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1.
Immunology ; 159(1): 109-120, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31606893

RESUMO

Serpins are evolutionarily conserved serine protease inhibitors that are widely distributed in animals, plants and microbes. In this study, we reported the cloning and functional characterizations of two novel serpin genes, HlSerpin-a and HlSerpin-b, from the hard tick Haemaphysalis longicornis of China. Recombinant HlSerpin-a and HlSerpin-b displayed protease inhibitory activities against multiple mammalian proteases. Similar to other tick serpins, HlSerpin-a and HlSerpin-b suppressed the expression of inflammatory cytokines such as TNF-α, interleukin (IL)-6 and IL-1ß from lipopolysaccharide-stimulated mouse bone-marrow-derived macrophages (BMDMs) or mouse bone-marrow-derived dendritic cells (BMDCs). The minimum active region (reaction centre loop) of HlSerpin-a, named SA-RCL, showed similar biological activities as HlSerpin-a in the protease inhibition and immune suppression assays. The immunosuppressive activities of full-length HlSerpin-a and SA-RCL are impaired in Cathepsin G or Cathepsin B knockout mouse macrophages, suggesting that the immunomodulation functions of SA and SA-RCL are dependent on their protease inhibitory activity. Finally, we showed that both full-length HlSerpins and SA-RCL can relieve the joint swelling and inflammatory response in collagen-induced mouse arthritis models. These results suggested that HlSerpin-a and HlSerpin-b are two functional arthropod serpins, and the minimal reactive peptide SA-RCL is a potential candidate for drug development against inflammatory diseases.


Assuntos
Artrite Experimental/prevenção & controle , Proteínas de Artrópodes/farmacologia , Células Dendríticas/efeitos dos fármacos , Imunossupressores/farmacologia , Ixodidae/metabolismo , Articulações/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Serpinas/farmacologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/isolamento & purificação , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunossupressores/isolamento & purificação , Ixodidae/genética , Articulações/imunologia , Articulações/metabolismo , Articulações/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Conformação Proteica , Células RAW 264.7 , Saliva/metabolismo , Serpinas/genética , Serpinas/isolamento & purificação , Relação Estrutura-Atividade
2.
Nat Commun ; 10(1): 4601, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601798

RESUMO

During pregnancy, trophoblast cells sustain the maternal-fetal tolerance via expressing and secreting various chemokines and cytokines. Our previous study revealed the expression of interleukin-35 (IL-35) in human first-trimester trophoblasts. Here we show that IL-35 is expressed in both human first-trimester primary trophoblast cells and a trophoblast cell line. Trophoblast cells inhibit the proliferation of human naive conventional T cells (Tconv cells) and convert suppressed Tconv cells into iTR35 in an IL-35-dependent manner. Mechanistically, trophoblast cell derived IL-35 mediates its function through phosphorylation of STAT1 and STAT3. In vivo studies confirm that mice with immunologically spontaneous abortion have lower levels of IL-35 and iTR35 cells at the maternal-fetal interface, and neutralizing anti-IL-35 mAb enhances abortion rates. Meanwhile, exogenous IL-35 induces iTR35 and prevents immunological abortion. Our findings thus suggest that trophoblast cells have a critical function in preserving maternal-fetal tolerance via secreting IL-35 during pregnancy.


Assuntos
Interleucinas/metabolismo , Troca Materno-Fetal/fisiologia , Linfócitos T Reguladores/imunologia , Trofoblastos/citologia , Animais , Proliferação de Células , Feminino , Humanos , Tolerância Imunológica , Interleucinas/sangue , Interleucinas/imunologia , Interleucinas/farmacologia , Masculino , Troca Materno-Fetal/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Placenta/citologia , Placenta/imunologia , Gravidez , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T Reguladores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Trofoblastos/imunologia , Trofoblastos/metabolismo
3.
Nat Commun ; 10(1): 4361, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554804

RESUMO

Age-related tissue alterations have been associated with a decline in stem cell number and function. Although increased cell-to-cell variability in transcription or epigenetic marks has been proposed to be a major hallmark of ageing, little is known about the molecular diversity of stem cells during ageing. Here we present a single cell multi-omics study of mouse muscle stem cells, combining single-cell transcriptome and DNA methylome profiling. Aged cells show a global increase of uncoordinated transcriptional heterogeneity biased towards genes regulating cell-niche interactions. We find context-dependent alterations of DNA methylation in aged stem cells. Importantly, promoters with increased methylation heterogeneity are associated with increased transcriptional heterogeneity of the genes they drive. These results indicate that epigenetic drift, by accumulation of stochastic DNA methylation changes in promoters, is associated with the degradation of coherent transcriptional networks during stem cell ageing. Furthermore, our observations also shed light on the mechanisms underlying the DNA methylation clock.


Assuntos
Envelhecimento , Senescência Celular , Metilação de DNA , Células-Tronco/metabolismo , Transcriptoma/genética , Animais , Células Cultivadas , Epigênese Genética , Epigenômica/métodos , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Humanos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Músculos/citologia , Regiões Promotoras Genéticas/genética , Análise de Célula Única , Células-Tronco/citologia
4.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(8): 957-963, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31511217

RESUMO

OBJECTIVE: To observe the therapeutic effect of tetramethylpyrazine on immune-mediated bone marrow failure (BMF) induced by different doses of X-ray exposure in C57 mice. METHODS: C57BL6 mice were randomized into 4 groups, including a blank control group and 3 X-ray exposure groups with X-ray exposure at low (5.0 Gy), moderate (5.75 Gy), and high (6.5 Gy) doses. After total body irradiation with 0.98 Gy/min X-ray. The mice as recipient received injections of 4×106 lymphocytes from DBA/2 mice via the tail vein within 4 h. The survival rate of the recipient mice, peripheral blood cell counts, bone marrow nucleated cell count, and bone marrow pathology were examined at 14 days after the exposure. In the subsequent experiment, C57 mice were exposed to 5.0 Gy X-ray and treated with intraperitoneal injection of tetramethylpyrazine at the low (5 mg/mL), moderate (10 mg/mL), or high (20 mg/mL) doses (12 mice in each group) for 14 consecutive days, and the changes in BMF were observed. RESULTS: X-ray exposure, especially at the high dose, resulted in significantly lowered survival rate in the mouse models of BMF at 14 days. As the X-ray dose increased, the mice showed significantly reduced peripheral blood counts of red blood cells, white blood cells, platelets and lowered bone marrow nucleated cell counts with obvious bone marrow congestion and reduction of nucleated cells (P < 0.05 or 0.001). In the mice exposed to 5.0 Gy X-ray, tetramethylpyrazine at the high dose most obviously increased bone marrow nucleated cells (P < 0.01) and red blood cells (P < 0.001), and even at the low dose, tetramethylpyrazine significantly increased the counts of white blood cells (P < 0.05) and platelets (P < 0.01) following the exposure. Tetramethylpyrazine dose-dependently alleviated bone marrow hyperemia, increased bone marrow nucleated cell counts, and lowered Fas protein expression in the bone marrow. CONCLUSIONS: X-ray irradiation at 5.0 Gy is suitable for establish mouse models of immune-mediated BMF. Tetramethylpyrazine promotes bone marrow repair by regulating Fas cell apoptosis signals, which further expands the traditional Chinese medicine theory of "removing blood stasis to create new."


Assuntos
Medula Óssea , Irradiação Corporal Total , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Pirazinas
5.
Arch Oral Biol ; 108: 104510, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446118

RESUMO

OBJECTIVE: The anti-citrullinated protein antibody (ACPA), an autoantibody of rheumatoid arthritis (RA), is very specific in the diagnosis of RA and has been detected in early cases and several years before the onset of the disease. In this study, we focused on ACPA and examined whether it could be detected in saliva whether it is associated with periodontal disease. DESIGN: Porphyromonas gingivalis (Pg) or Escherichia coli (Ec) was administered into the oral cavity of DBA/1JJmsSlc mice. The arthritis index was measured in foot bones, and collected saliva and serum. The amount of ACPA in serum and saliva was measured using ELISA, and antibodies in serum, saliva, and foot bones were detected and analysed by western blotting. RESULT: Histopathological analysis of foot bones of the Pg/RA group detected greater inflammatory cell infiltration than in the RA group, and bone resorption was evident. Furthermore, ELISA results show that the amount of ACPA in serum was significantly higher in the Pg/RA group (P < 0.05), with a tendency to also increase in the saliva. In addition, western blotting results show a 55 kDa citrullinated protein in the serum and saliva of the RA and Pg/RA groups. CONCLUSIONS: We conclude that Pg infection increases ACPA in the serum and is reflected in the saliva, and may be involved in the inflammatory progression of RA.


Assuntos
Anticorpos Anti-Proteína Citrulinada , Artrite Reumatoide , Infecções por Bacteroidaceae , Porphyromonas gingivalis , Animais , Anticorpos Anti-Proteína Citrulinada/metabolismo , Infecções por Bacteroidaceae/metabolismo , Ensaio de Imunoadsorção Enzimática , Camundongos , Camundongos Endogâmicos DBA , Peptídeos Cíclicos , Porphyromonas gingivalis/patogenicidade , Saliva
6.
Biol Pharm Bull ; 42(8): 1419-1422, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366877

RESUMO

The pathogenic relationship of ulcerative colitis and rheumatoid arthritis is not known. Therefore, we examined dextran sodium sulfate (DSS)-induced colitis separately and in combination with a mouse arthritis model that mimics rheumatoid arthritis and evaluated the deterioration-related factors of each condition. Arthritis was induced in a collagen-induced arthritis mouse model using DBA/1JJmsSlc mice and ulcerative colitis was induced by the administration of drinking water containing 3.0% (w/v) DSS. The arthritis/DSS-treated mice developed worse colitis scores compared to that of the other groups of mice. The arthritis/DSS-treated mice did not demonstrate changes in hind foot volumes or in the concentration of matrix metalloproteinase-3 (MMP-3) in the plasma; however, plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α were increased. Our results showed that IL-6 and TNF-α may influence the deterioration effect of colitis in arthritic mice.


Assuntos
Artrite Experimental/imunologia , Colite Ulcerativa/imunologia , Interleucina-6/sangue , Fator de Necrose Tumoral alfa/sangue , Animais , Artrite Experimental/sangue , Artrite Experimental/patologia , Colite Ulcerativa/sangue , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colo/patologia , Sulfato de Dextrana , Edema/sangue , Edema/imunologia , Edema/patologia , Pé/patologia , Metaloproteinase 3 da Matriz/sangue , Camundongos Endogâmicos DBA
7.
Invest Ophthalmol Vis Sci ; 60(10): 3283-3296, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31369031

RESUMO

Purpose: Glaucoma is a complex disease with major risk factors including advancing age and increased intraocular pressure (IOP). Dissecting these earliest events will likely identify new avenues for therapeutics. Previously, we performed transcriptional profiling in DBA/2J (D2) mice, a widely used mouse model relevant to glaucoma. Here, we use these data to identify and test regulators of early gene expression changes in DBA/2J glaucoma. Methods: Upstream regulator analysis (URA) in Ingenuity Pathway Analysis was performed to identify potential master regulators of differentially expressed genes. The function of one putative regulator, mesenchyme homeobox 2 (Meox2), was tested using a combination of genetic, biochemical, and immunofluorescence approaches. Results: URA identified Meox2 as a potential regulator of early gene expression changes in the optic nerve head (ONH) of DBA/2J mice. Meox2 haploinsufficiency did not affect the characteristic diseases of the iris or IOP elevation seen in DBA/2J mice but did cause a significant increase in the numbers of eyes with axon damage compared to controls. While young mice appeared normal, aged Meox2 haploinsufficient DBA/2J mice showed a 44% reduction in MEOX2 protein levels. This correlated with modulation of age- and disease-specific vascular and myeloid alterations. Conclusions: Our data support a model whereby Meox2 controls IOP-dependent vascular remodeling and neuroinflammation to promote axon survival. Promoting these earliest responses prior to IOP elevation may be a viable neuroprotective strategy to delay or prevent human glaucoma.


Assuntos
Axônios/patologia , Glaucoma/genética , Haploinsuficiência/genética , Proteínas de Homeodomínio/genética , Degeneração Neural/genética , Disco Óptico/patologia , Células Ganglionares da Retina/patologia , Animais , Pressão Sanguínea/fisiologia , Western Blotting , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/fisiologia , Glaucoma/patologia , Pressão Intraocular/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Degeneração Neural/patologia , Microscopia com Lâmpada de Fenda
8.
Drug Deliv ; 26(1): 820-830, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31389248

RESUMO

Arthritis treatment has been challenging because of low drug exposure to the articular cavity. This study was intended to develop hyaluronic acid (HA)-functionalized bilosomes for targeted delivery of tripterine (Tri), an antiphlogistic phytomedicine, to the inflamed joint via ligand-receptor interaction. Tri-loaded bilosomes (Tri-BLs) with cationic lipid (DOTAP) were prepared by a thin film hydration method followed by HA coating to form HA@Tri-BLs. HA@Tri-BLs were then characterized by particle size (PS), entrapment efficiency (EE), and structural morphology. The in vitro drug release, hemocompatibility test and cellular uptake were performed to examine the formulation performances of HA@Tri-BLs. The in vivo pharmacokinetics and antiarthritic efficacy were evaluated in arthritic models, respectively. The obtained HA@Tri-BLs possessed a PS of 118.5 nm around with an EE of 99.56%. HA@Tri-BLs exhibited excellent cellular uptake and targeted delivery efficiency for Tri, which resulted in elongation of circulatory residence time and enhancement of intra-arthritic bioavailability (799.9% relative to Tri solution). The in vivo antiarthritic efficacy of HA@Tri-BLs was also significantly superior to uncoated Tri-BLs that gave rise to obvious inflammation resolution. Our findings suggest that HA-functionalized bilosomes are a promising vehicle for articular delivery of antiphlogistic drugs to potentiate their efficacy.


Assuntos
Artrite/tratamento farmacológico , Ácido Hialurônico/química , Inflamação/tratamento farmacológico , Lipossomos/química , Triterpenos/administração & dosagem , Triterpenos/química , Animais , Disponibilidade Biológica , Cátions/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Ácido Hialurônico/administração & dosagem , Lipídeos/química , Masculino , Camundongos , Camundongos Endogâmicos DBA , Tamanho da Partícula , Células RAW 264.7 , Ratos Sprague-Dawley
9.
Immunogenetics ; 71(7): 489-499, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31297569

RESUMO

Epigenetic modifications have been shown to be important for immune cell differentiation by regulating gene transcription. However, the role and mechanism of histone methylation in the development and differentiation of iNKT cells in rheumatoid arthritis (RA) mice have yet to be deciphered. The DBA/1 mouse RA model was established by using a modified GPI mixed peptide. We demonstrated that total peripheral blood, thymus, and spleen iNKT cells in RA mice decreased significantly, while iNKT1 in the thymus and spleen was increased significantly. PLZF protein and PLZF mRNA levels were significantly decreased in thymus DP T cells, while T-bet protein and mRNA were significantly increased in thymus iNKT cells. We found a marked accumulation in H3K27me3 around the promoter regions of the signature gene Zbtb16 in RA mice thymus DP T cells, and an accumulation of H3K4me3 around the promoters of the Tbx21 gene in iNKT cells. The expression levels of UTX in the thymus of RA mice were significantly reduced. The changes in the above indicators were particularly significant in the progressive phase of inflammation (11 days after modeling) and the peak phase of inflammation (14 days after modeling) in RA mice. Developmental and differentiation defects of iNKT cells in RA mice were associated with abnormal methylation levels (H3K27me3 and H3K4me3) in the promoters of key genes Zbtb16 (encoding PLZF) and Tbx21 (encoding T-bet). Decreased UTX of thymus histone demethylase levels resulted in the accumulation of H3K27me3 modification.


Assuntos
Artrite Reumatoide/patologia , Lisina/metabolismo , Células T Matadoras Naturais/patologia , Regiões Promotoras Genéticas , Timo/fisiologia , Animais , Artrite Experimental/patologia , Diferenciação Celular , Epigênese Genética , Regulação da Expressão Gênica , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Metilação , Camundongos Endogâmicos DBA , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Baço/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo
10.
Bull Exp Biol Med ; 167(3): 339-342, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31346869

RESUMO

Activities of superoxide dismutase and catalase and content of reduced glutathione in cells of drug-resistant murine leukemia P388 strains were studied without or after administration of antitumor compounds. In the absence of chemotherapeutic agents, no significant differences in activities of the studied enzymes in cells of the initial strain and strains resistant to cyclophosphamide, cisplatin, and rubomycin were observed. Compounds to which resistance was developed did not significantly affect activity of enzymes in cells of drug-resistant strains, while the use of compounds that were not resistance inductors was accompanied by a significant decrease in enzyme activity in cells resistant to cisplatin and rubomycin. In cells of strains resistant to cisplatin and cyclophosphamide, the content of reduced glutathione significantly differed from that in the initial strain. In addition, the concentration of reduced glutathione in cells of cyclophosphamide-resistant strain considerably decreased upon addition of the drug producing a therapeutic effect. Our findings suggest that the mechanism of resistance of in vivo derived cyclophosphamide resistant cell strain is related to increased level of reduced glutathione and activity of its metabolism.


Assuntos
Antineoplásicos/farmacologia , Catalase/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Glutationa/análise , Leucemia P388/tratamento farmacológico , Superóxido Dismutase/metabolismo , Animais , Antioxidantes/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Ciclofosfamida/farmacologia , Daunorrubicina/farmacologia , Doxorrubicina/farmacologia , Camundongos , Camundongos Endogâmicos DBA , Espécies Reativas de Oxigênio/metabolismo
11.
Environ Toxicol ; 34(10): 1137-1148, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31318498

RESUMO

The substances associated with PM2.5-induced inflammatory response were investigated using an elimination method. PM2.5 were heated at temperatures of 120, 250, and 360°C. The results demonstrated microbial substances such as LPS and b-glucan, and chemicals including BaP, 1,2-NQ, and 9,10-PQ were reduced drastically in PM2.5 heated at 120°C. On the other hand, DBA, 7,12-BAQ, and BaP-1,6-Q were not noticeably reduced. Most of these substances had disappeared in PM2.5 heated at 250°C and 360°C. Metals (eg, Fe, Cu, Cr, Ni) in PM2.5 exhibited a slight thermo-dependent increase. RAW264.7 macrophages with or without NAC were exposed to unheated PM2.5, oxidative stress-related and unrelated inflammatory responses were induced. PM2.5-induced lung inflammation in mice is caused mainly by thermo-sensitive substances (LPS, b-glucan, BaP, 1,2-NQ, 9,10-PQ, etc.). Also, a slight involvement of thermo-resistant substances (DBA, 7,12-BAQ, BaP-1,6-Q, etc.) and transition metals was observed. The thermal decomposition method could assist to evaluate the PM2.5-induded lung inflammation.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/química , Material Particulado/efeitos adversos , Material Particulado/química , Pneumonia/etiologia , Pneumonia/imunologia , Animais , Temperatura Alta , Humanos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Pneumonia/genética
12.
Phytomedicine ; 63: 153006, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31299594

RESUMO

BACKGROUND: Bone destructive diseases like rheumatoid arthritis (RA), osteoporosis and bone metastatic tumors are mainly mediated by over-activated osteoclasts. Asperosaponin VI (AVI), isolated from the rhizome of Dipsacus asper, belongs to triterpenoid saponins. It has multiple physiological activities but its effects on RA, especially on osteoclast differentiation and activation are still unclear. PURPOSE: Explore the protective role of AVI on collagen induced arthritis (CIA) in vivo and RANKL induced osteoclastogenesis in vitro. METHODS: The effects of AVI on cell viability and RANKL-induced osteoclastogenesis, actin ring formation, bone resorption activity as well as on osteoclast specific gene and protein expression were tested using bone marrow derived monocytes (BMMs). Paws from CIA mice were used for micro-CT, HE and TRAP staining, real-time PCR and western blot. Sera were used for cytokine analysis by ELISA. The signaling pathways were detected using western blot, real-time PCR and immunofluorescence assay. RESULTS: AVI significantly inhibited RANKL-induced osteoclast formation and bone resorption activity by suppressing the formation of actin ring. It also inhibited the expression of various osteoclatogenesis marker genes and signaling pathways. AVI protected arthritis in vivo by suppressing inflammation and bone loss. CONCLUSION: AVI exerts its anti-osteoclastogenic activity both in vitro and in vivo by inhibiting RANKL-induced osteoclast differentiation and function. Thus, our studies demonstrate a potential therapeutic role for AVI in preventing or inhibiting RANKL-mediated osteolytic bone diseases.


Assuntos
Artrite Experimental/tratamento farmacológico , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Saponinas/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Reabsorção Óssea/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Colágeno/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Osteoclastos/patologia , Osteogênese/fisiologia , Ligante RANK/metabolismo , Ligante RANK/toxicidade , Transdução de Sinais/efeitos dos fármacos
13.
Phytother Res ; 33(6): 1726-1735, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31155798

RESUMO

Rheumatoid arthritis (RA) is a complex chronic inflammatory disease that is associated with the aberrant activation of fibroblast-like synoviocytes (FLS). Kaempferitrin is a natural flavonoid glycoside that possesses anti-inflammatory bioactivity. However, the effect of kaempferitrin on RA has not yet been revealed. The aim of the present study was to investigate the effect of kaempferitrin on human RA-FLS MH7A cell line. We found that kaempferitrin inhibited proliferation and induced apoptosis of MH7A cells. Kaempferitrin decreased the levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, matrix metalloproteinase (MMP)-1, and MMP-3 in MH7A cells. Moreover, kaempferitrin blocked the activation of nuclear factor-κB (NF-κB) and protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathways. Furthermore, treatment with kaempferitrin decreased paw thickness and arthritis scores, and reduced the serum levels of IL-1ß, IL-6, and TNF-α in a collagen-induced arthritis mouse model. In conclusion, kaempferitrin inhibited cell proliferation, induced cell apoptosis, and ameliorated inflammation of RA-FLS by suppressing the NF-κB and Akt/mTOR pathways.


Assuntos
Apoptose/efeitos dos fármacos , Artrite Reumatoide/patologia , Proliferação de Células/efeitos dos fármacos , Inflamação/prevenção & controle , Quempferóis/farmacologia , Sinoviócitos/efeitos dos fármacos , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Experimental/prevenção & controle , Artrite Reumatoide/metabolismo , Artrite Reumatoide/prevenção & controle , Células Cultivadas , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/metabolismo , Metaloproteinase 3 da Matriz , Camundongos , Camundongos Endogâmicos DBA , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sinoviócitos/patologia , Sinoviócitos/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
14.
Biomed Pharmacother ; 116: 109025, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154267

RESUMO

Rheumatoid arthritis (RA) is a chronic, inflammatory, synovitis-dominated systemic disease with unknown etiology. RA is characterized by the involvement of multiple affected joints, symmetry, and invasive arthritis of the limbs, which can lead to joint deformity, cartilage destruction, and loss of function. Cannabinoid receptor 2 (CB2) has potent immunomodulatory and anti-inflammatory effects and is predominantly expressed in non-neuronal tissues. In the current study, the role of CB2 in the process of inflammatory bone erosion in RA was examined. The selective agonist or high-affinity ligand of CB2 (4-quinolone-3-carboxamides CB2 agonist, 4Q3C CB2 agonist, 4Q3C) significantly reduced the severity of arthritis, decreased histopathological findings, and markedly reduced bone erosion in collagen-induced arthritis (CIA) mice. In addition, 4Q3C prevented an increase in the nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio and inhibited the formation of osteoclasts in CIA mice. Furthermore, the expression of tumor necrosis factor-alpha, interleukin-1ß, cyclooxygenase-2, and inducible nitric oxide synthase was lower in 4Q3C-treated CIA mice than in control CIA mice. Micro-computed tomography corroborated the finding that 4Q3C reduced joint destruction. These data clearly indicate that the CB2-selective agonist, 4Q3C, may have anti-inflammatory and anti-osteoclastogenesis effects in RA and may be considered to be a novel treatment for RA.


Assuntos
Artrite Experimental/tratamento farmacológico , Inflamação/tratamento farmacológico , Articulações/patologia , Substâncias Protetoras/uso terapêutico , Receptor CB2 de Canabinoide/agonistas , Animais , Artrite Experimental/complicações , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/patologia , Biomarcadores/metabolismo , Osso e Ossos/patologia , Citocinas/sangue , Inflamação/complicações , Inflamação/diagnóstico por imagem , Inflamação/patologia , Mediadores da Inflamação/sangue , Articulações/diagnóstico por imagem , Masculino , Camundongos Endogâmicos DBA , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Microtomografia por Raio-X
15.
J Agric Food Chem ; 67(24): 6773-6784, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31154759

RESUMO

The aim of this study was to evaluate the immunomodulatory effects of atractylodin, a polyethylene alkyne, on the maturation of bone marrow-derived dendritic cells (BM-DC) as well as its antirheumatic effect on collagen-induced arthritis (CIA) in DBA/1 mice. Our results indicate that atractylodin effectively suppressed the secretion of pro-inflammatory cytokines, expression of costimulatory molecules, and p38 MAPK, ERK, and NF-κBp65 signaling pathways in LPS-incubated dendritic cells (DCs). Additionally, the proliferation and cytokine secretion (IFN-γ and IL-17A) of CD8+ and CD4+ T cells were reduced. In a murine CIA model, intraperitoneal injection of atractylodin significantly alleviated the severity of the disease progression, as indicated by reduced paw swelling, clinical arthritis scores, and pathological changes of joint tissues. In addition, the overall proliferation of T cells stimulated by type II collagen and the abundance of Th1 and Th17 in the spleens were also significantly decreased with atractylodin treatments. Furthermore, atractylodin significantly downregulated the expression levels of CD40, CD80, and CD86 of DCs in the spleens. In conclusion, this study shows for the first time that atractylodin has potential to manipulate the maturation of BM-DCs and should be further explored as a therapeutic agent in the treatment of rheumatoid arthritis (RA).


Assuntos
Artrite Reumatoide/tratamento farmacológico , Atractylodes/química , Diferenciação Celular/efeitos dos fármacos , Colágeno Tipo II/efeitos adversos , Células Dendríticas/citologia , Furanos/administração & dosagem , Animais , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Células Th17/imunologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia
16.
Int Immunopharmacol ; 73: 461-470, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31170675

RESUMO

Cilostazol exerts potent anti-inflammatory effects and celecoxib, a COX-2 specific inhibitor, improves the unsatisfactory profile of NSAIDs. It was aimed to assess the anti-arthritic potential of celecoxib add-on for cilostazol therapy in collagen induced arthritis (CIA), and to elucidate the implication of interleukin (IL)-10 in the action of cilostazol and celecoxib cotreatment. Cotreatment of RAW 264.7 cells with 10 µM cilostazol and 0.3 µM celecoxib synergistically suppressed RANKL-induced increases in RANK mRNA and protein levels. When cultured in the presence of RANKL for 5 days, RANKL-stimulated expressions of osteoclastogenic genes (OSCAR, DC-STAMP, and cathepsin K mRNA) and the expression of RANK mRNA were markedly elevated. Furthermore, these gene expressions, including that of RANK, were significantly suppressed by cotreatment with cilostazol (10 µM) and celecoxib (0.3 µM). In addition, this co-treatment strongly down-regulated RANKL-induced NFATc1 protein and TRAP activity (key osteoclastogenic factors), and these down-regulations were significantly prevented by pretreating cells with IL-10 neutralizing antibody. Furthermore, increased osteoclast formation and extensive resorption pit formation by bone marrow-derived monocytes obtained from C57BL/6 mice cultured in the presence of M-CSF/RANKL were markedly suppressed by cilostazol and celecoxib cotreatment. Consequently, hindlimb paw thicknesses in DBA/1J CIA mice were significantly reduced by cilostazol (10 mg/kg/d) and celecoxib (5 mg/kg/d) cotreatment. These results were accompanied by synergistic suppression of cartilage depletion and bone erosion and reductions in arthritis scores in the CIA mice. In conclusion, serum IL-10 levels in these mice were markedly increased by cilostazol and celecoxib cotreatment, whereas elevated serum IL-1ß levels were markedly reduced. Cotreatment with low-dose cilostazol and celecoxib may ensure the synergistic anti-arthritic potential.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/tratamento farmacológico , Celecoxib/uso terapêutico , Cilostazol/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Catepsina K/genética , Celecoxib/farmacologia , Cilostazol/farmacologia , Citocinas/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Proteínas do Tecido Nervoso/genética , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Ligante RANK/farmacologia , Células RAW 264.7 , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Receptores de Superfície Celular/genética
17.
Virology ; 534: 54-63, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31176924

RESUMO

Influenza A virus (IAV) infections result in ∼500,000 global deaths annually. Host kinases link multiple signaling pathways at various stages of infection and are attractive therapeutic target. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, regulates several cellular processes including NFkB and antiviral responses. We investigated how FAK kinase activity regulates IAV pathogenesis. Using a severe infection model, we infected IAV-susceptible DBA/2 J mice with a lethal dose of H1N1 IAV. We observed reduced viral load and pro-inflammatory cytokines, delayed mortality, and increased survival in FAK inhibitor (Y15) treated mice. In vitro IAV-induced NFkB-promoter activity was reduced by Y15 or a dominant negative kinase-dead FAK mutant (FAK-KD) independently of the viral immune modulator, NS1. Finally, we observed reduced IAV-induced nuclear localization of NFkB in FAK-KD expressing cells. Our data suggest a novel mechanism where IAV hijacks FAK to promote viral replication and limit its ability to contribute to innate immune responses.


Assuntos
Proteína-Tirosina Quinases de Adesão Focal/imunologia , Vírus da Influenza A Subtipo H1N1/patogenicidade , Influenza Humana/enzimologia , NF-kappa B/imunologia , Provírus/patogenicidade , Animais , Feminino , Proteína-Tirosina Quinases de Adesão Focal/genética , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/fisiologia , Influenza Humana/genética , Influenza Humana/imunologia , Influenza Humana/virologia , Camundongos , Camundongos Endogâmicos DBA , NF-kappa B/genética , Regiões Promotoras Genéticas , Provírus/genética , Provírus/fisiologia , Carga Viral , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Virulência , Replicação Viral
18.
Int Immunopharmacol ; 73: 539-551, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177080

RESUMO

OBJECTIVE: We aimed to investigate the immunologic mechanisms by which arsenic trioxide (As2O3) may inhibit T helper 17 (Th17) cell differentiation while promoting regulatory T (Treg) cell generation by modulating signal transducer and activator of transcription 3 (STAT3) in treatment-naïve rheumatoid arthritis (RA) patients. METHODS: Naïve CD4+T cells isolated by fluorescence-activated cell sorting from treatment-naïve RA patients and healthy controls were used to investigate the effect of As2O3 on the process of polarization and the related cytokines. STAT3 transfection experiments were conducted with small interfering RNA (siRNA) and lentivirus STAT3 to verify the mechanism of As2O3 on Th17-Treg balance in vitro. A collagen-induced arthritis (CIA) model was used to detect the clinical scores, histopathological change, bone destruction, Th17-Treg proportion and joint tissue immunohistochemistry. RESULTS: We found that As2O3 prevented activated naïve CD4+T-cells from differentiating into Th17 cells and reduced cytokine production by activated Th17 cells by downregulating their signature transcription factors, STAT3 and orphan nuclear receptors. Notably, As2O3 reduced Th17 cells frequency while increasing Treg cells frequency under specific polarizing conditions in treatment-naïve RA patients by transfecting siRNA STAT3 and lentivirus STAT3. Furthermore, we noticed that applying As2O3 in the CIA model attenuated the infiltration of joint inflammation and bone destruction, and significantly improved the imbalanced Treg-Th17 ratio. CONCLUSIONS: These data indicate that As2O3 may be a potential immune modulator for treatment-naïve RA patients that helps to balance of Treg and Th17 cells through modulating STAT3.


Assuntos
Trióxido de Arsênio/farmacologia , Artrite Reumatoide/imunologia , Fatores Imunológicos/farmacologia , Fator de Transcrição STAT3/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Adulto , Animais , Trióxido de Arsênio/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Experimental/patologia , Citocinas/imunologia , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , Camundongos Endogâmicos DBA , Pessoa de Meia-Idade , Baço/efeitos dos fármacos , Baço/imunologia , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
19.
Bull Exp Biol Med ; 167(1): 50-52, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31177449

RESUMO

Dose-dependent protective effects of lanthanum nitrate solution and gel were shown on the model of experimental infection caused by a virulent strain of Shigella flexneri 2a or opportunistic bacteria Klebsiella pneumoniae in outbred and DBA mice.


Assuntos
Lantânio/farmacologia , Animais , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/patogenicidade , Camundongos , Camundongos Endogâmicos DBA , Shigella flexneri/efeitos dos fármacos , Shigella flexneri/patogenicidade , Simplexvirus/efeitos dos fármacos , Simplexvirus/patogenicidade
20.
Immunology ; 158(1): 19-34, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31215020

RESUMO

Studies with gene-deficient and gnotobiotic mice have identified many host and microbial factors that contribute to induced colitis, but information on whether specific factors determine susceptibility under more physiological conditions is lacking. Using wild-type strains that differ in their IgA response but harbor a diverse gut microbiome, we found that the IgA-high strain CBA/CaJ (CBA) is resistant to acute colitis induced with dextran sodium sulfate (DSS), unlike the IgA-low strain C57BL/6 (B6). Resistance was associated with extensive IgA-coating of fecal bacteria, lower fecal bacterial loads and greater abundance of barrier-protective transcripts in colonic tissues under homeostatic conditions. Fecal microbial transplant (FT) experiments revealed that disease induction in B6 mice was associated with a cohort of bacteria that are not targeted by IgA. However, CBA mice continued to be resistant to colitis induction following FTs from B6 mice, indicating that they are able to contain such colitogenic members. In support of a role for bacterial exclusion in resistance, oral administration of immunoglobulins decreased DSS-induced disease in B6 mice. In F1 mice derived separately with CBA and B6 dams and in F1 mice backcrossed to the two parental strains, resistance segregated with the IgA response of the pups and not with barrier-associated transcripts or bacterial loads. Interestingly, B6 pups foster-nursed on CBA dams continued to be susceptible in later life, whereas CBA pups foster-nursed on B6 dams continued to be resistant. Together, the data indicate that a high-IgA response in adult life can protect against colitis and compensate for IgA deficiency in early life.


Assuntos
Bactérias/imunologia , Colite/prevenção & controle , Colo/microbiologia , Sulfato de Dextrana , Microbioma Gastrointestinal/imunologia , Imunoglobulina A/imunologia , Animais , Animais Recém-Nascidos , Carga Bacteriana , Colite/induzido quimicamente , Colite/imunologia , Colite/microbiologia , Colo/imunologia , Colo/metabolismo , Cruzamentos Genéticos , Modelos Animais de Doenças , Transplante de Microbiota Fecal , Fezes/microbiologia , Feminino , Imunoglobulina A/metabolismo , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Lactação , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Permeabilidade , Gravidez , Especificidade da Espécie
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