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1.
Int J Nanomedicine ; 14: 7309-7322, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571855

RESUMO

Introduction: The only treatment for aseptic loosening is the replacement of the prosthesis through revision surgery. A preventive approach, achieved through anti-inflammatory drugs released from the device, has shown to be a viable strategy; however, the performance of these devices is not yet satisfactory thus further improvements are necessary. Methods: We used titanium nanoparticles as a model for implant surfaces and developed a coating containing dexamethasone (DEX) using layer-by-layer deposition. Results: The amount of deposited drug depended on the number of layers and the release was sustained for months. The efficiency of the released DEX in reducing inflammation markers (tumor necrosis factor alpha and IL-6) produced by human monocytes and macrophages was similar to the pure drug at the same concentration without negative impacts on the viability and morphology of these cells. Conclusion: These coatings were not inferior to medical grade titanium (the standard material used in uncemented devices) regarding their ability to sustain osteoblasts and fibroblasts growth.


Assuntos
Anti-Inflamatórios/farmacologia , Cimentos para Ossos/farmacologia , Materiais Revestidos Biocompatíveis/farmacologia , Liberação Controlada de Fármacos , Nanopartículas/química , Falha de Prótese , Linhagem Celular , Forma Celular/efeitos dos fármacos , Dexametasona/farmacologia , Fibroblastos/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Monócitos/efeitos dos fármacos , Nanopartículas/ultraestrutura , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Tamanho da Partícula , Termogravimetria
2.
Chem Biol Interact ; 314: 108844, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31600484

RESUMO

Using data from Schink et al. (2018), a large number of herbal extracts were assessed for their capacity to induce pro- and anti-inflammatory effects based on TLR4 expression normalized for cell viability in two immune cell models (i.e., HeLa-TLR4 transfected reporter cell line, and THP-1 monocytes) applying seven concentrations (0.01-3.0%). The analysis revealed that 70-80% of the extracts satisfying the a priori entry criteria also satisfied a priori evaluative criteria for hormetic concentration responses. These findings demonstrate that a large proportion of herbal extracts display hormetic dose responses in immune cells, indicating that hormetic mechanisms mediate pro- and anti-inflammatory processes and may provide a means to guide optimal dosing strategies. The identification of doses eliciting only anti-inflammatory therapeutic activity as well as the use of dose-variable herbal extracts in the treatment of inflammatory diseases will be challenging.


Assuntos
Anti-Inflamatórios/farmacologia , Hormese/efeitos dos fármacos , Extratos Vegetais/química , Plantas Medicinais/química , Anti-Inflamatórios/química , Linhagem Celular , Células HeLa , Humanos , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Extratos Vegetais/farmacologia , Plantas Medicinais/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
3.
Int J Nanomedicine ; 14: 7861-7878, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576128

RESUMO

Background and purpose: Nanogels (NGs) are promising drug delivery tools but are typically limited to hydrophilic drugs. Many potential new drugs are hydrophobic. Our study systematically investigates amphiphilic NGs with varying hydrophobicity, but similar colloidal features to ensure comparability. The amphiphilic NGs used in this experiment consist of a hydrophilic polymer network with randomly distributed hydrophobic groups. For the synthesis we used a new synthetic platform approach. Their amphiphilic character allows the encapsulation of hydrophobic drugs. Importantly, the hydrophilic/hydrophobic balance determines drug loading and biological interactions. In particular, protein adsorption to NG surfaces is dependent on hydrophobicity and critically determines circulation time. Our study investigates how network hydrophobicity influences protein binding, biocompatibility and cellular uptake. Methods: Biocompatibility of the NGs was examined by WST-1 assay in monocytic-like THP-1 cells. Serum protein corona formation was investigated using dynamic light scattering and two-dimensional gel electrophoresis. Proteins were identified by liquid chromatography-tandem mass spectrometry. In addition, cellular uptake was analyzed via flow cytometry. Results: All NGs were highly biocompatible. The protein binding patterns for the two most hydrophobic NGs were very similar to each other but clearly different from the hydrophilic ones. Overall, protein binding was increased with increasing hydrophobicity, resulting in increased cellular uptake. Conclusion: Our study supports the establishment of structure-property relationships and contributes to the accurate balance between maximum loading capacity with low protein binding, optimal biological half-life and good biocompatibility. This is an important step to derive design principles of amphiphilic NGs to be applied as drug delivery vehicles.


Assuntos
Materiais Biocompatíveis/farmacologia , Endocitose , Géis/química , Interações Hidrofóbicas e Hidrofílicas , Nanopartículas/química , Coroa de Proteína/química , Tensoativos/química , Adsorção , Sobrevivência Celular/efeitos dos fármacos , Análise por Conglomerados , Humanos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Nanopartículas/ultraestrutura , Tamanho da Partícula , Células THP-1
4.
Life Sci ; 235: 116817, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476309

RESUMO

AIMS: In the tumor microenvironment, dysregulated immune cells could promote tumor progression, invasion and metastasis, by establishing a symbiotic relationship with cancer cells. A pivotal role is played by monocyte recruitment and induction of tumor-associated macrophages (TAMs), which provide immunosuppression and tumorigenesis. The effect of nemorosone, an antiproliferative phytocomponent present in Cuban Propolis, on TAM-induced tumor progression remains to be elucidated. Here we investigated the symbiotic relationship between monocytic leukemia THP-1 and hepatocellular carcinoma HepG2 cells, and the role of nemorosone in preventing TAM-induced tumor growth. MAIN METHODS: Macrophage differentiation induced by HepG2-conditioned medium was assessed by flow cytometry, analysis of secreted molecules and cytokine expression. The effect of nemorosone and/or conditioned THP-1-medium on HepG2 proliferation was evaluated by MTT assay, colony formation, cells cycle and migration assays. KEY FINDINGS: HepG2 cells induced THP-1 recruitment and differentiation to macrophages. When compared with control THP-1 cells, differentiated THP-1 showed a significant increase of the matrix metalloproteinases MMP-2 and MMP-9 expression (P < 0.01), and slightly induced HepG2 cells growth. This effect was counteracted by nemorosone, which also significantly inhibited colony formation (P < 0.01) and migratory capacity of HepG2 cells, driving a high percentage of cells (80%) to the G0/G1 phase. SIGNIFICANCE: HepG2-conditioned medium is a suitable model for THP-1 modulation and differentiation. Moreover, nemorosone significantly inhibits the proliferation of HepG2 cells, both in presence and absence of the soluble factors secreted by TAMs. Further studies are needed to elucidate the role of this natural compound in the HCC-TAM relationship.


Assuntos
Benzofenonas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Monócitos/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Diferenciação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Monócitos/citologia , Monócitos/metabolismo , Células THP-1
5.
Anticancer Res ; 39(8): 4475-4478, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366547

RESUMO

Chronic inflammation is involved in the development of cancer, lifestyle-related diseases, and autoimmune diseases. It also influences the severity of these diseases. Macrophages that accumulate in tumor tissues and adipose tissues of obesity have been shown to increase expression of inflammatory cytokines, thereby inducing inflammatory changes in these tissues. The macrophage phenotype is believed to be important in mediating inflammatory changes in tissues. Recently, monocytes/macrophages activated with low-dose lipopolysaccharide (LPS) were demonstrated to suppress increased expression of monocyte chemotactic protein (MCP)-1 and inflammatory cytokines (interleukin (IL)-1 ß, IL-8, and tumor necrosis factor (TNF)-α). By suppressing the increased expression of chemotaxis-related and inflammation-related factors, monocytes/macrophages activated with low-dose LPS are considered to suppress the migration of macrophages into tissues and to regulate inflammatory changes in these tissues, respectively. The effects of macrophages activated with low-dose LPS were different from those of macrophages activated with high-dose LPS. In this review, we discuss the usefulness of monocytes/macrophages activation by low-dose LPS.


Assuntos
Inflamação/tratamento farmacológico , Lipopolissacarídeos/uso terapêutico , Neoplasias/tratamento farmacológico , Obesidade/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Quimiocina CCL2/genética , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Interleucina-1beta/genética , Interleucina-8/genética , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Neoplasias/genética , Obesidade/patologia , Fator de Necrose Tumoral alfa/genética
6.
J Food Sci ; 84(7): 1920-1928, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31264720

RESUMO

Vanillin, a kind of phenolic compound, is naturally found in food and beverage and widely used as a flavoring agent. In view of the safety and universality of vanillin, exploring the functions of vanillin on human is of great value. Thus, lipopolysaccharide (LPS)-activated THP-1 cells were selected as the cell model to evaluate the anti-inflammatory effect of vanillin in this study. On the basis of the results, vanillin markedly suppressed the expression of inflammatory cytokines (that is, TNF-α, IL-1ß, IL-6, and IL-8), mediators (NO, iNOS, PGE2, and COX-2), and NLRP3 inflammasome (that is, NLRP3, ASC, and caspase-1), blocked the LPS-induced activation of the NF-κB/IκBα/AP-1 signaling pathway, and activated the gene expression of the Nrf2/HO-1 signaling pathway. In addition, it was confirmed that vanillin was unable to react with LPS due to the results of quantification by HS-SPME-GC-MS. Hence, vanillin could effectively attenuate LPS-induced inflammatory response by regulating the expression of intracellular signaling pathways in THP-1 cells. It is a potent anti-inflammatory component found in food and beverage. These findings might contribute to the overall understanding of the potential health benefits of vanillin for food application. PRACTICAL APPLICATION: In this study, the anti-inflammatory effect of vanillin (VA) was evaluated by ELISA, real-time PCR, and western blot in LPS-induced THP-1 cells. The hypothesis that VA could react with LPS was excluded due to the results of quantification by HS-SPME-GC-MS. On the basis of the result, vanillin could effectively attenuate LPS-induced inflammatory response in THP-1 cells and was a potent anti-inflammatory component natural in food and beverage. These findings might contribute to the overall understanding of the potential health benefits of vanillin for food application.


Assuntos
Anti-Inflamatórios/farmacologia , Benzaldeídos/farmacologia , Lipopolissacarídeos/farmacologia , Monócitos/efeitos dos fármacos , Ciclo-Oxigenase 2/imunologia , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Interleucina-1beta/imunologia , Lipopolissacarídeos/imunologia , Monócitos/imunologia , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Óxido Nítrico Sintase Tipo II/imunologia , Células THP-1
7.
Life Sci ; 232: 116624, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276689

RESUMO

AIMS: Monocyte-endothelial adhesion is considered to be the primary initiator of inflammatory vascular diseases, such as atherosclerosis. Connexin 43 (Cx43) has been reported to play an important part in this process, however, the underlying mechanisms are not fully understood. Intravenous anesthetics, propofol is commonly used in the perioperative period and in the intensive care unit, and considered to have good anti-inflammatory and antioxidant effects. Thus, we speculate that propofol could influence monocyte-endothelial adhesion, and explore whether its possible mechanism is relative with Cx43 expression in U937 monocytes influencing cell adhesion of U937 monocytes to human umbilical vein endothelial cells (HUVEC). MAIN METHODS: Cx43-siRNAs or pc-DNA-Cx43 were used to alter Cx43 expression in U937 monocytes. Propofol was given as pretreatments to U937 monocytes. Then, cell adhesion, ZO-1, LFA-1, VLA-4, COX and MCP-1 were determined. PI3K/AKT/NF-κB signaling pathway was explored to clarify the possible mechanism. KEY FINDINGS: Alternation of Cx43 expression affects cell adhesion and adhesion molecules significantly, such as ZO-1, LFA-1, VLA-4, COX-2 and MCP-1, the mechanism of which is relative with Cx43 influencing the activation of PI3K/AKT/NF-κB signaling pathway. Preconditioning with propofol at its clinically relevant anesthesia concentration attenuates cell adhesion. Propofol not only decreases Cx43 expression in U937 monocytes, but also depresses the activation of PI3K/AKT/NF-κB signaling pathway. SIGNIFICANCE: Modulation Cx43 expression in U937 monocytes could affect cell adhesion via regulating the activation of PI3K/AKT/NF-κB signaling pathway. Propofol attenuates cell adhesion via inhibiting Cx43 and its downstream signaling pathway of PI3K/AKT/NF-κB.


Assuntos
Adesão Celular/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Propofol/farmacologia , Aterosclerose/metabolismo , Moléculas de Adesão Celular/metabolismo , Conexina 43/efeitos dos fármacos , Conexina 43/genética , Conexina 43/metabolismo , Endotélio Vascular/metabolismo , Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Monócitos/fisiologia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Propofol/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células U937/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
8.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(4): 307-312, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31167689

RESUMO

Objective To explore the effect of pexidartinib on the recruitment of monocytes into the tumor microenvironment and the polarization of M2 macrophages. Methods The colon cancer mouse model was established with the subcutaneous rejection of MC38 cells. After the tumor-bearing mice were treated with pexidartinib, we observed the effects of pexidartinib on the tumor growth, the survival of tumor-bearing mouse and the number of intratumoral tumor-associated macrophages (TAMs). Peripheral blood mononuclear cells were isolated from the enhanced green fluorescent protein (EGFPTg/+) transgenic mice and then transferred into the tumor-bearing mice via tail vein. After the tumor-bearing mice were treated with pexidartinib, the monocyte recruitment and the proportions of F4/80 and CD206-positive cells were detected by the immunofluorescence and flow cytometry. Results Pexidartinib alleviated the growth of MC38 cells in vivo and improved the survival rate in tumor-bearing mice. Pexidartinib reduced the number of TAMs and the formation of M2 TAMs in the tumor microenvironment, and inhibited the recruitment of monocytes from peripheral blood to the tumor microenvironment. Conclusion Pexidartinib can inhibit the tumor growth by suppressing the aggregation of macrophages and the number of M2 TAMs in the tumor microenvironment.


Assuntos
Aminopiridinas/farmacologia , Neoplasias do Colo/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Pirróis/farmacologia , Microambiente Tumoral , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Citometria de Fluxo , Leucócitos Mononucleares , Camundongos
9.
Artif Cells Nanomed Biotechnol ; 47(1): 1839-1845, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31066305

RESUMO

Atherosclerosis is the chronic inflammatory disease, and inflammation-elicited endothelial activation is an early event in the development of atherosclerosis. The P2Y11 receptor is a purinergic receptor and a member of the P2 family of G coupled protein which has been shown to modulate vascular function. Progress in the study of purine receptors has been tremendous and these receptors have become pharmacological targets for various diseases. In this study, we show that the P2Y11R antagonist NF157 can mitigate oxidized LDL (ox-LDL)-induced endothelial inflammation. Our study demonstrates that P2Y11R is expressed to a fair degree in human aortic endothelial cells and is induced by treatment with ox-LDL. Blockage of P2Y11R by its selective antagonist NF157 ameliorates ox-LDL-induced adhesion of THP-1 monocytes to endothelial cells. NF157 inhibits ox-LDL-induced expression of adhesion molecules including E-selectin and VCAM-1. NF157 also suppresses ox-LDL-associated ROS production and induction of the NADPH oxidase subunit NOX-4. Moreover, NF157 has an inhibitory effect on the production of major cytokines including IL-6 and TNF-α. Mechanistically, we show that NF157 mitigates ox-LDL-induced phosphorylation of MAPK kinase p38 and NF-κB activation. Our findings indicate that blockage of P2Y11R signalling by its antagonist NF157 may protect endothelial cells from ox-LDL-induced endothelial inflammation. Therefore, NF157 may have therapeutic implications in the modulation of atherosclerosis-associated inflammation.


Assuntos
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , Receptores Purinérgicos P2/metabolismo , Suramina/análogos & derivados , Adesão Celular/efeitos dos fármacos , Selectina E/genética , Ativação Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Inflamação/tratamento farmacológico , Interleucina-6/biossíntese , Monócitos/citologia , Monócitos/efeitos dos fármacos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Suramina/farmacologia , Suramina/uso terapêutico , Fator de Necrose Tumoral alfa/biossíntese , Molécula 1 de Adesão de Célula Vascular/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
Food Chem Toxicol ; 129: 162-168, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31042592

RESUMO

Treatment of many inflammatory diseases involves a chronic use of NSAIDs in large doses increasing acute kidney injury risk. This study was designed to evaluate a potential renoprotective effect of Gum Acacia (GA) on diclofenac (DICF) induced nephrotoxicity. Six groups of rats were used: normal group; control group (deprived from water during week 13), DICF group (deprived from water during week 13 and injected DICF i.p. 15 mg/kg/12 h at days 4 through 6 of water deprivation days, GA groups (1, 2 or 3 g/kg/day in drinking water) for 12 weeks followed by water deprivation and DICF injection as described. Kidney function, oxidative stress and anti-oxidant biomarkers were measured. Interleukin-1ß, IL-10, TNF-α, complement receptor (CR)-1, monocyte chemoattractant protein (MCP)-1 and caspase-3 were assessed. Kidney sections were scored for fibrosis, tubular injury and inflammatory cells. An elevation in renal biomarkers, inflammatory cytokines, malondialdehyde and apoptotic markers was observed after DICF injection (p < 0.001). Gum Acacia (mostly 3 g/kg) markedly reduced fibrosis, tubular injury, IL-1ß, TNF-α, caspase-3 and MCP-1 levels (p < 0.01). It increased IL-10, anti-oxidant capacity, CR-1 level in the kidney (p < 0.001). Protective effect may be mediated by antioxidant, anti-inflammatory and anti-apoptotic mechanisms besides interfering with monocytes and complement mediated tissue damage pathways.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Anti-Inflamatórios não Esteroides/toxicidade , Apoptose/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Diclofenaco/toxicidade , Goma Arábica/farmacologia , Rim/efeitos dos fármacos , Receptores de Complemento/metabolismo , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Interleucina-1beta/metabolismo , Rim/metabolismo , Masculino , Monócitos/efeitos dos fármacos , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
11.
J Immunol Res ; 2019: 2198508, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31093509

RESUMO

Transferon® is a complex drug based on a mixture of low molecular weight peptides. This biotherapeutic is employed as a coadjuvant in clinical trials of several diseases, including viral infections and allergies. Given that macrophages play key roles in pathogen recognition, phagocytosis, processing, and antigen presentation, we evaluated the effect of Transferon® on phenotype and function of macrophage-like cells derived from THP-1 monocytes. We determined the surface expression of CD80 and CD86 by flow cytometry and IL-1ß, TNF-α, and IL-6 levels by ELISA. Transferon® alone did not alter the steady state of PMA-differentiated macrophage-like THP-1 cells. On the contrary, simultaneous stimulation of cells with Transferon® and LPS elicited a significant increase in CD80 (P ≤ 0.001) and CD86 (P ≤ 0.001) expression, as well as in IL-6 production (P ≤ 0.05) compared to the LPS control. CD80 expression and IL-6 production exhibited a positive correlation (r = 0.6, P ≤ 0.05) in cells exposed to Transferon® and LPS. Our results suggest that the administration of Transferon® induces the expression of costimulatory molecules and the secretion of cytokines in LPS-activated macrophages. Further studies are necessary to determine the implication of these findings in the therapeutic properties of Transferon®.


Assuntos
Antígeno B7-1/genética , Interleucina-6/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Fator de Transferência/farmacologia , Antígeno B7-1/imunologia , Antígeno B7-2/genética , Antígeno B7-2/imunologia , Diferenciação Celular/efeitos dos fármacos , Citocinas/imunologia , Citometria de Fluxo , Humanos , Contagem de Leucócitos , Monócitos/efeitos dos fármacos , Células THP-1
12.
Mol Immunol ; 112: 30-39, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31075560

RESUMO

Traumatic brain injury (TBI) is a major cause of motor and cognitive impairment in young adults. It is associated with high mortality rates and very few effective treatment options. Bisperoxovanadium (pyridine-2-carboxyl) [bpV(pic)] is an commercially available inhibitor of Phosphatase and tensin homolog (PTEN). Previous studies have shown that bpV(pic) has protective effects in central nervous system. However, the role of bpV(pic) in TBI is unclear. In this study we aimed to investigate the neuroprotective role of bpV(pic) in rat TBI model. We found that injection of bpV(pic) significantly reduces brain edema and neurological dysfunction after TBI and this is mediated by AKT pathway. TBI is known to promote the M1 pro-inflammatory phenotype of microglial polarization and this effect is inhibited by bpV(pic) treatment which, instead promotes M2 microglial polarization in vivo and in vitro. We also found evidence of bpV(pic)-regulated neuroinflammation mediated by AKT activation and NF-κB p65 inhibition. BpV(pic) treatment also suppressed microglia in the peri-TBI region. MCP-1 is known to recruit monocytes and macrophages to promote inflammation, we show that bpV(pic) can inhibit TBI-induced up-regulation of MCP-1 via the AKT/NF-κB p65 signaling pathway. Taken together, our findings demonstrate that bpV(pic) plays a neuroprotective role in rat TBI, which may be achieved by inhibiting M1 microglia polarization and MCP-1 expression by modulating AKT/NF-κB p65 signaling pathway.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Quimiocina CCL2/metabolismo , Microglia/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Microglia/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , NF-kappa B/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley
13.
Microb Pathog ; 133: 103546, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31112769

RESUMO

With this study, we investigated the effect of synthetic antimicrobial peptides Pep19-2.5 and Pep194LF alone or in combination with antibiotics on S. mutans growth and biofilm formation/disruption. We also examined the cytotoxic effect of each peptide on monocytes. S. mutans was cultured in the presence of different concentrations of each peptide. We showed that Pep19-2.5 and Pep19-4LF were able to significantly (p ≤ 0.01) inhibit the growth of S. mutans. The synthetic peptides also decreased biofilm formation by S. mutans. Furthermore, both peptides reduced the viability of S. mutans in already formed biofilms. The combination of each peptide with antibiotics (penicillin/streptomycin, P/S) produced additive interactions which inhibited S. mutans growth and biofilm formation. Pep19-2.5 and Pep19-4LF were nontoxic, as they did not decrease monocyte viability and did not increase the lactate dehydrogenase activity of the exposed cells. In conclusion, synthetic peptides Pep19-2.5 and Pep19-4LF did inhibit S. mutans growth and its capacity to form biofilm. Both peptides were found to be nontoxic to monocytes. These data provide new insight into the efficacy of synthetic peptides Pep19-2.5 and Pep19-4LF against S. mutans. These peptides may thus be useful in controlling the adverse effects of this cariogenic bacterium in human.


Assuntos
Anti-Infecciosos/farmacologia , Biofilmes/efeitos dos fármacos , Proteínas do Tecido Nervoso/farmacologia , Peptídeos/farmacologia , Streptococcus mutans/efeitos dos fármacos , Peptídeos Catiônicos Antimicrobianos , Biofilmes/crescimento & desenvolvimento , Sobrevivência Celular/efeitos dos fármacos , Combinação de Medicamentos , Sinergismo Farmacológico , Humanos , L-Lactato Desidrogenase/metabolismo , Testes de Sensibilidade Microbiana , Monócitos/efeitos dos fármacos , Proteínas do Tecido Nervoso/síntese química , Penicilinas/farmacologia , Peptídeos/síntese química , Streptococcus mutans/crescimento & desenvolvimento
14.
Nat Commun ; 10(1): 1999, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31040289

RESUMO

Mononuclear phagocytes (MPs) including monocytes, macrophages and dendritic cells (DCs) are critical innate immune effectors and initiators of the adaptive immune response. MPs are present in the alveolar airspace at steady state, however little is known about DC recruitment in acute pulmonary inflammation. Here we use lipopolysaccharide inhalation to induce acute inflammation in healthy volunteers and examine the impact on bronchoalveolar lavage fluid and blood MP repertoire. Classical monocytes and two DC subsets (DC2/3 and DC5) are expanded in bronchoalveolar lavage fluid 8 h after lipopolysaccharide inhalation. Surface phenotyping, gene expression profiling and parallel analysis of blood indicate recruited DCs are blood-derived. Recruited monocytes and DCs rapidly adopt typical airspace-resident MP gene expression profiles. Following lipopolysaccharide inhalation, alveolar macrophages strongly up-regulate cytokines for MP recruitment. Our study defines the characteristics of human DCs and monocytes recruited into bronchoalveolar space immediately following localised acute inflammatory stimulus in vivo.


Assuntos
Células Dendríticas/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Macrófagos Alveolares/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Humanos , Lipopolissacarídeos/administração & dosagem
15.
Phytother Res ; 33(7): 1805-1814, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31094018

RESUMO

A previous report indicated that the flavonoid-rich extract of bergamot juice (BJe) exerts an anti-inflammatory effect through the activation of SIRT1 in leukemic monocytes THP-1 exposed to lipopolysaccharide (LPS). In this study, we deeply investigate the mode of action of BJe, along with its major flavonoids on SIRT1 through cell-free, in silico, and in vitro experimental models. In the cell-free assay, all the tested compounds as well as the whole BJe inhibited the deacetylase activity of SIRT1. This finding was reinforced by the results of the in silico study. In THP-1 cells exposed to LPS, a reduction of SIRT1 activity was observed, effect that was reverted by the pre-incubation with either BJe or its major flavonoids. This effect was also observed at gene level. Employing an activator and an inhibitor of AMP-activated protein kinase (AMPK; AICAR and dorsomorphin, respectively), we discovered its involvement in the activation of SIRT1 elicited by BJe or its major flavonoids in whole cell. Our study indicates the dual role of BJe and its components, depending on the employed experimental model as well as reveals their mode of action on the AMPK/SIRT1 axis, suggesting their role as promising candidates in pathologies in which this axis is implied.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Citrus , Flavonoides/farmacologia , Extratos Vegetais/farmacologia , Sirtuína 1/metabolismo , Simulação por Computador , Humanos , Lipopolissacarídeos/farmacologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Células THP-1
16.
Phytomedicine ; 59: 152902, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30981184

RESUMO

BACKGROUND: Curcuminoids, mainly present in the plant rhizomes of turmeric (Curcuma longa), consist of mainly three forms (curcumin (CUR), bisdemethoxycurcumin (BDMC) and demethoxycurcumin (DMC)). It has been reported that different forms of curcuminoids possess different biological activities. However, the mechanisms associated with these differences are not well-understood. Recently, our laboratory found differences in the cellular uptake of these curcuminoids. Therefore, it has been inferred that these differences contribute to the different biological activities. PURPOSE: In this study, we investigated the mechanisms of differential cellular uptake of these curcuminoids. METHOD: Based on our previous study, we hypothesized the differential cellular uptake is caused by (I) polarity, (II) transporters, (III) metabolism rate of curcuminoids and (IV) medium components. These four hypotheses were each investigated by (I) neutralizing the polarities of curcuminoids by encapsulation into poly(lactic-co-glycolic) acid nanoparticles (PLGA-NPs), (II) inhibition of polyphenol-related absorption transporters, (III) analysis of the cellular curcuminoids and their metabolites by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and (IV) use of different mediums in cell study. RESULTS: The differential cellular uptake was not affected by (I-III). However, when investigating (IV), not only CUR but also BDMC and DMC were incorporated into cells when serum free media was used. Furthermore, when we used the serum free medium containing bovine serum albumin (BSA), only CUR was taken up but BDMC and DMC were not. Therefore, we identified that the differential cellular uptake of curcuminoids is caused by the medium components, especially BSA. Also, the fluorescence quenching study suggested that differential cellular uptake is due to the different interaction between BSA and each curcuminoid. CONCLUSION: The differential cellular uptake of curcuminoids was caused by the different interaction between curcuminoids and BSA. The results from this study might give clues on the mechanisms by which curcuminoids exhibit different physiological activities.


Assuntos
Albuminas/metabolismo , Curcumina/análogos & derivados , Curcumina/farmacocinética , Albuminas/química , Linhagem Celular , Cromatografia Líquida , Curcuma/química , Curcumina/química , Humanos , Monócitos/efeitos dos fármacos , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Espectrometria de Massas em Tandem/métodos
17.
Int J Mol Sci ; 20(8)2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31010051

RESUMO

Interleukin (IL)-32θ, a newly identified IL-32 isoform, has been reported to exert pro-inflammatory effects through the association with protein kinase C delta (PKCδ). In this study, we further examined the effects of IL-32θ on IL-13 and IL-13Rα2 expression and the related mechanism in THP-1 cells. Upon stimulating IL-32θ-expressing and non-expressing cells with phorbol 12-myristate 13-acetate (PMA), the previous microarray analysis showed that IL-13Rα2 and IL-13 mRNA expression were significantly decreased by IL-32θ. The protein expression of these factors was also confirmed to be down-regulated. The nuclear translocation of transcription factors STAT3 and STAT6, which are necessary for IL-13Rα2 and IL-13 promoter activities, was suppressed by IL-32θ. Additionally, a direct association was found between IL-32θ, PKCδ, and signal transducer and activator of transcription 3 (STAT3), but not STAT6, revealing that IL-32θ might act mainly through STAT3 and indirectly affect STAT6. Moreover, the interaction of IL-32θ with STAT3 requires PKCδ, since blocking PKCδ activity eliminated the interaction and consequently limited the inhibitory effect of IL-32θ on STAT3 activity. Interfering with STAT3 or STAT6 binding by decoy oligodeoxynucleotides (ODNs) identified that IL-32θ had additive effects with the STAT3 decoy ODN to suppress IL-13 and IL-13Rα2 mRNA expression. Taken together, our data demonstrate the intracellular interaction of IL-32θ, PKCδ, and STAT3 to regulate IL-13 and IL-13Rα2 synthesis, supporting the role of IL-32θ as an inflammatory modulator.


Assuntos
Subunidade alfa2 de Receptor de Interleucina-13/metabolismo , Interleucina-13/metabolismo , Interleucinas/farmacologia , Monócitos/metabolismo , Proteína Quinase C-delta/metabolismo , Fator de Transcrição STAT3/metabolismo , Sítios de Ligação , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Humanos , Subunidade alfa2 de Receptor de Interleucina-13/genética , Interleucinas/metabolismo , Modelos Biológicos , Monócitos/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais/efeitos dos fármacos
18.
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
19.
Molecules ; 24(8)2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010153

RESUMO

Preeclampsia (PE) is a human pregnancy-specific syndrome with abnormal activation of cells from the innate immune system. The present study evaluated whether silibinin (SB) treatment of monocytes from preeclamptic women could modulate NLRP1 and NLRP3 inflammasomes as well as TLR4/NF-κB pathway activation. Peripheral blood monocytes from 20 preeclamptic and 20 normotensive (NT) pregnant women, as well as the THP-1 cell line, were cultured with or without monosodium urate (MSU) or SB. NLRP1, NLRP3, Caspase-1, TLR4, MyD88, NF-κB, IL-1ß, IL-18, TNF-α and IL-10 gene expression by monocytes was analysed by quantitative real-time polymerase chain reaction (qPCR), while inflammatory cytokine production and p65NF-κB activity were determined by enzyme-linked immunosorbent assays (ELISAs). TLR4/MyD88/NF-κB and NLRP1/NLRP3 inflammasomes pathways in THP-1 cells were evaluated by flow cytometry and western blot respectively. Compared with NT women, monocytes from preeclamptic women showed The Ethics Committee of the Botucatu Medical School approved the study (protocol number 2.333.216)higher endogenous activation of NLRP1/NLRP3 inflammasomes and the TLR4/NF-κB pathway as well as higher gene and protein expression of IL-1ß, IL-18 and TNF-α, and lower expression of IL-10. Monocyte stimulation with MSU increased inflammation-related genes as well as NF-κB activity. In vitro, SB treatment of monocytes from preeclamptic women reduced the basal activation of these cells by decreasing NLRP1/NLRP3 inflammasomes and p65NF-κB activity. THP-1 cells exhibited a similar immunological response profile to monocytes from preeclamptic women when cultured with or without MSU or SB. These results suggest uric acid participates in the systemic inflammatory response characteristic of preeclampsia and that in vitro SB treatment can modulate the sterile inflammation established in monocytes from preeclamptic women.


Assuntos
Inflamassomos/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Monócitos/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/metabolismo , Feminino , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Monócitos/efeitos dos fármacos , Gravidez , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Células THP-1 , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
EBioMedicine ; 43: 392-410, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30981648

RESUMO

BACKGROUND: Multiple Sclerosis (MS) results from genetic predisposition and environmental variables, including elevated Body Mass Index (BMI) in early life. This study addresses the effect of BMI on the epigenome of monocytes and disease course in MS. METHODS: Fifty-four therapy-naive Relapsing Remitting (RR) MS patients with high and normal BMI received clinical and MRI evaluation. Blood samples were immunophenotyped, and processed for unbiased plasma lipidomic profiling and genome-wide DNA methylation analysis of circulating monocytes. The main findings at baseline were validated in an independent cohort of 91 therapy-naïve RRMS patients. Disease course was evaluated by a two-year longitudinal follow up and mechanistic hypotheses tested in human cell cultures and in animal models of MS. FINDINGS: Higher monocytic counts and plasma ceramides, and hypermethylation of genes involved in negative regulation of cell proliferation were detected in the high BMI group of MS patients compared to normal BMI. Ceramide treatment of monocytic cell cultures increased proliferation in a dose-dependent manner and was prevented by DNA methylation inhibitors. The high BMI group of MS patients showed a negative correlation between monocytic counts and brain volume. Those subjects at a two-year follow-up showed increased T1 lesion load, increased disease activity, and worsened clinical disability. Lastly, the relationship between body weight, monocytic infiltration, DNA methylation and disease course was validated in mouse models of MS. INTERPRETATION: High BMI negatively impacts disease course in Multiple Sclerosis by modulating monocyte cell number through ceramide-induced DNA methylation of anti-proliferative genes. FUND: This work was supported by funds from the Friedman Brain Institute, NIH, and Multiple Sclerosis Society.


Assuntos
Índice de Massa Corporal , Ceramidas/metabolismo , Metilação de DNA , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Animais , Biomarcadores , Encéfalo/patologia , Ceramidas/farmacologia , Metilação de DNA/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Epigênese Genética , Epigenômica/métodos , Feminino , Humanos , Contagem de Leucócitos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Metaboloma , Metabolômica/métodos , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Obesidade/complicações , Obesidade/metabolismo , Tamanho do Órgão , Transcrição Genética
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