Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 25.478
Filtrar
1.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 56(9): 945-950, 2021 Sep 09.
Artigo em Chinês | MEDLINE | ID: mdl-34496547

RESUMO

Pyroptosis is a pro-inflammatory form of programmed cell death that has been gradually recognized in recent years. It plays an important role in recognizing the invasion of exogenous pathogens and sensing endogenous danger signals. The initiation of pyroptosis depends on the activation of intracellular inflammasome and its downstream caspases, as well as the active fragment of the key protein Gasdermin. The invasion of periodontal pathogens induces an inflammatory response of the host, involving the activation of inflammasome and triggering pyroptosis as well. Meanwhile, it leads to the release of a large number of inflammatory cytokines such as interleukin (IL)-1ß and IL-18 to amplify the inflammatory response and mediate periodontal tissue destruction eventually. This article reviews the research progress of the signaling pathways of pyroptosis, as well as its mechanism induced by periodontal pathogens and the mechanism of periodontal tissue damage in periodontitis in order to provide new targets and ideas for the prevention and treatment of periodontitis.


Assuntos
Doenças Periodontais , Piroptose , Apoptose , Caspases , Humanos , Inflamassomos , Interleucina-1beta
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(9): 844-850, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34533131

RESUMO

Severe inflammatory responses are considered responsible for acute lung damage in COVID-19. SARS-CoV-2 enters lung cells via ACE2, and the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the pro-caspase-1 are then activated, followed by release of mature IL-1ß and IL-18 and other inflammatory cytokines, thereby leading to inflammation and apoptosis. This inflammatory process induces syndromes such as inflammatory cell infiltration, congestion, and edema in the lungs of COVID-19 patients. Some severe cases reported complications including acute respiratory distress syndrome (ARDS) and diffuse intravascular coagulation (DIC). There is no specific drug available for the treatment of COVID-19 at present. MCC950, colchicine and other NLRP3 inflammasome inhibitors, have been widely used in the treatment of various inflammatory diseases, and are currently in clinical trials for the treatment of COVID-19 patients. Here we reviewed the pathogenesis of COVID-19 and the SARS-CoV activation pathway of NLRP3 inflammasome, in order to reveal the role and mechanism of NLRP3 inflammasome in the process of SARS-CoV-2 infection, and provide a theoretical basis for the development of related targeted drugs.


Assuntos
COVID-19 , Lesão Pulmonar , Humanos , Inflamassomos , Interleucina-1beta , Proteína 3 que Contém Domínio de Pirina da Família NLR , SARS-CoV-2
3.
Ann Palliat Med ; 10(8): 9078-9087, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34488393

RESUMO

BACKGROUND: Periodontitis (PD) is a chronic inflammatory disease caused by infection of the periodontal supporting tissues. Clinical studies have reported that rheumatoid arthritis (RA) patients have a higher prevalence of PD. This study aimed to explore the correlation between RA and PD. METHODS: A total of 307 RA patients (RA group) and 324 healthy individuals (control group) who received physical examinations during the same period were recruited to this study. The incidence of PD in the two groups was analyzed, and the periodontal disease index (PDI) and bleeding on probing (BOP) were recorded. Then, 42 RA patients with PD and 56 control group patients with PD were selected for further analysis. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of interleukin 1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in the gingival crevicular fluid (GCF) of the two groups. For patients with both RA and PD, the level of serum C-reactive protein (CRP) and the duration of morning stiffness were also recorded. RESULTS: The prevalence of PD in the RA group (51.5%) was significantly higher than that in the control group (31.2%), and the prevalence of PD also increased notably with the increase of age and the duration of the disease in RA patients. The levels of TNF-α and IL-1ß in the PDI and the GCF in the concurrent RA and PD group were significantly higher than those in the PD group (P<0.05). Partial correlation analysis showed that TNF-α in the GCF positively correlated with the BOP of patients with RA and PD. Multiple linear regression analysis showed that the level of TNF-α in the GCF and serum CRP were independent influencing factors of the level of IL-1ß in the GCF (the r values were 1.074 and 3.851, respectively; P<0.01). CONCLUSIONS: The presence of RA can increase risk of PD occurrence and is positively correlated with the levels of IL-1ß and TNF-α in the GCF.


Assuntos
Artrite Reumatoide , Periodontite , Líquido do Sulco Gengival/química , Humanos , Interleucina-1beta/análise , Periodontite/epidemiologia , Fator de Necrose Tumoral alfa
4.
Life Sci ; 284: 119938, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34506837

RESUMO

AIMS: The relationship between stress to endoplasmic reticulum (ER) and periodontitis has been known, and ER stress induced by Porphyromonas gingivalis results in the loss of alveolar bone. Salubrinal is a small synthetic compound and attenuates ER stress through inhibition of de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). In this study, we examined whether salubrinal attenuates periodontitis in a mouse model of experimental periodontal disease. MATERIALS AND METHODS: We evaluated loss of alveolar bone and attachment levels in periodontium using micro-computed tomography (µCT) and hematoxylin-eosin (HE) staining, respectively. Furthermore, we measured osteoclast numbers using tartrate-resistant acid phosphatase (TRAP) staining and osteoblast numbers using HE staining for bone resorption and for bone formation, respectively. To examine the inhibitory effects of salubrinal against pro-inflammatory cytokines, we measured TNF-α and IL1-ß score in periodontium using immunohistostaining. KEY FINDINGS: The results revealed that salubrinal suppressed loss of alveolar bone and attachment levels in periodontium induced by periodontitis. It decreased osteoclast numbers and increased osteoblasts. It also suppressed the expression levels of TNF-α in periodontium. SIGNIFICANCE: These results show that salubrinal alleviates periodontitis through suppression of alveolar bone resorption and the pro-inflammatory cytokine, and promotion of the bone formation. Since salubrinal has been shown to have these beneficial effects for periodontal disease, it may provide a novel therapeutic possibility for the disease.


Assuntos
Perda do Osso Alveolar/tratamento farmacológico , Cinamatos/uso terapêutico , Tioureia/análogos & derivados , Perda do Osso Alveolar/complicações , Perda do Osso Alveolar/diagnóstico por imagem , Perda do Osso Alveolar/patologia , Animais , Contagem de Células , Cinamatos/administração & dosagem , Cinamatos/farmacologia , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Interleucina-1beta/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Periodontite/complicações , Periodontite/tratamento farmacológico , Periodontite/patologia , Tioureia/administração & dosagem , Tioureia/farmacologia , Tioureia/uso terapêutico , Fator de Transcrição CHOP/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Microtomografia por Raio-X
5.
BMC Cancer ; 21(1): 1017, 2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34511060

RESUMO

BACKGROUND: Neutrophils are important for immune surveillance of tumour cells. Neutrophils may also be epigenetically programmed in the tumour microenvironment to promote tumour progression. In addition to the commonly known high-density neutrophils (HDN) based on their separation on density gradient, recent studies have reported the presence of high levels of low-density neutrophils (LDN) in tumour-bearing mice and cancer patients. We reported previously that estrogen promotes the growth of estrogen receptor α-negative mammary tumours in mice undergoing mammary involution through stimulating pro-tumoral activities of neutrophils in the mammary tissue. METHODS: Female BALB/cAnNTac mice at 7-8 weeks old were mated and bilateral ovariectomy was performed 2 days post-partum. At 24 h after forced-weaning of pups to induce mammary involution, post-partum female mice were injected with either E2V, or vehicle control on alternative days for 2-weeks. On 48 h post-weaning, treated female mice were inoculated subcutaneously with 4 T1-Luc2 cells into the 9th abdominal mammary gland. Age-matched nulliparous female was treated similarly. Animals were euthanized on day 14 post-tumour inoculation for analysis. To evaluate the short-term effect of estrogen, post-partum females were treated with only one dose of E2V on day 12 post-tumour inoculation. RESULTS: Estrogen treatment for 2-weeks reduces the number of blood LDN by more than 10-fold in tumour-bearing nulliparous and involuting mice, whilst it had no significant effect on blood HDN. The effect on tumour-bearing mice is associated with reduced number of mitotic neutrophils in the bone marrow and increased apoptosis in blood neutrophils. Since estrogen enhanced tumour growth in involuting mice, but not in nulliparous mice, we assessed the effect of estrogen on the gene expression associated with pro-tumoral activities of neutrophils. Whilst 48 h treatment with estrogen had no effect, 2-weeks treatment significantly increased the expression of Arg1, Il1b and Tgfb1 in both HDN and LDN of involuting mice. In contrast, estrogen increased the expression of Arg1 and Ccl5 in HDN and LDN of nulliparous mice. CONCLUSIONS: Prolonged estrogenic stimulation in tumour-bearing mice markedly hampered tumour-associated increase of LDN plausibly by inhibiting their output from the bone marrow and by shortening their life span. Estrogen also alters the gene expression in neutrophils that is not seen in tumour-free mice. The results imply that estrogen may significantly influence the tumour-modulating activity of blood neutrophils.


Assuntos
Estrogênios/farmacologia , Neoplasias Mamárias Animais/sangue , Neutrófilos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Arginase/genética , Arginase/metabolismo , Biomarcadores Tumorais/metabolismo , Células da Medula Óssea/citologia , Centrifugação com Gradiente de Concentração , Estrogênios/administração & dosagem , Feminino , Citometria de Fluxo , Expressão Gênica/efeitos dos fármacos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Glândulas Mamárias Animais , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Neutrófilos/citologia , Neutrófilos/metabolismo , Ovariectomia/métodos , Paridade , Período Pós-Parto , Fatores de Tempo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
6.
Arch Oral Biol ; 131: 105268, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34571395

RESUMO

OBJECTIVES: The dentin therapeutic agent chlorhexidine has inflammatory and cytotoxic characteristics urging investigation of alternatives like the natural compound epigallocatechin-gallate. The aim is to verify the effect of epigallocatechin-gallate and chlorhexidine on viability, interleukin-1ß (IL-1ß) and differential protein expression of MDPC-23 odontoblast-like cells stimulated by Streptococcus mutans. DESIGN: Cells were stimulated with heat-killed S. mutans at multiplicity of infection (MOI) of 100-1000 and subsequently treated with 100-1 µM of epigallocatechin-gallate. Cells with no treatment or chlorhexidine were controls. Combined stimulated/treated cells were tested for cytotoxicity (Alamar-Blue, N = 3, n = 3), total protein (N = 3, n = 3), IL-1ß (ELISA, N = 3, n = 3), and differential protein expression by liquid chromatography-tandem mass spectrometry (LC-MS/MS, n = 2). RESULTS: Cells stimulated at MOI 100/1000 and treated with 10 µM epigallocatechin-gallate and chlorhexidine did not present cytotoxicity. IL-1ß significantly increased in both un-stimulated and stimulated chlorhexidine 10 µM groups when compared to un-treated control (p < 0.05). MOI 100 chlorhexidine 10 µM group significantly increased IL-1ß compared to un-stimulated chlorhexidine 10 µM and epigallocatechin-gallate 10 µM groups, as well as to MOI 100 epigallocatechin-gallate 10 µM group (p < 0.05). LC-MS/MS revealed S. mutans and mammalian proteins, with tooth-specific proteins exhibiting different abundance levels, depending on the tested condition. CONCLUSIONS: Odontoblast-like cells stimulated with S. mutans at different MOI combined with epigallocatechin-gallate treatment did not cause cytotoxicity. S. mutans stimulation combined with chlorhexidine 100 µM treatment decreased cell viability, while treatment with chlorhexidine 10 µM concentration significantly increased IL-1ß. S. mutans stimulation and treatment of cells resulted in varied protein expression.


Assuntos
Catequina , Streptococcus mutans , Animais , Catequina/análogos & derivados , Catequina/farmacologia , Clorexidina/toxicidade , Cromatografia Líquida , Interleucina-1beta , Odontoblastos , Proteômica , Espectrometria de Massas em Tandem
7.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575945

RESUMO

We investigated the effects of adipose-derived extract (AE) on cultured chondrocytes and in vivo cartilage destruction. AE was prepared from human adipose tissues using a nonenzymatic approach. Cultured human chondrocytes were stimulated with interleukin-1 beta (IL-1ß) with or without different concentrations of AE. The effects of co-treatment with AE on intracellular signaling pathways and their downstream gene and protein expressions were examined using real-time PCR, Western blotting, and immunofluorescence staining. Rat AE prepared from inguinal adipose tissues was intra-articularly delivered to the knee joints of rats with experimental osteoarthritis (OA), and the effect of AE on cartilage destruction was evaluated histologically. In vitro, co-treatment with IL-1ß combined with AE reduced activation of the p38 and ERK mitogen-activated protein kinase (MAPK) pathway and nuclear translocation of the p65 subunit of nuclear factor-kappa B (NF-κB), and subsequently downregulated the expressions of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, IL-6, and IL-8, whereas it markedly upregulated the expression of IL-1 receptor type 2 (IL-1R2) in chondrocytes. Intra-articular injection of homologous AE significantly ameliorated cartilage destruction six weeks postoperatively in the rat OA model. These results suggested that AE may exert a chondroprotective effect, at least in part, through modulation of the IL-1ß-induced inflammatory signaling pathway by upregulation of IL-1R2 expression.


Assuntos
Inflamação/tratamento farmacológico , Interleucina-1beta/genética , Osteoartrite/tratamento farmacológico , Receptores Tipo II de Interleucina-1/genética , Tecido Adiposo/química , Animais , Cartilagem/efeitos dos fármacos , Cartilagem/patologia , Condrócitos/efeitos dos fármacos , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/patologia , Osteoartrite/genética , Osteoartrite/patologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Extratos de Tecidos/química , Extratos de Tecidos/farmacologia
8.
Biosens Bioelectron ; 194: 113608, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34500224

RESUMO

There are still huge challenges from clinical real-world data to accurate targets and critical quality attributes (CQAs) for effective treatment of allergic rhinitis (AR). Here, we present a novel integrated strategy that biosensors and intelligent algorithms were used to angle AR targets and CQAs from clinical real world. Firstly, bagging and boosting partial least squares discrimination analysis (PLS-DA) and Monte-Carlo sampling were proposed to screen accurate AR targets. Macrophage migration inhibitory factor (MIF) and Interleukin-1beta (IL-1ß) potential targets were obtained based on large-scale analysis of one thousand proteins and in-depth precise screening of seventy proteins. Furthermore, high electron mobility transistor (HEMT) biosensors were fabricated and successfully modified by MIF and IL-1ß potential targets with a low detection concentration as 1 pM and quantitative range from 1 pM to 10 nM. Surprisingly, through MIF/IL-1ß biosensors, we angled 5-O-methylvisammioside, amygdalin, and cimicifugoside three CQAs. The strong interaction was discovered among three CQAs and MIF/IL-1ß biosensors with almost all KD up to 10-11 M. Finally, interaction among three CQAs and MIF/IL-1ß biosensors were evaluated by in vitro and vivo experiments. In this paper, two critical potential targets and three effective CQAs for AR treatment were discovered and validated by biosensor and advanced algorithms. It provides a superior integrated idea for angling critical targets and CQAs from clinical real-world data by biosensors and informatics.


Assuntos
Técnicas Biossensoriais , Fatores Inibidores da Migração de Macrófagos , Rinite Alérgica , Algoritmos , Humanos , Interleucina-1beta , Oxirredutases Intramoleculares , Rinite Alérgica/diagnóstico , Rinite Alérgica/tratamento farmacológico
9.
Front Cell Infect Microbiol ; 11: 691445, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34513725

RESUMO

Aeromonas sobria, a common conditional pathogenic bacteria, is widely distributed in the environment and causes gastroenteritis in humans or septicemia in fish. Of all Aeromonas species, A. sobria is the most frequently isolated from human infections especially in immunocompromised subjects. Innate immunity is the first protection system of organism to resist non-specific pathogens invasion; however, the immune response process of hosts against A. sobria infection re\mains unexplored. The present study established an A. sobria infection model using primary mouse peritoneal macrophages (PMφs). The adherence and cytotoxicity of A. sobria on PMφs were determined by May-Grünwald Giemsa staining and LDH release measurement. Pro-inflammatory cytokine expression levels were measured using qPCR, western blotting, and ELISA methods. We also investigated the levels of ASC oligomerization and determined the roles of active caspase-1 in IL-1ß secretion through inhibition assays and explored the activated pattern recognition receptors through immunofluorescence. We further elucidated the roles of activated inflammasome in regulating the host's inflammatory response through inhibition combined with ELISA assays. Our results showed that A. sobria induced lytic cell death and LDH release, whereas it had no adhesive properties on PMφs. A. sobria triggered various proinflammatory cytokine transcription level upregulation, and IL-1ß occupied the highest levels. The pro-IL-1ß protein expression levels increased in a dose-dependent manner with MOI ranging from 1 to 100. This process was regulated by ASC-dependent inflammasome, which cleavage pro-IL-1ß into active IL-1ß p17 with activated caspase-1 p20. Meanwhile, the expression levels of NLRP3 receptor significantly increased, location analysis revealed puncta-like surrounding nuclear, and inhibition of NLRP3 inflammasome downregulated caspase-1 activation and IL-1ß secretion. Blocking of NLRP3 inflammasome activation through K+ efflux and cathepsin B or caspase approaches downregulated A. sobria-induced proinflammatory cytokine production. Overall, these data indicated that A. sobria induced proinflammatory cytokine production in PMφs through activating NLRP3 inflammasome signaling pathways.


Assuntos
Aeromonas , Inflamassomos , Animais , Caspase 1 , Citocinas , Interleucina-1beta , Macrófagos Peritoneais , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR
10.
Front Immunol ; 12: 661323, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531850

RESUMO

Tumors evade the immune system by inducing inflammation. In melanoma, tumor-derived IL-1ß drives inflammation and the expansion of highly immunosuppressive myeloid-derived suppressor cells (MDSCs). Similar in many tumors, melanoma is also linked to the downstream IL-6/STAT3 axis. In this study, we observed that both recombinant and tumor-derived IL-1ß specifically induce pSTAT3(Y705), creating a tumor-autoinflammatory loop, which amplifies IL-6 signaling in the human melanoma cell line 1205Lu. To disrupt IL-1ß/IL-6/STAT3 axis, we suppressed IL-1ß-mediated inflammation by inhibiting the NOD-like receptor protein 3 (NLRP3) using OLT1177, a safe-in-humans specific NLRP3 oral inhibitor. In vivo, using B16F10 melanoma, OLT1177 effectively reduced tumor progression (p< 0.01); in primary tumors, OLT1177 decreased pSTAT3(Y705) by 82% (p<0.01) and II6 expression by 53% (p<0.05). Disruption of tumor-derived NLRP3, either pharmacologically or genetically, reduced STAT3 signaling in bone marrow cells. In PMN-MDSCs isolated from tumor-bearing mice treated with OLT1177, we observed significant reductions in immunosuppressive genes such as Pdcd1l1, Arg1, Il10 and Tgfb1. In conclusion, the data presented here show that the inhibition of NLRP3 reduces IL-1ß induction of pSTAT3(Y705) preventing expression of immunosuppressive genes as well as activity in PMN-MDSCs.


Assuntos
Interleucina-1beta/imunologia , Interleucina-6/imunologia , Melanoma/imunologia , Células Supressoras Mieloides/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Fator de Transcrição STAT3/imunologia , Animais , Linhagem Celular Tumoral , Humanos , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Imunológicos , Células Supressoras Mieloides/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nitrilas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia
11.
J Int Med Res ; 49(9): 3000605211036845, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34551597

RESUMO

OBJECTIVES: In this prospective case-control study, we explored the regulatory roles of the NLRP3 inflammasome in hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF). METHODS: Thirty patients with HBV-ACLF, 30 patients with chronic hepatitis B, and 30 healthy individuals were enrolled. Real-time reverse transcription polymerase chain reaction was used to assess mRNA levels in peripheral blood mononuclear cells and serum protein levels were assessed by enzyme-linked immunosorbent assay. RESULTS: Serum levels of alanine aminotransferase, asparagine aminotransferase, total bilirubin, and direct bilirubin in patients with HBV-ACLF were increased. Transcript levels of NLRP3 and ASC and protein levels of interleukin (IL)-1ß, IL-18, and sCD40L were elevated in patients with HBV-ACLF. Expression of the NLRP3 inflammasome signaling pathway components procaspase-1 and pro-IL-1ß was elevated in patients with HBV-ACLF. CONCLUSIONS: This prospective case-control study demonstrated that significant activation of the NLRP3 inflammasome occurs in patients with HBV-ACLF. The activated NLRP3 inflammasome mediated liver failure by stimulating procaspase-1 and pro-IL-1 ß and regulating downstream CD40-CD40L signaling.


Assuntos
Insuficiência Hepática Crônica Agudizada , Inflamassomos , Ligante de CD40/genética , Estudos de Casos e Controles , Caspase 1/genética , Humanos , Inflamassomos/genética , Interleucina-1beta/genética , Leucócitos Mononucleares , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
12.
Nat Cell Biol ; 23(9): 953-966, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34475534

RESUMO

While the acquisition of cellular plasticity in adult stem cells is essential for rapid regeneration after tissue injury, little is known about the underlying mechanisms governing this process. Our data reveal the coordination of airway progenitor differentiation plasticity by inflammatory signals during alveolar regeneration. Following damage, interleukin-1ß (IL-1ß) signalling-dependent modulation of Jag1 and Jag2 expression in ciliated cells results in the inhibition of Notch signalling in secretory cells, which drives the reprogramming and acquisition of differentiation plasticity. We identify the transcription factor Fosl2 (also known as Fra2) for secretory cell fate conversion to alveolar type 2 cells that retain the distinct genetic and epigenetic signatures of secretory lineages. We also reveal that human secretory cells positive for KDR (also known as FLK-1) display a conserved capacity to generate alveolar type 2 cells via Notch inhibition. Our results demonstrate the functional role of an IL-1ß-Notch-Fosl2 axis in the fate decision of secretory cells during injury repair, proposing a potential therapeutic target for human lung alveolar regeneration.


Assuntos
Diferenciação Celular/fisiologia , Antígeno 2 Relacionado a Fos/metabolismo , Interleucina-1beta/metabolismo , Receptores Notch/metabolismo , Regeneração/fisiologia , Animais , Antígeno 2 Relacionado a Fos/genética , Regulação da Expressão Gênica/fisiologia , Interleucina-1beta/genética , Camundongos , Sistema Respiratório/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/metabolismo
13.
Zhongguo Zhong Yao Za Zhi ; 46(17): 4480-4487, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34581053

RESUMO

This study investigated the mechanism of improving impaired glucose tolerance(IGT) of rats by Huanglian Wendan Decoction from the perspective of the skeletal muscle Nod-like receptor protein 3(NLRP3)/cysteinyl aspartate specific proteinase-1(caspase-1)/interleukin-1ß(IL-1ß), interleukin-18(IL-18) pathway. Healthy male SD rats were fed with the diet containing 45% fat for 20 weeks, accompanied by a high-temperature and high-humidity environment and an inactive lifestyle, for the establishment of the IGT rat model. The rats were divided into the blank control group, model control group, metformin hydrochloride group(positive drug group, 0.05 g·kg~(-1)·d~(-1)) and Huanglian Wendan Decoction group(7.8 g·kg~(-1)·d~(-1)). After continuous intragastric administration for 4 weeks, the obesity and glycemic indexes of all the rats were measured. The fasting serum insulin(FINS) level was determined by ELISA, with the insulin sensitivity index(ISI) and insulin resistance index(IRI) calculated. The mRNA and protein expression le-vels of nuclear factor kappaB(NF-κB), NLRP3, caspase-1, IL-1ß and IL-18 in skeletal muscle tissue were detected by real-time polymerase chain reaction(PCR), Western blot and immunofluorescence. Compared with the blank control group, the model control group witnessed significantly increased mRNA and protein expression of NF-κB, NLRP3, caspase-1, IL-1ß and IL-18. As revealed by the comparison with the model control group, Huanglian Wendan Decoction could effectively regulate the obesity status, reduce body weight, correct the abnormal levels of 2-hour plasma glucose(2 hPG), insulin resistance index(IRI), insulin sensitivity index(ISI), and lower the mRNA and protein expression of NF-κB, NLRP3, caspase-1, IL-1ß and IL-18 in the skeletal muscle tissue of IGT rats. Combined with previous studies, the above results showed that the occurrence and development of IGT was closely related to inflammatory response and the classic pyroptosis pathway in skeletal muscle, such as NLRP3/caspase-1/IL-1ß, IL-18. It is inferred that the mechanism of Huanglian Wendan Decoction was to alleviate insulin resistance(IR) and then reverse the course of IGT lies in the regulation of the abnormal insulin receptor signaling pathway based on the NLRP3 inflammasome pathway.


Assuntos
Intolerância à Glucose , Interleucina-18 , Animais , Caspase 1/genética , Medicamentos de Ervas Chinesas , Interleucina-18/genética , Interleucina-1beta , Masculino , Músculo Esquelético , NF-kappa B/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Ratos , Ratos Sprague-Dawley
14.
J Appl Oral Sci ; 29: e20210160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34586188

RESUMO

OBJECTIVE: This study aims to evaluate the effect of ellagic acid (EA) by measuring the levels of alveolar bone resorption and inflammatory and oxidative stress markers in the periodontal tissues and serum on the periodontal repair process related to experimental periodontitis in rats. METHODOLOGY: Forty Wistar rats were divided into four study groups as follows: Group 1=healthy control (n=10); Group 2=EA control (15 mg/kg)(n=10); Group 3=periodontitis (n=10); Group 4=periodontitis+EA (15 mg/kg) (n=10). The periodontitis model was established by ligating bilateral mandibular first molars for 14 days. Then, rats were given normal saline or EA for another 14 days by gavage administration. Serum and gingiva myeloperoxidase (MPO) activity, 8-hydroxydeoxyguanosine(8-OHdG), and glutathione (GSH) levels were analyzed by ELISA. Immunohistochemical analysis was used to detect Interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha (TNF-α) immunoreactivities in the periodontal tissues. Alveolar bone loss (ABL) and attachment loss (AL) was evaluated by histomorphometry analysis. RESULTS: ABL and AL were statistically higher in group 3 than in groups 1, 2 and 4 and in group 4 than in groups 1 and 2 (p<0.05). MPO activities in gingival tissue and serum were significantly increased in group 3 compared to groups 1 and 2 (p<0.05). Significantly higher serum GSH levels, lower gingiva, and serum 8-OHdG levels, and MPO activity were observed in group 4 compared to group 3 (p<0.05). Rats with periodontitis (group 3) expressed significantly higher immunoreactivities of IL-6 and TNF-α and lower IL-10 immunoreactivity compared to those other groups (p<0.05). IL-6 and TNF-α immunoreactivities significantly decreased and IL-10 immunoreactivity increased in group 4 after the use of EA compared to group 3 (p<0.001). CONCLUSIONS: Our findings showed that EA provides significant improvements on gingival oxidative stress and inflammatory markers and alveolar bone resorption in the repair process associated with experimental periodontitis. Therefore, EA may have a therapeutic potential on periodontitis.


Assuntos
Perda do Osso Alveolar , Periodontite , Animais , Ácido Elágico/farmacologia , Interleucina-1beta , Periodontite/tratamento farmacológico , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa
15.
Nat Commun ; 12(1): 5143, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446704

RESUMO

Residual systemic inflammation and mucosal immune dysfunction persist in people living with HIV, despite treatment with combined anti-retroviral therapy, but the underlying immune mechanisms are poorly understood. Here we report that the altered immune landscape of the oral mucosa of HIV-positive patients on therapy involves increased TLR and inflammasome signaling, localized CD4+ T cell hyperactivation, and, counterintuitively, enrichment of FOXP3+ T cells. HIV infection of oral tonsil cultures in vitro causes an increase in FOXP3+ T cells expressing PD-1, IFN-γ, Amphiregulin and IL-10. These cells persist even in the presence of anti-retroviral drugs, and further expand when stimulated by TLR2 ligands and IL-1ß. Mechanistically, IL-1ß upregulates PD-1 expression via AKT signaling, and PD-1 stabilizes FOXP3 and Amphiregulin through a mechanism involving asparaginyl endopeptidase, resulting in FOXP3+ cells that are incapable of suppressing CD4+ T cells in vitro. The FOXP3+ T cells that are abundant in HIV-positive patients are phenotypically similar to the in vitro cultured, HIV-responsive FOXP3+ T cells, and their presence strongly correlates with CD4+ T cell hyper-activation. This suggests that FOXP3+ T cell dysregulation might play a role in the mucosal immune dysfunction of HIV patients on therapy.


Assuntos
Anfirregulina/imunologia , Fatores de Transcrição Forkhead/imunologia , Infecções por HIV/imunologia , Mucosa Bucal/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia , Anfirregulina/genética , Linfócitos T CD4-Positivos/imunologia , Fatores de Transcrição Forkhead/genética , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Ativação Linfocitária , Receptor de Morte Celular Programada 1/genética
16.
Molecules ; 26(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34361701

RESUMO

Arthritis is a chronic inflammatory disease accompanied by pathological reactions such as swelling, redness, fever, and pain in various joint areas. The drugs currently available to treat arthritis are associated with diverse side-effects. Therefore, there is a need for safer and more effective treatments to alleviate the inflammation of arthritis with fewer side-effects. In this study, a new sterol, Δ8(14)-ergostenol, was discovered, and its glycosides were synthesized and found to be more efficient in terms of synthesis or anti-inflammatory activity than either spinasterol or 5,6-dihydroergosterol is. Among these synthetic glycosides, galactosyl ergostenol inhibited the expression of inflammatory mediators in TNF-α-stimulated FLS and TNF-α-induced MMPs and collagen type II A1 degradation in human chondrocytes. These results suggest the new galactosyl ergostenol as a treatment candidate for arthritis.


Assuntos
Anti-Inflamatórios/farmacologia , Condrócitos/efeitos dos fármacos , Ergosterol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glicosídeos/farmacologia , Sinoviócitos/efeitos dos fármacos , Anti-Inflamatórios/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/metabolismo , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Ergosterol/química , Glicosídeos/síntese química , Humanos , Inflamação/prevenção & controle , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Modelos Biológicos , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Transdução de Sinais , Sinoviócitos/citologia , Sinoviócitos/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/farmacologia
17.
Zool Res ; 42(5): 633-636, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34423606

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent responsible for the global coronavirus disease 2019 (COVID-19) pandemic. Numerous studies have demonstrated that cardiovascular disease may affect COVID-19 progression. In the present study, we investigated the effect of hypertension on viral replication and COVID-19 progression using a hypertensive mouse model infected with SARS-CoV-2. Results revealed that SARS-CoV-2 replication was delayed in hypertensive mouse lungs. In contrast, SARS-CoV-2 replication in hypertensive mice treated with the antihypertensive drug captopril demonstrated similar virus replication as SARS-CoV-2-infected normotensive mice. Furthermore, antihypertensive treatment alleviated lung inflammation induced by SARS-CoV-2 replication (interleukin (IL)-1ß up-regulation and increased immune cell infiltration). No differences in lung inflammation were observed between the SARS-CoV-2-infected normotensive mice and hypertensive mice. Our findings suggest that captopril treatment may alleviate COVID-19 progression but not affect viral replication.


Assuntos
Anti-Hipertensivos/uso terapêutico , COVID-19/complicações , Captopril/uso terapêutico , Hipertensão/complicações , Pneumopatias/tratamento farmacológico , SARS-CoV-2 , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Captopril/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/complicações , Inflamação/tratamento farmacológico , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Pneumopatias/etiologia , Pneumopatias/virologia , Camundongos , Replicação Viral/efeitos dos fármacos
18.
Beijing Da Xue Xue Bao Yi Xue Ban ; 53(4): 716-720, 2021 Aug 18.
Artigo em Chinês | MEDLINE | ID: mdl-34393234

RESUMO

OBJECTIVE: To investigate the role of rebamipide in the treatment of acute gout arthritis rats induced by monosodium urate (MSU) crystal. METHODS: Forty-two male rats were randomly divided into three groups (n=14). Group A was treated with oral rebamipide, group B with oral colchicine, and group C with oral placebo. The rats were monitored for the induction of arthritis with clinical manifestations and pathological changes, and the levels of interleukin (IL)-1ß、IL-6、IL-10, and tumor necrosis factor (TNF)-α in serum were measured. RESULTS: In group C, the clinical score and swelling index reached the maximum in 24 h, and then gradually decreased to 72 h. After 24 h of model induced, the clinical scores in group C were significantly higher than those in group A and group B [2 (1-3) vs. 0 (0-1) vs. 1 (0-2), P < 0.01], the swelling indexes in group C were significantly higher than those in group A and group B [0.36 (0.16-0.52) vs. 0.11 (0-0.20) vs. 0.12 (0-0.16), P < 0.01]. Histologically, after 24 h of model induced, there was a large number of neutrophil infiltration in the synovium of group C [scale score: 4 (2-4)], and there was no significant inflammatory cell infiltration in group A [1 (0-2)] and group B [1 (0-2)], the difference was statistically significant (P < 0.001). After 24 h of model induced, the levels of IL-1ß, IL-6, IL-10, and TNF-α in serum of group C were significantly higher than those in group A and B [IL-1ß: (41.86±5.72) vs. (27.35±7.47) vs. (27.76±5.28) ng/L, IL-6: (1 575.55±167.11) vs. (963.53±90.22) vs. (964.08±99.31) ng/L, IL-10: (37.96±3.76) vs. (21.68±4.83) vs. (16.20±2.49) ng/L, TNF-α: (21.32±1.34) vs. (15.82±2.54) vs. (17.35±7.47) µg/L, P < 0.001]. CONCLUSION: Rebamipide has a protective effect on acute gout arthritis rats induced by MUS crystals.


Assuntos
Artrite Gotosa , Quinolonas , Alanina/análogos & derivados , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Interleucina-1beta , Masculino , Ratos , Ácido Úrico
19.
Biomolecules ; 11(8)2021 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-34439835

RESUMO

Increasing evidence has demonstrated that oxidized low-density lipoproteins (oxLDL) and lipopolysaccharide (LPS) enhance accumulation of interleukin (IL)-1 beta-producing macrophages in atherosclerotic lesions. However, the potential synergistic effect of native LDL (nLDL) and LPS on the inflammatory ability and migration pattern of monocyte subpopulations remains elusive and is examined here. In vitro, whole blood cells from healthy donors (n = 20) were incubated with 100 µg/mL nLDL, 10 ng/mL LPS, or nLDL + LPS for 9 h. Flow cytometry assays revealed that nLDL significantly decreases the classical monocyte (CM) percentage and increases the non-classical monocyte (NCM) subset. While nLDL + LPS significantly increased the number of NCMs expressing IL-1 beta and the C-C chemokine receptor type 2 (CCR2), the amount of NCMs expressing the CX3C chemokine receptor 1 (CX3CR1) decreased. In vivo, patients (n = 85) with serum LDL-cholesterol (LDL-C) >100 mg/dL showed an increase in NCM, IL-1 beta, LPS-binding protein (LBP), and Castelli's atherogenic risk index as compared to controls (n = 65) with optimal LDL-C concentrations (≤100 mg/dL). This work demonstrates for the first time that nLDL acts in synergy with LPS to alter the balance of human monocyte subsets and their ability to produce inflammatory cytokines and chemokine receptors with prominent roles in atherogenesis.


Assuntos
Receptor 1 de Quimiocina CX3C/genética , LDL-Colesterol/farmacologia , Interleucina-1beta/genética , Lipopolissacarídeos/farmacologia , Monócitos/efeitos dos fármacos , Receptores CCR2/genética , Proteínas de Fase Aguda/genética , Proteínas de Fase Aguda/imunologia , Adolescente , Adulto , Proteína C-Reativa/genética , Proteína C-Reativa/imunologia , Receptor 1 de Quimiocina CX3C/imunologia , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/imunologia , HDL-Colesterol/sangue , Sinergismo Farmacológico , Feminino , Citometria de Fluxo , Expressão Gênica , Voluntários Saudáveis , Humanos , Interleucina-1beta/imunologia , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Monócitos/citologia , Monócitos/imunologia , Cultura Primária de Células , Receptores CCR2/imunologia , Triglicerídeos/sangue
20.
Biomolecules ; 11(8)2021 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-34439837

RESUMO

Repeated mechanical stress causes injuries in the adult skeletal muscle that need to be repaired. Although muscle regeneration is a highly efficient process, it fails in some pathological conditions, compromising tissue functionality. This may be caused by aberrant cell-cell communication, resulting in the deposition of fibrotic and adipose infiltrates. Here, we investigate in vivo changes in the profile of skeletal muscle secretome during the regeneration process to suggest new targetable regulatory circuits whose failure may lead to tissue degeneration in pathological conditions. We describe the kinetic variation of expression levels of 76 secreted proteins during the regeneration process. In addition, we profile the gene expression of immune cells, endothelial cells, satellite cells, and fibro-adipogenic progenitors. This analysis allowed us to annotate each cell-type with the cytokines and receptors they have the potential to synthetize, thus making it possible to draw a cell-cell interaction map. We next selected 12 cytokines whose receptors are expressed in FAPs and tested their ability to modulate FAP adipogenesis and proliferation. We observed that IL1α and IL1ß potently inhibit FAP adipogenesis, while EGF and BTC notably promote FAP proliferation. In addition, we characterized the cross-talk mediated by extracellular vesicles (EVs). We first monitored the modulation of muscle EV cargo during tissue regeneration. Using a single-vesicle flow cytometry approach, we observed that EVs differentially affect the uptake of RNA and proteins into their lumen. We also investigated the EV capability to interact with SCs and FAPs and to modulate their proliferation and differentiation. We conclude that both cytokines and EVs secreted during muscle regeneration have the potential to modulate adipogenic differentiation of FAPs. The results of our approach provide a system-wide picture of mechanisms that control cell fate during the regeneration process in the muscle niche.


Assuntos
Adipogenia/genética , Vesículas Extracelulares/metabolismo , Interleucina-1alfa/genética , Interleucina-1beta/genética , Músculo Esquelético/efeitos dos fármacos , Regeneração/genética , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Cardiotoxinas/toxicidade , Comunicação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/classificação , Citocinas/genética , Citocinas/metabolismo , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Vesículas Extracelulares/química , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Mioblastos/citologia , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Proteoma/classificação , Proteoma/genética , Proteoma/metabolismo , Regeneração/efeitos dos fármacos , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...