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1.
Zhongguo Zhong Yao Za Zhi ; 46(12): 3034-3042, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34467693

RESUMO

To explore the mechanism of anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium based on network pharmacology and inflammatory or pain mouse models. The effective components of Zanthoxyli Pericarpium were screened out by TCMSP database. And their potential corresponding targets were predicted by PharmMapper software. The possible targets relating to inflammation and pain were mainly collected through DrugBank, TTD and DisGeNET databases. The "active ingredient-gene-disease" network diagram was constructed by Cytoscape 3.7.0 software. The network pharmacology results showed 5 potential effective compounds, which were related to 29 targets; 132 targets relating to inflammation and pain were screened out in the DrugBank, TTD and DisGeNET databases. The network analysis results indicated that the phosphatidylinositol 3-kinase catalytic subunit gamma isoform(PIK3 CG) gene may be the key to the anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium. The anti-inflammatory and analgesic effects of essential oil extract and dichloromethane extract of Zanthoxyli Pericarpium were explored through the mouse model of inflammation induced by xylene or carrageenan and the mouse model of pain induced by acetic acid or formalin. The experimental results showed that essential oil extract and dichloromethane extract of Zanthoxyli Pericarpium could reduce xylene-induced ear swelling and carrageenan-induced paw swelling and decrease the number of writhing responses in mice induced by acetic acid and the licking foot time of mice in phase Ⅱ induced by formalin. Western blot results showed that Zanthoxyli Pericarpium extract could inhibit the expressions of PIK3 CG, phosphonated nuclear factor kappaB(p-NF-κB) and phosphonated p38(p-p38 MAPK) protein. The present study showed the anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium through multiple components and targets, so as to provide a pharmacodynamic basis for the study of Zanthoxyli Pericarpium and its mechanism.


Assuntos
Medicamentos de Ervas Chinesas , Óleos Voláteis , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Edema/induzido quimicamente , Edema/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/genética , Camundongos , Extratos Vegetais
2.
Zhen Ci Yan Jiu ; 46(8): 649-55, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34472749

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) of "Zusanli"(ST36) and "Sanyinjiao"(SP6) on serum TNF-α, IL-1ß, and IL-6 and expression of synovial matrimetalloproteinases (MMPs) and articular morphology in collagen-induced arthritis (CIA) rats, so as to explore its mechanisms underlying relief of arthritis. METHODS: Thirty male SD rats were randomly divided into normal control, CIA model and EA groups (n=10 rats per group). The arthritis model was induced by multi-point intradermal injection of bovine type Ⅱ collagen emulsion. EA (2 Hz/100 Hz, 1 mA) was applied to bilateral ST36 and SP6 for 30 min, once a day for 28 days. The hind-limb paw volume was measured and the arthritis index (AI) score given according to the swelling degree, rigidity and deformity of the ankle joint (0-4 points). After EA intervention, the morphological damage of the affected ankle joints was revealed by H.E. staining, safranin O-fast green staining, and tartrate-resistant acid phosphatase (TRAP) staining, separately. The levels of serum TNF-α, IL-1ß, and IL-6 were measured by ELISA, and the expression levels of MMP-1, MMP-3, MMP-13, and receptor activator of nuclear factor Kappa B ligand (RANKL) in the synovial tissue were detected by Western blot. RESULTS: Compared with the normal control group, the paw volume, AI score, TRAP-revealed number of osteoclasts, contents of serum TNF-α, IL-1ß and IL-6, and expression levels of MMP-1, MMP-3, MMP-13 and RANKL proteins were significantly increased in the model group (P<0.01, P<0.05). Following the intervention, the paw volume, AI score, number of osteoclasts, contents of serum TNF- α, IL-1ß and IL-6, and expression levels of MMP-1, MMP-3, MMP-13 and RANKL proteins were significantly decreased in the EA group (P<0.05, P<0.01) in contrast to the model group. H.E. and safranin O-fast green staining showed rough articular cartilage surface with thinned cartilage layer, obvious hyperplasia of the synovial tissue with many inflammatory cells, and serious damage and degradation of the cartilage matrix in the model group, these situations were relatively milder in the EA group. CONCLUSION: EA of ST36 and SP6 can reduce the articular damage in collagen-induced arthritis rats, which is associated with its function in reducing inflammatory response and down-regulating the expression of synovial MMP-1, MMP-3, MMP-13 and RANKL proteins.


Assuntos
Artrite Experimental , Eletroacupuntura , Animais , Artrite Experimental/genética , Artrite Experimental/terapia , Bovinos , Inflamação/genética , Inflamação/terapia , Masculino , Ratos , Ratos Sprague-Dawley , Membrana Sinovial
3.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445542

RESUMO

Endoglin (Eng) is an endothelial cell (EC) transmembrane glycoprotein involved in adhesion and angiogenesis. Eng mutations result in vessel abnormalities as observed in hereditary hemorrhagic telangiectasia of type 1. The role of Eng was investigated in endothelial functions and permeability under inflammatory conditions, focusing on the actin dynamic signaling pathway. Endothelial Colony-Forming Cells (ECFC) from human cord blood and mouse lung/aortic EC (MLEC, MAEC) from Eng+/+ and Eng+/- mice were used. ECFC silenced for Eng with Eng-siRNA and ctr-siRNA were used to test tubulogenesis and permeability +/- TNFα and +/- LIM kinase inhibitors (LIMKi). In silico modeling of TNFα-Eng interactions was carried out from PDB IDs 5HZW and 5HZV. Calcium ions (Ca2+) flux was studied by Oregon Green 488 in epifluorescence microscopy. Levels of cofilin phosphorylation and tubulin post-translational modifications were evaluated by Western blot. F-actin and actin-tubulin distribution/co-localization were evaluated in cells by confocal microscopy. Eng silencing in ECFCs resulted in a decrease of cell sprouting by 50 ± 15% (p < 0.05) and an increase in pseudo-tube width (41 ± 4.5%; p < 0.001) compared to control. Upon TNFα stimulation, ECFC Eng-siRNA displayed a significant higher permeability compared to ctr-siRNA (p < 0.01), which is associated to a higher Ca2+ mobilization (p < 0.01). Computational analysis suggested that Eng mitigated TNFα activity. F-actin polymerization was significantly increased in ECFC Eng-siRNA, MAEC+/-, and MLEC+/- compared to controls (p < 0.001, p < 0.01, and p < 0.01, respectively) as well as actin/tubulin distribution (p < 0.01). Furthermore, the inactive form of cofilin (P-cofilin at Ser3) was significantly decreased by 36.7 ± 4.8% in ECFC Eng-siRNA compared to ctr-siRNA (p < 0.001). Interestingly, LIMKi reproduced the absence of Eng on TNFα-induced ECFC-increased permeability. Our data suggest that Eng plays a critical role in the homeostasis regulation of endothelial cells under inflammatory conditions (TNFα), and loss of Eng influences ECFC-related permeability through the LIMK/cofilin/actin rearrangement-signaling pathway.


Assuntos
Fatores de Despolimerização de Actina/metabolismo , Permeabilidade da Membrana Celular , Endoglina/metabolismo , Células Endoteliais/patologia , Inflamação/patologia , Quinases Lim/metabolismo , Neovascularização Patológica/patologia , Fatores de Despolimerização de Actina/genética , Animais , Endoglina/genética , Células Endoteliais/metabolismo , Inflamação/genética , Inflamação/metabolismo , Quinases Lim/genética , Camundongos , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo
4.
J Med Food ; 24(8): 852-859, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34382871

RESUMO

CYJ-27, a synthetic analog of decursin, prevents the generation of proinflammatory cytokines and oxidative stress. In this study, the effects of CYJ-27 on the regulation of inducible nitric oxide synthase (iNOS), heme oxygenase (HO)-1, and cyclooxygenase (COX-)2 were characterized in lipopolysaccharide (LPS)-treated human umbilical vein endothelial cells (HUVECs). In addition, the effects of CYJ-27 on the production of iNOS and representative proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, were tested in the lung tissues of LPS-treated mice. CYJ-27 promoted the expression of HO-1, suppressed NF-κB-luciferase activity, and reduced COX-2/PGE2 and iNOS/NO, resulting in a diminution in phosphorylated-STAT-1. Furthermore, CYJ-27 promoted the nuclear translocation of Nrf2, enhanced the combination of Nrf2 to antioxidant response elements, and diminished IL-1ß production in LPS-activated HUVECs. CYJ-27-downregulated iNOS/NO expression was rescued after the RNAi suppression of HO-1. In LPS-treated mice, CYJ-27 significantly diminished iNOS production in the lung tissues and TNF-α expression in the bronchoalveolar lavage fluid. These findings indicate that CYJ-27 exerts anti-inflammatory activities by regulating iNOS through downregulation of both NF-κB activation and phosphorylated-STAT-1. Hence, it can act as a template for the development of novel substances to treat inflammatory diseases.


Assuntos
Inflamação , NF-kappa B , Animais , Benzopiranos , Butiratos , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Lipopolissacarídeos , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo
5.
Int J Oral Maxillofac Implants ; 36(4): 690-701, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34411207

RESUMO

PURPOSE: To determine the profile of gene expression of soft connective tissue covering bone grafted with deproteinized bovine bone mineral (DBBM) or demineralized freeze-dried bone allograft (DFDBA) in comparison to that without grafting. MATERIALS AND METHODS: Calvaria defects of mice were created and treated as follows: (1) defect without a graft as a control, (2) grafted with DBBM, or (3) grafted with DFDBA. After 1 month, the animals were sacrificed. Soft connective tissue covering the defect area was collected by a punch technique. RNA was isolated and processed to cDNA. Gene expression was evaluated with the microarray technique. Pathway analyses were performed via the PANTHER Overrepresentation test and WikiPathway analysis. Inflammatory marker genes were chosen for mRNA expression using reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). Tissue sections were used for the histologic and immunohistologic evaluation. RESULTS: The numbers of genes that were significantly differently expressed were 312 (DBBM vs control), 82 (DFDBA vs control), and 113 (DBBM vs DFDBA). Inflammation-related genes were upregulated in DBBM vs control (16 genes), DFDBA vs control (3 genes), and DBBM vs DFDBA (15 genes). Two of these genes, Bcl2a1 and Cxcl9, were significantly upregulated in both the DBBM and DFDBA groups compared with the control. Pathway analysis indicated that Bcl2a1 and Cxcl9 are dominantly expressed in inflammation-related pathways. RT-qPCR and immunohistochemistry showed upregulation of Bcl2a1 and Cxcl9 in DBBM compared with the control and DFDBA groups. Cxcl9 showed a significantly higher expression in the DBBM group. Bcl2a1 at the protein level was equally expressed in all groups. Any sign of inflammation, however, was not seen by histology in any of the groups. CONCLUSION: After a 1-month healing period, soft tissue covering bone grafted with DBBM expressed a higher number of inflammation-related genes compared with those non-grafted or grafted with DFDBA. DFDBA resulted in a decreased expression of inflammation-related genes.


Assuntos
Transplante Ósseo , Tecido Conjuntivo , Aloenxertos , Animais , Regeneração Óssea , Bovinos , Liofilização , Imuno-Histoquímica , Inflamação/genética , Camundongos , Minerais
6.
Nat Commun ; 12(1): 5074, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417463

RESUMO

ß cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human ß cells with inflammation but its expression is reduced in surviving ß cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate ß cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO ß cells show reduced expression of IFNγ-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between ß cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in ß cells may reduce activating pathologic immune cells and killing of ß cells.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus Tipo 1/patologia , Inflamação/patologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Proteínas Proto-Oncogênicas/metabolismo , Animais , Sequência de Bases , Citotoxicidade Imunológica , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Feminino , Humanos , Imunidade , Inflamação/genética , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Linfócitos T/imunologia , Transcrição Genética
7.
Oxid Med Cell Longev ; 2021: 9998697, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457122

RESUMO

The pandemic of the coronavirus disease 2019 (COVID-19) has posed huge threats to healthcare systems and the global economy. However, the host response towards COVID-19 on the molecular and cellular levels still lacks full understanding and effective therapies are in urgent need. Here, we integrate three datasets, GSE152641, GSE161777, and GSE157103. Compared to healthy people, 314 differentially expressed genes were identified, which were mostly involved in neutrophil degranulation and cell division. The protein-protein network was established and two significant subsets were filtered by MCODE: ssGSEA and CIBERSORT, which comprehensively revealed the alternation of immune cell abundance. Weighted gene coexpression network analysis (WGCNA) as well as GO and KEGG analyses unveiled the role of neutrophils and T cells during the progress of the disease. Based on the hospital-free days after 45 days of follow-up and statistical methods such as nonnegative matrix factorization (NMF), submap, and linear correlation analysis, 31 genes were regarded as the signature of the peripheral blood of COVID-19. Various immune cells were identified to be related to the prognosis of the patients. Drugs were predicted for the genes in the signature by DGIdb. Overall, our study comprehensively revealed the relationship between the inflammatory response and the disease course, which provided strategies for the treatment of COVID-19.


Assuntos
COVID-19/genética , COVID-19/imunologia , Redes Reguladoras de Genes , Inflamação/genética , Inflamação/imunologia , SARS-CoV-2/imunologia , Transcriptoma , COVID-19/complicações , COVID-19/virologia , Estudos de Casos e Controles , Perfilação da Expressão Gênica , Humanos , Inflamação/virologia , Mapas de Interação de Proteínas
8.
Arthritis Res Ther ; 23(1): 216, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34412663

RESUMO

BACKGROUND: Excessive osteoclast activity, which is strongly stimulated by pro-inflammatory mediators, results in bone and cartilage degeneration as central features of many arthritides. Levels of the alarmin S100A8/A9 and interleukin (IL)-1ß are both increased in arthritis patients and correlate with disease activity and progression of tissue erosion. We previously presented S100A8/A9 as a good biomarker for joint inflammation and arthritis pathology under circumstances of high IL-1 signaling in mice that lack the gene encoding IL-1 receptor antagonist (Il1rn-/- mice). Here, we investigated whether S100A8/A9 is also actively involved in the development of joint inflammation and both cartilage and bone pathology under these conditions by comparing Il1rn-/- mice with mice that have an additional deficiency for S100a9 (Il1rn-/-XS100a9-/-). METHODS: Il1rn-/-XS100a9-/- on a BALB/c background were obtained by crossing S100a9-/- mice and Il1rn-/- mice. Arthritis incidence and severity were macroscopically scored. Myeloid cell populations in the bone marrow and spleen were determined using flow cytometry. In vitro osteoclastogenesis of bone marrow cells was evaluated with TRAP staining. Microscopic joint inflammation, cartilage degeneration, and bone destruction were evaluated using histology of ankle joints of 12- and 20-week-old mice. RESULTS: Macroscopically scored arthritis severity was comparable between Il1rn-/- and Il1rn-/-XS100a9-/- mice. Inflammation, cartilage erosion, and bone erosion were clearly present in 12-week-old mice of both strains lacking Il1rn-/-, but not significantly different between Il1rn-/-XS100a9-/- and Il1rn-/-. Moreover, we observed that the numbers of neutrophils and monocytes were increased by the absence of Il1rn, which was affected by the absence of S100a9 only in the spleen but not in the bone marrow. In line with our other findings, the absence of S100a9 did not affect the osteoclastogenic potential of osteoclast precursors in the absence of Il1rn. Finally, in agreement with the findings in early arthritis development in 12-week-old mice, cartilage and bone erosion in 20-week-old mice was significantly higher in both Il1rn-/- strains, but the additional absence of S100a9 did not further affect tissue pathology. CONCLUSION: S100A8/A9 deficiency does not significantly affect inflammation and joint destruction in mice with high IL1ß signaling suggesting that S100A8/A9 is not essential for the development of arthritis under these conditions.


Assuntos
Artrite Experimental , Calgranulina A , Calgranulina B , Proteína Antagonista do Receptor de Interleucina 1 , Animais , Artrite Experimental/genética , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Humanos , Inflamação/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout
9.
FASEB J ; 35(9): e21798, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34339064

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic threatens human species with mortality rate of roughly 2%. We can hardly predict the time of herd immunity against and end of COVID-19 with or without success of vaccine. One way to overcome the situation is to define what delineates disease severity and serves as a molecular target. The most successful analogy is found in BCR-ABL in chronic myeloid leukemia, which is the golden biomarker, and simultaneously, the most effective molecular target. We hypothesize that S100 calcium-binding protein A8 (S100A8) is one such molecule. The underlying evidence includes accumulating clinical information that S100A8 is upregulated in severe forms of COVID-19, pathological similarities of the affected lungs between COVID-19 and S100A8-induced acute respiratory distress syndrome (ARDS) model, homeostatic inflammation theory in which S100A8 is an endogenous ligand for endotoxin sensor Toll-like receptor 4/Myeloid differentiation protein-2 (TLR4/MD-2) and mediates hyper-inflammation even after elimination of endotoxin-producing extrinsic pathogens, analogous findings between COVID-19-associated ARDS and pre-metastatic lungs such as S100A8 upregulation, pulmonary recruitment of myeloid cells, increased vascular permeability, and activation coagulation cascade. A successful treatment in an animal COVID-19 model is given with a reagent capable of abrogating interaction between S100A8/S100A9 and TLR4. In this paper, we try to verify our hypothesis that S100A8 governs COVID-19-associated ARDS.


Assuntos
COVID-19/complicações , Calgranulina A/fisiologia , Síndrome da Liberação de Citocina/etiologia , Inflamação/etiologia , Pandemias , Síndrome do Desconforto Respiratório/etiologia , SARS-CoV-2/genética , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/fisiologia , Animais , Antivirais/farmacologia , COVID-19/genética , COVID-19/patologia , Calgranulina A/sangue , Calgranulina A/genética , Quimiocina CXCL11/sangue , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/patologia , Dissacarídeos/farmacologia , Dissacarídeos/uso terapêutico , Modelos Animais de Doenças , Descoberta de Drogas , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Humanos , Inflamação/genética , Inflamação/patologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Antígeno 96 de Linfócito/fisiologia , Macaca mulatta , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Mutação , Síndrome do Desconforto Respiratório/genética , Síndrome do Desconforto Respiratório/metabolismo , Especificidade da Espécie , Fosfatos Açúcares/farmacologia , Fosfatos Açúcares/uso terapêutico , Receptor 4 Toll-Like/fisiologia , Regulação para Cima , Internalização do Vírus
10.
FASEB J ; 35(9): e21833, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34365659

RESUMO

Macrophages are the principal component of the innate immune system. They play very crucial and multifaceted roles in the pathogenesis of inflammatory vascular diseases. There is an increasing recognition that transcriptionally dynamic macrophages are the key players in the pathogenesis of inflammatory vascular diseases. In this context, the accumulation and aberrant activation of macrophages in the subendothelial layers govern atherosclerotic plaque development. Macrophage-mediated inflammation is an explicitly robust biological response that involves broad alterations in inflammatory gene expression. Thus, cell-intrinsic negative regulatory mechanisms must exist which can restrain inflammatory response in a spatiotemporal manner. In this study, we identified CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as one such cell-intrinsic negative regulator of inflammation. Our in vivo studies show that myeloid-CITED2-deficient mice on the Apoe-/- background have larger atherosclerotic lesions on both control and high-fat/high-cholesterol diets. Our integrated transcriptomics and gene set enrichment analyses studies show that CITED2 deficiency elevates STAT1 and interferon regulatory factor 1 (IRF1) regulated pro-inflammatory gene expression in macrophages. At the molecular level, our studies identify that CITED2 deficiency elevates IFNγ-induced STAT1 transcriptional activity and STAT1 enrichment on IRF1 promoter in macrophages. More importantly, siRNA-mediated knockdown of IRF1 completely reversed elevated pro-inflammatory target gene expression in CITED2-deficient macrophages. Collectively, our study findings demonstrate that CITED2 restrains the STAT1-IRF1 signaling axis in macrophages and limits the development of atherosclerotic plaques.


Assuntos
Aterosclerose/genética , Fator Regulador 1 de Interferon/genética , Proteínas Repressoras/genética , Fator de Transcrição STAT1/genética , Transdução de Sinais/genética , Transativadores/genética , Animais , Feminino , Inflamação/genética , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , Células RAW 264.7 , Transcrição Genética/genética
11.
FASEB J ; 35(9): e21332, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34423867

RESUMO

Emerging research has highlighted the capacity of microRNA-23a-3p (miR-23a-3p) to alleviate inflammatory pain. However, the molecular mechanism by which miR-23a-3p attenuates inflammatory pain is yet to be fully understood. Hence, the current study aimed to elucidate the mechanism by which miR-23a-3p influences inflammatory pain. Bioinformatics was initially performed to predict the inflammatory pain related downstream targets of miR-23a-3p in macrophage-derived extracellular vesicles (EVs). An animal inflammatory pain model was established using Complete Freund's Adjuvant (CFA). The miR-23a-3p expression was downregulated in the microglia of CFA-induced mice, after which the inflammatory factors were determined by ELISA. FISH and immunofluorescence were performed to analyze the co-localization of miR-23a-3p and microglia. Interestingly, miR-23a-3p was transported to the microglia via M2 macrophage-EVs, which elevated the mechanical allodynia and the thermal hyperalgesia thresholds in mice model. The miR-23a-3p downstream target, USP5, was found to stabilize HDAC2 via deubiquitination to promote its expression while inhibiting the expression of NRF2. Taken together, the key findings of the current study demonstrate that macrophage-derived EVs containing miR-23a-3p regulates the HDAC2/NRF2 axis by decreasing USP5 expression to alleviate inflammatory pain, which may provide novel therapeutic targets for the treatment of inflammatory pain.


Assuntos
Vesículas Extracelulares/metabolismo , Histona Desacetilase 2/metabolismo , Inflamação/metabolismo , Macrófagos/citologia , Fator 2 Relacionado a NF-E2/metabolismo , Dor/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Animais , Linhagem Celular , Enzimas Desubiquitinantes/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Estabilidade Enzimática , Vesículas Extracelulares/genética , Inflamação/genética , Inflamação/terapia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Microglia/metabolismo , Modelos Biológicos , Dor/genética , Manejo da Dor , Proteases Específicas de Ubiquitina/genética , Ubiquitinação
12.
Genes (Basel) ; 12(7)2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34356070

RESUMO

Chronic inflammatory lung diseases are characterized by uncontrolled immune response in the airways as their main pathophysiological manifestation. The lack of specific diagnostic and therapeutic biomarkers for many pulmonary diseases represents a major challenge for pulmonologists. The majority of the currently approved therapeutic approaches are focused on achieving disease remission, although there is no guarantee of complete recovery. It is known that angiotensin-converting enzyme 2 (ACE2), an important counter-regulatory component of the renin-angiotensin-aldosterone system (RAAS), is expressed in the airways. It has been shown that ACE2 plays a role in systemic regulation of the cardiovascular and renal systems, lungs and liver by acting on blood pressure, electrolyte balance control mechanisms and inflammation. Its protective role in the lungs has also been presented, but the exact pathophysiological mechanism of action is still elusive. The aim of this study is to review and discuss recent findings about ACE2, including its potential role in the pathophysiology of chronic inflammatory lung diseases:, i.e., chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. Additionally, in the light of the coronavirus 2019 disease (COVID-19), we will discuss the role of ACE2 in the pathophysiology of this disease, mainly represented by different grades of pulmonary problems. We believe that these insights will open up new perspectives for the future use of ACE2 as a potential biomarker for early diagnosis and monitoring of chronic inflammatory lung diseases.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Asma/diagnóstico , Teste para COVID-19 , COVID-19/enzimologia , Hipertensão Pulmonar/diagnóstico , Pulmão/enzimologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Asma/enzimologia , Asma/genética , COVID-19/genética , Humanos , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/genética , Inflamação/diagnóstico , Inflamação/enzimologia , Inflamação/genética , Pulmão/patologia , Doença Pulmonar Obstrutiva Crônica/enzimologia , Doença Pulmonar Obstrutiva Crônica/genética , Sistema Renina-Angiotensina
13.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360662

RESUMO

A well-functioning placenta is crucial for normal gestation and regulates the nutrient, gas, and waste exchanges between the maternal and fetal circulations and is an important endocrine organ producing hormones that regulate both the maternal and fetal physiologies during pregnancy. Placental insufficiency is implicated in spontaneous preterm birth (SPTB). We proposed that deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy may ultimately result in SPTB. To explore our hypothesis, we performed a RNA-seq study in male and female placentas from women with SPTB (<36 weeks gestation) compared to normal pregnancies (≥38 weeks gestation) to assess the alterations in the gene expression profiles. We focused exclusively on Black women (cases and controls), who are at the highest risk of SPTB. Six hundred and seventy differentially expressed genes were identified in male SPTB placentas. Among them, 313 and 357 transcripts were increased and decreased, respectively. In contrast, only 61 differentially expressed genes were identified in female SPTB placenta. The ingenuity pathway analysis showed alterations in the genes and canonical pathways critical for regulating inflammation, oxidative stress, detoxification, mitochondrial function, energy metabolism, and the extracellular matrix. Many upstream regulators and master regulators important for nutrient-sensing and metabolism were also altered in SPTB placentas, including the PI3K complex, TGFB1/SMADs, SMARCA4, TP63, CDKN2A, BRCA1, and NFAT. The transcriptome was integrated with published human placental metabolome to assess the interactions of altered genes and metabolites. Collectively, significant and biologically relevant alterations in the transcriptome were identified in SPTB placentas with fetal sex disparities. Altered energy metabolism, mitochondrial function, inflammation, and detoxification may underly the mechanisms of placental dysfunction in SPTB.


Assuntos
Metabolismo Energético , Inflamação/patologia , Doenças Placentárias/patologia , Placenta/patologia , Nascimento Prematuro/patologia , Transcriptoma , Adulto , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Placenta/imunologia , Placenta/metabolismo , Doenças Placentárias/genética , Doenças Placentárias/imunologia , Doenças Placentárias/metabolismo , Gravidez , Nascimento Prematuro/genética , Nascimento Prematuro/imunologia , Nascimento Prematuro/metabolismo , Fatores Sexuais
14.
EBioMedicine ; 70: 103525, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34392148

RESUMO

BACKGROUND: While our battle with the COVID-19 pandemic continues, a multitude of Omics data have been generated from patient samples in various studies. Translation of these data into clinical interventions against COVID-19 remains to be accomplished. Exploring host response to COVID-19 in the upper respiratory tract can unveil prognostic markers and therapeutic targets. METHODS: We conducted a meta-analysis of published transcriptome and proteome profiles of respiratory samples of COVID-19 patients to shortlist high confidence upregulated host factors. Subsequently, mRNA overexpression of selected genes was validated in nasal swabs from a cohort of COVID-19 positive/negative, symptomatic/asymptomatic individuals. Guided by this analysis, we sought to check for potential drug targets. An FDA-approved drug, Auranofin, was tested against SARS-CoV-2 replication in cell culture and Syrian hamster challenge model. FINDINGS: The meta-analysis and validation in the COVID-19 cohort revealed S100 family genes (S100A6, S100A8, S100A9, and S100P) as prognostic markers of severe COVID-19. Furthermore, Thioredoxin (TXN) was found to be consistently upregulated. Auranofin, which targets Thioredoxin reductase, was found to mitigate SARS-CoV-2 replication in vitro. Furthermore, oral administration of Auranofin in Syrian hamsters in therapeutic as well as prophylactic regimen reduced viral replication, IL-6 production, and inflammation in the lungs. INTERPRETATION: Elevated mRNA level of S100s in the nasal swabs indicate severe COVID-19 disease, and FDA-approved drug Auranofin mitigated SARS-CoV-2 replication in preclinical hamster model. FUNDING: This study was supported by the DBT-IISc partnership program (DBT (IED/4/2020-MED/DBT)), the Infosys Young Investigator award (YI/2019/1106), DBT-BIRAC grant (BT/CS0007/CS/02/20) and the DBT-Wellcome Trust India Alliance Intermediate Fellowship (IA/I/18/1/503613) to ST lab.


Assuntos
COVID-19/genética , Nasofaringe/virologia , Proteoma/genética , Transcriptoma/genética , Adulto , Animais , Biomarcadores/metabolismo , COVID-19/patologia , COVID-19/virologia , Linhagem Celular , Chlorocebus aethiops , Estudos de Coortes , Feminino , Células HEK293 , Humanos , Inflamação/genética , Inflamação/virologia , Interleucina-6/genética , Masculino , Mesocricetus , Pessoa de Meia-Idade , Nasofaringe/patologia , Pandemias , Prognóstico , RNA Mensageiro/genética , SARS-CoV-2/patogenicidade , Regulação para Cima/genética , Células Vero , Replicação Viral/genética
15.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(7): 965-971, 2021 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-34308844

RESUMO

OBJECTIVE: To investigate the expression of long non-coding RNA (lncRNA) Linc00638 in rheumatoid arthritis (RA) and its regulatory role in inflammation and oxidative stress of synovial fibroblasts in RA patients (RA-FLS). METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from 20 healthy individuals and 35 RA patients for detecting the expression of Linc00638 using RT-qPCR to analyze the correlation of Linc00638 expression with the clinical indicators of RA patients. A Linc00638 overexpression plasmid and siRNA targeting Linc00638 were transfected into RA-FLS, and the changes in cell viability was observed using CCK8 assay; the changes in the expression levels of interleukin-4 (IL-4), IL-6, reactive oxygen species (ROS) and superoxide dismutase (SOD) in the supernatant were detected using ELISA. RESULTS: Compared with the healthy control subjects, RA patients had significantly increased ESR, CRP, RF, anti-CCP, IgA, and C4 levels (P < 0.05) and significantly decreased Linc00638 expression in the PBMCs (P < 0.01). The area under the receiver-operating characteristic (ROC) curve of Linc00638 was 91.86% with the best cut-off value of 0.74 for diagnosis of RA. Spearman correlation analysis showed that Linc00638 expression level was negatively correlated with age, course of disease, DAS28, ESR, CRP, RF and anti-CCP, and positively correlated with IL-4 and SOD levels (P < 0.05). Association rule analysis showed that a decreased Linc00638 expression was strongly correlated with an increase of age (>60 years), a longer disease course (>10 years), elevated levels of ESR, RF and anti-CCP, and decreased levels of IL-4 and SOD. In RA-FLS, overexpression of Linc00638 significantly inhibited while Linc00638 interference obviously enhanced the cell viability. Over-expression of Linc00638 also significantly increased the levels of IL-4 and SOD (P < 0.05) and decreased the expressions of IL-6 and ROS (P < 0.05), while interference of Linc00638 produced the opposite effects in the cells (P < 0.05). CONCLUSION: RA patients have low expression levels of Linc00638, which may participate in disease progression by regulating inflammation and oxidative stress.


Assuntos
Artrite Reumatoide , RNA Longo não Codificante , Artrite Reumatoide/genética , Humanos , Inflamação/genética , Leucócitos Mononucleares , Pessoa de Meia-Idade , Estresse Oxidativo , RNA Longo não Codificante/genética
16.
Cytokine ; 146: 155634, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34247039

RESUMO

Thrombopoietin (TPO) is most recognized for its function as the primary regulator of megakaryocyte (MK) expansion and differentiation. MKs, in turn, are best known for their role in platelet production. Research indicates that MKs and platelets play an extensive role in the pathologic thrombosis at sites of high inflammation. TPO, therefore, is a key mediator of thromboinflammation. Silencing of TPO has been shown to decrease platelets levels and rates of pathologic thrombosis in patients with various inflammatory disorders (Barrett et al, 2020; Bunting et al, 1997; Desai et al, 2018; Kaser et al, 2001; Shirai et al, 2019). Given the high rates of thromboinflammmation in the novel coronavirus 2019 (COVID-19), as well as the well-documented aberrant MK activity in affected patients, TPO silencing offers a potential therapeutic modality in the treatment of COVID-19 and other pathologies associated with thromboinflammation. The current review explores the current clinical applications of TPO silencing and offers insight into a potential role in the treatment of COVID-19.


Assuntos
COVID-19/terapia , Inativação Gênica , Inflamação/genética , Trombocitose/genética , Trombopoetina/genética , Trombose/genética , COVID-19/complicações , COVID-19/virologia , Humanos , Inflamação/complicações , Inflamação/metabolismo , Megacariócitos/metabolismo , SARS-CoV-2/fisiologia , Trombocitose/complicações , Trombocitose/metabolismo , Trombopoese/genética , Trombopoetina/metabolismo , Trombose/complicações , Trombose/metabolismo
17.
Ann Palliat Med ; 10(6): 6410-6418, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34237962

RESUMO

BACKGROUND: Sepsis is common in intensive care units and has a high mortality rate; yet, its pathogenesis and treatment remain unclear. Recent studies have shown that long non-coding RNA plasmacytoma variant translocation 1 (lncRNA-PVT1) plays a pro-inflammatory role in immune-related inflammatory diseases. Therefore, we investigated whether lncRNA-PVT1 plays an important pro-inflammatory effect in the inflammatory response of sepsis. METHODS: Quantitative real-time PCR (RT-qPCR) was employed for the detection of lncRNA-PVT1, interleukin 1ß (IL-1ß), and tumor necrosis factor α (TNF-α) mRNA, and the correlations between their expressions were analyzed. After lncRNA-PVT1 knockdown by lncRNA Smart Silencer, abnormal expressions of lncRNA-PVT1, and IL-1ß and TNF-α mRNA were detected. The expressions of total and phosphorylated protein of p38 were detected by western blotting. The effect of silencing lncRNA-PVT1 on p38 mitogen-activated protein kinase (MAPK) signaling pathway during lipopolysaccharide (LPS)-induced inflammation was subsequently analyzed. The MAPK selective inhibitor, SB202190, was used to block this signaling pathway, and the expressions of lncRNA-PVT1 and TNF-α were detected by RT-qPCR. Furthermore, the effect of partial blockade of the p38 MAPK signaling pathway by SB202190 on the levels of lncRNA-PVT1 was explored. RESULTS: Following treatment of THP-1-derived macrophages with different concentrations of LPS, the levels of lncRNA-PVT1 and IL-1ß, TNF-α mRNA were increased in a dose-dependent manner. Silencing of lncRNA-PVT1 reduced the expressions of IL-1ß and TNF-α mRNA via inhibition of the p38 MAPK signaling pathway. Specifically, inhibiting the p38 MAPK pathway significantly decreased the LPS-induced lncRNA-PVT1 elevation. CONCLUSIONS: Our observations suggest that lncRNA-PVT1 can be silenced to ameliorate LPS-induced inflammation in macrophages via inhibition of the p38 MAPK pathway. Further, the p38 MAPK pathway can regulate the expression of lncRNA-PVT1 via a positive feedback loop.


Assuntos
Lipopolissacarídeos , RNA Longo não Codificante , Humanos , Inflamação/genética , Sistema de Sinalização das MAP Quinases , Macrófagos/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Mol Med Rep ; 24(4)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34328196

RESUMO

Inflammation and oxidative stress have indispensable roles in the development of acute lung injury (ALI). MicroRNA (miRNA/miR)­351­5p was initially identified as a myogenesis­associated miRNA; however, its role in lipopolysaccharide (LPS)­induced ALI remains unclear. The aim of the present study was to investigate the role and potential mechanisms of miR­351­5p in ALI. ALI was induced through a single intratracheal injection of LPS for 12 h, and miR­351­5p agomir, antagomir or their corresponding negative controls were injected into the tail vein before LPS stimulation. Compound C, 2',5'­dideoxyadenosine and H89 were used to inhibit AMP­activated protein kinase (AMPK), adenylate cyclase and protein kinase A (PKA), respectively. miR­351­5p levels in the lungs were significantly increased in response to LPS injection. miR­351­5p antagomir alleviated, while miR­351­5p agomir aggravated LPS­induced oxidative stress and inflammation in the lungs. The present results also demonstrated that miR­351­5p antagomir attenuated LPS­induced ALI via activating AMPK, and that the cAMP/PKA axis was required for the activation of AMPK by the miR­351­5p antagomir. In conclusion, the present study indicated that miR­351­5p aggravated LPS­induced ALI via inhibiting AMPK, suggesting that targeting miR­351­5p may help to develop efficient therapeutic approaches for treating ALI.


Assuntos
Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Animais , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Inflamação/genética , Lipopolissacarídeos/toxicidade , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/genética
19.
Nat Commun ; 12(1): 4314, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262047

RESUMO

Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Here, we analyze the transcriptomes of 611,398 single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in patients with chronic lung diseases. We observe a similar cellular distribution and relative expression of SARS-CoV-2 entry factors in control and CLD lungs. CLD AT2 cells express higher levels of genes linked directly to the efficiency of viral replication and the innate immune response. Additionally, we identify basal differences in inflammatory gene expression programs that highlight how CLD alters the inflammatory microenvironment encountered upon viral exposure to the peripheral lung. Our study indicates that CLD is accompanied by changes in cell-type-specific gene expression programs that prime the lung epithelium for and influence the innate and adaptive immune responses to SARS-CoV-2 infection.


Assuntos
Pneumopatias/genética , SARS-CoV-2/fisiologia , Transcriptoma , Internalização do Vírus , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/genética , COVID-19/patologia , Doença Crônica , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Imunidade Inata/genética , Inflamação/genética , Pulmão/metabolismo , Pulmão/patologia , Pneumopatias/patologia , SARS-CoV-2/patogenicidade , Replicação Viral/genética
20.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203467

RESUMO

Chitinases belong to the evolutionarily conserved glycosyl hydrolase family 18 (GH18). They catalyze degradation of chitin to N-acetylglucosamine by hydrolysis of the ß-(1-4)-glycosidic bonds. Although mammals do not synthesize chitin, they possess two enzymatically active chitinases, i.e., chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase), as well as several chitinase-like proteins (YKL-40, YKL-39, oviductin, and stabilin-interacting protein). The latter lack enzymatic activity but still display oligosaccharides-binding ability. The physiologic functions of chitinases are still unclear, but they have been shown to be involved in the pathogenesis of various human fibrotic and inflammatory disorders, particularly those of the lung (idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, sarcoidosis, and asthma) and the gastrointestinal tract (inflammatory bowel diseases (IBDs) and colon cancer). In this review, we summarize the current knowledge about chitinases, particularly in IBDs, and demonstrate that chitinases can serve as prognostic biomarkers of disease progression. Moreover, we suggest that the inhibition of chitinase activity may be considered as a novel therapeutic strategy for the treatment of IBDs.


Assuntos
Quitinases/metabolismo , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Animais , Proteína 1 Semelhante à Quitinase-3/genética , Proteína 1 Semelhante à Quitinase-3/metabolismo , Quitinases/genética , Humanos , Inflamação/genética , Doenças Inflamatórias Intestinais/genética
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