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1.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445073

RESUMO

Human immunodeficiency virus (HIV-1) is still a major problem, not only in developing countries but is also re-emerging in several developed countries, thus the development of new compounds able to inhibit the virus, either for prophylaxis or treatment, is still needed. Nanotechnology has provided the science community with several new tools for biomedical applications. G2-S16 is a polyanionic carbosilane dendrimer capable of inhibiting HIV-1 in vitro and in vivo by interacting directly with viral particles. One of the main barriers for HIV-1 eradication is the reservoirs created in primoinfection. These reservoirs, mainly in T cells, are untargetable by actual drugs or immune system. Thus, one approach is inhibiting HIV-1 from reaching these reservoir cells. In this context, macrophages play a main role as they can deliver viral particles to T cells establishing reservoirs. We showed that G2-S16 dendrimer is capable of inhibiting the infection from infected macrophages to healthy T CD4/CD8 lymphocytes by eliminating HIV-1 infectivity inside macrophages, so they are not able to carry infectious particles to other body locations, thus preventing the reservoirs from forming.


Assuntos
Alcanossulfonatos/farmacologia , Fármacos Anti-HIV/farmacologia , Dendrímeros/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Compostos de Organossilício/farmacologia , Silanos/farmacologia , Linhagem Celular , Células Cultivadas , Infecções por HIV/transmissão , Humanos , Macrófagos/virologia , Polieletrólitos/farmacologia
2.
Am J Physiol Cell Physiol ; 321(3): C607-C614, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34378992

RESUMO

Bovine milk exosomes (BMEs) are being explored in drug delivery despite their rapid elimination by macrophages. We aimed at identifying the BME transporter in murine bone marrow-derived macrophages (BMDMs). Fluorophore-labeled BMEs were used in transport studies in BMDMs from C57BL/6J and class A scavenger receptor type 1/2 (CASR-1/2) knockout mice and tissue accumulation in macrophage-depleted C57BL/6J mice. Parametric and nonparametric statistics tests for pairwise and multiple comparisons were used. Chemical inhibitors of phagocytosis by cytochalasin D led to a 69 ± 18% decrease in BME uptake compared with controls (P < 0.05), whereas inhibitors of endocytic pathways other than phagocytosis had a modest effect on uptake (P > 0.05). Inhibitors of class A scavenger receptors (CASRs) including CASR-1/2 caused a 70% decrease in BME uptake (P < 0.05). The uptake of BMEs by BMDMs from CASR-1/2 knockout mice was smaller by 58 ± 23% compared with wild-type controls (P < 0.05). Macrophage depletion by clodronate caused a more than 44% decrease in BME uptake in the spleen and lungs (P < 0.05), whereas the decrease observed in liver was not statistically significant. In conclusion, CASR-1/2 facilitates the uptake of BMEs in BMDMs and C57BL/6J mice.


Assuntos
Exossomos/metabolismo , Macrófagos/metabolismo , Leite/química , Receptores Depuradores Classe A/genética , Animais , Bovinos , Ácido Clodrônico/farmacologia , Citocalasina D/farmacologia , Endocitose/efeitos dos fármacos , Exossomos/química , Feminino , Corantes Fluorescentes/química , Expressão Gênica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose/efeitos dos fármacos , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Receptores Depuradores Classe A/deficiência , Baço/efeitos dos fármacos , Baço/metabolismo , Coloração e Rotulagem/métodos
3.
Nutrients ; 13(7)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34371846

RESUMO

Aside from its role in bone metabolism, vitamin D is a key immunomodulatory micronutrient. The active form of vitamin D (1,25(OH)D) seems to modulate the innate immune system through different mechanisms. The vitamin is involved in the differentiation of monocytes into macrophages, increasing the phagocytic and chemotactic functions of these cells. At the same time, vitamin D enables efferocytosis and prevents immunopathology. In addition, vitamin D is involved in other processes related to immune function, such as inflammation. Regarding muscle tissue, vitamin D plays an active role in muscle inflammatory response, protein synthesis, and regulation of skeletal muscle function. Two mechanisms have been proposed: A direct role of 1,25(OH)D binding to vitamin D receptors (VDRs) in muscle cells and the modulation of calcium transport in the sarcoplasmic reticulum. This second mechanism needs additional investigation. In conclusion, vitamin D seems to be effective in cases of deficiency and/or if there is a great muscular commitment, such as in high intensity exercises.


Assuntos
Imunomodulação/efeitos dos fármacos , Músculo Esquelético/imunologia , Doenças Musculares/imunologia , Vitamina D/farmacologia , Diferenciação Celular/efeitos dos fármacos , Exercício Físico/fisiologia , Treinamento Intervalado de Alta Intensidade/efeitos adversos , Humanos , Inflamação , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Doenças Musculares/etiologia , Receptores de Calcitriol/imunologia
4.
Biomed Res Int ; 2021: 3376496, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34337004

RESUMO

Lactobacillus rhamnoides, a human intestinal colonizer, can act through various pathways to induce microglia/macrophages to produce cytokines and to polarize microglia/macrophages to different phenotypes to reduce the inflammatory response. In this article, we evaluated the treatment potential of the Lactobacillus rhamnoides GG conditioned medium (LGG-CM) in rat model with SCI (acute spinal cord injury), including functional, neurophysiological, and histological outcomes and the underlying neuroprotective mechanisms. In our experiment, LGG-CM (30 mg/kg) was injected directly into the injury site in rats immediately after SCI. Measured by the BBB scale (Basso, Beattie, and Bresnahan locomotor rating scale) and inclined plane test, rats in the LGG-CM-treated group showed better locomotor scores. Moreover, compared to the vehicle treatment group, LGG-CM increased the mRNA level of the M2 marker (CD206), and decreased that of the M1 marker (iNOS). Western blot assays showed that LGG-CM-treated SCI rats had a higher grayscale ratio of p65 and a lower ratio of p-IκBα/IκBα. Our study shows that local injection of LGG-CM after acute SCI can inhibit inflammatory responses and improve motor function recovery. These effects may be related with the inhibition to the NF-κB (The nuclear factor-kappa B) signal pathway which leads to M2 microglia/macrophage polarization.


Assuntos
Polaridade Celular , Meios de Cultivo Condicionados/farmacologia , Lactobacillus rhamnosus/química , Macrófagos/patologia , Microglia/patologia , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/fisiopatologia , Animais , Polaridade Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Recuperação de Função Fisiológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
5.
FASEB J ; 35(9): e21870, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34436790

RESUMO

COVID-19 is often characterized by dysregulated inflammatory and immune responses. It has been shown that the Traditional Chinese Medicine formulation Qing-Fei-Pai-Du decoction (QFPDD) is effective in the treatment of the disease, especially for patients in the early stage. Our network pharmacology analyses indicated that many inflammation and immune-related molecules were the targets of the active components of QFPDD, which propelled us to examine the effects of the decoction on inflammation. We found in the present study that QFPDD effectively alleviated dextran sulfate sodium-induced intestinal inflammation in mice. It inhibited the production of pro-inflammatory cytokines IL-6 and TNFα, and promoted the expression of anti-inflammatory cytokine IL-10 by macrophagic cells. Further investigations found that QFPDD and one of its active components wogonoside markedly reduced LPS-stimulated phosphorylation of transcription factor ATF2, an important regulator of multiple cytokines expression. Our data revealed that both QFPDD and wogonoside decreased the half-life of ATF2 and promoted its proteasomal degradation. Of note, QFPDD and wogonoside down-regulated deubiquitinating enzyme USP14 along with inducing ATF2 degradation. Inhibition of USP14 with the small molecular inhibitor IU1 also led to the decrease of ATF2 in the cells, indicating that QFPDD and wogonoside may act through regulating USP14 to promote ATF2 degradation. To further assess the importance of ubiquitination in regulating ATF2, we generated mice that were intestinal-specific KLHL5 deficiency, a CUL3-interacting protein participating in substrate recognition of E3s. In these mice, QFPDD mitigated inflammatory reaction in the spleen, but not intestinal inflammation, suggesting CUL3-KLHL5 may function as an E3 for ATF2 degradation.


Assuntos
Fator 2 Ativador da Transcrição/metabolismo , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Flavanonas/farmacologia , Glucosídeos/farmacologia , Inflamação/tratamento farmacológico , Proteólise/efeitos dos fármacos , Ubiquitina Tiolesterase/deficiência , Animais , Linhagem Celular , Colite/induzido quimicamente , Colite/tratamento farmacológico , Proteínas Culina/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/farmacologia , Sulfato de Dextrana/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Flavanonas/uso terapêutico , Glucosídeos/uso terapêutico , Inflamação/induzido quimicamente , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Pirróis/farmacologia , Pirrolidinas/farmacologia , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitinação
6.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360840

RESUMO

Obesity is characterized as a chronic, low-grade inflammation state accompanied by the infiltration of immune cells into adipose tissue and higher levels of inflammatory cytokines and chemokines. This study aimed to investigate the mechanisms and effects of Coptidis Rhizoma (CR) on obesity and its associated inflammation. First, we applied a network pharmacology strategy to search the target genes and pathways regulated by CR in obesity. Next, we performed in vivo experiments to confirm the antiobesity and anti-inflammatory effects of CR. Mice were assigned to five groups: normal chow (NC), control (high-fat diet (HFD)), HFD + CR 200 mg/kg, HFD + CR 400 mg/kg, and HFD + metformin 200 mg/kg. After 16 weeks of the experimental period, CR administration significantly reduced the weight of the body, epididymal fat, and liver; it also decreased insulin resistance, as well as the area under the curve of glucose in the oral glucose tolerance test and triglyceride in the oral fat tolerance test. We observed a decrease in adipose tissue macrophages (ATMs) and inflammatory M1 ATMs, as well as an increase in anti-inflammatory M2 ATMs. Gene expression levels of inflammatory cytokines and chemokines, including tumor necrosis factor-α, F4/80, and C-C motif chemokine (CCL)-2, CCL4, and CCL5, were suppressed in adipose tissue in the CR groups than levels in the control group. Additionally, histological analyses suggested decreased fat accumulation in the epididymal fat pad and liver in the CR groups than that in the control group. Taken together, these results suggest that CR has a therapeutic effect on obesity-induced inflammation, and it functions through the inhibition of macrophage-mediated inflammation in adipose tissue.


Assuntos
Citocinas/genética , Medicamentos de Ervas Chinesas/farmacologia , Inflamação/tratamento farmacológico , Macrófagos/metabolismo , Obesidade/complicações , Tecido Adiposo/citologia , Tecido Adiposo/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Simulação por Computador , Dieta Hiperlipídica , Regulação da Expressão Gênica , Inflamação/etiologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
7.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360887

RESUMO

The fruits of the mulberry tree (Morus alba L.), known as white mulberry, have been consumed in various forms, including tea, beverages, and desserts, worldwide. As part of an ongoing study to discover bioactive compounds from M. alba fruits, the anti-inflammatory effect of compounds from M. alba were evaluated in lipopolysaccharide (LPS)-stimulated mouse RAW 264.7 macrophages. Phytochemical analysis of the ethanol extract of the M. alba fruits led to the isolation of 22 compounds. Among the isolated compounds, to the best of our knowledge, compounds 1, 3, 5, 7, 11, 12, and 14-22 were identified from M. alba fruits for the first time in this study. Inhibitory effects of 22 compounds on the production of the nitric oxide (NO) known as a proinflammatory mediator in LPS-stimulated RAW 264.7 macrophages were evaluated using NO assays. Western blot analysis was performed to evaluate the anti-inflammatory effects of cyclo(L-Pro-L-Val) (5). We evaluated whether the anti-inflammatory effects of cyclo(L-Pro-L-Val) (5) following LPS stimulation in RAW 264.7 macrophages occurred because of phosphorylation of IκB kinase alpha (IKKα), IκB kinase beta (IKKß), inhibitor of kappa B alpha (IκBα), nuclear factor kappa B (NF-κB) and activations of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Cyclo(L-Pro-L-Val) (5) significantly suppressed phosphorylations of IKKα, IKKß, IκBα, and NF-κB and activations of iNOS and COX-2 in a concentration-dependent manner. Taken together, these results indicate that cyclo(L-Pro-L-Val) (5) can be considered a potential therapeutic agent for the treatment of inflammation-associated disorders.


Assuntos
Anti-Inflamatórios/farmacologia , Dipeptídeos/farmacologia , Frutas/química , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Morus/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
8.
Cell Rep ; 36(8): 109614, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34433041

RESUMO

Zoonotic pathogens, such as COVID-19, reside in animal hosts before jumping species to infect humans. The Carnivora, like mink, carry many zoonoses, yet how diversity in host immune genes across species affect pathogen carriage is poorly understood. Here, we describe a progressive evolutionary downregulation of pathogen-sensing inflammasome pathways in Carnivora. This includes the loss of nucleotide-oligomerization domain leucine-rich repeat receptors (NLRs), acquisition of a unique caspase-1/-4 effector fusion protein that processes gasdermin D pore formation without inducing rapid lytic cell death, and the formation of a caspase-8 containing inflammasome that inefficiently processes interleukin-1ß. Inflammasomes regulate gut immunity, but the carnivorous diet has antimicrobial properties that could compensate for the loss of these immune pathways. We speculate that the consequences of systemic inflammasome downregulation, however, can impair host sensing of specific pathogens such that they can reside undetected in the Carnivora.


Assuntos
Carnívoros/metabolismo , Evolução Molecular , Inflamassomos/metabolismo , Zoonoses/patologia , Animais , Caspase 1/genética , Caspase 1/metabolismo , Caspase 8/metabolismo , Caspases Iniciadoras/genética , Caspases Iniciadoras/metabolismo , Morte Celular , Linhagem Celular , Humanos , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas NLR/genética , Proteínas NLR/metabolismo , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Salmonella typhi/patogenicidade , Zoonoses/imunologia , Zoonoses/parasitologia
9.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445501

RESUMO

Lipid dysregulation in diabetes mellitus escalates endothelial dysfunction, the initial event in the development and progression of diabetic atherosclerosis. In addition, lipid-laden macrophage accumulation in the arterial wall plays a significant role in the pathology of diabetes-associated atherosclerosis. Therefore, inhibition of endothelial dysfunction and enhancement of macrophage cholesterol efflux is the important antiatherogenic mechanism. Rosmarinic acid (RA) possesses beneficial properties, including its anti-inflammatory, antioxidant, antidiabetic and cardioprotective effects. We previously reported that RA effectively inhibits diabetic endothelial dysfunction by inhibiting inflammasome activation in endothelial cells. However, its effect on cholesterol efflux remains unknown. Therefore, in this study, we aimed to assess the effect of RA on cholesterol efflux and its underlying mechanisms in macrophages. RA effectively reduced oxLDL-induced cholesterol contents under high glucose (HG) conditions in macrophages. RA enhanced ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) expression, promoting macrophage cholesterol efflux. Mechanistically, RA differentially regulated ABCA1 expression through JAK2/STAT3, JNK and PKC-p38 and ABCG1 expression through JAK2/STAT3, JNK and PKC-ERK1/2/p38 in macrophages. Moreover, RA primarily stabilized ABCA1 rather than ABCG1 protein levels by impairing protein degradation. These findings suggest RA as a candidate therapeutic to prevent atherosclerotic cardiovascular disease complications related to diabetes by regulating cholesterol efflux in macrophages.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Colesterol/metabolismo , Cinamatos/farmacologia , Depsídeos/farmacologia , Glucose/efeitos adversos , Lipoproteínas LDL/efeitos adversos , Macrófagos/citologia , Transportador 1 de Cassete de Ligação de ATP/química , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Modelos Biológicos , Proteólise/efeitos dos fármacos , Transdução de Sinais , Células THP-1
10.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445510

RESUMO

Microglia are resident immune cells of the central nervous system that act as brain-specific macrophages and are also known to regulate the innate immune functions of astrocytes through secretory molecules. This communication plays an important role in brain functions and homeostasis as well as in neuropathologic disease. In this study, we aimed to elucidate whether astrocytes and microglia could crosstalk to induce microglial polarization and proliferation, which can be further regulated under a microenvironment mimicking that of brain stroke. Microglia in a mixed glial culture showed increased survival and proliferation and were altered to M2 microglia; CD11b-GFAP+ astrocytes resulted in an approximately tenfold increase in microglial cell proliferation after the reconstitution of astrocytes. Furthermore, GM-CSF stimulated microglial proliferation approximately tenfold and induced them to become CCR7+ M1 microglia, which have a phenotype that could be suppressed by anti-inflammatory cytokines such as IL-4, IL-10, and substance P. In addition, the astrocytes in the microglial co-culture showed an A2 phenotype; they could be activated to A1 astrocytes by TNF-α and IFN-γ under the stroke-mimicking condition. Altogether, astrocytes in the mixed glial culture stimulated the proliferation of the microglia and M2 polarization, possibly through the acquisition of the A2 phenotype; both could be converted to M1 microglia and A1 astrocytes under the inflammatory stroke-mimicking environment. This study demonstrated that microglia and astrocytes could be polarized to M2 microglia and A2 astrocytes, respectively, through crosstalk in vitro and provides a system with which to explore how microglia and astrocytes may behave in the inflammatory disease milieu after in vivo transplantation.


Assuntos
Astrócitos/citologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Macrófagos/citologia , Microglia/citologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Comunicação Celular , Polaridade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Microglia/efeitos dos fármacos , Microglia/imunologia , Ratos
11.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360629

RESUMO

Macrophages play a critical role in the inflammatory response to environmental triggers, such as lipopolysaccharide (LPS). Inflammatory signaling through macrophages and the innate immune system are increasingly recognized as important contributors to multiple acute and chronic disease processes. Nitric oxide (NO) is a free radical that plays an important role in immune and inflammatory responses as an important intercellular messenger. In addition, NO has an important role in inflammatory responses in mucosal environments such as the ocular surface. Histatin peptides are well-established antimicrobial and wound healing agents. These peptides are important in multiple biological systems, playing roles in responses to the environment and immunomodulation. Given the importance of macrophages in responses to environmental triggers and pathogens, we investigated the effect of histatin-1 (Hst1) on LPS-induced inflammatory responses and the underlying molecular mechanisms in RAW264.7 (RAW) macrophages. LPS-induced inflammatory signaling, NO production and cytokine production in macrophages were tested in response to treatment with Hst1. Hst1 application significantly reduced LPS-induced NO production, inflammatory cytokine production, and inflammatory signaling through the JNK and NF-kB pathways in RAW cells. These results demonstrate that Hst1 can inhibit LPS-induced inflammatory mediator production and MAPK signaling pathways in macrophages.


Assuntos
Histatinas/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Animais , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Células RAW 264.7
12.
Molecules ; 26(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34443495

RESUMO

Phytochemical investigation and chromatographic separation of extracts from the actinobacteria strain Saccharomonospora piscinae that was isolated from dried fishpond sediment of Kouhu township, in the south of Taiwan, led to the isolation of three new compounds, saccharpiscinols A-C (1-3, respectively), and three new natural products, namely (2S)-5,7,3',4'-tetrahydroxy-6,8-dimethylflavanone (4), methyl-4-hydroxy-2-methoxy-6-methylbenzoate (5), and (±)-7-acetyl-4,8-dihydroxy-6-methyl-1-tetralone (6). Compounds 4-6 were reported before as synthesized products, herein, they are reported from nature for the first time. The structures of the new compounds were unambiguously elucidated on the basis of extensive spectroscopic data analysis (1D- and 2D-NMR, MS, and UV) and comparison with literature data. The effect of some isolates on the inhibition of NO production in lipopolysaccharide-activated RAW 264.7 murine macrophages was evaluated. Saccharpiscinol A showed inhibitory activities against LPS-induced NO production.


Assuntos
Actinobacteria/química , Anti-Inflamatórios/farmacologia , Flavonoides/farmacologia , Animais , Anti-Inflamatórios/química , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Misturas Complexas , Flavonoides/química , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/biossíntese , Células RAW 264.7
13.
FASEB J ; 35(9): e21866, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34416031

RESUMO

Macrophage migration inhibitory factor (MIF), an immunoregulatory cytokine plays an important role in inflammation and the immune response, and has been described as having a potential role in immune evasion by parasites. Thelazia callipaeda, a vector-borne zoonotic eye worm with a broad host range, has been documented as an agent of ocular infection of thelaziosis. The ability of T. callipaeda to persist in an immunologically competent host has led to the suggestion that it has evolved specific measures to counter immune defenses. To date, whether the immune evasion of T. callipaeda is related to MIF and the possible related signaling pathway and molecular mechanism have remained unclear. In the present study, we examined the effect of T. callipaeda MIF (T. cp-MIF) on macrophages. We analyzed the antigenic epitopes of the candidate T. cp-MIF and found that it exhibited an ideal antigenic index. Morphology, Flow cytometry, and cytokine analysis showed that T. cp-MIF induced the dynamic polarization of THP-1 macrophages from the M1-like phenotype to the M2-like phenotype. The chemotaxis assay revealed an inhibitory effect of T. cp-MIF on THP-1 macrophages. Western blotting suggested that, compared to the control, THP-1 macrophages exposed to T. cp-MIF had higher TLR4 protein expression and the phosphatidylinositol 3'-kinase (PI3K) -Akt pathway activation. In conclusion, T. cp-MIF induces M2-like macrophage polarization through TLR4-mediated activation of the PI3K-Akt pathway, which might provide a basis for future research on how it affects the immune system of the host.


Assuntos
Fatores Inibidores da Migração de Macrófagos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/imunologia , Epitopos , Humanos , Células THP-1
14.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361073

RESUMO

This study evaluated the immunonutritional effects caused by protease inhibitors from Avena sativa and Triticum durum to human macrophage-like cells. Macrophages were exposed (3 h) to extracts obtained from flours, and mitochondrial-associated oxygen consumption rates and inflammatory, metabolic, and proteome adaptations were quantified. Mass spectrometry 'm/z' signals of the extracts obtained from T. durum and A. sativa revealed molecular weights of 18-35 kDa and 16-22 kDa, respectively, for the compounds present at highest concentrations. Extracts from T. durum exhibited lower susceptibility to degradation by gastrointestinal enzymes than those from A. sativa: 9.5% vs 20.2%. Despite their different botanical origin, both extracts increased TLR4 expression. Metabolic protein levels were indicative of a decreased glycolytic to lactate flux in cell cultures upon stimulation with A. sativa extracts, which improved mitochondrial respiration in relation to those from T. durum. Principal components analysis confirmed relative similarities between immune-metabolic events triggered by immunonutritional ingredients in T. durum and A. sativa. Collectively, immunonutritional effects help to interpret the differences between both crops, worsening or improving, macrophage immune reactivity (tolerogenicity), and better control of inflammatory processes.


Assuntos
Avena/química , Macrófagos/imunologia , Macrófagos/metabolismo , Extratos Vegetais/farmacologia , Inibidores de Proteases/farmacologia , Proteoma/efeitos dos fármacos , Triticum/química , Humanos , Macrófagos/efeitos dos fármacos
15.
Nutrients ; 13(7)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34371919

RESUMO

Besides its well-known psychoactive effects, caffeine has a broad range of actions. It regulates several physiological mechanisms as well as modulates both native and adaptive immune responses by various ways. Although caffeine is assumed to be a negative regulator of inflammation, the effect on the secretion of pro- and anti-inflammatory cytokines is highly controversial. Macrophages are major mediators of inflammatory responses; however, the various subpopulations develop different effects ranging from the initiation to the resolution of inflammation. Here we report a comparative analysis of the effect of caffeine on two subpopulations of human monocyte-derived macrophages differentiated in the presence of macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), resulting in M-MΦs and GM-MΦs, respectively. We showed that although TNF-α secretion was downregulated in both LPS-activated MΦ subtypes by caffeine, the secretion of IL-8, IL-6, and IL-1ß as well as the expression of Nod-like receptors was enhanced in M-MΦs, while it did not change in GM-MΦs. We showed that caffeine (1) altered adenosine receptor expression, (2) changed Akt/AMPK/mTOR signaling pathways, and (3) inhibited STAT1/IL-10 signaling axis in M-MΦs. We hypothesized that these alterations play an important modulatory role in the upregulation of NLRP3 inflammasome-mediated IL-1ß secretion in LPS-activated M-MΦs following caffeine treatment.


Assuntos
Cafeína/farmacologia , Citocinas/metabolismo , Fatores Imunológicos/farmacologia , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Células Cultivadas , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Fenótipo , Receptor A2A de Adenosina/metabolismo , Receptor A2B de Adenosina/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
16.
Anticancer Res ; 41(8): 4071-4076, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281876

RESUMO

BACKGROUND/AIM: Increased expression of inflammatory cytokine genes through cell interactions in tissues may cause chronic inflammation, leading to the development of lifestyle-related diseases. Since the activation of inflammatory cytokine genes in monocytes/macrophages by co-culturing with cancer cells or adipocytes was suppressed by pre-treatment with low-dose lipopolysaccharide (LPS), we hypothesized that low-dose LPS-activated macrophages may regulate the expression of immune response-related genes in other cells. MATERIALS AND METHODS: Phorbol myristate acetate-treated human monocytes (THP-1) were activated by LPS. The conditioned medium of LPS-activated THP-1 cells was added to human adipocytes. After 5 days, the expression of genes encoding interleukin (IL)-6 (IL6), IL-8 (IL8), monocyte chemotactic protein (MCP)-1 (CCL2), adiponectin (ADIPOQ), and plasminogen activator inhibitor (PAI)-1 (SERPINE1) was analyzed using quantitative real-time PCR. RESULTS: The increased expression of inflammation-related genes and SERPINE1 in adipocytes was suppressed by the conditioned medium of THP-1 cells activated by low-dose LPS, whereas the expression of ADIPOQ was significantly increased. CONCLUSION: Low-dose LPS-activated macrophages convert adipocytes to anti-inflammatory phenotypes.


Assuntos
Adipócitos/metabolismo , Adiponectina/genética , Citocinas/genética , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/genética , Linhagem Celular , Humanos , Ativação de Macrófagos
17.
Anticancer Res ; 41(8): 4093-4100, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281880

RESUMO

BACKGROUND/AIM: We investigated the effect of Kumaizasa leaf extract (KLE) on innate immunity using the HEK293 and RAW 264.7 cell lines. MATERIALS AND METHODS: KLE, lipopolysaccharides (LPS), or KLE with LPS were added to RAW 264.7 cells. The TNF-α and IL-1ß mRNA expression was then quantified. The expression of MAPKs, NFĸB, TNF-α and IL-1ß proteins was also quantified. In addition, KLE was added to HEK293 cells and the IL-8 concentration was measured. RESULTS: In RAW 264.7 cells, KLE increased the levels of TNF-α and IL-1ß mRNA. By contrast, when KLE and LPS were added to RAW 264.7 cells, the increase in TNF-α and IL-1ß mRNA was ameliorated. Similarly, the expression of JNK and ERK proteins was reduced. The addition of KLE to HEK293 cells induced IL-8 production. CONCLUSION: Based on these results, a KLE-mediated mechanism may regulate immunity by suppressing the expression of JNK and ERK, which are involved in inflammatory signal transduction.


Assuntos
Imunidade Inata/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Sasa , Animais , Citocinas/genética , Citocinas/imunologia , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Células HEK293 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Camundongos , Folhas de Planta , Células RAW 264.7
18.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203170

RESUMO

Acidovorax avenae is a flagellated, pathogenic bacterium to various plant crops that has also been found in human patients with haematological malignancy, fever, and sepsis; however, the exact mechanism for infection in humans is not known. We hypothesized that the human innate immune system could be responsive to the purified flagellin isolated from A. avenae, named FLA-AA. We observed the secretion of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-8 by treating FLA-AA to human dermal fibroblasts, as well as macrophages. This response was exclusively through TLR5, which was confirmed by using TLR5-overexpression cell line, 293/hTLR5, as well as TLR5-specific inhibitor, TH1020. We also observed the secretion of inflammatory cytokine, IL-1ß, by the activation of NLRC4 with FLA-AA. Overall, our results provide a molecular basis for the inflammatory response caused by FLA-AA in cell-based assays.


Assuntos
Comamonadaceae/química , Flagelina/farmacologia , Imunidade Inata/fisiologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Imunidade Inata/genética , Interleucina-18/metabolismo , Interleucina-6/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
19.
Molecules ; 26(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299479

RESUMO

A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against Leishmania infantum and Leishmania donovani intracellular amastigotes, against Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the substituents of the heterocyclic ring (tail) and the oligomethylene spacer between the head group and the heterocyclic ring was found to affect the activity and toxicity of these compounds leading to a significantly improved understanding of their structure-activity relationships. The early ADMET profile of the new derivatives did not reveal major liabilities for the potent compounds. The 1,2,3-triazole derivative 27 substituted by a decyl tail, an undecyl spacer and a choline head group exhibited broad spectrum antiparasitic activity. It possessed low micromolar activity against the intracellular amastigotes of two L. infantum strains and T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes, while its cytotoxicity concentration (CC50) against THP-1 macrophages ranged between 50 and 100 µM. Altogether, our work paves the way for the development of improved ether phospholipid derivatives to control neglected tropical diseases.


Assuntos
Antiparasitários/síntese química , Antiparasitários/farmacologia , Doença de Chagas/tratamento farmacológico , Desenho de Fármacos , Leishmaniose/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Fosfolipídeos/farmacologia , Doença de Chagas/parasitologia , Química Click , Humanos , Leishmania/efeitos dos fármacos , Leishmaniose/parasitologia , Relação Estrutura-Atividade , Trypanosoma cruzi/efeitos dos fármacos
20.
Chem Commun (Camb) ; 57(66): 8166-8169, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34318802

RESUMO

An "AND"-logic-gate-based fluorescent probe NAP-DCP-4 with dual reactive sites is reported, which has improved selectivity for methylglyoxal over glyoxal, featuring formaldehyde-enhanced methylglyoxal detection and irreversible and reversible turn-on fluorescence responses at different excitation wavelengths. Its cell-impermeability enables facile monitoring of extracellular methylglyoxal level changes in the supernatant of activated macrophages.


Assuntos
Corantes Fluorescentes/química , Macrófagos/química , Aldeído Pirúvico/análise , Animais , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Aldeído Pirúvico/metabolismo , Células RAW 264.7
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