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1.
Life Sci ; 274: 119312, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33667521

RESUMO

AIMS: Piperine, the major pharmacological ingredient of pepper, can delay the procession of "obesity to diabetes". However, the underlying mechanism remains unclear. This study aims to investigate whether piperine protects against ß-cell dysfunction by inhibiting macrophage accumulation and M1-like polarization. MATERIALS AND METHODS: Pre-diabetic model was induced by feeding 60% high-fat diet (HFD) in C57BL/6C mice, piperine (15 or 30 mg/kg/day) and rosiglitazone (4 mg/kg/day) were given orally for 8 weeks. Oral glucose tolerance test (OGTT), insulin tolerance test (ITT), fasting blood glucose (FBG), total cholesterol (TC) and triglyceride (TG) were used to assay the disorder of glycolipid metabolism. Serum levels of cytokines and insulin were measured by Elisa. Hyperglycemic clamp assay was carried out to evaluate ß-cell function. RT-PCR, immunofluorescence and western blot were used to detect the expression of biomarkers associated with macrophage polarization and ß-cell dedifferentiation. KEY FINDINGS: Piperine protected against ß-cell dysfunction, indicated by the improvement of hyperinsulinemia, OGTT and increased glucose infusion rate (GIR). Piperine dramatically reduced the serum levels of lipopolysaccharide (LPS), interleukin-1ß (IL-1ß) and Galectin-3 (Gal-3), suppressed the expression of M1-like cytokines (CD11c, IL-1ß and Gal-3) in epididymal adipose tissues and islets. Furthermore, piperine partially reversed the down-regulation of Pdx1, inhibited the up-regulation of ALDH1A3 in ß-cell, and these effects were closely related to the mTOR/S6/4E-BP1 signal pathway. SIGNIFICANCE: Piperine markedly ameliorates the dedifferentiation and dysfunction of ß-cell by inhibiting the accumulation and M1-like polarization of macrophages in visceral adipose tissues and islets.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Alcaloides/farmacologia , Benzodioxóis/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Inflamação/tratamento farmacológico , Células Secretoras de Insulina/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Obesidade/complicações , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Animais , Inflamação/etiologia , Inflamação/patologia , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos
2.
Nat Commun ; 12(1): 773, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536439

RESUMO

Macrophages are plastic and, in response to different local stimuli, can polarize toward multi-dimensional spectrum of phenotypes, including the pro-inflammatory M1-like and the anti-inflammatory M2-like states. Using a high-throughput phenotypic screen in a library of ~4000 FDA-approved drugs, bioactive compounds and natural products, we find ~300 compounds that potently activate primary human macrophages toward either M1-like or M2-like state, of which ~30 are capable of reprogramming M1-like macrophages toward M2-like state and another ~20 for the reverse repolarization. Transcriptional analyses of macrophages treated with 34 non-redundant compounds identify both shared and unique targets and pathways through which the tested compounds modulate macrophage activation. One M1-activating compound, thiostrepton, is able to reprogram tumor-associated macrophages toward M1-like state in mice, and exhibit potent anti-tumor activity. Our compound-screening results thus help to provide a valuable resource not only for studying the macrophage biology but also for developing therapeutics through modulating macrophage activation.


Assuntos
Anti-Inflamatórios/farmacologia , Produtos Biológicos/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Produtos Biológicos/química , Linhagem Celular Tumoral , Células Cultivadas , Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Humanos , Macrófagos/classificação , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Experimentais/prevenção & controle , Fenótipo , Células THP-1 , Tioestreptona/química , Tioestreptona/farmacologia
3.
Nat Commun ; 12(1): 102, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397994

RESUMO

Pro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.


Assuntos
Tecido Adiposo/metabolismo , Sistemas de Liberação de Medicamentos , Macrófagos/metabolismo , Mitocôndrias/metabolismo , Obesidade/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Animais , Peso Corporal/efeitos dos fármacos , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Inflamação/genética , Inflamação/patologia , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Obesidade/genética , Obesidade/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Perda de Peso/efeitos dos fármacos
4.
Drug Res (Stuttg) ; 71(4): 173-179, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33434935

RESUMO

Coronavirus disease (COVID-19) emerged from Wuhan, has now become pandemic and the mortality rate is growing exponentially. Clinical complication and fatality rate is much higher for patients having co-morbid issues. Compromised immune response and hyper inflammation is hall mark of pathogenesis and major cause of mortality. Cytokine release syndrome (CRS) or cytokine storm is a term used to affiliate the situation of hyper inflammation and therefore use of anti-cytokine and anti-inflammatory drugs is used to take care of this situation. Looking into the clinical benefit of these anti-inflammatory drugs, many of them enter into clinical trials. However, understanding the immunopathology of COVID-19 is important otherwise, indiscriminate use of these drugs could be fetal as there exists a very fine line of difference between viral clearing cytokines and inflammatory cytokines. If any drug suppresses the viral clearing cytokines, it will worsen the situation and hence, the use of these drugs must be based on the clinical condition, viral load, co-existing disease condition and severity of the infection.


Assuntos
/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/metabolismo , Drogas em Investigação/uso terapêutico , Ativação de Macrófagos/efeitos dos fármacos , Anti-Inflamatórios/uso terapêutico , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo
5.
ACS Appl Mater Interfaces ; 13(2): 2230-2244, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33403850

RESUMO

Efficient reconstruction of a fully functional skin after wounds requires multiple functionalities of wound dressing due to the complexity of healing. In these regards, topical administration of functionalized nanoparticles capable of sustainably releasing bioactive agents to the wound site may significantly accelerate wound repair. Among the various nanoparticles, superparamagnetic iron oxide (Fe3O4) nanoparticles gain increasing attractiveness due to their intrinsic response to an external magnetic field (eMF). Herein, based on the Fe3O4 nanoparticle, we developed a fibroblast growth factor (bFGF)-loaded Fe3O4 nanoparticle using a simple mussel-inspired surface immobilization method. This nanoparticle, named as bFGF-HDC@Fe3O4, could stabilize bFGF in various conditions and exhibited sustained release of bFGF. In addition, an in vitro study discovered that bFGF-HDC@Fe3O4 could promote macrophage polarization toward an anti-inflammatory (pro-healing) M2 phenotype especially under eMF. Further, in vivo full-thickness wound animal models demonstrated that bFGF-HDC@Fe3O4 could significantly accelerate wound healing through M2 macrophage polarization and increased cell proliferation. Therefore, this approach of realizing sustained the release of the growth factor with magnetically macrophage regulating behavior through modification of Fe3O4 nanoparticles offers promising potential to tissue-regenerative applications.


Assuntos
Preparações de Ação Retardada/química , Dopamina/análogos & derivados , Fatores de Crescimento de Fibroblastos/administração & dosagem , Heparina/química , Nanopartículas de Magnetita/química , Cicatrização/efeitos dos fármacos , Animais , Materiais Biomiméticos/química , Bivalves/química , Fatores de Crescimento de Fibroblastos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Propriedades de Superfície
6.
Mol Cell ; 81(5): 953-968.e9, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33503407

RESUMO

While the role of transcription factors and coactivators in controlling enhancer activity and chromatin structure linked to gene expression is well established, the involvement of corepressors is not. Using inflammatory macrophage activation as a model, we investigate here a corepressor complex containing GPS2 and SMRT both genome-wide and at the Ccl2 locus, encoding the chemokine CCL2 (MCP-1). We report that corepressors co-occupy candidate enhancers along with the coactivators CBP (H3K27 acetylase) and MED1 (mediator) but act antagonistically by repressing eRNA transcription-coupled H3K27 acetylation. Genome editing, transcriptional interference, and cistrome analysis reveals that apparently related enhancer and silencer elements control Ccl2 transcription in opposite ways. 4C-seq indicates that corepressor depletion or inflammatory signaling functions mechanistically similarly to trigger enhancer activation. In ob/ob mice, adipose tissue macrophage-selective depletion of the Ccl2 enhancer-transcribed eRNA reduces metaflammation. Thus, the identified corepressor-eRNA-chemokine pathway operates in vivo and suggests therapeutic opportunities by targeting eRNAs in immuno-metabolic diseases.


Assuntos
Quimiocina CCL2/genética , Proteínas Correpressoras/genética , Elementos Facilitadores Genéticos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Correpressor 2 de Receptor Nuclear/genética , Obesidade/genética , Elementos Silenciadores Transcricionais , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Animais , Sistemas CRISPR-Cas , Quimiocina CCL2/imunologia , Proteínas Correpressoras/imunologia , Edição de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Histona Acetiltransferases/genética , Histona Acetiltransferases/imunologia , Histonas/genética , Histonas/imunologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Subunidade 1 do Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/imunologia , Camundongos , Camundongos Obesos , Correpressor 2 de Receptor Nuclear/imunologia , Obesidade/imunologia , Obesidade/patologia , Células RAW 264.7 , RNA não Traduzido/genética , RNA não Traduzido/imunologia , Transdução de Sinais
7.
Methods Mol Biol ; 2201: 209-217, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32975802

RESUMO

The immune system is a complex and finely orchestrated system, and many soluble molecules and receptors contribute to its regulation.Recent studies have suggested that many of the modulatory effects induced by morphine on innate immunity, and in particular the effects on macrophage activation and function, can be due to the modulation of an important macrophage surface receptor, the toll-like receptor (TLR), that is primarily involved in early regulatory steps. In this chapter we describe a RT-real-time PCR method for assessing TLR expression in macrophage after in vivo morphine treatment.


Assuntos
Macrófagos/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Receptor 4 Toll-Like/análise , Analgésicos Opioides/imunologia , Analgésicos Opioides/farmacologia , Animais , Citocinas/biossíntese , Fenômenos do Sistema Imunológico , Imunidade Inata/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Morfina/efeitos adversos , Morfina/metabolismo , Morfina/farmacologia , Receptores Opioides/imunologia , Receptor 4 Toll-Like/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
8.
Life Sci ; 267: 118943, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33359248

RESUMO

AIMS: Astaxanthin is a natural carotenoid, can readily cross the blood-brain barrier and exerts a powerful neuroprotective effect. In this study, experiments were performed to explore the underlying molecular mechanisms of which Astaxanthin inhibiting the microglia M1 activation. MAIN METHODS: BV2 cells and mice were pre-treated with Astaxanthin and treated by Lipopolysaccharide (LPS). The expressions of M1-related factors (pro-inflammatory cytokines and M1 markers) were measured by RT-qPCR and western blot. The target association between miR-31-5p and Numb was explored via luciferase activity assay. MiR-31-5p mimic was transfected into BV2 cells, then the cells were treated with Astaxanthin in combination with LPS. The expression of M1-related factors and Notch pathway-related molecules were measured via RT-qPCR, western blot and immunofluorescence assay. KEY FINDINGS: Precondition of BV2 cells with Astaxanthin inhibited the expression of M1-related factors triggered by LPS. In addition, Astaxanthin decreased the number of Iba1-positive microglia and downregulated the levels of M1-related factors in hippocampus in LPS-treated mice. Further investigation revealed that Astaxanthin-mediated suppression of M1-related factors levels was reversed by miR-31-5p mimic in BV2 cells stimulated by LPS. Subsequently, we verified that miR-31-5p repressed Numb expression by binding to the 3'-UTR of Numb mRNA. Also, Astaxanthin suppressed the expression of Notch1, Hes1 and Hes5 and improved the expression of Numb in BV2 cells challenged by LPS, but this alteration can be reversed by miR-31-5p mimic. SIGNIFICANCE: Our study demonstrated that down-regulating miR-31-5p by Astaxanthin could be a potential therapeutic approach to suppress neuroinflammation via regulating microglia M1 activation.


Assuntos
MicroRNAs/genética , Microglia/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Linhagem Celular , Citocinas/metabolismo , Hipocampo/metabolismo , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Microglia/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Xantofilas/metabolismo , Xantofilas/farmacologia
9.
Life Sci ; 266: 118903, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33340526

RESUMO

AIMS: We will investigate the anti-inflammatory activities of berberine (BBR) in treating chronic atrophic gastritis (CAG) induced by Helicobacter pylori (H. pylori). Furthermore, the underlying molecular mechanisms of BBR also will be explored systematically. MATERIALS AND METHODS: Rats were infected by H. pylori. Lipopolysaccharide (LPS) and H. pylori were applied to induce M1 Mφs polarization, interleukin 4 (IL-4) and BBR were used to induce M2 Mφs polarization. Supernatants of polarized Mφs were collected as conditioned media (CM) for investigating the impact of Mφs and its' secreted cytokine on gastric epithelial cells (GES-1). Cell viability, morphology, proliferation, and quantitative analysis of RAW 264.7 cells and GES-1 cells were detected by high-content screening (HCS) imaging assay. To further investigate the potential mechanisms of BBR, relative mRNA, immunohistochemistry and protein expression were measured. KEY FINDINGS: BBR inhibited M1-polarized Mφs, which was induced by H. pylori and LPS, and advocated M2-polarized Mφs. The M1-specific markers (TNF-α and IFN-γ) in supernatants were reduced significantly and M2 specific markers (TGF-ß and IL-10) were increased obviously under BBR intervention. In addition, BBR significantly protected GES-1 from M1-polarized Mφs injury. The mRNA expression of M1-polarized Mφs, including TNF-α, NOS2, CCR7, and IRF-8, were suppressed by BBR administration and the mRNA expression of M2-polarized Mφs, including IL-4, STAT6, IL-10 and Chil3, were increased by BBR intervention. Meanwhile, BBR activated IL-4-STAT6 signaling pathway in vivo and in vitro when H. pylori infection and presented anti-inflammatory activities. SIGNIFICANCE: BBR promotes M2-polarized Mφs when H. pylori infection. The anti-inflammatory properties of BBR tightly related to M1-polarized Mφs inhibition and M2-polarized Mφs promotion. BBR activates IL-4-STAT6 signaling pathway, which is crucial exceedingly in M2 Mφs activation and anti-inflammatory response.


Assuntos
Berberina/farmacologia , Gastrite Atrófica/tratamento farmacológico , Infecções por Helicobacter/complicações , Helicobacter pylori/isolamento & purificação , Interleucina-4/metabolismo , Ativação de Macrófagos/imunologia , Fator de Transcrição STAT6/metabolismo , Animais , Gastrite Atrófica/etiologia , Gastrite Atrófica/patologia , Regulação da Expressão Gênica , Infecções por Helicobacter/microbiologia , Humanos , Interleucina-4/genética , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Ratos , Fator de Transcrição STAT6/genética
10.
Biomed Pharmacother ; 134: 111171, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33383312

RESUMO

Periodontitis is a multifactorial chronic infectious disease leading to a host immune response involving inflammatory cytokines, especially IL-1ß, which is the main reason for further developing this disease. IL-1 receptor antagonist (IL-1ra) binds IL-1 receptor, inhibiting IL-1ß signaling and reducing the levels of other cytokines closely related to periodontitis, such as IL-6 and TNF-α. Therefore, the use of IL-1ra to inhibit periodontitis development in a system, ensuring its sustained release, might be an effective way to combat this disease. Hence, in this study, a novel IL-1ra-loaded dextran/PLGA microsphere was developed to allow the sustained release of IL-1ra and enhance the anti-inflammatory properties. Therefore, this study's purposes were to develop a novel periodontal treatment for inhibition and treatment of periodontitis and evaluate the sustained-release effect and anti-inflammatory properties of IL-1ra-loaded dextran/PLGA microspheres in vitro by cell experiments and in vivo by animal experiments. The results showed that IL-1ra-loaded dextran/PLGA microspheres were non-toxic both in vitro and in vivo and could be used as a safe and effective treatment. In addition, these microspheres could significantly prolong the half-life of IL-1ra drug, exerting a useful anti-inflammatory effect in macrophages stimulated with P. gingivalis lipopolysaccharide and in rats with periodontitis. In conclusion, IL-1ra-loaded dextran/PLGA microsphere might be a useful tool to combat periodontal disease.


Assuntos
Anti-Inflamatórios/farmacologia , Dextranos/química , Portadores de Fármacos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Periodontite/prevenção & controle , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Anti-Inflamatórios/química , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Composição de Medicamentos , Proteína Antagonista do Receptor de Interleucina 1/química , Lipopolissacarídeos/isolamento & purificação , Lipopolissacarídeos/toxicidade , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Microesferas , Periodontite/imunologia , Periodontite/metabolismo , Porphyromonas gingivalis/química , Células RAW 264.7 , Ratos Sprague-Dawley
11.
Mol Immunol ; 130: 113-121, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33308900

RESUMO

Macrophages are the most abundant cells in tumor stroma and their polarization within tumor microenvironment exert the key roles in tumorigenesis. Astragaloside IV is a natural extract from traditional Chinese herbal Radix Astragali, and fulfills pleiotropic function in several cancers. Nevertheless, its function in ovarian cancer microenvironment remains elusive. In the present research, astragaloside IV exhibited little cytotoxicity within a certain dose range in THP-1 cells. Moreover, astragaloside IV suppressed the ratio of CD14+CD206+ cells in IL-4/IL-13-treated THP-1 macrophages and transcripts of M2 macrophage markers (including CD206, CCL24, PPARγ, Arg-1, IL-10), indicating the inhibitory effects of astragaloside IV on IL-4/IL-13-induced macrophage M2 polarization. Intriguingly, astragaloside IV antagonized M2 macrophages coculture-evoked cell proliferation, invasion and migration in ovarian cancer cells. During this process, administration with astragaloside IV restrained the high expression of high-mobility group box1 (HMGB1) and TLR4 in macrophages co-cultured with ovarian cancer cells, concomitant with decreases in release of M2 marker TGF-ß, MMP-9 and IL-10. Moreover, targeting the HMGB1 signaling reversed M2 macrophages-induced ovarian cancer cell proliferation, invasion and migration. Noticeably, exogenous HMGB1 overturned the inhibitory efficacy of astragaloside IV against macrophage M2 polarization-evoked malignant potential in ovarian cancer cells. Together, these findings suggest that astragaloside IV may protect against M2 macrophages-evoked malignancy in ovarian cancer cells by suppressing the HMGB1-TLR4 signaling. Therefore, astragaloside may alleviate the progression of ovarian cancer by regulating macrophage M2 polarization within tumor microenvironment, implying a promising therapeutic strategy against ovarian cancer.


Assuntos
Polaridade Celular/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Neoplasias Ovarianas/patologia , Saponinas/farmacologia , Triterpenos/farmacologia , Movimento Celular/efeitos dos fármacos , Polaridade Celular/imunologia , Progressão da Doença , Feminino , Proteína HMGB1/metabolismo , Humanos , Macrófagos/fisiologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Receptor 4 Toll-Like/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
12.
J Ethnopharmacol ; 269: 113684, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33309583

RESUMO

Ethnopharmacological relevance Ainsliaea fragrans Champ. (A. fragrans) is used to treat infection of the lower genital tract in gynecology, such as cervicitis and pelvic inflammatory disease. This study analyzed the therapeutic efficiency of A. fragrans on cervicitis and the inhibition mechanism of AF-p2 in MALP-2-stimulated RAW264.7 cells. Materials and methods The anti- Ureaplasma urealyticum (Uu) activity of A. fragrans and AF-p2 were determined by antimicrobial susceptibility testing. The activity of A. fragrans extracts (AFext) was evaluated in female BALB/c mice with cervicitis induced by Uu. Furthermore, the therapeutic mechanism of AFext and AF-p2 on myeloid differentiation factor 88 (MyD88) pathway were studied in macrophage activating lipopeptide-2 (MALP-2) irritated RAW264.7 cells. Results AFext could suppress the proliferation of Uu in vitro, including the azithromycin resistant strains. Meanwhile, AFext prevented cervicitis caused by Uu infection in BALB/c mice. Moreover, both AFext and AF-p2 could significantly suppress the nitric oxide (NO) production as well as other proinflammatory cytokines (IL-1ß,IL-6,TNF-α) in MALP-2 stimulated RAW264.7 cells. Moreover, AF-p2 also down-regulated iNOS, p65, Iκ-Bα, MyD88 and cyclooxygenase-2 (COX-2) levels in RAW264.7 cells. Conclusion This study indicated that AFext had a therapeutic effect in cervicitis induced by Uu infection. Furthermore, the lead compound AF-p2 showed an anti-infectious effect in MALP-2 irritated RAW264.7 cells through downregulating MyD88-NF-κB signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Lipopeptídeos/toxicidade , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Cervicite Uterina/induzido quimicamente , Cervicite Uterina/prevenção & controle , Animais , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Cervicite Uterina/metabolismo
13.
Nat Commun ; 11(1): 6343, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311467

RESUMO

D-mannose is a monosaccharide approximately a hundred times less abundant than glucose in human blood. Previous studies demonstrated that supraphysiological levels of D-mannose inhibit tumour growth and stimulate regulatory T cell differentiation. It is not known whether D-mannose metabolism affects the function of non-proliferative cells, such as inflammatory macrophages. Here, we show that D-mannose suppresses LPS-induced macrophage activation by impairing IL-1ß production. In vivo, mannose administration improves survival in a mouse model of LPS-induced endotoxemia as well as decreases progression in a mouse model of DSS-induced colitis. Phosphomannose isomerase controls response of LPS-activated macrophages to D-mannose, which impairs glucose metabolism by raising intracellular mannose-6-phosphate levels. Such alterations result in the suppression of succinate-mediated HIF-1α activation, imposing a consequent reduction of LPS-induced Il1b expression. Disclosing an unrecognized metabolic hijack of macrophage activation, our study points towards safe D-mannose utilization as an effective intervention against inflammatory conditions.


Assuntos
Interleucina-1beta/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Manose/metabolismo , Manose/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Colite/metabolismo , Colite/patologia , Regulação da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/metabolismo , Interleucina-1beta/genética , Lipopolissacarídeos/efeitos adversos , Manosefosfatos/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica , Monócitos/metabolismo
14.
J Toxicol Sci ; 45(11): 673-680, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33132241

RESUMO

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have been approved for non-small cell lung cancer. Although EGFR TKIs are less toxic than traditional cytotoxic therapies, they cause many severe idiosyncratic drug reactions. Reactive metabolites can cause cellular damage with the release of danger-associated molecular patterns (DAMPs), which is thought to be involved in immune activation. Inflammasomes can be activated by DAMPs, and this may be a common mechanism by which DAMPs initiate an immune response. We tested the ability of afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib to induce the release of DAMPs that activate inflammasomes. Human hepatocarcinoma functional liver cell-4 (FLC-4) cells were used for bioactivation of drugs, and the detection of inflammasome activation was performed with the human macrophage cell line, THP-1 cells. Gefitinib is known to be oxidized to a reactive iminoquinone metabolite. We found that the supernatant from the incubation of gefitinib with FLC-4 cells for 7 days led to increased caspase-1 activity and production of IL-1ß by THP-1 cells. In the supernatant of FLC-4 cells with gefitinib, the heat shock protein (HSP) 40, 70 and 90 were significantly increased. In addition, activated THP-1 cells secreted high mobility group box 1 (HMGB1) protein. These results support the hypothesis that the reactive iminoquinone metabolite can cause the release of DAMPs from hepatocytes, which in turn, can activate inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by gefitinib, which in some patients, can cause immune-related adverse events.


Assuntos
Meios de Cultura/efeitos adversos , Gefitinibe/efeitos adversos , Hepatócitos , Inflamassomos/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Células THP-1/imunologia , Alarminas/metabolismo , Caspase 1/metabolismo , Linhagem Celular , Gefitinibe/metabolismo , Proteína HMGB1/metabolismo , Humanos , Interleucina-1beta/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Quinonas/efeitos adversos , Quinonas/metabolismo , Células THP-1/metabolismo
15.
Nat Commun ; 11(1): 4909, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999291

RESUMO

Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a 'don't eat me' signal that interacts with signal regulatory protein alpha (SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.


Assuntos
Micropartículas Derivadas de Células/imunologia , Imunoterapia/métodos , Macrófagos/imunologia , Melanoma/terapia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias de Mama Triplo Negativas/terapia , Animais , Antígeno CD47/metabolismo , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Melanoma/imunologia , Melanoma/secundário , Proteínas de Membrana/agonistas , Proteínas de Membrana/imunologia , Camundongos , Nanopartículas/administração & dosagem , Recidiva Local de Neoplasia/imunologia , Nucleotídeos Cíclicos/administração & dosagem , Receptores Imunológicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia
16.
Int J Nanomedicine ; 15: 7763-7774, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116499

RESUMO

Background: The proper topography of implant surface can induce macrophages polarization, whereas the regulation mechanism has not been fully deciphered. The study aimed to examine the regulation mechanism of macrophages M2 polarization by titanium (Ti) implant surface micro/nano topography. Results: Firstly, the titanium implant micropits-nanotubular surface with ~30 nm diameters (MNT) can induce the M2 polarization of RAW264.7 spontaneously, as indicated by the spindle-like cell morphological alteration and specific molecular marker arginase-1 (Arg1) expression. Next, the autophagic vacuoles (AVs) number is significantly increased on MNT surface, as confirmed by the monodansylcadaverine (MDC) and CYTO-ID staining as well as the transmission electron microscope (TEM) observation. In addition, increasing or decreasing the autophagosomes number by rapamycin or 3-methyladenine (3-MA) will result in augmentation or attenuation of Arg1. Furthermore, blocking the fusion between autophagosomes and lysosomes by bafilomycin also significantly reduces Arg1, even in the presence of rapamycin. Finally, the ERK phosphorylation is selectively upregulated on MNT surface and the AVs number and Arg1 expression are significantly suppressed by U0126 treatment. Conclusion: Our findings suggest that the ERK-Beclin-1-autophagy axis may play a pivotal role in the regulation of M2 polarization induced by nanotopography.


Assuntos
Autofagia/efeitos dos fármacos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Nanoestruturas/química , Titânio/química , Titânio/farmacologia , Animais , Autofagossomos/metabolismo , Proteína Beclina-1/metabolismo , Biomarcadores/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Células RAW 264.7
17.
Nanotoxicology ; 14(8): 1137-1155, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32916084

RESUMO

Bystander effects in biological systems are the responses shown by nontargeted neighboring cells, and critical to the bio-nano interface interactions. In addition to direct effects, bystander effects also determine the design, applications and safety of nanomaterials, although the related information of nanomaterial-induced bystander effects remain largely unknown. A coculture system of A549 and THP-1 was established to mimic the lung microenvironment to study the bystander effects of WS2 nanosheets (representative transition-metal dichalcogenide nanosheets) on microenvironment macrophages during the inhalation exposure or the nanomaterial biomedical application in the lung. Lung cells exposed to WS2 nanosheet resulted in an increase in reactive oxygen species and the depolarization of mitochondrial membrane potential in neighboring macrophages. Bystander exposure also induced macrophage polarization toward the anti-inflammatory M2 phenotype, which is adverse to disease therapy. Metabolomics showed that WS2 nanosheets disturbed the energy metabolism and amino acid metabolism of macrophages, consistent with the metabolic characteristics of M2 macrophages. Nitric oxide-transforming growth factor-ß1 played an important mediator in the bystander effects. Importantly, WS2 nanosheet bystander exposure affected macrophage phagocytosis and migration and altered the macrophage immune response to endotoxin. This study improves the current understanding of bio-nano interactions and highlights the importance of neighboring cell responses, allowing us to use the maximum benefits of nanomaterials while limiting their adverse bystander effects.


Assuntos
Efeito Espectador/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Nanoestruturas/toxicidade , Sulfetos/toxicidade , Compostos de Tungstênio/toxicidade , Células A549 , Animais , Efeito Espectador/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Humanos , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nanoestruturas/química , Óxido Nítrico/metabolismo , Tamanho da Partícula , Fagocitose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sulfetos/química , Propriedades de Superfície , Células THP-1 , Compostos de Tungstênio/química
18.
Cell Prolif ; 53(10): e12907, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32951298

RESUMO

OBJECTIVE: Tissue engineering is a promising strategy for repair of large bone defect. However, the immune system reactions to biological scaffold are increasingly being recognized as a crucial factor influencing regeneration efficacy. In this study, a bone-bioactive hydrogel bead loaded with interleukin-4 (IL-4) was used to regulate macrophages polarization and accelerate bone regeneration. METHODS: IL-4-loaded calcium-enriched gellan gum (Ca-GG + IL-4) hydrogel beads were synthesised. And the effect on cell behaviour was detected. Furthermore, the effect of the Ca-GG + IL-4 hydrogel bead on macrophage polarization and the effect of macrophage polarization on bone mesenchymal stem cells (BMSCs) apoptosis and osteogenic differentiation were evaluated in vitro and in vivo. RESULTS: BMSCs were able to survive in the hydrogel regardless of whether IL-4 was incorporated. Immunofluorescence staining and qPCR results revealed that Ca-GG + IL-4 hydrogel bead could promote M2 macrophage polarization and increase transforming growth factor (TGF)-ß1 expression level, which activates the TGF-ß1/Smad signalling pathway in BMSCs and promotes osteogenic differentiation. Moreover, immunohistochemical analysis demonstrated Ca-GG + IL-4 hydrogel bead could promote M2 macrophage polarization and reduce cell apoptosis in vivo. In addition, micro-CT and immunohistochemical analysis at 12 weeks post-surgery showed that Ca-GG + IL-4 hydrogel bead could achieve superior bone defect repair efficacy in vivo. CONCLUSIONS: The Ca-GG + IL-4 hydrogel bead effectively promoted bone defect regeneration via regulating macrophage polarization, reducing cell apoptosis and promoting BMSCs osteogenesis through TGF-ß1/Smad pathway. Therefore, it is a promising strategy for repair of bone defect.


Assuntos
Regeneração Óssea , Diferenciação Celular/efeitos dos fármacos , Hidrogéis/química , Interleucina-4/farmacologia , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tecidos Suporte/química , Animais , Apoptose/efeitos dos fármacos , Regeneração Óssea/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Interleucina-4/química , Interleucina-4/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Polissacarídeos Bacterianos/química , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Proteínas Smad/metabolismo , Engenharia Tecidual , Fator de Crescimento Transformador beta1/metabolismo
19.
Nat Commun ; 11(1): 4064, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792542

RESUMO

Regulation of the programming of tumour-associated macrophages (TAMs) controls tumour growth and anti-tumour immunity. We examined the role of FGF2 in that regulation. Tumours in mice genetically deficient in low-molecular weight FGF2 (FGF2LMW) regress dependent on T cells. Yet, TAMS not T cells express FGF receptors. Bone marrow derived-macrophages from Fgf2LMW-/- mice co-injected with cancer cells reduce tumour growth and express more inflammatory cytokines. FGF2 is induced in the tumour microenvironment following fractionated radiation in murine tumours consistent with clinical reports. Combination treatment of in vivo tumours with fractionated radiation and a blocking antibody to FGF2 prolongs tumour growth delay, increases long-term survival and leads to a higher iNOS+/CD206+ TAM ratio compared to irradiation alone. These studies show for the first time that FGF2 affects macrophage programming and is a critical regulator of immunity in the tumour microenvironment.


Assuntos
Fator 2 de Crescimento de Fibroblastos/metabolismo , Radioterapia/métodos , Animais , Linhagem Celular Tumoral , Fator 2 de Crescimento de Fibroblastos/genética , Células HT29 , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/efeitos da radiação , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Life Sci ; 261: 118360, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32861799

RESUMO

AIM: Diabetic patients are reported to have a higher incidence of cataract surgery-induced retinal complications, possibly due to retinal inflammation. Our goal is to identify the key inflammatory cytokines, cells and regulatory pathways involved. MAIN METHODS: Diabetes mellitus (DM) induced by streptozotocin and control mice received extracapsular lens extraction (ECLE) in one eye. Neuroretinas were collected at postoperative day1(P1), day2(P2), and day7(P7). BV2 cells were harvested under the treatment of high glucose, lipopolysaccharide (LPS) and inhibitors. The method of qPCR, western blot and immunohistochemistry were used to identify the expression of cytokines and signaling pathways. KEY FINDINGS: ECLE induced increased inflammation in the neuroretina of surgery eye with a peak at P1. MCP-1 surge in long-term diabetes mellitus (LDM) mice at P1 is higher than short-term diabetes mellitus (SDM) mice and normal mice. Significant activation of c-jun and c-fos were found in LDM compared to normal and SDM. Advanced activation of stat1 and ERK was found at P1 in LDM instead of at P2 in SDM and Normal. Activation of microglia/macrophage was also detected in the LDM mice. Besides the inhibition of c-jun/JNK, MCP-1 expression can be attenuated by inhibiting stat1 and ERK under high glucose condition after LPS stimulation. SIGNIFICANCE: Enhancement of lens extraction-induced MCP-1 upregulation and microglia response in long-term diabetes might be due to the activation of cjun, stat1 and ERK, which provided potential therapeutic targets to attenuate retinal inflammation after surgery in diabetic individuals.


Assuntos
Extração de Catarata , Quimiocina CCL2/metabolismo , Diabetes Mellitus Experimental/genética , Sistema de Sinalização das MAP Quinases , Microglia/patologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fator de Transcrição STAT1/metabolismo , Regulação para Cima/genética , Animais , Glucose/toxicidade , Inflamação/genética , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Retina/patologia , Regulação para Cima/efeitos dos fármacos
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