activator blocked the OTA-induced immunosuppression. Phosphorylation of Akt1 plays a positive role in autophagy inhibition. In conclusion, long-time instead of short-time exposure of OTA in vitro induced immunosuppression. The immunosuppression mechanism of OTA in vitro involved inhibition of autophagy through upregulating p-Akt1. Our results provide new insight into research on the mechanism of mycotoxin-induced immunosuppression in vitro.


Assuntos
Imunossupressores/toxicidade , Macrófagos Alveolares/efeitos dos fármacos , Ocratoxinas/toxicidade , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Citocinas/genética , Citocinas/imunologia , Imunossupressores/administração & dosagem , Macrófagos Alveolares/imunologia , Ocratoxinas/administração & dosagem , Fagocitose/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Suínos , Fatores de Tempo
9.
Appl Microbiol Biotechnol ; 103(12): 4825-4838, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31053913

RESUMO

Arginase I has been documented to impair T cell function and attenuate cellular immunity, however, there is little evidence to reveal the effect of arginase I on macrophage function. Recently, recombinant human arginase I (rhArg) has been developed for cancer therapy and is in clinical trial for hepatocellular carcinoma, whereas the potential immunosuppression induced by rhArg limited its therapeutic efficacy. To improve the clinical outcome of rhArg, addressing the immune suppression appears to be particularly important. In this study, we found that rhArg attenuated macrophage functions, including inhibiting macrophage cell proliferation, nitric oxide (NO) and reactive oxygen species (ROS) production, cytokine secretion, MHC-II surface expression, and phagocytosis, thereby inducing immunosuppression in lipopolysaccharides (LPS)/interferon-γ (IFN-γ)-activated macrophages. Notably, we observed that rhArg downregulated autophagy in activated macrophages. Moreover, application of trehalose (an autophagy inducer) significantly restored the impaired immune function in activated macrophages, suggesting the essential role of autophagy in rhArg-induced immunosuppression. To further illustrate the effect of autophagy in immunosuppression, we then observed the effect of 3-MA (an autophagy inhibitor) on the immune function of macrophages. As expected, inhibiting autophagy by 3-MA attenuated immune functions in activated macrophages. Collectively, this study elucidated that rhArg induced immunosuppression in activated macrophages via inhibiting autophagy, providing potential strategy to ameliorate the immune suppression which is of great significance to cancer therapy and facilitating the development of rhArg as a potential therapy for malignant carcinomas.


Assuntos
Arginase/imunologia , Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Imunossupressores/farmacologia , Macrófagos/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Arginase/genética , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Citocinas/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Neoplasias Hepáticas/terapia , Macrófagos/patologia , Camundongos , Óxido Nítrico/metabolismo , Fagocitose/efeitos dos fármacos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/imunologia , Trealose/farmacologia
10.
Enzyme Microb Technol ; 127: 50-57, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31088616

RESUMO

Macrophages eliminate and destroy invading bacteria and contaminants by engulfing them or secreting cytokines that trigger downstream immune responses. Consequently, impairment of the phagocytic functions of macrophages and/or suppressing their cytokine secretion are dangerous to organisms that rely on immune protection. Accordingly, exposure to environmental nanoparticles (NPs) that display immunomodulatory properties are serious. In this work, two types of NPs, i.e., mild-toxicity CuInS2 NPs and high-toxicity CdTe NPs, were used to evaluate the effects of NP exposure for macrophages. Following incubation for 24 h, THP-1-derived macrophage viability was assessed using an MTT method after exposing the THP-1 cells to different concentrations of CuInS2 or CdTe NPs. Phagocytosis assays demonstrated that both CuInS2 and CdTe NPs impair phagocytic activity toward Staphylococcus aureus (S. aureus). After pretreatment with CuInS2 and CdTe NPs at 4 µmol/L, THP-1 macrophages exhibited decreases in phagocytic ratio from ca. 32.9% to ca. 18.5% and 18.7%, respectively. Since the zeta potentials of intact and weathered CuInS2 NPs were distributed over a wide range from positive to negative, large quantities of intact and weathered CuInS2 NPs bore sufficient positive charge on their surfaces to induce membrane depolarization, thus theoretically providing electrostatic forces between S. aureus and THP-1, which could induce downstream intracellular events that increase phagocytosis. However, real time polymerase chain reaction arrays revealed that transcription of the pro-inflammatory factors IL-1ß, IL-6, and TNF-α decreased while that of the anti-inflammatory factor IL-10 increased after treatment with CuInS2 NPs. Furthermore, transcription of TNF-α decreased while IL-10 increased after treatment with CdTe NPs. Thus, both kinds of NPs inhibited phagocytosis of S. aureus by THP-1 to some extent, confirming that immunosuppression can occur when macrophages are exposed to environmental NPs.


Assuntos
Citocinas/metabolismo , Fatores Imunológicos/metabolismo , Macrófagos/efeitos dos fármacos , Nanopartículas/metabolismo , Fagocitose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Fatores Imunológicos/química , Macrófagos/metabolismo , Nanopartículas/química , Staphylococcus aureus/imunologia , Células THP-1
11.
Cell Mol Biol (Noisy-le-grand) ; 65(4): 43-47, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31078151

RESUMO

The immune system is an important physiological defense system. Its balance and stability are closely related to the body's health. Once the immune system loses its dynamic balance, the immune response will be blocked, which will lead to the occurrence of various diseases. Hesperetin is a kind of natural flavonoids extracted from citrus fruits of Rutaceae and it has many pharmacological activities. However, its water solubility and liposolubility are poor, and it is easy to be quickly metabolized in vivo, so it is difficult to maintain high blood drug concentration. Therefore, its derivative (HES) was found by structural modification. In this study, THP-1 cells were used as experimental model to investigate the immunomodulatory effect of HES in vitro. The results showed that HES participates in immune response by enhancing phagocytosis of macrophages to promote the release of NO, IL-6 and IL-1ß, and enhancing immunity by up-regulating the expression of Bcl-2 and Bcl-XL proteins. This study provides a theoretical and practical basis for the development of HES as an immunomodulator in the future.


Assuntos
Hesperidina/farmacologia , Fatores Imunológicos/farmacologia , Macrófagos/imunologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Hesperidina/química , Humanos , Fatores Imunológicos/química , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Óxido Nítrico/biossíntese , Fagocitose/efeitos dos fármacos , Células THP-1 , Proteína bcl-X/metabolismo
12.
J Microbiol ; 57(8): 711-716, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31089970

RESUMO

Low-density lipoprotein (LDL) was recently reported to be an opsonin, enhancing the phagocytosis of group A Streptococcus (GAS) by human monocytic leukemia U937 cells due to the binding of LDL to some GAS strains. We postulated that LDL might also promote the opsonophagocytosis of Pseudomonas aeruginosa by U937 cells since this bacterium interacts with LDL. In this study, P. aeruginosa (CMCC10104), U937 cells, and human LDL were used in phagocytosis assays to test our hypothesis. Escherichia coli strain BL21, which does not interact with LDL, was used as a negative control. Colony counting and fluorescence microscopy were used to determine the bacterial quantity in the opsonophagocytosis assays. After incubation of U937 cells and P. aeruginosa with LDL (100 µg/ml) for 15 and 30 min, phagocytosis was observed to be increased by 22.71% and 32.90%, respectively, compared to that seen in the LDL-free group. However, LDL did not increase the phagocytosis of E. coli by U937 cells. In addition, we identified CD36 as a major opsonin receptor on U937 cells, since an anti-CD36 monoclonal antibody, but not an anti-CD4 monoclonal antibody, almost completely abolished the opsonophagocytosis of P. aeruginosa by U937 cells.


Assuntos
Anticorpos Monoclonais/imunologia , Lipoproteínas LDL , Proteínas Opsonizantes/imunologia , Fagocitose , Pseudomonas aeruginosa/imunologia , Escherichia coli/metabolismo , Humanos , Lipoproteínas LDL/imunologia , Lipoproteínas LDL/farmacologia , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Células U937
13.
Nature ; 568(7751): 187-192, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30944478

RESUMO

Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR-Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-ß oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.


Assuntos
Envelhecimento/fisiologia , Encéfalo/citologia , Homeostase/efeitos dos fármacos , Microglia/efeitos dos fármacos , Ácido N-Acetilneuramínico/farmacologia , Fagocitose/efeitos dos fármacos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Cognição/efeitos dos fármacos , Cognição/fisiologia , Feminino , Homeostase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Ácido N-Acetilneuramínico/química , Fagocitose/genética , Análise de Sequência de RNA , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo
14.
Int J Biol Macromol ; 132: 1024-1030, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30959132

RESUMO

ADPs-1a and ADPs-3a were two kinds of pure polysaccharide in Angelica dahurica. The immunomodulatory effects of ADPs-1a and ADPs-3a were assayed on phagocytosis, nitric oxide (NO) and cytokines of RAW264.7 cells, and the mechanism was investigated through NF-κB and MAPKs signaling pathway. RAW264.7 cells were stimulated by different concentrations of ADPs-1a and ADPs-3a with LPS (1 µg/mL) as positive control. The results showed that ADPs-1a and ADPs-3a could significantly enhance the phagocytic activity of RAW264.7 cells, and enhance the ability of RAW264.7 cells to release NO, TNF-α and IL-6 in a concentration-dependent manner. At the same time, ADPs-1a and ADPs-3a could significantly up-regulate the mRNA expression of iNOS, TNF-α, IL-6 and the phosphorylation level of p65, p38, ERK, JNK proteins. The immunomodulatory mechanism of ADPs-1a and ADPs-3a on macrophages was related to the up-regulation of phosphorylation of MAPKs and NF-kB.


Assuntos
Angelica/química , Fatores Imunológicos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Polissacarídeos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Interleucina-6/genética , Camundongos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Fagocitose/efeitos dos fármacos , Células RAW 264.7 , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/genética
15.
J Neuroinflammation ; 16(1): 69, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940161

RESUMO

BACKGROUND: Acute liver failure resulting from drug-induced liver injury can lead to the development of neurological complications called hepatic encephalopathy (HE). Hepatic transforming growth factor beta 1 (TGFß1) is upregulated due to liver failure in mice and inhibiting circulating TGFß reduced HE progression. However, the specific contributions of TGFß1 on brain cell populations and neuroinflammation during HE are not known. Therefore, the aim of this study was to characterize hepatic and brain TGFß1 signaling during acute liver failure and its contribution to HE progression using a combination of pharmacological and genetic approaches. METHODS: C57Bl/6 or neuron-specific transforming growth factor beta receptor 2 (TGFßR2) null mice (TGFßR2ΔNeu) were treated with azoxymethane (AOM) to induce acute liver failure and HE. The activity of circulating TGFß1 was inhibited in C57Bl/6 mice via injection of a neutralizing antibody against TGFß1 (anti-TGFß1) prior to AOM injection. In all mouse treatment groups, liver damage, neuroinflammation, and neurological deficits were assessed. Inflammatory signaling between neurons and microglia were investigated in in vitro studies through the use of pharmacological inhibitors of TGFß1 signaling in HT-22 and EOC-20 cells. RESULTS: TGFß1 was expressed and upregulated in the liver following AOM injection. Pharmacological inhibition of TGFß1 after AOM injection attenuated neurological decline, microglia activation, and neuroinflammation with no significant changes in liver damage. TGFßR2ΔNeu mice administered AOM showed no effect on liver pathology but significantly reduced neurological decline compared to control mice. Microglia activation and neuroinflammation were attenuated in mice with pharmacological inhibition of TGFß1 or in TGFßR2ΔNeu mice. TGFß1 increased chemokine ligand 2 (CCL2) and decreased C-X3-C motif ligand 1 (CX3CL1) expression in HT-22 cells and reduced interleukin-1 beta (IL-1ß) expression, tumor necrosis factor alpha (TNFα) expression, and phagocytosis activity in EOC-20 cells. CONCLUSION: Increased circulating TGFß1 following acute liver failure results in activation of neuronal TGFßR2 signaling, driving neuroinflammation and neurological decline during AOM-induced HE.


Assuntos
Córtex Cerebral/patologia , Encefalopatia Hepática/etiologia , Falência Hepática Aguda/complicações , Falência Hepática Aguda/patologia , Neurônios/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/deficiência , Fator de Crescimento Transformador beta1/sangue , Animais , Anticorpos/uso terapêutico , Azoximetano/toxicidade , Benzamidas/farmacologia , Carcinógenos/toxicidade , Linhagem Celular Transformada , Modelos Animais de Doenças , Encefalopatia Hepática/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/etiologia , Isoquinolinas/farmacologia , Fígado/metabolismo , Fígado/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Fagocitose/genética , Pirazóis/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
16.
Molecules ; 24(8)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018502

RESUMO

Several Ajuga species are used in Romanian folk medicine for their antioxidant, antimicrobial and anti-inflammatory properties, to treat pain, fever or arthritis. Still, the active compounds responsible for these effects and their mechanism of action are scarcely known. This research was designed to investigate the phytochemical profile (e.g. iridoids, polyphenolic compounds, phytosterols), as well as the biological potential (antioxidant, antibacterial, antifungal, anti-inflammatory properties) of two selected Ajuga species collected from different regions of Romanian spontaneous flora. The main compounds identified in A. reptans aerial parts extracts were 8-O-acetylharpagide, isoquercitrin and ß-sitosterol, whilst in A. genevensis were 8-O-acetylharpagide, luteolin and campesterol. The extracts were screened for their antioxidant potential using different methods (DPPH, TEAC, EPR) and the results showed a good activity, in accordance with the polyphenol content (18-26 mg GAE/g dw). The antifungal activity on the tested strains was good. The determination of few parameters linked with the inflammatory mechanism allowed the assessment of in vivo anti-inflammatory potential. Ajuga reptans and A. genevensis ethanol extracts had anti-inflammatory activity through lowering the oxidative stress, phagocytosis, PMN and total leukocytes. The best anti-oxidative and anti-inflammatory activity was observed for the Ajuga reptans 100 mg dw/mL extract when compared with diclofenac, thus the dose could be correlated with the pharmacological effect. These findings provide substantial evidence that both selected Ajuga species have the potential to be valued as sources of phytochemicals in effective anti-inflammatory herbal preparations.


Assuntos
Ajuga/química , Iridoides/farmacologia , Fitosteróis/farmacologia , Fitoterapia/métodos , Polifenóis/farmacologia , Animais , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Fungos/efeitos dos fármacos , Fungos/crescimento & desenvolvimento , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Humanos , Inflamação/tratamento farmacológico , Iridoides/química , Iridoides/isolamento & purificação , Testes de Sensibilidade Microbiana , Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Fitosteróis/química , Fitosteróis/isolamento & purificação , Picratos/antagonistas & inibidores , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Plantas Medicinais , Polifenóis/química , Polifenóis/isolamento & purificação , Ratos , Ratos Wistar , Romênia
17.
Mar Drugs ; 17(5)2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31027390

RESUMO

PT-peptide is derived from the anti-lipopolysaccharide factor of the swimming crab Portunus trituberculatus. The peptide, consisting of 34 amino acids, contains a lipopolysaccharide binding domain. In this study, we investigated the effect of PT-peptide encapsulated in raw milk-derived extracellular vesicles (EVs), designated as EVs-PT peptide, on immune regulation. The results showed that raw milk-derived EVs efficaciously delivered the PT-peptide into monocytes and elevated immune activity, including reactive oxygen species level, superoxide anion production, and phagocytosis. PT-peptide and EVs-PT peptide also elevated the secretion of cytokines, such as interferon-γ, interleukin-6, and tumor necrosis factor-α in human monocytic THP-1 cells. These results suggest that the PT-peptide could be developed as an immune stimulator.


Assuntos
Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Proteínas de Artrópodes/administração & dosagem , Braquiúros , Sistemas de Liberação de Medicamentos/métodos , Monócitos/efeitos dos fármacos , Animais , Linhagem Celular , Citocinas/metabolismo , Composição de Medicamentos/métodos , Vesículas Extracelulares/química , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/metabolismo , Leite/química , Monócitos/imunologia , Monócitos/metabolismo , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Espécies Reativas de Oxigênio/metabolismo
18.
Bull Exp Biol Med ; 166(6): 754-758, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31028579

RESUMO

We studied immunocorrecting effects of Semax (Met-Glu-His-Phe-Pro-Gly-Pro) on the model of "social" stress caused by sensory contact and intermale confrontation. Functional activity of the immune system of laboratory animals was evaluated in standard immunopharmacological tests: delayed-type hypersensitivity reaction, direct agglutination test, latex test for studying phagocytic activity of peripheral blood neutrophils, changes in differential leukocyte count, and weight of immunocompetent organs. It was found that changes in the immune response caused by "social" stress are multidirectional, which confirms the theory of stress-induced "immune imbalance". Semax acted as effective immune corrector restoring cellular and humoral immunogenesis reactions and phagocytic activity of neutrophils. This attested to the presence of immunomodulating properties in Semax and necessitates further studies in this field.


Assuntos
Hormônio Adrenocorticotrópico/análogos & derivados , Fatores Imunológicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Fragmentos de Peptídeos/farmacologia , Estresse Psicológico/tratamento farmacológico , Hormônio Adrenocorticotrópico/farmacologia , Agressão , Animais , Animais não Endogâmicos , Hipersensibilidade Tardia/tratamento farmacológico , Hipersensibilidade Tardia/imunologia , Imunidade Inata/efeitos dos fármacos , Testes de Fixação do Látex , Contagem de Leucócitos , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Fagocitose/efeitos dos fármacos , Estresse Psicológico/imunologia , Estresse Psicológico/fisiopatologia
19.
BMC Res Notes ; 12(1): 228, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30992057

RESUMO

OBJECTIVE: Intravenous immune globulin (IVIG), pooled from human blood, is a polyspecific antibody preparation that inhibits the super-antigenic proteins associated with streptococcal and staphylococcal toxic shock, and the Shiga toxin. In addition to this toxin-neutralising activity, IVIG contains other pathogen-reactive antibodies that may confer additional therapeutic benefits. We sought to determine if pathogen-reactive antibodies that promote opsonophagocytosis of different organisms can be sequentially affinity-purified from one IVIG preparation. RESULTS: Antibodies that recognise cell wall antigens of Streptococcus pyogenes, Staphylococcus aureus, and vancomycin-resistant enterococcus (VRE) were sequentially affinity-purified from a single preparation of commercial IVIG and opsonophagocytic activity was assessed using a flow cytometry assay of neutrophil uptake. Non-specific IgG-binding proteins were removed from the S. aureus preparations using an immobilised Fc fragment column, produced using IVIG cleaved with the Immunoglobulin G-degrading enzyme of S. pyogenes (IdeS). Affinity-purified anti-S. aureus and anti-VRE immunoglobulin promoted significantly higher levels of opsonophagocytic uptake by human neutrophils than IVIG when identical total antibody concentrations were compared, confirming activity previously shown for affinity-purified anti-S. pyogenes immunoglobulin. The opsonophagocytic activities of anti-S. pyogenes, anti-S. aureus, and anti-VRE antibodies that were sequentially purified from a single IVIG preparation were undiminished compared to antibodies purified from previously unused IVIG.


Assuntos
Anticorpos Antibacterianos/farmacologia , Imunoglobulinas Intravenosas/química , Neutrófilos/efeitos dos fármacos , Proteínas Opsonizantes/farmacologia , Fagocitose/efeitos dos fármacos , Anticorpos Antibacterianos/isolamento & purificação , Antígenos de Bactérias/química , Antígenos de Bactérias/imunologia , Parede Celular/química , Cromatografia de Afinidade/métodos , Humanos , Fragmentos Fc das Imunoglobulinas/química , Neutrófilos/citologia , Neutrófilos/imunologia , Proteínas Opsonizantes/isolamento & purificação , Cultura Primária de Células , Staphylococcus aureus/química , Staphylococcus aureus/imunologia , Staphylococcus aureus/patogenicidade , Streptococcus pyogenes/química , Streptococcus pyogenes/imunologia , Streptococcus pyogenes/patogenicidade , Enterococos Resistentes à Vancomicina/química , Enterococos Resistentes à Vancomicina/imunologia , Enterococos Resistentes à Vancomicina/patogenicidade
20.
BMC Vet Res ; 15(1): 105, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943971

RESUMO

BACKGROUND: A previous study showed that prebiotics and synbiotics administered in ovo into the egg air cell on the 12th day of incubation enhance the growth and development of chickens. However, the influence of this procedure on the development and efficiency of the innate immune system of broiler chickens is unclear. Therefore, the aim of this study was to evaluate whether the early (on the 12th day of embryo development) in ovo administration of selected prebiotics (inulin - Pre1 and Bi2tos - Pre2) and synbiotics (inulin + Lactococcus lactis subsp. lactis IBB SL1 - Syn1 and Bi2tos + L. lactis subsp. cremoris IBB SC1 - Syn2) influences the innate immune system. RESULTS: Chickens (broiler, Ross 308) that were treated with Pre1 exhibited a decreased H/L ratio on D7, but an increased H/L ratio was observed on D21 and D35. In the remaining experimental groups, an increase in the H/L ratio was observed on D21 and D35. The oxidative potential of leukocytes measured using the NBT test increased on D21 in Pre2 and Syn1 groups. The rate of the phagocytic ability of leukocytes increased in Pre1 and Syn1 groups on D21. The phagocytic index decreased in Pre1 and Syn2 groups on D21 and D35. Concurrently, the count of WBC in circulating blood decreased on D21 in Pre1, Pre2, and Syn1 groups. The hematocrit value was increased in Syn1 chickens on D21, in Pre1 chickens on D35, and in Syn2 chickens on both time points. CONCLUSIONS: Early in ovo treatment of chicken embryos with prebiotics and synbiotics may temporarily modulate not only the production/maturation of leukocytes but also their reactivity.


Assuntos
Embrião de Galinha/efeitos dos fármacos , Galinhas/imunologia , Imunidade Inata/efeitos dos fármacos , Prebióticos/administração & dosagem , Simbióticos/administração & dosagem , Animais , Proteínas Sanguíneas/análise , Embrião de Galinha/imunologia , Galinhas/sangue , Hematócrito/veterinária , Contagem de Leucócitos/veterinária , Fagocitose/efeitos dos fármacos
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