Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 125.964
Filtrar
1.
Int J Nanomedicine ; 16: 2461-2475, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33814910

RESUMO

Aim: To explore the effects of Radix Sophorae Flavescentis carbonisata-based carbon dots (RSFC-CDs) on an ethanol-induced acute gastric ulcer rat model. Methods: The structure, optical properties, functional groups and elemental composition of RSFC-CDs synthesized by one-step pyrolysis were characterized. The gastric protective effects of RSFC-CDs were evaluated and confirmed by applying a rat model of ethanol-induced acute gastric ulcers. The underlying mechanisms were investigated through the nuclear factor-kappa B (NF-κB) signalling pathway and oxidative stress. Results: RSFC-CDs with a diameter ranging from 2-3 nm mainly showed gastric protective effects by reducing the levels of NF-κB, tumour necrosis factor-α (TNF-α), interleukin (IL)-6, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione (GSH), malondialdehyde (MDA) and inducible nitric oxide synthase (iNOS) to inhibit ethanol-induced inflammation and oxidative stress. Conclusion: RSFC-CDs have anti-inflammatory and anti-oxidative effects, making them promising for application in ethanol-induced gastric injury.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Carbono/química , Medicamentos de Ervas Chinesas/uso terapêutico , Substâncias Protetoras/uso terapêutico , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Doença Aguda , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Etanol/efeitos adversos , Interleucina-6/metabolismo , Masculino , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espectroscopia Fotoeletrônica , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Úlcera Gástrica/patologia , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
5.
J Med Microbiol ; 70(4)2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33830910

RESUMO

Introduction. Clostridioides difficile infection (CDI) causes toxin-mediated enteropathy, such as antibiotic-associated diarrhoea and pseudomembranous colitis. Rho-glucosylating toxin A (TcdA) and toxin B (TcdB) have been clearly implicated in pathogenesis, whereas the virulence of binary toxin (CDT) is still debated.Hypothesis statement. We hypothesized that CDT is involved in the host immune response and plays a pivotal role in establishing virulence by modulating pro-inflammatory cytokine production; this is achieved through the integral Toll-like receptor (TLR) signalling pathways.Aim. The aim of the present study was to determine whether and how CDT impacts macrophages compared to TcdA or TcdB by examining the induction of CXC chemokine ligand 2 (CXCL2) and tumour necrosis factor-α (TNF-α), both of which are crucial in mediating local and systematic inflammatory responses.Methodology. RAW264.7 cells or transfected human embryonic kidney (HEK) 293 T cells were incubated with TcdA, TcdB, or CDT. In some experiments, a neutralizing antibody against TLR2 or TLR4, or myeloid differentiation 88 inhibitory peptide were added. The amount of CXCL2 and TNF-α secreted was then measured.Results. In RAW264.7 macrophages, CXCL2 and TNF-α were produced via the Toll-like receptor 2 (TLR2) or Toll-like receptor 4 (TLR4) pathway in a TcdA, TcdB, or CDT dose-dependent manner. Interleukin-8 secretion was induced in TLR4/MD2/CD14-transfected, but not in TLR2-transfected, HEK 293 T cells following TcdB or CDT exposure.Conclusion. Our results showed that C. difficile toxins, including CDT, enhanced macrophage-mediated CXCL2 and TNF-α production via TLR2 and TLR4, indicating that CDT affects host immune responses.


Assuntos
Toxinas Bacterianas/farmacologia , Quimiocina CXCL2/metabolismo , Macrófagos/efeitos dos fármacos , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Células HEK293 , Humanos , Macrófagos/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Fator 88 de Diferenciação Mieloide/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Receptor 2 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/antagonistas & inibidores , Virulência
6.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809777

RESUMO

Since Otto Warburg reported in 1924 that cancer cells address their increased energy requirement through a massive intake of glucose, the cellular energy level has offered a therapeutic anticancer strategy. Methionine restriction (MetR) is one of the most effective approaches for inducing low-energy metabolism (LEM) due to the central position in metabolism of this amino acid. However, no simple in vitro system for the rapid analysis of MetR is currently available, and this study establishes the murine cell line L929 as such a model system. L929 cells react rapidly and efficiently to MetR, and the analysis of more than 150 different metabolites belonging to different classes (amino acids, urea and tricarboxylic acid cycle (TCA) cycles, carbohydrates, etc.) by liquid chromatography/mass spectrometry (LC/MS) defines a metabolic fingerprint and enables the identification of specific metabolites representing normal or MetR conditions. The system facilitates the rapid and efficient testing of potential cancer therapeutic metabolic targets. To date, MS studies of MetR have been performed using organisms and yeast, and the current LC/MS analysis of the intra- and extracellular metabolites in the murine cell line L929 over a period of 5 days thus provides new insights into the effects of MetR at the cellular metabolic level.


Assuntos
Fibroblastos/metabolismo , Metionina/metabolismo , Animais , Morte Celular , Linhagem Celular , Proliferação de Células , Ligantes , Metaboloma , Camundongos , Fator de Necrose Tumoral alfa/metabolismo
7.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803624

RESUMO

A central part of the complement system, the anaphylatoxin C5a was investigated in this study to learn its effects on tenocytes in respect to understanding the potential expression of other crucial complement factors and pro-inflammatory mediators involved in tendinopathy. Human hamstring tendon-derived tenocytes were treated with recombinant C5a protein in concentrations of 25 ng/mL and 100 ng/mL for 0.5 h (early phase), 4 h (intermediate phase), and 24 h (late phase). Tenocytes survival was assessed after 24 h stimulation by live-dead assay. The gene expression of complement-related factors C5aR, the complement regulatory proteins (CRPs) CD46, CD55, CD59, and of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 was monitored using qPCR. Tenocytes were immunolabeled for C5aR and CD55 proteins. TNFα production was monitored by ELISA. Tenocyte survival was not impaired through C5a stimulation. Interestingly, the gene expression of C5aR and that of the CRPs CD46 and CD59 was significantly reduced in the intermediate and late phase, and that of TNFα only in an early phase, compared to the control group. ELISA analysis indicated a concomitant not significant trend of impaired TNFα protein synthesis at 4 h. However, there was also an early significant induction of CD55 and CD59 mediated by 25 ng/mL anaphylatoxin C5a. Hence, exposure of tenocytes to C5a obviously evokes a time and concentration-dependent response in their expression of complement and pro-inflammatory factors. C5a, released in damaged tendons, might directly contribute to tenocyte activation and thereby be involved in tendon healing and tendinopathy.


Assuntos
Complemento C5a/metabolismo , Proteínas do Sistema Complemento/metabolismo , Tenócitos/metabolismo , Adulto , Antígenos CD55/metabolismo , Ativação do Complemento , Regulação da Expressão Gênica , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Receptor da Anafilatoxina C5a/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
8.
Wiad Lek ; 74(1): 11-16, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33851579

RESUMO

OBJECTIVE: The aim: Of this study was to improve the efficiency of complex medicamental treatment of generalized periodontitis (GP) in patients with concomitant CAD using of differentiated immunotropic therapy, especially herbal medicine «Immuno-ton¼. PATIENTS AND METHODS: Material and methods: 130 patients with GP were observed (43 without and 81 with chronic CAD - stable angina, functional classes II-III (CCS)) with detection of oral hygiene indices for Green-Vermillion, inflammation of gums PMA, bleeding of gums PBI, depth of periodontal pockets (determined by direct method). The levels of TNF-α and sPECAM-1 in gingival fluid were detected by ELISA method. RESULTS: Results: The following article is dedicated to studying on the effectiveness of the proposed method of GP I and II degree of development treatment in patients with a concomitant coronary artery disease (CAD) using of herbal medicines with immunomodulating effect. The offered methods provide disappearance of clinical signs of inflammation in the periodontal tissues and prevention of inflammation recurrence in the long terms. Also, it was proved that usage of the forward method of the GP immunotropic therapy with including of herbal immunomodulators leads to normalization of dynamics of tumor necrosis factor -alfa (TNF-α) and soluble platelet-endothelial cell adhesion molecule -1 (sPECAM-1) in oral fluid of abovementioned contingent of patients. CONCLUSION: Conclusions: The progression of generalized periodontitis in patients with stable coronary heart disease is accompanied with manifestation of systemic inflammation, which have been reduced by immunomodulator Immuno-Ton and extratemporal gel with "Enterosgel" and herbal concentrate "Dzherelo".


Assuntos
Periodontite Crônica , Doença da Artéria Coronariana , Periodontite , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/tratamento farmacológico , Humanos , Bolsa Periodontal , Periodontite/complicações , Periodontite/tratamento farmacológico , Periodonto , Fator de Necrose Tumoral alfa
9.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 56(4): 335-341, 2021 Apr 09.
Artigo em Chinês | MEDLINE | ID: mdl-33832034

RESUMO

Objective: To study the effect of various concentrations of Enterococcus faecalis (Ef) supernatants on human periodontal ligament cell (hPDLC) and the inflammatory response of hPDLC under static pressure. Methods: The method of methyl thiazolyl tetrazolium (MTT) was used to detect the effect of various concentrations of Ef supernatants on the proliferation of hPDLCs and the flow cytometry was used to detect the expression of Toll-like receptor 2 (TLR-2) on the surface of hPDLC after 24-hour-stimulation of Ef supernatant. Furthermore, the hPDLCs were divided into non inducing group without Ef supernatant and inducing group with 5% Ef supernatant, and hPDLCs in each group were loaded with 0, 49 and 196 Pa static pressures respectively. The expressions of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) mRNA and protein were detected by reverse transcription-PCR (RT-PCR) and enzyme linked immunosorbent assay (ELISA) after 24 hours. Results: MTT results showed that the supernatant of Ef with concentration≥5% could significantly inhibit the proliferation activity of hPDLCs at 48 hours of cell culture (P<0.05). Flow cytometry showed that the positive cell rates of TLR-2 increased with increasing volume fractions of the Ef supernatants. The values were (2.12±0.07)%, (2.41±0.32)%, (2.65±0.27)%, (4.76±0.46)%, (9.91±0.92)% and (12.01±1.35)%, respectively. The differences were statistically significant when the concentrations≥5% (P<0.05). There were no significant differences in the expressions of IL-1ß and TNF-α mRNA between the non inducing group and the control group under the pressure of 49 Pa (P>0.05). However, there were significant differences in the expressions of IL-1ß and TNF-α mRNA between the non inducing group and the control group under the pressure of 196 Pa (P<0.05), while the expressions of IL-1ß and TNF-α in the inducing group were significantly lower than that in the control group under the pressures of 49 and 196 Pa (P<0.05). Compared with the control group, the mRNA expression was significantly increased (P<0.05). The result of ELISA was consistent with that of PCR. Conclusions: High concentration of Ef supernatant could inhibit the proliferation of hPDLC. Ef supernatant might promote the expression of TLR-2 on the surface of hPDLC. Excessive mechanical pressure induced the inflammatory response of hPDLC. The presence of inflammatory mediators could lead to the intolerance of hPDLC to pressures and small pressure could aggravate the inflammatory response.


Assuntos
Enterococcus faecalis , Ligamento Periodontal , Humanos , Interleucina-1beta , Lipopolissacarídeos , RNA Mensageiro , Fator de Necrose Tumoral alfa
10.
Int J Mol Sci ; 22(6)2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33804769

RESUMO

SARS-CoV-2 infection can cause cytokine storm and may overshoot immunity in humans; however, it remains to be determined whether virus-induced soluble mediators from infected cells are carried by exosomes as vehicles to distant organs and cause tissue damage in COVID-19 patients. We took an unbiased proteomic approach for analyses of exosomes isolated from plasma of healthy volunteers and COVID-19 patients. Our results revealed that tenascin-C (TNC) and fibrinogen-ß (FGB) are highly abundant in exosomes from COVID-19 patients' plasma compared with that of healthy normal controls. Since TNC and FGB stimulate pro-inflammatory cytokines via the Nuclear factor-κB (NF-κB) pathway, we examined the status of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-C motif chemokine ligand 5 (CCL5) expression upon exposure of hepatocytes to exosomes from COVID-19 patients and observed significant increase compared with that from healthy subjects. Together, our results demonstrate that TNC and FGB are transported through plasma exosomes and potentially trigger pro-inflammatory cytokine signaling in cells of distant organ.


Assuntos
/sangue , Exossomos/química , Exossomos/genética , Fibrinogênio/metabolismo , Inflamação/metabolismo , Tenascina/metabolismo , Idoso , Linhagem Celular , Quimiocina CCL5/metabolismo , Exossomos/metabolismo , Exossomos/ultraestrutura , Feminino , Hepatócitos/metabolismo , Humanos , Inflamação/etiologia , Interleucina-6/metabolismo , Masculino , Espectrometria de Massas , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Mapas de Interação de Proteínas , Proteoma/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Ecotoxicol Environ Saf ; 215: 112108, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33799132

RESUMO

Fluoride which is widespread in our environment and food due to its geological origin and industrial pollution has been identified as a developmental neurotoxicant. Gut-brain axis provides new insight into brain-derived injury. We previously found the psychoactive effects of a probiotic strain, Lactobacillus johnsonii BS15 against fluoride-induced memory dysfunction in mice by modulating the gut-brain axis. In this study, we aimed to detect the link between the reconstruction of gut microbiota and gut-brain axis through which probiotic alleviate fluoride-induced memory impairment. We also added an hour of water avoidance stress (WAS) before behavioral tests and sampling, aiming to demonstrate the preventive effects of the probiotic on fluoride-induced memory impairment after psychological stress. Mice were given fluoridated drinking water (sodium fluoride 100 ppm, corresponding to 37.8 ± 2.4 ppm F¯) for 70 days and administered with PBS or a probiotic strain, Lactobacillus johnsonii BS15 for 28 days prior to and throughout a 70 day exposure to sodium fluoride. Results showed that fluoride increases the hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis and reduces the exploration ratio in novel object recognition (NOR) test and the spontaneous exploration during the T-maze test in mice following WAS, which were significantly improved by the probiotic. 16S rRNA sequencing showed a significant separation in ileal microbiota between the fluoride-treated mice and control mice. Lactobacillus was the main targeting bacteria and significantly reduced in fluoride-treated mice. BS15 reconstructed the fluoride-post microbiota and increased the relative abundance of Lactobacillus. D-lactate content and diamine oxidase (DAO) activity, two biomarkers of gut permeability were reduced in the serum of probiotic-inoculated mice. ZO-1, an intestinal tight junction protein was reduced by fluoride in mRNA, and its protein levels were increased by the probiotic treatment. Moreover, the hippocampus which is essential to learning and memory, down-regulated mRNA level of both the myelin-associated glycoprotein (MAG), and protein levels of brain-derived neurotrophic factor (BDNF), including the improvement of cAMP response element-binding protein (CREB) by BS15 in fluoride-exposed mice after WAS. Via spearman correlation analysis, Lactobacillus displayed significantly positive associations with the behavioral tests, levels of nerve development related factors, and intestinal tight junction proteins ZO-1, and negative association with TNF-α of the hippocampus, highlighting regulatory effects of gut bacteria on memory potential and gut barrier. These results suggested the psychoactive effects of BS15 on fluoride-induced memory dysfunction after psychological stress. In addition, there may be some correlations between fluoride-induced memory dysfunction and reconstruction of gut microbiota. AVAILABILITY OF DATA AND MATERIALS: 16S rRNA sequencing reads have uploaded to NCBI. The accession code of 16S rRNA sequencing reads in the National Center for Biotechnology Information (NCBI) BioProject database: PRJNA660154.


Assuntos
Fluoretos/metabolismo , Microbioma Gastrointestinal/fisiologia , Probióticos/farmacologia , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Lactobacillus/metabolismo , Masculino , Memória , Transtornos da Memória/induzido quimicamente , Camundongos , Microbiota , Sistema Hipófise-Suprarrenal/metabolismo , RNA Ribossômico 16S/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
12.
Artigo em Inglês | MEDLINE | ID: mdl-33806304

RESUMO

Periodontitis, a bacterial-induced infection of the supporting soft and hard tissues of the teeth (the periodontium), is common in patients with rheumatoid arthritis (RA). As RA and periodontitis underlie common inflammatory pathways, targeting the progression of RA might mediate both periodontitis and RA. On the other hand, patients with RA on immunosuppressive medication have an increased risk of infection. Therefore, the objective of this longitudinal observation study was to assess the effect of methotrexate (MTX) and anti-tumor necrosis factor-α (anti-TNF, etanercept) treatment on the periodontal condition of RA patients. Overall, 14 dentate treatment-naive RA patients starting with MTX and 12 dentate RA patients starting with anti-TNF therapy in addition to MTX were included. Follow-up was scheduled matching the routine protocol for the respective treatments. Prior to the anti-rheumatic treatment with MTX or the anti-TNF therapy in addition to MTX, and during follow-up, i.e., 2 months for MTX, and 3 and 6 months for the anti-TNF therapy in addition to MTX, the periodontal inflamed surface area (PISA) was measured. The efficacy of the anti-rheumatic treatment was assessed by determining the change in RA disease activity (DAS28-ESR). Furthermore, the erythrocyte sedimentation rates were determined and the levels of C-reactive protein, IgM-rheumatoid factor, anti-cyclic citrullinated protein antibodies, and antibodies to the periodontal pathogen Porphyromonas gingivalis, were measured. Subgingival sampling and microbiological characterization of the subgingival microflora was done at baseline. MTX or anti-TNF treatment did not result in an improvement of the periodontal condition, while both treatments significantly improved DAS28 scores (both p < 0.01), and reduced C-reactive protein levels and erythrocyte sedimentation rates (both p < 0.05). It is concluded that anti-rheumatic treatment (MTX and anti-TNF) has negligible influence on the periodontal condition of RA patients.


Assuntos
Antirreumáticos , Artrite Reumatoide , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Etanercepte/uso terapêutico , Humanos , Estudos Longitudinais , Metotrexato/uso terapêutico , Resultado do Tratamento , Fator de Necrose Tumoral alfa/uso terapêutico
13.
Zhongguo Gu Shang ; 34(4): 363-7, 2021 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-33896138

RESUMO

OBJECTIVE: To investigate the expression and clinical significance of receptor interacting protein serine-threonine kinases 1 (RIPK1) in the nucleus pulposus of patients with lumbar disc herniation (LDH). METHODS: Nucleus pulposus tissue specimens of 40 patients with LDH patients underwent surgical treatment from January 2016 to January 2018 as the case group, and nucleus pulposus tissue specimens of 30 patients with lumbar spine fracture underwent surgical treatment at the same time as the control group. The expression of RIPK1 mRNA and protein of receptor interaction were detected by polymerase chain reaction (PCR) and Western blot, respectively. The expression of RIPK1 protein in the nucleus pulposus were detected by immunohistochemical staining. The concentrations of RIPK1 and tumor necrosis factor-α (TNF-α) in nucleus pulposus were detected by ELISA method. The relationship between the concentrations of RIPK1, TNF-α in nucleus pulposus and the Pearce grade of LDH patients was analyzed by one-way ANOVA. The correlation between RIPK1 and TNF-α was analyzed by Pearson. RESULTS: RIPK1 was weakly positively expressed in nucleus pulposus of control group, and RIPK1 protein was positively or strongly positively expressed in case group. The expression of RIPK1 mRNA in nucleus pulposus of case group was higher than that of control group (P<0.05). The expression of RIPK1 protein in nucleus pulposus of case group was higher than that of control group(P<0.05). The RIPK1 concentration in nucleus pulposus of case group was higher than that of control group (P=0.012). The concentration of TNF-α in nucleus pulposus of case group was significantly higher than that of control group (P=0.009). There were significantdifferences in concentrations of RIPK1 and TNF-α in nucleus pulposus of LDH patients with different Pearce classification (P>0.05). The concentration of RIPK1 and TNF-α in nucleus pulposus increased significantly with the increase of Pearce grade. Pearson correlation analysis showed that there was a significant positive correlation between RIPK1 and TNF-α in nucleus pulposus of LDH patients (r=0.781, P<0.001). CONCLUSION: The expression levels of RIPK1 mRNA and protein in the intervertebral disc tissues of LDH patients are higher than those of normal intervertebral disc tissues, and increased with the increase of Pearce grade, which may be an important factor involved in LDH inflammatory disease.


Assuntos
Degeneração do Disco Intervertebral , Deslocamento do Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Humanos , Disco Intervertebral/metabolismo , Deslocamento do Disco Intervertebral/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
14.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800290

RESUMO

Tumor necrosis factor alpha (TNF-α) was initially recognized as a factor that causes the necrosis of tumors, but it has been recently identified to have additional important functions as a pathological component of autoimmune diseases. TNF-α binds to two different receptors, which initiate signal transduction pathways. These pathways lead to various cellular responses, including cell survival, differentiation, and proliferation. However, the inappropriate or excessive activation of TNF-α signaling is associated with chronic inflammation and can eventually lead to the development of pathological complications such as autoimmune diseases. Understanding of the TNF-α signaling mechanism has been expanded and applied for the treatment of immune diseases, which has resulted in the development of effective therapeutic tools, including TNF-α inhibitors. Currently, clinically approved TNF-α inhibitors have shown noticeable potency in a variety of autoimmune diseases, and novel TNF-α signaling inhibitors are being clinically evaluated. In this review, we briefly introduce the impact of TNF-α signaling on autoimmune diseases and its inhibitors, which are used as therapeutic agents against autoimmune diseases.


Assuntos
Doenças Autoimunes , Fatores Imunológicos/uso terapêutico , Transdução de Sinais , Fator de Necrose Tumoral alfa , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Doença Crônica , Humanos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
15.
Cells ; 10(3)2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33801959

RESUMO

We herein characterize the immunopathological features of two Italian COVID-19 patients who underwent bilateral lung transplantation (bLTx). Removed lungs underwent histopathological evaluation. Gene expression profiling (GEP) for immune-related signatures was performed on lung specimens and SARS-CoV-2-stimulated peripheral blood mononuclear cells (PBMCs). Cytokine levels were measured on lungs, bronchoalveolar lavage fluids and in culture supernatants. Pathological assessment showed extensive lung damage with the pattern of proliferative to fibrotic phases, with diffuse alveolar damage mimicking usual interstitial pneumonia (UIP). Lungs' GEP revealed overexpression of pathogen recognition receptors, effector cytokines and chemokines, immune activation receptors and of the inflammasome components. Multiplex cytokine analysis confirmed a proinflammatory state, with high levels of monocyte/macrophage chemotactic and activating factors and of IL-6 and TNF-α. A similar profile was observed in SARS-CoV-2-stimulated PBMCs collected 7 days after transplant. The pattern of tissue damage observed in the lungs suggests that this may represent the output of protracted disease, resembling a diffuse UIP-like picture. The molecular immune profiling supports the paradigm of a persistent proinflammatory state and sustained humoral immunity, conditions that are maintained despite the iatrogenic immunosuppression.


Assuntos
/cirurgia , Quimiocinas/metabolismo , Citocinas/metabolismo , Leucócitos Mononucleares/metabolismo , Transplante de Pulmão , Pulmão/patologia , /cirurgia , Adolescente , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/virologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/imunologia , Genótipo , Humanos , Inflamassomos/metabolismo , Interleucina-6/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , Linfonodos/patologia , Linfonodos/virologia , Masculino , Pessoa de Meia-Idade , Plasma/virologia , Polimorfismo de Nucleotídeo Único , /patologia , Fator de Necrose Tumoral alfa/metabolismo
16.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802409

RESUMO

Novel 1,8-naphthyridine-2-carboxamide derivatives with various substituents (HSR2101-HSR2113) were synthesized and evaluated for their effects on the production of pro-inflammatory mediators and cell migration in lipopolysaccharide (LPS)-treated BV2 microglial cells. Among the tested compounds, HSR2104 exhibited the most potent inhibitory effects on the LPS-stimulated production of inflammatory mediators, including nitric oxide (NO), tumor necrosis factor-α, and interleukin-6. Therefore, this compound was chosen for further investigation. We found that HSR2104 attenuated levels of inducible NO synthase and cyclooxygenase 2 in LPS-treated BV2 cells. In addition, it markedly suppressed LPS-induced cell migration as well as the generation of intracellular reactive oxygen species (ROS). Moreover, HSR2104 abated the LPS-triggered nuclear translocation of nuclear factor-κB (NF-κB) through inhibition of inhibitor kappa Bα phosphorylation. Furthermore, it reduced the expressions of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) in LPS-treated BV2 cells. Similar results were observed with TAK242, a specific inhibitor of TLR4, suggesting that TLR4 is an upstream regulator of NF-κB signaling in BV2 cells. Collectively, our findings demonstrate that HSR2104 exhibits anti-inflammatory and anti-migratory activities in LPS-treated BV2 cells via the suppression of ROS and TLR4/MyD88/NF-κB signaling pathway. Based on our observations, HSR2104 may have a beneficial impact on inflammatory responses and microglial cell migration involved in the pathogenesis of various neurodegenerative disorders.


Assuntos
Anti-Inflamatórios/farmacologia , Movimento Celular/efeitos dos fármacos , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Naftiridinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Mediadores da Inflamação/farmacologia , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
17.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802689

RESUMO

Palmitoylethanolamide (PEA) is an endogenous lipid produced on demand by neurons and glial cells that displays neuroprotective properties. It is well known that inflammation and neuronal damage are strictly related processes and that microglia play a pivotal role in their regulation. The aim of the present work was to assess whether PEA could exert its neuroprotective and anti-inflammatory effects through the modulation of microglia reactive phenotypes. In N9 microglial cells, the pre-incubation with PEA blunted the increase of M1 pro-inflammatory markers induced by lipopolysaccharide (LPS), concomitantly increasing those M2 anti-inflammatory markers. Images of microglial cells were processed to obtain a set of morphological parameters that highlighted the ability of PEA to inhibit the LPS-induced M1 polarization and suggested that PEA might induce the anti-inflammatory M2a phenotype. Functionally, PEA prevented Ca2+ transients in both N9 cells and primary microglia and antagonized the neuronal hyperexcitability induced by LPS, as revealed by multi-electrode array (MEA) measurements on primary cortical cultures of neurons, microglia, and astrocyte. Finally, the investigation of the molecular pathway indicated that PEA effects are not mediated by toll-like receptor 4 (TLR4); on the contrary, a partial involvement of cannabinoid type 2 receptor (CB2R) was shown by using a selective receptor inverse agonist.


Assuntos
Amidas/farmacologia , Etanolaminas/farmacologia , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Ácidos Palmíticos/farmacologia , Trifosfato de Adenosina/farmacologia , Animais , Cálcio/metabolismo , Polaridade Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Ratos , Receptor CB2 de Canabinoide/metabolismo , Células THP-1 , Acetato de Tetradecanoilforbol/farmacologia , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
18.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805757

RESUMO

Tumor necrosis factor-alpha (TNF-α) is a multifunctional Th1 cytokine and one of the most important inflammatory cytokines. In pregnancy, TNF-α influences hormone synthesis, placental architecture, and embryonic development. It was also shown that increased levels of TNF-α are associated with pregnancy loss and preeclampsia. Increased TNF-α levels in complicated pregnancy draw attention to trophoblast biology, especially migratory activity, syncytialisation, and endocrine function. Additionally, elevated TNF-α levels may affect the maternal-fetal relationship by altering the secretory profile of placental immunomodulatory factors, which in turn affects maternal immune cells. There is growing evidence that metabolic/pro-inflammatory cytokines can program early placental functions and growth in the first trimester of pregnancy. Furthermore, early pregnancy placenta has a direct impact on fetal development and maternal immune system diseases that release inflammatory (e.g., TNF-α) and immunomodulatory factors, such as chronic inflammatory rheumatic, gastroenterological, or dermatological diseases, and may result in an abnormal release of cytokines and chemokines in syncytiotrophoblasts. Pregnancy poses a challenge in the treatment of chronic disease in patients who plan to have children. The activity of the disease, the impact of pregnancy on the course of the disease, and the safety of pharmacotherapy, including anti-rheumatic agents, in pregnancy should be considered.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Gastrite/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Primeiro Trimestre da Gravidez/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Aleitamento Materno , Certolizumab Pegol/uso terapêutico , Etanercepte/uso terapêutico , Feminino , Gastrite/imunologia , Gastrite/patologia , Humanos , Infliximab/uso terapêutico , Parto/efeitos dos fármacos , Gravidez , Primeiro Trimestre da Gravidez/imunologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologia
19.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807620

RESUMO

Glycyrrhizin (GL), an important active ingredient of licorice root, which weakens the proinflammatory effects of high-mobility group box 1 (HMGB1) by blocking HMGB1 signaling. In this study, we investigated whether GL could suppress inflammation and carcinogenesis in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced murine model of colorectal cancer. ICR mice were divided into four groups (n = 5, each)-control group, GL group, colon cancer (CC) group, and GL-treated CC (CC + GL) group, and sacrificed after 20 weeks. Plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were measured using an enzyme-linked immunosorbent assay. The colonic tissue samples were immunohistochemically stained with DNA damage markers (8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxy-guanosine), inflammatory markers (COX-2 and HMGB1), and stem cell markers (YAP1 and SOX9). The average number of colonic tumors and the levels of IL-6 and TNF-α in the CC + GL group were significantly lower than those in the CC group. The levels of all inflammatory and cancer markers were significantly reduced in the CC + GL group. These results suggest that GL inhibits the inflammatory response by binding HMGB1, thereby inhibiting DNA damage and cancer stem cell proliferation and dedifferentiation. In conclusion, GL significantly attenuates the pathogenesis of AOM/DSS-induced colorectal cancer by inhibiting HMGB1-TLR4-NF-κB signaling.


Assuntos
Carcinogênese/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Ácido Glicirrízico/farmacologia , Inflamação/tratamento farmacológico , Animais , Azoximetano/farmacologia , Colo/efeitos dos fármacos , Colo/metabolismo , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Feminino , Proteína HMGB1/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
20.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806404

RESUMO

A conditioned medium of a cell culture is widely used for various biological applications and frequently analyzed to characterize the functional proteins responsible for observed biological functions. However, a large number of abundant proteins in fetal bovine serum (FBS), usually included in the conditioned medium of a mammalian cell culture medium, hampers in-depth proteomic analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). For a deep proteomic analysis of a conditioned medium by LC-MS/MS, we developed a simple albumin depletion approach coupled with data-independent acquisition (DIA)-mode LC-MS/MS for the conditioned medium of mammalian cells in this study. The results showed that this approach enabled the detection of more than 3700 cell-derived proteins in the cell culture supernatant containing FBS. We further demonstrated the potency of this approach by analyzing proteins in the conditioned media of HeLa cells with and without tumor necrosis factor (TNF) stimulation: >40 differentially accumulated proteins, including four cytokines, upon TNF stimulation were identified in the culture media, which were hardly detected by conventional proteome approaches in the literature.


Assuntos
Técnicas de Cultura de Células/métodos , Meios de Cultivo Condicionados/química , Proteoma/análise , Animais , Bovinos , Cromatografia Líquida , Células HeLa , Humanos , Proteômica/métodos , Soroalbumina Bovina/química , Soroalbumina Bovina/isolamento & purificação , Espectrometria de Massas em Tandem , Fator de Necrose Tumoral alfa/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...