Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 13.437
Filtrar
1.
Medicine (Baltimore) ; 101(35): e29554, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36107502

RESUMO

BACKGROUND: Coronavirus (CoV) disease (COVID-19) identified in Wuhan, China, in 2019, is mainly characterized by atypical pneumonia and severe acute respiratory syndrome (SARS) and is caused by SARS CoV-2, which belongs to the Coronaviridae family. Determining the underlying disease mechanisms is central to the identification and development of COVID-19-specific drugs for effective treatment and prevention of human-to-human transmission, disease complications, and deaths. METHODS: Here, next-generation RNA sequencing (RNA Seq) data were obtained using Illumina Next Seq 500 from SARS CoV-infected A549 cells and mock-treated A549 cells from the Gene Expression Omnibus (GEO) (GSE147507), and quality control (QC) was assessed before RNA Seq analysis using CLC Genomics Workbench 20.0. Differentially expressed genes (DEGs) were imported into BioJupies to decipher COVID-19 induced signaling pathways and small molecules derived from chemical synthesis or natural sources to mimic or reverse COVID -19 specific gene signatures. In addition, iPathwayGuide was used to identify COVID-19-specific signaling pathways, as well as drugs and natural products with anti-COVID-19 potential. RESULTS: Here, we identified the potential activation of upstream regulators such as signal transducer and activator of transcription 2 (STAT2), interferon regulatory factor 9 (IRF9), and interferon beta (IFNß), interleukin-1 beta (IL-1ß), and interferon regulatory factor 3 (IRF3). COVID-19 infection activated key infectious disease-specific immune-related signaling pathways such as influenza A, viral protein interaction with cytokine and cytokine receptors, measles, Epstein-Barr virus infection, and IL-17 signaling pathway. Besides, we identified drugs such as prednisolone, methylprednisolone, diclofenac, compound JQ1, and natural products such as Withaferin-A and JinFuKang as candidates for further experimental validation of COVID-19 therapy. CONCLUSIONS: In conclusion, we have used the in silico next-generation knowledge discovery (NGKD) methods to discover COVID-19-associated pathways and specific therapeutics that have the potential to ameliorate the disease pathologies associated with COVID-19.


Assuntos
Produtos Biológicos , COVID-19 , Infecções por Vírus Epstein-Barr , Células A549 , COVID-19/tratamento farmacológico , Citocinas/metabolismo , Diclofenaco , Herpesvirus Humano 4/genética , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/genética , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/metabolismo , Interferon beta , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Metilprednisolona , RNA , Receptores de Citocinas/genética , SARS-CoV-2/genética , Fator de Transcrição STAT2 , Análise de Sequência de RNA , Proteínas Virais/genética
2.
Sci Rep ; 12(1): 15123, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068262

RESUMO

Brucellosis is a zoonotic disease caused by Brucella abortus. An efficient immune response is crucial for curing brucellosis. The inflammasome plays a significant role in the immune response. It is unclear which inflammasome is active in acute and chronic brucellosis and how its levels relate to inflammatory cytokines. A total of 40 patients with acute or chronic brucellosis and 20 healthy volunteers had peripheral blood samples collected. The expression levels of AIM2, NLRP3, ASC, and Caspase-1 were determined by a real-time polymerase chain reaction from RNA and serum samples, and IL-1ß, IL-18, and IFN-γ were measured by enzyme-linked immunosorbent assay. In the acute brucellosis group, AIM2 expression was significantly higher, while ACS expression was significantly lower than that of healthy volunteers. In patients with chronic brucellosis, AIM2 expression was significantly lower, while Caspase-1 expression was significantly higher than that of healthy volunteers. Serum IL-18 and IFN-γ levels were significantly higher in patients with acute brucellosis than in healthy controls. The IFN-γ level was also significantly higher in patients with chronic brucellosis than in healthy controls. The inflammasome responds differently in different stages of brucellosis. The inflammasome may be the site of action of immune escape in brucellosis.


Assuntos
Brucelose , Inflamassomos , Caspase 1/metabolismo , China , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Imunidade Inata , Inflamassomos/metabolismo , Interleucina-18 , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
3.
Arthritis Res Ther ; 24(1): 216, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068644

RESUMO

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disease. Extracellular matrix (ECM) degradation is essential for OA progression. Previous studies have shown that circular RNAs (circRNAs) are involved in the pathological process of OA. CircPRKCH has been shown to be upregulated in OA chondrocytes. The present study was aimed to explore the roles of circPRKCH in vivo and in vitro models of OA and its underlying molecular mechanisms. METHODS: IL-1ß-induced chondrocytes and mice injected with monosodium iodoacetate were used as OA models in vitro and in vivo, respectively. RT-qPCR was performed to measure the expression of circPRKCH, miR-145, and HGF in cartilage tissues and chondrocytes. The interaction between miR-145 and circPRKCH or HGF was verified by a dual-luciferase reporter assay. Chondrocyte apoptosis, viability, and ECM-related proteins were examined by flow cytometry, MTT assay, and Western blotting, respectively. Histopathological changes were detected by HE and Safranin O-fast green staining. RESULTS: The expression of circPRKCH and HGF was increased in OA cartilage tissues and IL-1ß-treated chondrocytes, while miR-145 expression was decreased. IL-1ß induced chondrocyte apoptosis and ECM degradation in chondrocytes. Moreover, circPRKCH promoted HGF expression and activated HGF/c-MET by directly binding to miR-145. miR-145 knockdown or HGF overexpression significantly reversed circPRKCH knockdown-mediated inhibition of apoptosis and ECM degradation in IL-1ß-induced chondrocytes. Besides, miR-145 overexpression alleviated IL-1ß-induced chondrocyte apoptosis and ECM degradation by inhibiting HGF/c-MET. Finally, circPRKCH knockdown reduced ECM degradation by regulating the miR-145/HGF axis in an experimental OA model in mice. CONCLUSION: Our study demonstrated that circPRKCH promoted chondrocyte apoptosis and ECM degradation via the miR-145/HGF axis in OA, which may provide a novel target for OA treatment.


Assuntos
MicroRNAs , Osteoartrite , Animais , Apoptose/genética , Cartilagem/metabolismo , Condrócitos/metabolismo , Matriz Extracelular/metabolismo , Interleucina-1beta/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoartrite/metabolismo
4.
Front Immunol ; 13: 945513, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119028

RESUMO

This systematic review aimed to investigate immune-inflammatory and hypothalamic-pituitary-adrenal (HPA) axis biomarkers in individuals with non-specific low back pain (NSLBP) compared to healthy control. The search was performed in five databases until 4 November 2021. Two reviewers independently conducted screenings, data extraction, risk of bias, and methodological quality assessment of 14 unique studies. All studies reported the source of the fluid analyzed: nine studies used serum, two used plasma, one used serum and plasma, and two studies used salivary cortisol. We found preliminary and limited evidence (only one study for each biomarker) of increased levels in growth differentiation factor 15 (GDF-15), interleukin-23 (IL-23), transforming growth factor-beta (TGF-ß), and soluble tumor necrosis factor receptor 1 (sTNF-R1) in NSLBP. Inconsistent and limited evidence was identified for interleukin-10 (IL-10). Although C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels appear to increase in NSLBP, only one study per each biomarker reported statistically significant differences. Interleukin-1 beta (IL-1ß), interleukin-17 (IL-17), interferon gamma (IFN-γ), and high-sensitivity CRP (hsCRP) showed no significant differences. Regarding cortisol, one study showed a significant increase and another a significant decrease. More robust evidence between GDF-15, IL-23, TGF-ß, and sTNF-R1 with NSLBP is needed. Moreover, contrary to the findings reported in previous studies, when comparing results exclusively with healthy control, insufficient robust evidence for IL-6, TNF-α, and CRP was found in NSLBP. In addition, cortisol response (HPA-related biomarker) showed a dysregulated functioning in NSLBP, with incongruent evidence regarding its directionality. Therefore, our effort is to find adjusted evidence to conclude which immune-inflammatory and HPA axis biomarkers are altered in NSLBP and how much their levels are affected. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020176153, identifier CRD42020176153.


Assuntos
Dor Lombar , Sistema Hipófise-Suprarrenal , Biomarcadores , Proteína C-Reativa/metabolismo , Fator 15 de Diferenciação de Crescimento/metabolismo , Humanos , Hidrocortisona , Sistema Hipotálamo-Hipofisário/metabolismo , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Interleucina-23/metabolismo , Interleucina-6/metabolismo , Dor Lombar/diagnóstico , Sistema Hipófise-Suprarrenal/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fatores de Crescimento Transformadores/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Front Immunol ; 13: 955175, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119099

RESUMO

Chronic inflammation is widely observed in aging, but it is unclear whether extracellular vesicles (EVs) play a role in chronic disease-associated senescence. In our study, LC/MS profiling revealed that senescent cell derived EVs (SEN EVs) activate the immune response pathways of macrophages. Significantly more EVs were found in the supernatant of SEN than of control (CON) cell cultures, and SEN EVs were enriched in miR-30b-5p, which directly target sirtuin1 (SIRT1). In vitro, we found that SEN EV treatment resulted in increased cellular levels of interleukin-1ß (IL-1ß) and IL-6 and decreased levels of SIRT1. Increased cytokine levels could be reversed by SIRT1 activation and miR-30b-5p inhibition. Furthermore, miR-30b-5p significantly increased with age in both mouse liver tissue and EVs harvested from the tissue, with differences in EVs observed both earlier and in the later magnitude of aging. Western blot and qPCR proved that miR-30b-5p downregulated the level of SIRT1 in mouse macrophages. Collectively, we propose that EVs carrying miR-30b-5p from SEN cells can induce chronic inflammation through macrophage activation. This occurs through the downregulation of SIRT1 and the corresponding activation of NF-κB pathways that enhance pro-inflammatory cytokine production. Collectively, these results demonstrate that EVs carrying pro-inflammatory signals are released by SEN cells and then activate immune cells in the SEN microenvironment, changing the inflammatory balance. Our results also explain why inflammation increases with age even though SEN cells can be immediately eliminated under rigorous immune surveillance.


Assuntos
Vesículas Extracelulares , MicroRNAs , Animais , Senescência Celular , Citocinas/metabolismo , Vesículas Extracelulares/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Macrófagos/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo
6.
Food Chem Toxicol ; 168: 113400, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36055550

RESUMO

Exposure to acrolein, one environmental and dietary pollutant, has been shown to cause inflammation. Here, we reported for the first time that acrolein aggravated lipopolysaccharide (LPS)-induced inflammation in Human umbilical vein endothelial cells (HUVEC) as evidenced by the further increased mRNA expression of three pro-inflammatory cytokines, including interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Acrolein also further increased the generation of reactive oxygen species (ROS) and decreased the activity of glutathione peroxidase (GSH-Px) in LPS-pretreated HUVEC. Moreover, acrolein treatment further increased the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) and apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) expression, caspase-1 cleavage, and downstream matures interleukin 18 (IL-18) and IL-1ß level in LPS-pretreated HUVEC. Acrolein treatment also further increased the expressions of high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and phospho-NF-κB P65 (P-P65) in the LPS pre-treated HUVEC. Thus, acrolein aggravated LPS-induced HUVEC inflammation through induction of oxidative stress, and activation of NLRP3 inflammasome and HMGB1/MYD88/NF-κB signaling pathway. In addition, apigenin and apigenin-7, 4'-O-dioctanoate attenuated acrolein-aggravated inflammation by targeting the above signaling pathways. Our findings could help to develop potential therapeutic strategies against acrolein-enhanced inflammation.


Assuntos
Poluentes Ambientais , Proteína HMGB1 , Acroleína/toxicidade , Apigenina , Caspase 1/genética , Glutationa Peroxidase/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamassomos/metabolismo , Inflamação/induzido quimicamente , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nucleotídeos/metabolismo , RNA Mensageiro/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
7.
Front Immunol ; 13: 832306, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091026

RESUMO

Neutrophils play major roles against bacteria and fungi infections not only due to their microbicide properties but also because they release mediators like Interleukin-1 beta (IL-1ß) that contribute to orchestrate the inflammatory response. This cytokine is a leaderless protein synthesized in the cytoplasm as a precursor (pro-IL-1ß) that is proteolytically processed to its active isoform and released from human neutrophils by secretory autophagy. In most myeloid cells, pro-IL-1ß is processed by caspase-1 upon inflammasome activation. Here we employed neutrophils from both healthy donors and patients with a gain-of-function (GOF) NLRP3-mutation to dissect IL-1ß processing in these cells. We found that although caspase-1 is required for IL-1ß secretion, it undergoes rapid inactivation, and instead, neutrophil serine proteases play a key role in pro-IL-1ß processing. Our findings bring to light distinctive features of the regulation of caspase-1 activity in human neutrophils and reveal new molecular mechanisms that control human neutrophil IL-1ß secretion.


Assuntos
Neutrófilos , Serina Proteases , Autofagia , Caspase 1/metabolismo , Humanos , Interleucina-1beta/metabolismo , Neutrófilos/metabolismo , Serina Endopeptidases , Serina Proteases/genética
8.
Front Immunol ; 13: 935692, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35983049

RESUMO

Murine macrophages activated by the Toll-like receptor 4 agonist lipopolysaccharide (LPS) polarize to the M1 type by inducing proinflammatory marker proteins and changing their energy metabolism to increased aerobic glycolysis and reduced respiration. We here show that the aliphatic isothiocyanate sulforaphane (Sfn) diminishes M1 marker expression (IL-1ß, IL-6, TNF-α, iNOS, NO, and ROS) and leads to highly energetic cells characterized by both high glycolytic and high respiratory activity as assessed by extracellular flux analysis. Focusing on a potential connection between high glycolytic activity and low IL-1ß expression in M1 (LPS/Sfn) macrophages, we reveal that Sfn impedes the moonlighting function of pyruvate kinase M2 (PKM2) in M1 macrophages. Sfn limits mono/dimerization and nuclear residence of PKM2 accompanied by reduced HIF-1α levels, Stat3 phosphorylation at tyrosine 705, and IL-1ß expression while preserving high levels of cytosolic PKM2 tetramer with high glycolytic enzyme activity. Sfn prevents glutathionylation of PKM2 in LPS-stimulated macrophages which may account for the reduced loss of PKM2 tetramer. Overall, we uncover PKM2 as a novel affected hub within the anti-inflammatory activity profile of Sfn.


Assuntos
Interleucina-1beta , Isotiocianatos , Macrófagos , Piruvato Quinase , Sulfóxidos , Animais , Interleucina-1beta/metabolismo , Isotiocianatos/farmacologia , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Piruvato Quinase/metabolismo , Sulfóxidos/farmacologia
10.
Shock ; 58(1): 56-67, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35984761

RESUMO

ABSTRACT: Objectives: Nucleus pulposus (NP) cell degeneration promotes the progression of intervertebral disc (IVD) degeneration. MicroRNAs (miRs) are associated with IVD degeneration. This study expounded the mechanism of microRNA (miR)-25-3p carried by extracellular vesicles (EVs) derived from platelet-rich plasma (PRP) in interleukin (IL)-1ß-induced NP cell degeneration. Methods: Platelet-rich plasma from mouse blood was obtained, and EVs were isolated from PRP (EVs derived from PRP [PRP-EVs]) and identified. Nucleus pulposus cells were isolated from the mouse lumbar IVD and treated with IL-1ß to induce NP cell degeneration. Extracellular vesicles derived from PRP were added into NP cell culture medium. Afterward, intracellular miR-25-3p, sex determining region Y-related high-mobility-group box 4 (SOX4), and CXC chemokine receptor 7 (CXCR7) levels were examined. Nucleus pulposus cell viability, apoptosis, and inflammation were detected. Extracellular vesicles derived from PRP were labeled by PKH67 to obverse the uptake of EVs by NP cells. The binding relations between SOX4 and miR-25-3p and CXCR7 were predicted and examined. Functional rescue experiments were performed to investigate the roles of miR-25-3p, SOX4, and CXCR7 in NP cell degeneration. Results: miR-25-3p was downregulated, whereas SOX4 and CXCR7 were upregulated in IL-1ß-induced NP cells. Extracellular vesicles derived from PRP increased the cell viability, and decreased apoptosis and inflammation. miR-25-3p carried by PRP-EVs into NP cells alleviated NP cell degeneration. miR-25-3p inhibited SOX4 expression and limited CXCR7 transcription. Silencing miR-25-3p or overexpressing SOX4 or CXCR7 reversed the alleviating role of PRP-EVs in NP cell degeneration. Conclusion: miR-25-3p carried by PRP-EVs into NP cells elevated intracellular miR-25-3p expression, which suppressed SOX4 expression and further limited CXCR7 transcription, thus alleviating IL-1ß-induced NP cell degeneration. Extracellular vesicles derived from PRP containing miR-25-3p may be a new method for IVD treatment.


Assuntos
Vesículas Extracelulares , Degeneração do Disco Intervertebral , MicroRNAs , Núcleo Pulposo , Plasma Rico em Plaquetas , Receptores CXCR , Animais , Apoptose/genética , Vesículas Extracelulares/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacologia , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/terapia , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Núcleo Pulposo/metabolismo , Plasma Rico em Plaquetas/metabolismo , Receptores CXCR/metabolismo , Fatores de Transcrição SOXC/metabolismo
11.
Int J Mol Sci ; 23(16)2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-36012214

RESUMO

Osteoarthritis (OA) is a degenerative and heterogeneous disease that affects all types of joint structures. Current clinical treatments are only symptomatic and do not manage the degenerative process in animals or humans. One of the new orthobiological treatment strategies being developed to treat OA is the use of drug delivery systems (DDS) to release bioactive molecules over a long period of time directly into the joint to limit inflammation, control pain, and reduce cartilage degradation. Two vasoactive peptides, endothelin-1 and bradykinin, play important roles in OA pathogenesis. In this study, we investigated the effects of two functionalized nanogels as DDS. We assessed the effect of chitosan functionalized with a type A endothelin receptor antagonist (BQ-123-CHI) and/or hyaluronic acid functionalized with a type B1 bradykinin receptor antagonist (R-954-HA). The biocompatibility of these nanogels, alone or in combination, was first validated on equine articular chondrocytes cultured under different oxic conditions. Further, in an OA equine organoid model via induction with interleukin-1 beta (IL-1ß), a combination of BQ-123-CHI and R-954-HA (BR5) triggered the greatest decrease in inflammatory and catabolic markers. In basal and OA conditions, BQ-123-CHI alone or in equimolar combinations with R-954-HA had weak pro-anabolic effects on collagens synthesis. These new nanogels, as part of a composite DDS, show promising attributes for treating OA.


Assuntos
Cartilagem Articular , Osteoartrite , Animais , Antagonistas dos Receptores da Bradicinina/metabolismo , Antagonistas dos Receptores da Bradicinina/farmacologia , Antagonistas dos Receptores da Bradicinina/uso terapêutico , Cartilagem/metabolismo , Cartilagem Articular/metabolismo , Células Cultivadas , Condrócitos/metabolismo , Endotelina-1/metabolismo , Cavalos , Humanos , Interleucina-1beta/metabolismo , Nanogéis , Organoides/metabolismo , Osteoartrite/metabolismo
12.
Am J Vet Res ; 83(10)2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-35986909

RESUMO

OBJECTIVE: To identify chondroprotective factors as potential disease-modifying osteoarthritis treatments using an unbiased, bottom-up proteomics approach. SAMPLES: Paired equine cartilage explants and synovial membrane were collected postmortem from 4 horses with no history of lameness and grossly normal joints at necropsy. PROCEDURES: Six groups were established: cartilage, synoviocytes, and cartilage + synoviocytes (coculture), all with or without interleukin (IL)-1ß. The catabolic effect of IL-1ß was verified by glycosaminoglycan (GAG) released from cartilage into media by 1,9-dimethyl-methylene blue assay and cartilage toluidine blue histochemistry. Conditioned media from cocultures with or with IL-1ß were submitted for bottom-up proteomic analysis. Synoviocyte gene expression was evaluated using reverse transcription-quantitative PCR (RT-qPCR) for proteins of interest identified in the proteomics scan. RESULTS: GAG content was retained in cartilage when in cocultures treated with IL-1ß. Fourteen proteins of interest were selected from the proteomic analysis. From these 14 proteins, metalloproteinase inhibitor 3 precursor (TIMP3), tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), insulin-like growth factor-binding protein 2 (IGFBP2), and alpha-2 macroglobulin (A2M) were selected for synoviocyte gene expression analysis by RT-qPCR. Gene expression of TIMP3 (P = .02) and TNFRSF11B (P = .04) were significantly increased in synoviocytes from cocultures treated with IL-1ß compared to controls. Contrary to expectations based on protein expression, IGFBP2 gene expression (P = .04) was significantly decreased in IL-1ß-stimulated coculture synoviocytes compared to control coculture synoviocytes. A2M gene expression in synoviocytes was not different between coculture groups. CLINICAL RELEVANCE: The secretome from synoviocytes could provide a milieu of bioactive factors to restore joint homeostasis in osteoarthritis.


Assuntos
Cartilagem Articular , Doenças dos Cavalos , Osteoartrite , Sinoviócitos , Animais , Cartilagem Articular/metabolismo , Glicosaminoglicanos/metabolismo , Doenças dos Cavalos/patologia , Cavalos , Interleucina-1beta/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Osteoartrite/veterinária , Proteômica , Secretoma , Membrana Sinovial/metabolismo
13.
Int Immunopharmacol ; 110: 109026, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35978503

RESUMO

Nerve injury and nerve pain are common diseases caused by neuroinflammation. Numerous studies have shown that the activation of NLRP3 (nod-like receptor family, pyrin domain-containing 3) inflammasome is involved in a various inflammatory response, such as Alzheimer's disease, diabetes, nerve damage and other diseases. The NLRP3 inflammasome is a complex containing NLRP3 protein, ASC (apoptosis-associated speckle-like protein), and pro-caspase-1, which is highly expressed and activated to promote the secretion of IL-1ß and IL-18 in response to the stimulation of danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) in immune cells such as macrophages and dendritic cells. The activation of NLRP3 inflammasome can cause cell death through caspase-1-mediated cell pyroptosis and plays an important role in the development of nervous system injury and inflammation-related diseases. This discussion aims to summarize the mechanisms of nerve damage and pain caused by excessive activation of the NLRP3 inflammasome.


Assuntos
Neuralgia , Traumatismos dos Nervos Periféricos , Caspase 1/metabolismo , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
14.
Int Immunopharmacol ; 110: 109029, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35978504

RESUMO

Chondrocyte apoptosis and dysfunction play an important role in osteoarthritis (OA), a chronic progressive arthropathy. Non-coding RNAs have been implicated in OA pathogenesis. In this study, microRNA (miR)-548d-5p was found to be downregulated in OA samples and IL-1ß-stimulated chondrocytes. miR-548d-5p overexpression partially reversed IL-1ß-induced chondrocyte damage in vitro, evidenced by the promotion of cell growth, the inhibition of apoptosis and inflammatory cytokine release, and the improvement in extracellular matrix (ECM) deposition. Furthermore, miR-548d-5p overexpression partially reversed papain-induced damages on OA rat's knee articular cartilage. Specificity protein 1 (SP1) was inhibited by miR-548d-5p and identified as its direct downstream target. In IL-1ß-stimulated chondrocytes, SP1 overexpression significantly attenuated the protective effects of miR-548d-5p overexpression against chondrocyte damage. In conclusion, miR-548d-5p was abnormally downregulated in OA samples and IL-1ß-stimulated chondrocytes. miR-548d-5p protects against IL-1ß-induced chondrocyte damage via direct inhibition of SP1.


Assuntos
MicroRNAs , Osteoartrite , Animais , Apoptose , Proliferação de Células , Condrócitos , Interleucina-1beta/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoartrite/metabolismo , Ratos
15.
Comput Math Methods Med ; 2022: 9073372, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35979044

RESUMO

Aims: The expression and clinical significance of tumor necrosis factor-α (INF-α) and interleukin 1-ß (IL-1ß) in retinal cells of patients with type 2 diabetes (T2DM) retinopathy were detected by flow cytometry. Materials and Methods: Fifty patients with T2DM who attended our ophthalmology clinic between May 2021 and May 2022 were selected as the observation group. Another 50 healthy individuals who were examined at our hospital during the same period were selected as the comparison group. Tear film rupture time (BUT), fluorescein staining (FL), basal tear secretion (Schirmer I) test, and conjunctival impression cytology (CIC) were detected in both groups, and the expression of TNF-α and IL-1ß in retinal cells was observed by immunohistochemical staining. Results: The levels of IL13 and TNF-α in the two groups were not exactly the same. The serum levels of IL13 and TNF-α in the observation group were significantly higher than those in the control group, and there was a statistically significant difference (P < 0.05). TNF-α and IL-1B expressions in the observation group were positively correlated with the fluorescence staining, and the expression of TNF-α and IL-1ß in the observation group was significantly negatively correlated with the BUT test and Schirmer I test. Conclusion: Serums TNF-α and IL-1ß are significantly elevated in patients with T2DM retinopathy and gradually increase with disease progression. Combined detection of serums TNF-α and IL-1ß can help determine the severity of the disease and assess the prognosis.


Assuntos
Diabetes Mellitus Tipo 2 , Doenças Retinianas , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Interleucina-13/metabolismo , Interleucina-1beta/metabolismo , Doenças Retinianas/metabolismo , Lágrimas/metabolismo , Fator de Necrose Tumoral alfa
16.
Biochem Biophys Res Commun ; 624: 157-163, 2022 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-35944388

RESUMO

Excessive release of inflammatory cytokines has been considered as a major cause of chronic inflammation, resulting in intestinal barrier disruption that leads to inflammatory bowel disease (IBD). Tumor necrosis factor α (TNFα) is one of the well-known inflammatory cytokines that activates formation of NLRP3 inflammasome, thus resulting in excessive secretion of inflammatory cytokines causing IBD. Although immunoproteasome inhibitors have been reported to inhibit inflammatory cytokine release, immunoproteasome inhibition has not yet been addressed for attenuation of NLRP3 inflammasome activity in intestinal epithelial cell. Here, we observed that NLRP3 inflammasome assembly was attenuated by peptide epoxyketone YU102, a LMP2 subunit immunoproteasome inhibitor, in intestinal epithelial cell. YU102 also inhibited maturation of active caspase-1 and secretion of IL-1ß, which are subsequent inflammatory cascade after the formation of NLRP3 inflammasome. Progression of epithelial-mesenchymal transition and increase of cellular permeability, which were induced by TNFα, were also suppressed through inhibition of immunoproteasome. Furthermore, we found that YU102 does not inhibit degradation of IкBα and its following NF-кB activation that leads to transcription of NLRP3. These findings suggest that inhibition of immunoproteasome with YU102 offers a potential therapeutic premise for prevention of TNFα-induced chronic inflammation through attenuation of NLRP3 inflammasome assembly.


Assuntos
Inflamassomos , Doenças Inflamatórias Intestinais , Caspase 1/metabolismo , Citocinas/metabolismo , Células Epiteliais/metabolismo , Humanos , Inflamassomos/metabolismo , Inflamação/patologia , Doenças Inflamatórias Intestinais/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
17.
Arthritis Res Ther ; 24(1): 196, 2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-35974386

RESUMO

Systemic sclerosis (SSc) is an autoimmune rheumatic disease with high mortality, which is featured by inflammation, vascular damage, and aggressive fibrosis. To date, the pathogenesis of SSc remains unclear and effective treatments are still under research. Active NLRP3 recruits downstream proteins such as ASC and caspase-1 and assembles into inflammasome, resulting in excretion of inflammatory cytokines including IL-1ß and IL-18, as well as in pyroptosis mediated by gasdermin D. Various studies demonstrated that NLRP3 inflammasome might be involved in the mechanism of tenosynovitis, arthritis, fibrosis, and vascular damage. The pathophysiological changes might be due to the activation of proinflammatory Th2 cells, profibrotic M2 macrophages, B cells, fibroblasts, and endothelial cells. Here, we review the studies focused on NLRP3 inflammasome activation, its association with innate and adaptive immune cells, endothelium injury, and differentiation of fibroblasts in SSc. Furthermore, we summarize the prospect of therapy targeting NLRP3 pathway.


Assuntos
Inflamassomos , Escleroderma Sistêmico , Caspase 1/metabolismo , Células Endoteliais/metabolismo , Fibrose , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Escleroderma Sistêmico/patologia
18.
Int Immunopharmacol ; 110: 108996, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35978501

RESUMO

BACKGROUND: Previous evidence has suggested that circular RNA (circRNA) is abnormally expressed in osteoarthritis (OA). However, the underlying mechanism of circRNA in OA progression remains unclear. The study aims to reveal the mechanism of circ_0128846 regulating OA. METHODS: Human chondrocytes (C28/I2 cells) were treated with interleukin-1ß (IL-1ß) to mimic an OA cell model. The expression levels of circ_0128846, miR-940 and protein tyrosine phosphatase 12 (PTPN12) were detected by qRT-PCR. Protein expression was checked by Western blotting. Cell viability, proliferation, and apoptosis were analyzed by a cell counting kit-8 assay, 5-Ethynyl-2'-deoxyuridine (EdU) assay and flow cytometry analysis, respectively. The production of tumor necrosis factor-α (TNF-α) and IL-6 was determined by an enzyme-linked immunosorbent assay (ELISA). The binding relationship between miR-940 and circ_0128846 or PTPN12 was identified by dual-luciferase reporter assay and RNA immunoprecipitation assay. RESULTS: Circ_0128846 and PTPN12 expression were significantly upregulated, whereas miR-940 was downregulated in the cartilage tissues of OA patients and IL-1ß-treated C28/I2 cells compared with controls. IL-1ß treatment inhibited C28/I2 cell proliferation and induced cell apoptosis and the production of inflammatory factors, TNF-α and IL-6; however, these effects were partly reversed after circ_0128846 depletion. In terms of mechanism, circ_0128846 acted as a miR-940 sponge, and miR-940 combined with PTPN12. Also, circ_0128846 depletion partly ameliorated IL-1ß-induced C28/I2 cell disorders through miR-940. PTPN12 overexpression also partly relieved miR-940-mediated effects in IL-1ß-treated C28/I2 cells. Further, circ_0128846 induced PTPN12 expression by interacting with miR-940. CONCLUSION: Circ_0128846 regulated human chondrocyte proliferation, apoptosis and inflammation through the miR-940/PTPN12 pathway in OA.


Assuntos
Condrócitos/metabolismo , MicroRNAs , Osteoartrite , Apoptose , Humanos , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 12/metabolismo , RNA Circular/genética , Fator de Necrose Tumoral alfa/metabolismo
19.
Int Immunopharmacol ; 110: 109064, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35978511

RESUMO

BACKGROUND: Osteoarthritis (OA), caused by the destruction of joint cartilage, is the most prevalent form of arthritis, causing pain and stiffness in joints among millions of patients worldwide. Increasing evidence suggests that non-coding RNAs, including circular RNAs, play important roles in the pathogenesis of OA, but the precise signaling pathway is still unclear. METHODS: To study OA, we established a mouse model by the destabilized medial meniscus (DMM) surgery and used IL-1ß stimulated human cell line C28/I2 as an in vitro study. To further study the role of circSPI1_005 in regulating cell proliferation and apoptosis, EdU staining and FACS-based (fluorescence-activated cell sorting) apoptosis examination were performed after the manipulation of the expression of circSPI1_005. Also, bioinformatics predictions were conducted to analyze the downstream microRNAs of circSPI1_005 and the protein regulated by circSPI1_005. The luciferase assay and the RNA immunoprecipitation (RIP) assay were used to confirm the binding between circSPI1_005 and the predicted microRNA. To verify the role of circSPI1_005 in regulating OA in vivo, we also over-expressed circSPI1_005 by injecting AAV into previously injured knees to improve the OA symptoms. RESULTS: In this study, we found that circSPI1_005 was significantly down-regulated in IL-1ß treated chondrocyte cell lines and cartilage tissues of the OA mouse model. Overexpression of circSPI1_005 ameliorated OA by increasing proliferation and inhibiting apoptosis, and knockdown of circSPI1_005 in chondrocytes mimicked OA phenotypes. Bioinformatics study showed circSPI1_005 could sponge to miR-370-3p, and mechanistic studies confirmed the functional binding between circSPI1_005 and miR-370-3p. Furthermore, we conducted a TargetScan analysis and found that MAP3K9 (mitogen-activated protein kinase kinase kinase 9) could be the downstream protein effector. The expression level of MAP3K9 was regulated by miR-370-3p and overexpression of MAP3K9 could efficiently ameliorate OA. Also, we over-expressed circSPI1_005 in vivo and found that the cartilage surface in the OA mouse model was improved with overexpression of circSPI1_005. CONCLUSIONS: Collectively, circSPI1_005 could sponge to miR-370-3p to regulate the expression of MAP3K9, ameliorating the progression of osteoarthritis.


Assuntos
Cartilagem Articular , MAP Quinase Quinase Quinases/metabolismo , MicroRNAs/metabolismo , Osteoartrite , Animais , Apoptose , Cartilagem Articular/patologia , Condrócitos/metabolismo , Humanos , Interleucina-1beta/metabolismo , Camundongos , MicroRNAs/genética , Osteoartrite/metabolismo
20.
Exp Neurol ; 357: 114207, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35985555

RESUMO

Inflammation-induced preterm birth is the leading cause of perinatal mortality and long-term sequelae in surviving children. IL-1ß is a major contributor to inflammation-induced preterm labor and its sequelae. It has recently been demonstrated that the cytokine storm and its progression depend on IL-1ß release into circulation and that the P2X7 receptor (P2X7R) is the key player of the ATP-driven NLRP3/caspase-1 activation, necessary for the cleavage of pro-IL-1ß to its mature form as well as its subsequent secretion. Being a key component to the inflammatory cascade, P2X7R illuminates a new therapeutic avenue to halt progression of inflammation prior to perinatal brain injury. In this review, we summarize the basic role of the P2X7 receptor in the inflammatory signaling cascade and the possibility of it being used as a therapeutic target in perinatal brain injury. We discuss the antagonists and agonists of the receptor as well as its role in other inflammatory diseases, showing the importance of discovering the functions of the receptor.


Assuntos
Lesões Encefálicas , Nascimento Prematuro , Trifosfato de Adenosina/farmacologia , Caspase 1/metabolismo , Criança , Feminino , Humanos , Recém-Nascido , Inflamação , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Gravidez , Receptores Purinérgicos P2X7
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...