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1.
J Sci Food Agric ; 102(1): 280-290, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34091920

RESUMO

BACKGROUND: A polysaccharide was purified in this study, which was acquired from the fermentation broth of Dendrobium officinale Kimura et Migo. We aimed to investigate the structural features and bioactivity of this polysaccharide. RESULTS: The polysaccharide was purified and the main polysaccharide fraction (i.e., DOP-1) was obtained. High-performance gel permeation chromatography (HPGPC) revealed that the molecular weight of DOP-1 was 447.48 kDa. Galactose, glucose and mannose were found to be present in DOP-1 via monosaccharide composition analysis, at a ratio of 1:1.79:6.71. Methylation and nuclear magnetic resonance spectroscopic analysis indicated that the backbone of DOP-1 was →4)-α-d-Glcp-(1 → 4)-α-d-Manp-(1 → 4)-α-d-Manp-(1 → 4,6)-α-d-Manp-(1→, and its repeating units were also preliminarily established. In vitro tests proved that DOP-1 not only protects RAW264.7 macrophages from the cytotoxic effect induced by lipopolysaccharide (LPS), but also inhibits cytokines (i.e., interleukin-6 and tumour necrosis factor-α) induced by LPS. DOP-1 demonstrated good scavenging activity in vitro toward 1,1-diphenyl-2-picrylhydrazyl and hydroxyl radicals, as well as good metal chelating activity. Therefore, DOP-1 has potential antioxidant applications. CONCLUSION: The structural characteristics of DOP-1 support its favourable biological activities and lay a strong foundation for further exploration of its structure-activity relationships and activity development, providing experimental data for the development and utilisation of fermentation broth of D. officinale. © 2021 Society of Chemical Industry.


Assuntos
Dendrobium/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polissacarídeos/química , Polissacarídeos/farmacologia , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Sequência de Carboidratos , Cromatografia em Gel , Fermentação , Interleucina-6/genética , Interleucina-6/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Peso Molecular , Extratos Vegetais/isolamento & purificação , Polissacarídeos/isolamento & purificação , Células RAW 264.7 , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
2.
Gene ; 807: 145933, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34464678

RESUMO

BACKGROUND: Cervical-cancer is among the most commonly diagnosed cancers in women, and infection with human papillomavirus (HPV) is associated with an increased risk of cervical cancer and altered serum concentrations of inflammatory cytokines. We have explored the association between a genetic variation in the Interleukin-10 (IL-10) gene (rs1800896) and cervical cancer risk and its relationship with tissue Interferon gamma (IFN-γ), Transforming growth factor beta (TGF-ß), Tumor necrosis factor alpha (TNF-α) concentrations in women with cervical cancer. METHODS: A total of 315 women with, or without cervical cancer, were recruited into the study. DNA was extracted from cervical cells, and genotyping was undertaken using Taq-man real-time PCR. The genotype frequency and allele distribution were analyzed together with their association with pathological data. The association of the rs1800896 gene variation with tissue levels of the inflammatory cytokines was also investigated. RESULTS: Our data showed a significant association between the A allele of the rs1800896 gene variant and the presence of cervical cancer. In particular, patients with AG/AA genotypes had an increased risk of cervical cancer with an odds ratio of 1.929 (95% confidence interval [CI]: 0.879-4.23, P < 0.001) in a recessive model, compared with the GG genotype. Also, the tissue concentrations of IFN-γ, TGF-ß, and TNF-α in cervical tissues were significantly higher in women with cervical cancer (P < 0.001) and were associated with the AA genotype. CONCLUSION: We have found an association between the polymorphism rs1800896 in the IL-10 gene and an increased risk of cervical cancer as well as a higher level of tissue inflammatory cytokines. Further investigations are necessary on the value of emerging biomarkers for the risk stratification for the management of cervical cancer patients.


Assuntos
Interleucina-10/genética , Neoplasias do Colo do Útero/genética , Adulto , Alelos , Alphapapillomavirus/genética , Alphapapillomavirus/patogenicidade , Citocinas , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Inflamação , Interferon gama , Interleucina-10/metabolismo , Pessoa de Meia-Idade , Razão de Chances , Papillomaviridae/genética , Papillomaviridae/patogenicidade , Polimorfismo de Nucleotídeo Único/genética , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
3.
Biochim Biophys Acta Mol Cell Res ; 1869(1): 119141, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34610348

RESUMO

It was realized in the 1990s that some membrane proteins such as TNFα, both TNF receptors, ligands of the EGF-R and the Interleukin-6 receptor are proteolytically cleaved and are shed from the cell membrane as soluble proteins. The major responsible protease is a metalloprotease named ADAM17. So far, close to 100 substrates, including cytokines, cytokine receptors, chemokines and adhesion molecules of ADAM17 are known. Therefore, ADAM17 orchestrates many different signaling pathways and is a central signaling hub in inflammation and carcinogenesis. ADAM17 plays an important role in the biology of Interleukin-6 (IL-6) since the generation of the soluble Interleukin-6 receptor (sIL-6R) is needed for trans-signaling, which has been identified as the pro-inflammatory activity of this cytokine. In contrast, Interleukin-6 signaling via the membrane-bound Interleukin-6 receptor is mostly regenerative and protective. Probably due to its broad substrate spectrum, ADAM17 is essential for life and most of the few human individuals identified with ADAM17 gene defects died at young age. Although the potential of ADAM17 as a therapeutic target has been recognized, specific blockade of ADAM17 is not trivial since the metalloprotease domain of ADAM17 shares high structural homology with other proteases, in particular matrix metalloproteases. Here, the critical functions of ADAM17 in IL-6, TNFα and EGF-R pathways and strategies of therapeutic interventions are discussed.


Assuntos
Proteína ADAM17/metabolismo , Receptores ErbB/metabolismo , Interleucina-17/metabolismo , Neoplasias/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Proteína ADAM17/antagonistas & inibidores , Proteína ADAM17/genética , Animais , Anti-Inflamatórios/farmacologia , Receptores ErbB/genética , Humanos , Interleucina-17/genética , Inibidores de Proteases/farmacologia , Fator de Necrose Tumoral alfa/genética
4.
J Exp Med ; 219(1)2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34901991

RESUMO

Defective DNA clearance in DNase II-/- mice leads to lethal inflammatory diseases that can be rescued by deleting cGAS or STING, but the role of distinct signaling pathways downstream of STING in the disease manifestation is not known. We found that the STING S365A mutation, which abrogates IRF3 binding and type I interferon induction, rescued the embryonic lethality of DNase II-/- mice. However, the STING S365A mutant retains the ability to recruit TBK1 and activate NF-κB, and DNase II-/-STING-S365A mice exhibited severe polyarthritis, which was alleviated by neutralizing antibodies against TNF-α or IL-6 receptor. In contrast, the STING L373A mutation or C-terminal tail truncation, which disrupts TBK1 binding and therefore prevents activation of both IRF3 and NF-κB, completely rescued the phenotypes of DNase II-/- mice. These results demonstrate that TBK1 recruitment to STING mediates autoinflammatory arthritis independently of type I interferons. Inhibiting TBK1 binding to STING may be a therapeutic strategy for certain autoinflammatory diseases instigated by self-DNA.


Assuntos
Artrite/metabolismo , DNA/metabolismo , Inflamação/metabolismo , Proteínas de Membrana/metabolismo , /metabolismo , Animais , Artrite/genética , DNA/genética , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Inflamação/genética , Fator Regulador 3 de Interferon/metabolismo , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-6/metabolismo , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , NF-kappa B/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
5.
Biomolecules ; 11(12)2021 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-34944476

RESUMO

Inflammation involves a complex biological response of the body tissues to damaging stimuli. When dysregulated, inflammation led by biomolecular mediators such as caspase-1 and tumor necrosis factor-alpha (TNF-alpha) can play a detrimental role in the progression of different medical conditions such as cancer, neurological disorders, autoimmune diseases, and cytokine storms caused by viral infections such as COVID-19. Computational approaches can accelerate the search for dual-target drugs able to simultaneously inhibit the aforementioned proteins, enabling the discovery of wide-spectrum anti-inflammatory agents. This work reports the first multicondition model based on quantitative structure-activity relationships and a multilayer perceptron neural network (mtc-QSAR-MLP) for the virtual screening of agency-regulated chemicals as versatile anti-inflammatory therapeutics. The mtc-QSAR-MLP model displayed accuracy higher than 88%, and was interpreted from a physicochemical and structural point of view. When using the mtc-QSAR-MLP model as a virtual screening tool, we could identify several agency-regulated chemicals as dual inhibitors of caspase-1 and TNF-alpha, and the experimental information later retrieved from the scientific literature converged with our computational results. This study supports the capabilities of our mtc-QSAR-MLP model in anti-inflammatory therapy with direct applications to current health issues such as the COVID-19 pandemic.


Assuntos
Anti-Inflamatórios/farmacologia , Inibidores de Caspase/farmacologia , Reposicionamento de Medicamentos/métodos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anti-Inflamatórios/química , COVID-19/tratamento farmacológico , Caspase 1/metabolismo , Inibidores de Caspase/química , Humanos , Inflamação/tratamento farmacológico , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo
6.
Biomolecules ; 11(12)2021 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-34944419

RESUMO

A common edible mushroom Lentinula edodes, is an important source of numerous biologically active substances, including polysaccharides, with immunomodulatory and antitumor properties. In the present work, the biological activity of the crude, homogenous (Se)-enriched fraction (named Se-Le-30), which has been isolated from L. edodes mycelium by a modified Chihara method towards human peripheral blood mononuclear cells (PBMCs) and peripheral granulocytes, was investigated. The Se-Le-30 fraction, an analog of lentinan, significantly inhibited the proliferation of human PBMCs stimulated with anti-CD3 antibodies or allostimulated, and down-regulated the production of tumor necrosis factor (TNF)-α by CD3+ T cells. Moreover, it was found that Se-Le-30 significantly reduced the cytotoxic activity of human natural killer (NK) cells. The results suggested the selective immunosuppressive activity of this fraction, which is non-typical for mushroom derived polysaccharides.


Assuntos
Polissacarídeos Fúngicos/farmacologia , Leucócitos Mononucleares/citologia , Selênio/química , Cogumelos Shiitake/química , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Granulócitos/citologia , Granulócitos/efeitos dos fármacos , Granulócitos/imunologia , Humanos , Células Matadoras Naturais/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Micélio/química , Superóxidos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
7.
Biomolecules ; 11(12)2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34944539

RESUMO

Dexamethasone is widely used in preclinical studies and clinical trials to treat inner ear disorders. The results of those studies vary widely, maybe due to the different dexamethasone formulations used. Laboratory (lab) and medical grade (med) dexamethasone (DEX, C22H29FO5) and dexamethasone dihydrogen phosphate-disodium (DPS, C22H28FNa2O8P) were investigated for biocompatibility and bio-efficacy in vitro. The biocompatibility of each dexamethasone formulation in concentrations from 0.03 to 10,000 µM was evaluated using an MTT assay. The concentrations resulting in the highest cell viability were selected to perform a bio-efficiency test using a TNFα-reduction assay. All dexamethasone formulations up to 900 µM are biocompatible in vitro. DPS-lab becomes toxic at 1000 µM and DPS-med at 2000 µM, while DEX-lab and DEX-med become toxic at 4000 µM. Bio-efficacy was evaluated for DEX-lab and DPS-med at 300 µM, for DEX-med at 60 µM, and DPS-lab at 150 µM, resulting in significantly reduced expression of TNFα, with DPS-lab having the highest effect. Different dexamethasone formulations need to be applied in different concentration ranges to be biocompatible. The concentration to be applied in future studies should carefully be chosen based on the respective dexamethasone form, application route and duration to ensure biocompatibility and bio-efficacy.


Assuntos
Dexametasona/análogos & derivados , Dexametasona/farmacologia , Orelha Interna/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Dexametasona/química , Dexametasona/uso terapêutico , Relação Dose-Resposta a Droga , Composição de Medicamentos , Humanos , Camundongos , Células NIH 3T3
8.
Cells ; 10(12)2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34944055

RESUMO

Biomarkers of disease severity might help with individualizing the management of patients with acute respiratory distress syndrome (ARDS). During sepsis, a sustained decreased expression of the antigen-presenting molecule human leucocyte antigen-DR (HLA-DR) on circulating monocytes is used as a surrogate marker of immune failure. This study aimed at assessing whether HLA-DR expression on alveolar monocytes in the setting of a severe lung infection is associated with their functional alterations. BAL fluid and blood from immunocompetent patients with pneumonia-related ARDS admitted between 2016 and 2018 were isolated in a prospective monocentric study. Alveolar and blood monocytes were immunophenotyped using flow cytometry. Functional tests were performed on alveolar and blood monocytes after in vitro lipopolysaccharide (LPS) stimulation. Phagocytosis activity and intracellular tumor necrosis factor (TNF) production were quantified using fluorochrome-conjugated-specific antibodies. Ten ARDS and seven non-ARDS control patients were included. Patients with pneumonia-related ARDS exhibited significantly lower HLA-DR expression both on circulating (p < 0.0001) and alveolar (p = 0.0002) monocytes. There was no statistically significant difference observed between patient groups (ARDS vs. non-ARDS) regarding both alveolar and blood monocytes phagocytosis activity. After LPS stimulation, alveolar (p = 0.027) and blood (p = 0.005) monocytes from pneumonia-related ARDS patients had a significantly lower intracellular TNF expression than non-ARDS patients. Monocytes from pneumonia-related ARDS patients have a deactivated status and an impaired TNF production capacity but display potent phagocytic activity. HLA-DR level expression should not be used as a surrogate marker of the phagocytic activity or the TNF production capacity of alveolar monocytes.


Assuntos
Monócitos/patologia , Pneumonia/complicações , Alvéolos Pulmonares/patologia , Síndrome do Desconforto Respiratório/complicações , Adulto , Idoso , Antígeno B7-H1/metabolismo , Líquido da Lavagem Broncoalveolar , Escherichia coli/fisiologia , Feminino , Antígenos HLA-DR/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fagocitose , Pneumonia/sangue , Alvéolos Pulmonares/metabolismo , Síndrome do Desconforto Respiratório/sangue , Fator de Necrose Tumoral alfa/metabolismo
9.
Cells ; 10(12)2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34944043

RESUMO

Polysaccharides from marine organisms produce an important regulatory effect on the mammalian immune system. In this study, the immunomodulatory properties of a polysaccharide that was isolated from the coral Pseudopterogorgia americana (PPA) were investigated. PPA increased the expression levels of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), but not inducible nitric oxide synthase and nitric oxide, in macrophages. A mechanistic study revealed that PPA activated macrophages through the toll-like receptor-4 and induced the generation of reactive oxygen species (ROS), increased the phosphorylation levels of protein kinase C (PKC)-α, PKC-δ and mitogen-activated protein kinases (MAPK), and activated NF-κB. The inhibition of ROS and knockdown of PKC-α reduced PPA-mediated TNF-α and IL-6 expression; however, the knockdown of PKC-δ significantly increased PPA-mediated TNF-α expression. In addition, the inhibition of c-Jun N-terminal kinase-1/2 and NF-κB reduced PPA-mediated TNF-α, IL-6 and COX-2 expression. Furthermore, the inhibition of ROS, MAPK and PKC-α/δ reduced PPA-mediated NF-κB activation, indicating that ROS, MAPK and PKC-α/δ function as upstream signals of NF-κB. Finally, PPA treatment decreased the phagocytosis activity of macrophages and reduced cytokine expression in bacteria-infected macrophages. Taken together, our current findings suggest that PPA can potentially play a role in the development of immune modulators in the future.


Assuntos
Antozoários/química , Fatores Imunológicos/farmacologia , Macrófagos/imunologia , Polissacarídeos/farmacologia , Animais , Ciclo-Oxigenase 2/metabolismo , Citocinas/biossíntese , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fagocitose/efeitos dos fármacos , Polissacarídeos/química , Proteína Quinase C-alfa/metabolismo , Proteína Quinase C-delta/metabolismo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Células THP-1 , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
10.
Cells ; 10(12)2021 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-34943917

RESUMO

Adipocytes interact with adipose tissue macrophages (ATMs) that exist as a form of M2 macrophage in healthy adipose tissue and are polarized into M1 macrophages upon cellular stress. ATMs regulate adipose tissue inflammation by secreting cytokines, adipokines, and chemokines. CXC-motif receptor 6 (CXCR6) is the chemokine receptor and interactions with its specific ligand CXC-motif chemokine ligand 16 (CXCL16) modulate the migratory capacities of human adipose-derived mesenchymal stem cells (hADMSCs). CXCR6 is highly expressed on differentiated adipocytes that are non-migratory cells. To evaluate the underlying mechanisms of CXCR6 in adipocytes, THP-1 human monocytes that can be polarized into M1 or M2 macrophages were co-cultured with adipocytes. As results, expression levels of the M1 polarization-inducing factor were decreased, while those of the M2 polarization-inducing factor were significantly increased in differentiated adipocytes in a co-cultured environment with additional CXCL16 treatment. After CXCL16 treatment, the anti-inflammatory factors, including p38 MAPK ad ERK1/2, were upregulated, while the pro-inflammatory pathway mediated by Akt and NF-κB was downregulated in adipocytes in a co-cultured environment. These results revealed that the CXCL16/CXCR6 axis in adipocytes regulates M1 or M2 polarization and displays an immunosuppressive effect by modulating pro-inflammatory or anti-inflammatory pathways. Our results may provide an insight into a potential target as a regulator of the immune response via the CXCL16/CXCR6 axis in adipocytes.


Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Polaridade Celular , Quimiocina CXCL16/metabolismo , Macrófagos/citologia , Células-Tronco Mesenquimais/citologia , Receptores CXCR6/metabolismo , Biomarcadores/metabolismo , Células Cultivadas , Humanos , Inflamação/patologia , Interleucina-10/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais , Células THP-1 , Fator de Necrose Tumoral alfa/metabolismo
11.
Medicine (Baltimore) ; 100(41): e27531, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34731147

RESUMO

ABSTRACT: To evaluate the relationship between uterine cesarean scar diverticulum (CSD) and subsequent infertility in patients who underwent cesarean section, and determine the effects of pelvic fluid-releasing inflammations on infertility.A retrospective analysis was designed among patients with CSD who were admitted to our hospital from January 1, 2018 to December 31, 2019. A total of 60 patients with CSD and uterine fibroids or benign ovarian tumors who underwent cesarean section were included, and divided into the CSD group and control group. Baseline characteristics of all patients were collected, and the pelvic adhesion scores and the percents of tubal patency were evaluated. Furthermore, the postoperative clinical outcomes were followed up. The levels of inflammatory factors in pelvic fluid were tested using Elisa kits.Preoperative data indicated that the size of the uterine scar diverticulum was (1.68 ±â€Š0.52) cm, the pelvic adhesion scores were higher in CSD group than control group (4.67 ±â€Š0.90 vs 0.47 ±â€Š0.90, P < .05), and 21 of 30 patients with unobstructed fallopian tubes. The levels of tumor necrosis factor-α, interleukin-1ß, and interleukin-6 in patients with CSD were obviously higher than control group (P < .05). After the follow-up, the data displayed that no CSD was found in all patients, the time of menstrual period in patients with CSD was shortened to 7.80 ±â€Š1.27 days, and the myometrial thickness at uterine scar was significantly increased (P < .05). Additionally, the pregnancy rate was increased, and 12 of 30 patients were repregnant. Correlation analysis showed that the levels of inflammatory factors (tumor necrosis factor-α, interleukin-1ß, interleukin-6), the size of uterine scar diverticulum, and the myometrial thickness at uterine scar were significantly correlated with subsequent infertility (r = 0.307, 0.083, 0.147, 0.405, 0.291, P < .05).Uterine scar diverticulum repair could improve menstrual prolongation, increased the thickness of myometrium and repregnant rate. Subsequent infertility was positively correlated with uterine scar diverticulum and the levels of inflammatory factors.


Assuntos
Cesárea/efeitos adversos , Cicatriz/patologia , Divertículo/complicações , Infertilidade/etiologia , Miométrio/patologia , Adulto , Estudos de Casos e Controles , China/epidemiologia , Divertículo/cirurgia , Feminino , Seguimentos , Humanos , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Leiomioma/patologia , Leiomioma/cirurgia , Menstruação/fisiologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Período Pós-Operatório , Gravidez , Taxa de Gravidez/tendências , Estudos Retrospectivos , Fator de Necrose Tumoral alfa/metabolismo , Útero/patologia , Útero/cirurgia
12.
Front Immunol ; 12: 667875, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603277

RESUMO

Translational research on immune checkpoint inhibitors (ICIs) has been underway. However, in the unselected population, only a few patients benefit from ICIs. Therefore, screening predictive markers of ICI efficacy has become the current focus of attention. We collected mutation and clinical data from an ICI-treated non-small cell lung cancer (NSCLC) cohort. Then, a univariate Cox regression model was used to analyze the relationship between tumor necrosis factor α signaling mutated (TNFα-MT) and the prognosis of immunotherapy for NSCLC. We retrospectively collected 36 NSCLC patients (local-cohort) from the Zhujiang Hospital of Southern Medical University and performed whole-exome sequencing (WES). The expression and mutation data of The Cancer Genome Atlas (TCGA)-NSCLC cohort were used to explore the association between TNFα-MT and the immune microenvironment. A local cohort was used to validate the association between TNFα-MT and immunogenicity. TNFα-MT was associated with significantly prolonged overall survival (OS) in NSCLC patients after receiving immunotherapy. Additionally, TNFα-MT is related to high immunogenicity (tumor mutational burden, neoantigen load, and DNA damage response signaling mutations) and enrichment of infiltrating immune cells. These results suggest that TNFα-MT may serve as a potential clinical biomarker for NSCLC patients receiving ICIs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/etiologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/etiologia , Modelos Biológicos , Terapia de Alvo Molecular , Mutação , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
13.
Ecotoxicol Environ Saf ; 226: 112851, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34619480

RESUMO

Long-term excessive intake of fluoride (F) can cause osseous and non-osseous damage. The kidney is the main fluoride excretion organ of the body. This study aimed to explore whether dietary calcium (Ca) supplementation can alleviate kidney damage caused by fluorosis and to further investigate the effects of Ca on the mitigation mechanism of renal cell apoptosis triggered by F. We evaluated the histopathological structure, renal function indicators, and gene and protein expression levels of death receptor-mediated apoptosis pathways in Sprague Dawley (SD) rats treated with sodium fluoride (NaF) and/or calcium carbonate (CaCO3) for 120 days. The results showed that 100 mg/L NaF induced kidney histopathological injury and apoptosis, increased the concentrations of Creatinine (CRE), uric acid (UA), blood urea nitrogen (BUN), potassium (K), phosphorus (P) and F (p < 0.05), and decrease the level of serum magnesium (Mg) (p < 0.05). Moreover, NaF increased the mRNA and protein expression levels of Fas cell surface death receptor (FAS), tumor necrosis factor (TNF), TNF-related apoptosis-inducing ligand (TRAIL), Caspase 8, Caspase 3 and poly ADP-ribose polymerase (PARP) (p < 0.01), which finally activated the death receptor pathway. Inversely, Ca supplementation reversed the decrease of CRE, BUN, UA, F and P levels induced by F, alleviated histopathological damage and apoptosis, and reduced the gene and protein expression levels of death receptor pathway-related markers. In conclusion, 1% Ca alleviates F-induced kidney apoptosis through FAS/FASL, TNFR/TNF, DR5/TRAIL signaling pathways.


Assuntos
Cálcio , Fluoretos , Animais , Apoptose , Cálcio/metabolismo , Cálcio na Dieta , Caspase 8 , Proteína Ligante Fas/genética , Fluoretos/toxicidade , Rim/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
14.
Chem Biol Interact ; 349: 109681, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34600870

RESUMO

Irigenin, an isoflavonoid isolated from the rhizome of Belamcanda chinensis, possess various pharmacological effects. However, the effect and mechanism of irigenin on intervertebral disc degeneration (IDD) remain unclear. The potential targets of irigenin or disease were predicted using PharmMapper or GeneCards databases, respectively. The overlapping targets were inputted into the String database to establish protein-protein interaction (PPI) network. The overlapping targets were also submitted to DAVID webserver to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Nucleus pulposus (NP) cells were exposed to 10 ng/mL tumor necrosis factor-α (TNF-α) to establish a cell model of IDD. Cell viability, LDH content, apoptosis and caspase-3 activity were evaluated by CCK-8, LDH release, TUNEL, and caspase-3 activity assays, respectively. The expression of collagen II, aggrecan, matrix metalloproteinase (MMP)-2, MMP-3, MMP-9, and MMP-13 were detected by qRT-PCR and western blot analyses. The network analysis revealed that MMP-2, MMP-3, MMP-9, MMP-13, caspase-3 (CASP3), vitamin D receptor (VDR), insulin-like growth factor 1 (IGF1), and transforming growth factor beta2 (TGFB2) play key roles in the effect of irigenin against IDD. TNF-α stimulation inhibited cell viability and increased LDH content, apoptosis, caspase-3 expression and caspase-3 activity in NP cells, which were reversed by irigenin treatment. TNF-α stimulation inhibited the expression of collagen II and aggrecan and upregulated MMPs (MMP-2, MMP-3, MMP-9, and MMP-13) in NP cells, while such changes were abolished by irigenin treatment. In conclusion, irigenin suppressed apoptosis and ECM degradation in TNF-α-stimulated NP cells by reducing the expression of caspase-3 and MMPs.


Assuntos
Caspase 3/metabolismo , Matriz Extracelular/metabolismo , Isoflavonas/fisiologia , Metaloproteinases da Matriz/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Células Cultivadas , Humanos
15.
Nat Commun ; 12(1): 6053, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663829

RESUMO

Tumor necrosis factor (TNF) is one of the few cytokines successfully targeted by therapies against inflammatory diseases. However, blocking this well studied and pleiotropic ligand can cause dramatic side-effects. Here, we reason that a systems-level proteomic analysis of TNF signaling could dissect its diverse functions and offer a base for developing more targeted therapies. Therefore, we combine phosphoproteomics time course experiments with subcellular localization and kinase inhibitor analysis to identify functional modules of protein phosphorylation. The majority of regulated phosphorylation events can be assigned to an upstream kinase by inhibiting master kinases. Spatial proteomics reveals phosphorylation-dependent translocations of hundreds of proteins upon TNF stimulation. Phosphoproteome analysis of TNF-induced apoptosis and necroptosis uncovers a key role for transcriptional cyclin-dependent kinase activity to promote cytokine production and prevent excessive cell death downstream of the TNF signaling receptor. This resource of TNF-induced pathways and sites can be explored at http://tnfviewer.biochem.mpg.de/ .


Assuntos
Quinases Ciclina-Dependentes/metabolismo , Proteoma/metabolismo , Transdução de Sinais , Células A549 , Apoptose , Morte Celular , Linhagem Celular , Citocinas/metabolismo , Humanos , Necroptose , Fosforilação , Fator de Necrose Tumoral alfa/metabolismo , Células U937
16.
J Immunol ; 207(10): 2405-2410, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34654691

RESUMO

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) causes severe acute respiratory syndrome. mRNA vaccines directed at the SARS-CoV-2 spike protein resulted in development of Abs and protective immunity. To determine the mechanism, we analyzed the kinetics of induction of circulating exosomes with SARS-CoV-2 spike protein and Ab following vaccination of healthy individuals. Results demonstrated induction of circulating exosomes expressing spike protein on day 14 after vaccination followed by Abs 14 d after the second dose. Exosomes with spike protein, Abs to SARS-CoV-2 spike, and T cells secreting IFN-γ and TNF-α increased following the booster dose. Transmission electron microscopy of exosomes also demonstrated spike protein Ags on their surface. Exosomes with spike protein and Abs decreased in parallel after four months. These results demonstrate an important role of circulating exosomes with spike protein for effective immunization following mRNA-based vaccination. This is further documented by induction of humoral and cellular immune responses in mice immunized with exosomes carrying spike protein.


Assuntos
Anticorpos Antivirais/metabolismo , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Exossomos/metabolismo , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Linfócitos T/metabolismo , Animais , Circulação Sanguínea , Células Cultivadas , Exossomos/imunologia , Voluntários Saudáveis , Humanos , Imunização , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Vacinação
17.
Molecules ; 26(19)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34641380

RESUMO

Endothelial dysfunction and inflammation are recognised factors in the development of atherosclerosis. Evidence suggests that intake of industrial trans fatty acids (TFAs) promotes endothelial dysfunction, while ruminant TFAs may have the opposite effect. The aim of this study was to compare the effects of elaidic acid (EA (18:1n-9t); an industrially produced TFA) and trans vaccenic acid (TVA (18:1n-7t); a natural TFA found in ruminant milk and meat) on inflammatory responses of endothelial cells (ECs). ECs (EA.hy926 cells) were cultured under standard conditions and exposed to TFAs (1 to 50 µM) for 48 h. Then, the cells were cultured for a further 6 or 24 h with tumour necrosis factor alpha (TNF-α, 1 ng/mL) as an inflammatory stimulant. ECs remained viable after treatments. TFAs were incorporated into ECs in a dose-dependent manner. Preincubation with EA (50 µM) increased production of MCP-1, RANTES, and IL-8 in response to TNF-α, while preincubation with TVA (1 µM) decreased production of ICAM-1 and RANTES in response to TNF-α. Preincubation with EA (50 µM) upregulated toll-like receptor 4 and cyclooxygenase 2 gene expression in response to TNF-α. In contrast, preincubation with TVA (1 µM) downregulated TNF-α induced nuclear factor kappa B subunit 1 gene expression. Preincubation of ECs with EA (50 µM) increased THP-1 monocyte adhesion. In contrast, preincubation of ECs with TVA (1 µM) reduced THP-1 monocyte adhesion, while preincubation of ECs with TVA (50 µM) decreased the level of surface expression of ICAM-1 seen following TNF-α stimulation. The results suggest that TVA has some anti-inflammatory properties, while EA enhances the response to an inflammatory stimulus. These findings suggest differential effects induced by the TFAs tested, fitting with the idea that industrial TFAs and ruminant TFAs can have different and perhaps opposing biological actions in an inflammatory context.


Assuntos
Anti-Inflamatórios/farmacologia , Radioisótopos de Carbono/análise , Endotélio Vascular/imunologia , Inflamação/imunologia , Ácidos Oleicos/farmacologia , Ruminantes/metabolismo , Ácidos Graxos trans/farmacologia , Animais , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
18.
Int J Mol Sci ; 22(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34638740

RESUMO

It is known that both psoriasis (PSO) limited to the skin and psoriatic arthritis (PSA) increase the risk of cardiovascular complications and atherosclerosis progression by inducing systemic inflammatory response. In recent decades, the introduction of biological medications directed initially against TNF-α and, later, different targets in the inflammatory cascade brought a significant breakthrough in the efficacy of PSO/PSA treatment. In this review, we present and discuss the most recent findings related to the interplay between the genetics and immunology mechanisms involved in PSO and PSA, atherosclerosis and the development of cardiac dysfunction, as well as the current PSO/PSA treatment in view of cardiovascular safety and prognosis.


Assuntos
Artrite Psoriásica , Aterosclerose , Produtos Biológicos/uso terapêutico , Pele , Artrite Psoriásica/complicações , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/metabolismo , Artrite Psoriásica/patologia , Aterosclerose/etiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Humanos , Pele/metabolismo , Pele/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
19.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638889

RESUMO

The response to DNA damage is the mechanism that allows the interaction between stress signals, inflammatory secretions, DNA repair, and maintenance of cell and tissue homeostasis. Adipocyte dysfunction is the cellular trigger for various disease states such as insulin resistance, diabetes, and obesity, among many others. Previously, our group demonstrated that adipogenesis per se, from mesenchymal/stromal stem cells derived from human adipose tissue (hASCs), involves an accumulation of DNA damage and a gradual loss of the repair capacity of oxidative DNA damage. Therefore, our objective was to identify whether healthy adipocytes differentiated for the first time from hASCs, when receiving inflammatory signals induced with TNFα, were able to persistently activate the DNA Damage Response and thus trigger adipocyte dysfunction. We found that TNFα at similar levels circulating in obese humans induce a sustained response to DNA damage response as part of the Senescence-Associated Secretory Phenotype. This mechanism shows the impact of inflammatory environment early affect adipocyte function, independently of aging.


Assuntos
Adipócitos/metabolismo , Diferenciação Celular , Dano ao DNA , Fator de Necrose Tumoral alfa/metabolismo , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaio Cometa/métodos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
20.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638941

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. An accumulation of fat, followed by inflammation, is the major cause of NAFLD progression. During inflammation, macrophages are the most abundant immune cells recruited to the site of injury. Macrophages are classified into "proinflammatory" M1 macrophages, and "anti-inflammatory" M2 macrophages. In NAFLD, M1 macrophages are the most prominent macrophages that lead to an excessive inflammatory response. Previously, we found that baicalin could polarize macrophages into anti-inflammatory M2c subtype macrophages with an increased level of MERTK expression. Several studies have also shown a strong correlation between MERTK expression and cholesterol efflux, efferocytosis, as well as phagocytosis capability. Therefore, in this study, we aim to elucidate the potential and efficacy of mononuclear-cell (MNC)-derived MERTK+/hi M2c macrophages induced by baicalin as a cell-based therapy for NAFLD treatment. In our results, we have demonstrated that a MERTK+/hi M2c macrophage injection to NAFLD mice contributes to an increased level of serum HDL secretion in the liver, a decline in the circulating CD4+CD25- and CD8+CD25- T cells and lowers the total NAFLD pathological score by lessening the inflammation, necrosis, and fibrosis. In the liver, profibrotic COL1A1 and FN, proinflammation TNFα, as well as the regulator of lipid metabolism PPARÉ£ expression, were also downregulated after injection. In parallel, the transcriptomic profiles of the injected MERTK+/hi M2c macrophages showed that the various genes directly or indirectly involved in NAFLD progression (e.g., SERPINE1, FADS2) were also suppressed. Downregulation of cytokines and inflammation-associated genes, such as CCR5, may promote a pro-resolving milieu in the NAFLD liver. Altogether, cell-based therapy using MERTK+/hi M2c macrophages is promising, as it ameliorates NAFLD in mice.


Assuntos
Transferência Adotiva/métodos , Transplante de Células/métodos , Flavonoides/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/transplante , Hepatopatia Gordurosa não Alcoólica/terapia , Transdução de Sinais/efeitos dos fármacos , c-Mer Tirosina Quinase/metabolismo , Animais , Colágeno Tipo I/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Lipoproteínas HDL/sangue , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/genética , PPAR gama/metabolismo , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Transcriptoma , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo
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