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1.
Cytokine ; 157: 155948, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35764025

RESUMO

Cellular communication mediated by cytokines is an important mechanism dictating immune responses, their cross talk and final immune output. Cytokines play a major role in dictating the immune outcome to cancer by regulating the events of development, differentiation and activation of innate immune cells. Cytokines are pleiotropic in nature, hence understanding their role individually or as member of network cytokines is critical to delineate their role in tumour immunity. Tumour systemically manipulates the immune system to evade and escape immune recognition for their uncontrollable growth and metastasis. The developing tumour comprise a large and diverse set of myeloid cells which are vulnerable to manipulation by the tumour-microenvironment. The innate immune cells of the monocytic lineage skew the fate of the adaptive immune cells and thus dictating cancer elimination or progression. Targeting cells at tumour cite is preposterous owing to their tight network, poor reach and abundance of immunosuppressive mechanisms. Monocytic lineage-derived cytokines (monokines) play crucial role in tumour regression or progression by either directly killing the tumour cells with TNFα or promoting its growth by TGFß. In addition, the monokines like IL-12, IL-1ß, IL-6, IL-10 and TGFß direct the adaptive immune cells to secrete anti-tumour cytokines, TNFα, IFNγ, perforin and granzyme or pro-tumour cytokines, IL-10 and TGFß. In this review, we elucidate the roles of monokines in dictating the fate of tumour by regulating responses at various stages of generation, differentiation and activation of immune cells along with the extensive cross talk. We have attempted to delineate the synergy and antagonism of major monokines among themselves or with tumour-derived or adaptive immune cytokines. The review provides an update on the possibilities of placing monokines to potential practical use as cytokine therapy against cancer.


Assuntos
Interleucina-10 , Neoplasias , Citocinas , Humanos , Monócitos/patologia , Monocinas , Fator de Crescimento Transformador beta , Microambiente Tumoral , Fator de Necrose Tumoral alfa
2.
Am J Obstet Gynecol ; 227(4): 627.e1-627.e23, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35609644

RESUMO

BACKGROUND: Immunomodulation is observed in human parturition. However, data from longitudinal studies for the prelabor phase and the active phase of labor are lacking, and no study had compared the immune responses during labor between nulliparous and multiparous women. OBJECTIVE: This study aimed to investigate the temporal changes of immune biomarkers in maternal blood from the prelabor phase to the latent and active phases of labor and to compare the dynamic changes between nulliparous and multiparous women. STUDY DESIGN: A prospective case-control study was conducted on women who had induction of labor at term followed by vaginal delivery. Maternal blood was serially collected at 3 consecutive time points: (1) before the onset of labor, (2) during the latent phase of labor, and (3) during the active phase of labor. Peripheral immune cells were measured by 4-color flow cytometry, and the plasma concentrations of cytokines and chemokines were measured by cytometric bead arrays. A longitudinal comparison was made to assess the dynamic changes in inflammatory parameters over 3 time points in nulliparous and multiparous women, respectively, and a cross-sectional comparison was made between nulliparous and multiparous women. RESULTS: A total of 40 women, including 20 nulliparous and 20 multiparous, were included in the study. Prelabor circulating levels of macrophage inflammatory protein-1ß, monokine induced by gamma interferon, and interferon gamma-induced protein-10 were higher in multiparous women than in nulliparous women. In the latent phase of labor, the innate immune system in both groups responded with increases in neutrophils and interleukin 6, and the nulliparous women showed a more pronounced response. During the active phase of labor, such innate immune response continued with both groups, with additional increases in natural killer cells, monocyte chemoattractant protein-1, interleukin 8, and interleukin 10. Conversely, the adaptive immune system in nulliparous women showed a reduction in both cytotoxic and helper T cells, whereas the adaptive immune system in multiparous women only had a reduction in helper T cells, showing a smaller reduction. CONCLUSION: Innate and adaptive immune responses partake in immunomodulation during human parturition. Nulliparous and multiparous women showed different responses in their blood levels of immune cells and biomarkers during the different phases of labor.


Assuntos
Interleucina-10 , Interleucina-8 , Biomarcadores , Estudos de Casos e Controles , Quimiocina CCL2 , Estudos Transversais , Feminino , Humanos , Interferon gama , Interleucina-6 , Trabalho de Parto Induzido , Proteínas Inflamatórias de Macrófagos , Monocinas , Paridade , Gravidez , Estudos Retrospectivos
3.
Cell Mol Life Sci ; 79(5): 282, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35511344

RESUMO

Several studies have implicated obesity-induced macrophage-adipocyte cross-talk in adipose tissue dysfunction and insulin resistance. However, the molecular cues involved in the cross-talk of macrophage and adipocyte causing insulin resistance are currently unknown. Here, we found that a lipid-induced monokine cyclophilin-A (CyPA) significantly attenuates adipocyte functions and insulin sensitivity. Targeted inhibition of CyPA in diet-induced obese zebrafish notably reduced adipose tissue inflammation and restored adipocyte function resulting in improvement of insulin sensitivity. Silencing of macrophage CyPA or pharmacological inhibition of CyPA by TMN355 effectively restored adipocytes' functions and insulin sensitivity. Interestingly, CyPA incubation markedly increased adipocyte inflammation along with an impairment of adipogenesis, however, mutation of its cognate receptor CD147 at P309A and G310A significantly waived CyPA's effect on adipocyte inflammation and its differentiation. Mechanistically, CyPA-CD147 interaction activates NF-κB signaling which promotes adipocyte inflammation by upregulating various pro-inflammatory cytokines gene expression and attenuates adipocyte differentiation by inhibiting PPARγ and C/EBPß expression via LZTS2-mediated downregulation of ß-catenin. Moreover, inhibition of CyPA or its receptor CD147 notably restored palmitate or CyPA-induced adipose tissue dysfunctions and insulin sensitivity. All these results indicate that obesity-induced macrophage-adipocyte cross-talk involving CyPA-CD147 could be a novel target for the management of insulin resistance and type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Tecido Adiposo/metabolismo , Animais , Ciclofilina A/genética , Ciclofilinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Inflamação/metabolismo , Resistência à Insulina/genética , Lipídeo A/metabolismo , Camundongos , Monocinas/metabolismo , Obesidade/metabolismo , Peixe-Zebra/genética
4.
Am J Physiol Lung Cell Mol Physiol ; 321(3): L566-L575, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34287085

RESUMO

The influence of smoke-derived or air pollution-derived cytoplasmic particulate matter (PM) can be detrimental and can lead to failed lung immunity. We investigated mycobacterial uptake, intracellular replication, and soluble immune-mediator responses of human bronchoalveolar lavage cells (BALCs) loaded with/without PM, to infection with mycobacterial strains. We observed that only BALCs containing PM display an ex vivo phenotypic profile dominated by spontaneous interleukin (IL)-10 production. PM-loaded BALCs retained the ability to phagocytose both Mycobacterium bovis Bacille Calmette Guérin (BCG) and Mycobacterium tuberculosis (M.tb) ΔleuDΔpanCD at equal efficacy as clear non-PM-loaded BALCs. However, immune responsiveness, such as the production of IL-6 (P = 0.015) and tumor necrosis factor-α (TNF)-α (P = 0.0172) immediately post M. bovis BCG infection, were dramatically lower in black BALCs loaded with PM versus clear non-PM-loaded BALCs. By 24 h post infection, differential immune responses to M. bovis BCG between black versus clear BALC waned, and instead, production of IL-6 (P = 0.03) and IL-1α (P = 0.04) by black BALCs was lower versus clear BALCs following M.tb ΔleuDΔpanCD infection. Considering that TNF-α and IL-6 are characterized as critical to host protection against mycobacteria, our findings suggest that BALCs loaded with inhaled PM, display lower levels of antimycobacterial mediators and that the response magnitude differs according to infective mycobacterial strain. Even though this did not translate into altered mycobacterial killing at early time points post infection, the long-term impact of such changes remains to be established.


Assuntos
Exposição por Inalação/efeitos adversos , Pulmão/imunologia , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Material Particulado/efeitos adversos , Fagócitos/imunologia , Líquido da Lavagem Broncoalveolar , Feminino , Humanos , Pulmão/microbiologia , Pulmão/patologia , Masculino , Monocinas/imunologia , Fagócitos/microbiologia , Fagócitos/patologia
5.
Acta Virol ; 65(2): 141-148, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34130465

RESUMO

Direct acting antiviral agents (DAAs) are a group of antiviral drugs that inhibit specific non-structural proteins of the virus and disrupt viral replication and infection. DAAs regimens for hepatitis C virus (HCV) infection provide a particular event to tackle mechanistic intracellular relationships between the innate immunity and HCV, potentially providing perceptions about the rate of the viral replication and complex decay. Interleukin 29 (IL-29) prevents the replication of HCV. IFN-inducible protein 10 (IP-10) plays a significant role in the pathogenesis of HCV infection. MIG/CXCL9 are produced by inflammatory and stromal cells such as hepatocytes following either stimulation by interferon lambda (IFNγ) or viral infection. This study aimed to evaluate the co-expression of IL-29, IP-10 and MIG in peripheral blood mononuclear cells (PBMCs) from untreated and treated chronic HCV patients with DAAs. This study included group of twenty naïve HCV patients, group of twenty sustained viral response (SVR) patients and a control group that consisted of 10 healthy subjects. All subjects were tested for liver enzymes, serum albumin level, total serum bilirubin, platelet count, prothrombin activity and viral load. Relative gene expression of IL-29, IP-10, and MIG in PBMCs from all subjects was determined using real time PCR. The mean value of IL-29, IP-10 and MIG gene expression significantly increased in both naïve HCV and SVR groups of patients as compared to normal subjects. The corresponding value was significantly lower in patients with SVR compared to naïve HCV patients. Infection with HCV significantly trigged the co-expression of IL-29, IP-10, and CXCL9 (MIG) genes in PBMCs of chronic hepatitis C patients and significantly down-regulated in those who achieved SVR after successful DAAs therapy. Keywords: IP10; MIG; IL29; HCV; DAAs; gene expression.


Assuntos
Hepatite C Crônica , Antivirais/uso terapêutico , Quimiocina CXCL10/genética , Egito , Hepacivirus , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Humanos , Interleucinas/genética , Leucócitos Mononucleares , Monocinas/uso terapêutico
6.
PLoS One ; 16(5): e0251578, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34038447

RESUMO

BACKGROUND: Ethyl ferulate (EF) is a derivative of ferulic acid (FA), which is a monomeric component purified from the traditional medicinal herb Ferula, but its effects have not been clear yet. The purpose of this study was to evaluate whether EF can reduce inflammation levels in macrophages by regulating the Nrf2-HO-1 and NF-кB pathway. METHODS: The LPS-induced raw 264.7 macrophage cells model was used to determine the anti-inflammatory and anti-oxidative stress effects of EF. The levels of IL-1ß, IL-6, TNF-α and PGE2 were analyzed by ELISA. The mRNA and protein of COX-2, iNOS, TNF-α, IL-6, HO-1 and Nrf2 were identified by RT-PCR analysis and western blotting. Intracellular ROS levels were assessed with DCFH oxidation staining. The expressions of NF-кB p-p65 and Nrf2 were analyzed by immunofluorescence assay. The inhibitory effect of Nrf2 inhibitor ML385 (2µM) on mediatation of antioxidant activity by raw 264.7 macrophage cells was evaluated. The effect of EF was confirmed in acute lung injury mice model. RESULTS: In our research, EF reduced the expression of iNOS, COX2 and the production of PGE2. EF could inhibit the production of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) in lipopolysaccharide (LPS) stimulated macrophages and decreased expression of IL-6 and TNF-α in LPS stimulated macrophages. Furthermore, EF inhibited NF-кB p65 from transporting to the nucleus, decreased the expression of p-IкBα, significantly decreased the level of intracellular reactive oxygen species (ROS) and activated Nrf2/HO-1 pathways. EF could attenuate the degree of leukocyte infiltration, reduced MPO activity, mRNA levels and secretion of TNF-α and IL-6 in vivo. EF exhibited potent protective effects against LPS-induced acute lung injury in mice. CONCLUSIONS: Collectively, our data showed that EF relieved LPS-induced inflammatory responses by inhibiting NF-κB pathway and activating Nrf2/HO-1 pathway, known to be involved in the regulation of inflammatory responses by Nrf2.


Assuntos
Lesão Pulmonar Aguda , Ácidos Cafeicos/farmacologia , Macrófagos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Heme Oxigenase-1/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Macrófagos/patologia , Proteínas de Membrana/metabolismo , Camundongos , Monocinas/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição RelA/metabolismo
7.
Molecules ; 26(2)2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33419109

RESUMO

Bidens pilosa L. (Asteraceae) has been used historically in traditional Asian medicine and is known to have a variety of biological effects. However, the specific active compounds responsible for the individual pharmacological effects of Bidens pilosa L. (B. pilosa) extract have not yet been made clear. This study aimed to investigate the anti-inflammatory phytochemicals obtained from B. pilosa. We isolated a flavonoids-type phytochemical, isookanin, from B. pilosa through bioassay-guided fractionation based on its capacity to inhibit inflammation. Some of isookanin's biological properties have been reported; however, the anti-inflammatory mechanism of isookanin has not yet been studied. In the present study, we evaluated the anti-inflammatory activities of isookanin using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We have shown that isookanin reduces the production of proinflammatory mediators (nitric oxide, prostaglandin E2) by inhibiting the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated macrophages. Isookanin also inhibited the expression of activator protein 1 (AP-1) and downregulated the LPS-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun NH2-terminal kinase (JNK) in the MAPK signaling pathway. Additionally, isookanin inhibited proinflammatory cytokines (tumor necrosis factor-a (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1ß (IL-1ß)) in LPS-induced THP-1 cells. These results demonstrate that isookanin could be a potential therapeutic candidate for inflammatory disease.


Assuntos
Anti-Inflamatórios , Bidens/química , Bioensaio , Chalconas , Macrófagos/metabolismo , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Chalconas/química , Chalconas/isolamento & purificação , Chalconas/farmacologia , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Monocinas/metabolismo , Células RAW 264.7 , Células THP-1
8.
J Immunol ; 206(4): 827-838, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33408258

RESUMO

Circulating nonadherent monocytes can migrate to extravascular sites by a process that involves adherence. Alterations in intracellular metabolism shape the immunological phenotype of phagocytes upon activation. To determine the effect of adherence on their metabolic and functional response human monocytes were stimulated with LPS under nonadherent and adherent conditions. Adherent monocytes (relative to nonadherent monocytes) produced less TNF and IL-1ß (proinflammatory) and more IL-10 (anti-inflammatory) upon LPS stimulation and had an increased capacity to phagocytose and produce reactive oxygen species. RNA sequencing analysis confirmed that adherence modified the LPS-induced response of monocytes, reducing expression of proinflammatory genes involved in TLR signaling and increasing induction of genes involved in pathogen elimination. Adherence resulted in an increased glycolytic response as indicated by lactate release, gene set enrichment, and [13C]-glucose flux analysis. To determine the role of glycolysis in LPS-induced immune responses, this pathway was inhibited by glucose deprivation or the glucose analogue 2-deoxy-d-glucose (2DG). Although both interventions equally inhibited glycolysis, only 2DG influenced monocyte functions, inhibiting expression of genes involved in TLR signaling and pathogen elimination, as well as cytokine release. 2DG, but not glucose deprivation, reduced expression of genes involved in oxidative phosphorylation. Inhibition of oxidative phosphorylation affected TNF and IL-10 release in a similar way as 2DG. Collectively, these data suggest that adherence may modify the metabolic and immunological profile of monocytes and that inhibition of glycolysis and oxidative phosphorylation, but not inhibition of glycolysis alone, has a profound effect on immune functions of monocytes exposed to LPS.


Assuntos
Reprogramação Celular , Imunidade Inata/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Monócitos/imunologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/imunologia , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/imunologia , Humanos , Monocinas/imunologia
9.
Int J Biol Macromol ; 165(Pt A): 619-624, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33007323

RESUMO

Kefiran is a water-soluble polysaccharide well recognized as a bioactive ingredient to enhance nutritional and health-promoting features. Also, some therapeutic properties have made this macromolecule an active ingredient in ointments and oral anti-inflammatory drugs. However, the details of the molecular and cellular aspects of these effects have not been addressed. In this study, lipopolysaccharides (LPS)-induced monocytes, lymphocytes, and monocyte-derived dendritic cells (MDDCs) as representative cells for both innate and adaptive immunity were treated with kefiran for 2 h. Kefiran had an anti-inflammatory effect on monocytes to reduce pro-inflammatory cytokines, interleukin 1 ß (IL-1ß) & tumor necrosis factor α (TNF-α), as well as nuclear factor kappa b (NF-kb). However, it did not affect lymphocytes. Overexpression of Toll-like receptor 4 (TLR4) in LPS-induced cells was not reduced after kefiran treatment. Kefiran balanced MDDCs secretion of pro/anti-inflammatory cytokines by reducing and enhancing the expression of IL-1ß and interleukin 10 (IL-10), respectively. Also, kefiran decreased the number of apoptotic immature MDDCs and promoted dose-dependent phagocytosis capacity of MDDCs. According to the results of the current study, it may be concluded that the immunomodulatory effects of kefiran are due to antagonist against innate immune receptors especially TLR4. The results of this study can be used as a guide to developing kefiran-based non-aggressive anti-inflammatory drugs. Furthermore, understanding the immunobiological effects of kefiran on monocytes and lymphocytes was another outcome of this study.


Assuntos
Anti-Inflamatórios/farmacologia , Células Dendríticas/imunologia , Imunidade Inata/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Monócitos/imunologia , Polissacarídeos/farmacologia , Adolescente , Adulto , Células Dendríticas/patologia , Humanos , Masculino , Monócitos/patologia , Monocinas/imunologia , Receptor 4 Toll-Like/imunologia
10.
J Leukoc Biol ; 108(5): 1615-1629, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32794339

RESUMO

Tuberculosis (TB), a highly infectious air-borne disease, has remained a global health problem. Conventional treatment and preventions such as antibiotics and Bacilli Calmette-Guerin (BCG) vaccine can be unreliable. In view of the increasing prevalence of anti-TB drug resistance, adjunctive therapy may be necessary to shorten the recovery time. We have previously shown that flavonoids in the medicinal herb Sophora flavescens exhibit anti-inflammatory and bactericidal activities. The aim of this study was to investigate the molecular and cellular characteristics of flavonoids of S. flavescens (FSF) in BCG-stimulated macrophages for assessing their roles in anti-inflammation and autophagy. Mouse alveolar macrophage (MH-S) cell line and primary mouse peritoneal macrophages were stimulated in vitro with heat-inactivated BCG and treated with FSF, with or without autophagy inhibitor Bafilomycin A1 (BafA1). Gene expression was analyzed using quantitative PCR, and cytokine/chemokine release was analyzed by Milliplex assay and ELISA. Autophagy-related proteins were quantified by Western blot and flow cytometry, and autophagolysosomes were detected using fluorescence microscopy. In both MH-S cell line and mouse peritoneal macrophages stimulated by heat-inactivated BCG, FSF was found to up-regulate autophagy-related proteins microtubule-associated protein 1A/1B-light chain 3 (LC3) and protein 62 (p62), and suppress the induced proinflammatory cytokine TNF-α, CCL5, and IL-6. FSF actively modulates immune processes through suppressing BCG-mediated inflammation by promoting autophagy in MH-S cells and mouse peritoneal macrophages. We suggest that FSF may be useful as an adjunctive therapeutic agent for TB infection by modulating cell survival through autophagy and reducing inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Autofagia/efeitos dos fármacos , Flavonoides/farmacologia , Macrófagos Peritoneais/imunologia , Mycobacterium bovis/imunologia , Sophora/química , Animais , Anti-Inflamatórios/química , Autofagia/imunologia , Linhagem Celular , Flavonoides/química , Macrófagos Peritoneais/patologia , Camundongos , Monocinas/imunologia
11.
Int J Biol Macromol ; 161: 779-786, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32512090

RESUMO

Cyclina sinensis is an edible clam widely distributed along the coastal waters of Asia. In the present study, a polysaccharide (CSP-1) isolated from C. sinensis was purified by a DEAE-Sepharose Fast Flow column, and it had an average molecular weight of 3.8 × 105 Da and a prevalent component monosaccharide of Glc. The results of methylation analysis and 1D/2D NMR indicated that CSP-1 was a glycogen constructed with α-1,4-Glc and branched at C-6 every 9 Glc residues. In addition, Cong red test suggests CSP-1 was not a helical conformation, and irregular and spherical lumps were observed by AFM. Moreover, CSP-1 was found to possess potent immunostimulatory activity on the basis of its significant abilities to enhance NO production and cytokines (TNF-α, IL-1ß and IL-6) secretion in RAW 264.7 macrophages.


Assuntos
Adjuvantes Imunológicos , Bivalves/química , Glucanos , Macrófagos/imunologia , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Configuração de Carboidratos , Glucanos/química , Glucanos/farmacologia , Camundongos , Monocinas/imunologia , Óxido Nítrico/imunologia , Células RAW 264.7
12.
Biomolecules ; 10(3)2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32182890

RESUMO

Immune response is a necessary self-defense mechanism that protects the host from infectious organisms. Many medicinal plants are popularly used in Asian folk medicine to increase body resistance. An herbal formulation named KM1608 was prepared from three medicinal plants: Saussurea lappa, Terminalia chebula, and Zingiber officinale. In this study, we evaluated the immune stimulatory effect of KM1608 on RAW 264.7 murine macrophages. Network pharmacological analyses were used to predict potential immune response pathways of major compounds from KM1608. The cytotoxicity and immuno-stimulating effect of KM1608 were determined using cell viability and nitric oxide assays. The underlying mechanism of immunomodulatory activity was evaluated by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) of pro-inflammatory cytokines. The results of network pharmacological analysis suggested that major compounds from KM1608 possess anticancer potential via immune signaling pathways. After treatment with KM1608 at 25-100 µg/mL for 24 h, the level of nitric oxide was increased in the dose-dependent manner. The results of quantitative real-time PCR showed that KM1608 stimulates the expression of immune cytokines (interferon (IFN)-α, -ß, IL-1ß, -6, IL-10, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2)) in macrophages. KM1608 extract is a potential agent for immune response enhancement.


Assuntos
Adjuvantes Imunológicos/farmacologia , Regulação da Expressão Gênica , Macrófagos/imunologia , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Transdução de Sinais , Adjuvantes Imunológicos/química , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Camundongos , Monocinas/imunologia , Óxido Nítrico Sintase Tipo II/imunologia , Extratos Vegetais/química , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
13.
J Innate Immun ; 12(2): 142-153, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31230049

RESUMO

The incidence of bacterial infections and sepsis, as well as the mortality risk from sepsis, is sex specific. These clinical findings have been attributed to sex differences in immune responsiveness. The aim of the present study was to investigate sex differences in monocyte-derived cytokine production response upon stimulation with the gram-negative stimulus lipopolysaccharide (LPS) using cytokine data from 15 study populations. Individual data on ex vivo cytokine production response upon stimulation with LPS in whole blood were available for 4,020 subjects originating from these 15 study populations, either from the general population or from patient populations with specific diseases. Men had a stronger cytokine production response than women to LPS for tumour necrosis factor-α, interleukin (IL)-6, IL-12, IL-1ß, IL-1RA, and IL-10, but not for interferon-γ. The granulocyte-macrophage colony-stimulating factor production response was lower in men than in women. These sex differences were independent of chronological age. As men had higher monocyte concentrations, we normalized the cytokine production responses for monocyte concentration. After normalization, the sex differences in cytokine production response to LPS disappeared, except for IL-10, for which the production response was lower in men than in women. A sex-based approach to interpreting immune responsiveness is crucial.


Assuntos
Lipopolissacarídeos/toxicidade , Monócitos/imunologia , Monocinas/imunologia , Caracteres Sexuais , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
J Diabetes Investig ; 11(3): 653-661, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31721467

RESUMO

AIMS/INTRODUCTION: Our aims were to examine the add-on effects of a sodium-glucose cotransporter 2 inhibitor, dapagliflozin, compared with existing antidiabetes treatments, on anthropometric/metabolic parameters, the levels of an endocrine regulator, fibroblast growth factor 21 (FGF21); a skeletal muscle mass (SMM) negative regulator, myostatin; and a metabolic regulator, irisin, in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 54 patients with type 2 diabetes were randomly divided into dapagliflozin and control groups. The dapagliflozin group received dapagliflozin 5 mg/day in addition to conventional therapy for 24 weeks. The primary outcome was the change in the level of serum FGF21 from baseline. The secondary outcomes included changes from baseline in anthropometric/metabolic parameters and serum levels of myostatin and irisin. RESULTS: Bodyweight decreased in the dapagliflozin group compared with the control group (P < 0.001), but the changes in SMM were not significant between the groups (P = 0.611), thereby elevating the ratio of SMM-to-bodyweight in the dapagliflozin group (P = 0.028). Myostatin levels were significantly decreased (P = 0.010), and irisin levels showed a nearly significant reduction (P = 0.052) in the dapagliflozin group compared with the control group, whereas FGF21 levels did not change significantly from baseline to the end of the intervention in both the dapagliflozin (P = 0.673) and the control (P = 0.823) groups. CONCLUSIONS: Dapagliflozin add-on therapy in patients with type 2 diabetes reduced myostatin levels significantly and maintained SMM, without significant changes in FGF21 levels.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/sangue , Glucosídeos/uso terapêutico , Monocinas/sangue , Músculo Esquelético/patologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
15.
Nanoscale ; 11(28): 13576-13586, 2019 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-31290914

RESUMO

Despite numerous advances in medical treatment, sepsis remains one of the leading causes of death worldwide. Sepsis is characterized by the involvement of all organs and tissues as a consequence of blood poisoning, resulting in organ failure and eventually death. Effective treatment remains an unmet need and novel approaches are urgently needed. The growing evidence of clinical and biological heterogeneity of sepsis suggests precision medicine as a possible key for achieving therapeutic breakthroughs. In this scenario, biomimetic nanomedicine represents a promising avenue for the treatment of inflammatory diseases, including sepsis. We investigated the role of macrophage-derived biomimetic nanoparticles, namely leukosomes, in a lipopolysaccharide-induced murine model of sepsis. We observed that treatment with leukosomes was associated with significantly prolonged survival. In vitro studies elucidated the potential mechanism of action of these biomimetic vesicles. The direct treatment of endothelial cells (ECs) with leukosomes did not alter the gene expression profile of EC-associated cell adhesion molecules. In contrast, the interaction of leukosomes with macrophages induced a decrease of pro-inflammatory genes (IL-6, IL-1b, and TNF-α), an increase of anti-inflammatory ones (IL-10 and TGF-ß), and indirectly an anti-inflammatory response on ECs. Taken together, these results showed the ability of leukosomes to regulate the inflammatory response in target cells, acting as a bioactive nanotherapeutic.


Assuntos
Anti-Inflamatórios , Materiais Biomiméticos , Células Endoteliais , Vesículas Extracelulares , Macrófagos , Nanopartículas/química , Sepse , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Linhagem Celular , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Vesículas Extracelulares/química , Vesículas Extracelulares/transplante , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Monocinas/metabolismo , Sepse/tratamento farmacológico , Sepse/metabolismo , Sepse/patologia
16.
Mol Immunol ; 105: 233-239, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30554084

RESUMO

Chlamydia trachomatis (Ct) infections can cause bacterial sexually-transmitted and preventable blindness. The Ct infections induced excessive cytokines generation which attributed to pathologic changes in host cells. However, the precise mechanisms of Ct-induced cytokines production are still unclear.CT143 protein was identified as a novel Ct specific protein with high immunogenicity. In the present study. The CT143 fusion protein was recombined and purified. The mice immune serum was prepared by immunizing BALB/c mice with the purified fusion protein. The specificity of the antibody was confirmed using Immunoblotting. Indirect immunoflurescence assay (IFA) and Immunoblotting assays were performed to detect the temporal and spatial characteristics of CT143 in Ct infected cells. ELISA was performed to analyze the secretion of proinflammatory cytokines IL-1ß, IL-8 and TNF-α by human macrophages under the stimulation of CT143 protein. Finally, the involvement of p38 signaling in CT143-induced cytokine secretion was validated. CT143 protein was located in the inclusion body and represented an Elementary body (EB)-related protein, which may be encoded by the mid- and late-stage expressing genes. CT143 protein could stimulate the secretion of inflammatory cytokines in macrophages which differentiated from THP-1 This induction may be mediated by the activation of p38 signaling. In summary, CT143 protein is involved in inflammatory processes during Ct infection.


Assuntos
Proteínas de Bactérias/imunologia , Chlamydia trachomatis/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Macrófagos/imunologia , Monocinas/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Animais , Proteínas de Bactérias/química , Proteínas de Bactérias/farmacologia , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/patologia , Chlamydia trachomatis/química , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Células THP-1
17.
PLoS One ; 13(8): e0201375, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30133465

RESUMO

Genetic and sexual factors influence the prevalence and the pathogenesis of many inflammatory disorders. In this study their relevance on the peripheral and central inflammatory status induced by a peripheral injection of lipopolysaccharide (LPS) was evaluated. BALB/c and CD-1 male and female mice were intraperitoneally injected with LPS. Spleens and brains were collected 2 and 72 hours later to study the levels of IL-6, TNF-α and IL-1ß. Percentage of microglia and astrocytes was determined in the cortex and hippocampus. Locomotor activity was registered before and during the 72 hours after LPS-treatment. Two hours after LPS-injection, a peripheral increase of the three cytokines was found. In brains, LPS increased TNF-α only in males with higher levels in CD-1 than BALB/c. IL-1ß increased only in CD-1 males. IL-6 increased in both strains with lower levels in BALB/c females. Peripheral and central levels of cytokines decline 72 hrs after LPS-treatment whilst a significantly increase of Iba-1 expression was detected. A dramatic drop of the locomotor activity was observed immediately after LPS injection. Our results show that acute systemic administration of LPS leads to peripheral and central increase of pro-inflammatory cytokines and microglia activation, in a strain and sex dependent manner.


Assuntos
Encéfalo , Lipopolissacarídeos/toxicidade , Microglia , Monocinas , Baço , Síndrome de Resposta Inflamatória Sistêmica , Animais , Encéfalo/imunologia , Encéfalo/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microglia/imunologia , Microglia/patologia , Monocinas/genética , Monocinas/imunologia , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Caracteres Sexuais , Especificidade da Espécie , Baço/imunologia , Baço/patologia , Síndrome de Resposta Inflamatória Sistêmica/induzido quimicamente , Síndrome de Resposta Inflamatória Sistêmica/genética , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/patologia
19.
Cytokine ; 103: 29-33, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29324257

RESUMO

Epidemiological evidence suggests cardioprotective effects of anthocyanin consumption. This study examined the predominant strawberry anthocyanin, pelargonidin-3-O-glucoside (Pg-3-glc), and three of its plasma metabolites (protocatechuic acid [PCA], 4-hydroxybenzoic acid, and phloroglucinaldehyde [PGA]) for effects on the production of selected cytokines by lipopolysaccharide-stimulated THP-1 monocytes and macrophages. Concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, IL-8 and IL-10 were determined using a cytometric bead array kit. PCA at 0.31, 1.25 and 20 µM and PGA at 5 and 20 µM decreased the concentration of IL-6 in the monocyte cultures, but there were no effects on TNF-α, IL-1ß, IL-8 and IL-10 and there were no effects of the other compounds. In the macrophage cultures, PGA at 20 µM decreased the concentrations of IL-6 and IL-10, but there was no effect on TNF-α, IL-1ß and IL-8 and there were no effects of the other compounds. In conclusion, while the effects of PGA were only observed at the higher, supraphysiological concentration and are thus considered of limited physiological relevance overall, the anti-inflammatory properties of PCA were observed at both the lower, physiologically relevant, and the higher concentrations; however, effects were modest and limited to IL-6 and monocytes. These preliminary data suggest potential for physiologically attainable PCA concentrations to modulate IL-6 production by monocytes.


Assuntos
Antocianinas/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Monócitos/metabolismo , Monocinas/metabolismo , Humanos , Macrófagos/citologia , Monócitos/citologia , Células THP-1
20.
Res Vet Sci ; 115: 211-220, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28505549

RESUMO

The immunoprotective effect of Panax ginseng (Pg) extract was investigated in a mouse mastitis model. Lactating female mice were intramammarily inoculated with Pg or placebo, and then were challenged with S. aureus, while other group was inoculated with S. aureus alone. The number of bacteria recovered from mammary glands was significantly lower in Pg-treated S. aureus-infected mice (group I) compared with placebo-treated S. aureus-infected mice (group II) and S. aureus-infected mice (group III). The mRNA expression of TLR2, TLR4, IL-1α and TNF-α was influenced by treatment; being the transcript levels for all genes higher in group I compared with group II and III. Activation of NF-κB and the number of monocytes-macrophages in mammary gland tissue was significantly increased in group I compared with group II and III. Pg extract was able to trigger an adequate immune response to confront an infection demonstrating its protective effect and potential for preventing bovine intramammary infections.


Assuntos
Glândulas Mamárias Animais/imunologia , Mastite Bovina/imunologia , Panax/química , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Infecções Estafilocócicas/veterinária , Staphylococcus aureus/fisiologia , Animais , Bovinos , Modelos Animais de Doenças , Feminino , Lactação , Mastite Bovina/microbiologia , Camundongos Endogâmicos BALB C , Monocinas/metabolismo , Extratos Vegetais/administração & dosagem , Substâncias Protetoras/administração & dosagem , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Receptores Toll-Like/metabolismo
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