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1.
Int Immunopharmacol ; 100: 108071, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34482267

RESUMO

COVID-19 is the cause of a pandemic associated with substantial morbidity and mortality. As yet, there is no available approved drug to eradicate the virus. In this review article, we present an alternative study area that may contribute to the development of therapeutic targets for COVID-19. Growing evidence is revealing further pathophysiological mechanisms of COVID-19 related to the disregulation of inflammation pathways that seem to play a critical role toward COVID-19 complications. The NF-kB and JAK/STAT signaling pathways are highly activated in acute inflammation, and the excessive activity of these pathways in COVID-19 patients likely exacerbates the inflammatory responses of the host. A group of non-coding RNAs (miRNAs) manage certain features of the inflammatory process. In this study, we discuss recent advances in our understanding of miRNAs and their connection to inflammatory responses. Additionally, we consider the link between perturbations in miRNA levels and the onset of COVID-19 disease. Furthermore, previous studies published in the online databases, namely web of science, MEDLINE (PubMed), and Scopus, were reviewed for the potential role of miRNAs in the inflammatory manifestations of COVID-19. Moreover, we disclosed the interactions of inflammatory genes using STRING DB and designed interactions between miRNAs and target genes using Cityscape software. Several miRNAs, particularly miR-9, miR-98, miR-223, and miR-214, play crucial roles in the regulation of NF-kB and JAK-STAT signaling pathways as inflammatory regulators. Therefore, this group of miRNAs that mitigate inflammatory pathways can be further regarded as potential targets for far-reaching-therapeutic strategies in COVID-19 diseases.


Assuntos
COVID-19/etiologia , Inflamação/etiologia , Janus Quinases/fisiologia , MicroRNAs/fisiologia , NF-kappa B/fisiologia , SARS-CoV-2 , Fatores de Transcrição STAT/fisiologia , Humanos , Transdução de Sinais/fisiologia
2.
J Am Soc Nephrol ; 32(9): 2117-2124, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108233

RESUMO

Ischemia reperfusion injury (IRI) is the most common cause of in-hospital AKI and is associated with increased morbidity and mortality. IRI is associated with an early phase of inflammation primarily regulated by the canonical NFκB signaling pathway. Despite recent advances in our understanding of the pathogenesis of IRI, few therapeutic strategies have emerged. The purpose of this manuscript is to review interventions targeting NFκB after IRI.


Assuntos
Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , NF-kappa B/fisiologia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/terapia , Injúria Renal Aguda/patologia , Humanos , Transdução de Sinais/fisiologia
3.
Front Immunol ; 12: 642842, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177892

RESUMO

The balance between pro- and anti-inflammatory immune system responses is crucial to face and counteract complex diseases such as cancer. Macrophages are an essential population that contributes to this balance in collusion with the local tumor microenvironment. Cancer cells evade the attack of macrophages by liberating cytokines and enhancing the transition to the M2 phenotype with pro-tumoral functions. Despite this pernicious effect on immune systems, the M1 phenotype still exists in the environment and can eliminate tumor cells by liberating cytokines that recruit and activate the cytotoxic actions of TH1 effector cells. Here, we used a Boolean modeling approach to understand how the tumor microenvironment shapes macrophage behavior to enhance pro-tumoral functions. Our network reconstruction integrates experimental data and public information that let us study the polarization from monocytes to M1, M2a, M2b, M2c, and M2d subphenotypes. To analyze the dynamics of our model, we modeled macrophage polarization in different conditions and perturbations. Notably, our study identified new hybrid cell populations, undescribed before. Based on the in vivo macrophage behavior, we explained the hybrid macrophages' role in the tumor microenvironment. The in silico model allowed us to postulate transcriptional factors that maintain the balance between macrophages with anti- and pro-tumoral functions. In our pursuit to maintain the balance of macrophage phenotypes to eliminate malignant tumor cells, we emulated a theoretical genetically modified macrophage by modifying the activation of NFκB and a loss of function in HIF1-α and discussed their phenotype implications. Overall, our theoretical approach is as a guide to design new experiments for unraveling the principles of the dual host-protective or -harmful antagonistic roles of transitional macrophages in tumor immunoediting and cancer cell fate decisions.


Assuntos
Macrófagos/fisiologia , Neoplasias/imunologia , Transcrição Genética , Microambiente Tumoral , Polaridade Celular , Redes Reguladoras de Genes , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Modelos Teóricos , NF-kappa B/fisiologia
4.
Front Immunol ; 12: 675909, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34113349

RESUMO

The lipopolysaccharides (LPSs) of Rhodobacter are reported to be TLR4 antagonists. Accordingly, the extract of Rhodobacter azotoformans (RAP99) is used as a health supplement for humans and animals in Japan to regulate immune responses in vivo. We previously analyzed the LPS structure of RAP99 (RAP99-LPS) and found it is different from that of E. coli-LPS but similar to lipid A from Rhodobacter sphaeroides (RSLA), a known antagonist of TLR4, with both having three C14 fatty acyl groups, two C10 fatty acyl groups, and two phosphates. Here we show that RAP99-LPS has an immune stimulatory activity and acts as a TLR4 agonist. Pretreatment of RAP99-LPS suppressed E. coli-LPS-mediated weight loss, suggesting it is an antagonist against E. coli-LPS like other LPS isolated from Rhodobacter. However, injections of RAP99-LPS caused splenomegaly and increased immune cell numbers in C57BL/6 mice but not in C3H/HeJ mice, suggesting that RAP99-LPS stimulates immune cells via TLR4. Consistently, RAP99-LPS suppressed the lung metastasis of B16F1 tumor cells and enhanced the expression of TLR3-mediated chemokines. These results suggest that RAP99-LPS is a TLR4 agonist that enhances the activation status of the immune system to promote anti-viral and anti-tumor activity in vivo.


Assuntos
Quimiocinas/genética , Lipopolissacarídeos/farmacologia , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Rhodobacter/química , Receptor 3 Toll-Like/fisiologia , Receptor 4 Toll-Like/agonistas , Animais , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , NF-kappa B/fisiologia , Fator de Transcrição STAT3/fisiologia
5.
Front Immunol ; 12: 676173, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34054865

RESUMO

Increased interleukin (IL)-17A has been identified in joints affected by osteoarthritis (OA), but it is unclear how IL-17A, and its family members IL-17AF and IL-17F, can contribute to human OA pathophysiology. Therefore, we aimed to evaluate the gene expression and signalling pathway activation effects of the different IL-17 family members in chondrocytes and synovial fibroblasts derived from cartilage and synovium of patients with end-stage knee OA. Immunohistochemistry staining confirmed that IL-17 receptor A (IL-17RA) and IL-17RC are expressed in end-stage OA-derived cartilage and synovium. Chondrocytes and synovial fibroblasts derived from end-stage OA patients were treated with IL-17A, IL-17AF, or IL-17F, and gene expression was assessed with bulk RNA-Seq. Hallmark pathway analysis showed that IL-17 cytokines regulated several OA pathophysiology-related pathways including immune-, angiogenesis-, and complement-pathways in both chondrocytes and synovial fibroblasts derived from end-stage OA patients. While overall IL-17A induced the strongest transcriptional response, followed by IL-17AF and IL-17F, not all genes followed this pattern. Disease-Gene Network analysis revealed that IL-17A-related changes in gene expression in these cells are associated with experimental arthritis, knee arthritis, and musculoskeletal disease gene-sets. Western blot analysis confirmed that IL-17A significantly activates p38 and p65 NF-κB. Incubation of chondrocytes and synovial fibroblasts with anti-IL-17A monoclonal antibody secukinumab significantly inhibited IL-17A-induced gene expression. In conclusion, the association of IL-17-induced transcriptional changes with arthritic gene-sets supports a role for IL-17A in OA pathophysiology. Future studies should further investigate the role of IL-17A in the OA joint to establish whether anti-IL-17 treatment could be a potential therapeutic option in OA patients with an inflammatory phenotype.


Assuntos
Condrócitos/imunologia , Interleucina-17/fisiologia , Osteoartrite do Joelho/etiologia , Membrana Sinovial/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Células Cultivadas , Condrócitos/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Humanos , Interleucina-17/farmacologia , NF-kappa B/fisiologia , Osteoartrite do Joelho/imunologia , Receptores de Interleucina-17/análise , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia
6.
Int J Mol Sci ; 22(7)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918134

RESUMO

The persistence of latent HIV provirus pools in different resting CD4+ cell subsets remains the greatest obstacle in the current efforts to treat and cure HIV infection. Recent efforts to purge out latently infected memory CD4+ T-cells using latency-reversing agents have failed in clinical trials. This review discusses the epigenetic and non-epigenetic mechanisms of HIV latency control, major limitations of the current approaches of using latency-reversing agents to reactivate HIV latency in resting CD4+ T-cells, and potential solutions to these limitations.


Assuntos
Linfócitos T CD4-Positivos/virologia , Epigênese Genética/imunologia , HIV/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Latência Viral , Humanos , Memória Imunológica , NF-kappa B/fisiologia , Fator B de Elongação Transcricional Positiva/fisiologia , Reinfecção
7.
Life Sci Alliance ; 4(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33858959

RESUMO

Tumor necrosis factor receptor 1 (TNFR1) activates NF-κB-dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-κB kinase (IKK)/NF-κB signaling in keratinocytes paradoxically unleashed spontaneous TNFR1-mediated skin inflammation in mice, but the underlying mechanisms remain poorly understood. Here, we show that TNFR1 causes skin inflammation in mice with epidermis-specific knockout of IKK2 by inducing receptor interacting protein kinase 1 (RIPK1)-dependent necroptosis, and to a lesser extent also apoptosis, of keratinocytes. Combined epidermis-specific ablation of the NF-κB subunits RelA and c-Rel also caused skin inflammation by inducing TNFR1-mediated keratinocyte necroptosis. Contrary to the currently established model that inhibition of NF-κB-dependent gene transcription causes RIPK1-independent cell death, keratinocyte necroptosis, and skin inflammation in mice with epidermis-specific RelA and c-Rel deficiency also depended on RIPK1 kinase activity. These results advance our understanding of the mechanisms regulating TNFR1-induced cell death and identify RIPK1-mediated necroptosis as a potent driver of skin inflammation.


Assuntos
Queratinócitos/metabolismo , Necroptose/fisiologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Apoptose/fisiologia , Feminino , Quinase I-kappa B/metabolismo , Inflamação/metabolismo , Queratinócitos/patologia , Masculino , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , NF-kappa B/fisiologia , Necroptose/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais , Pele/metabolismo , Pele/patologia , Fator de Necrose Tumoral alfa/farmacologia
8.
Endocrinology ; 162(7)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33912936

RESUMO

Secondary hyperparathyroidism (SHPT) in uremic patients is characterized by parathyroid gland (PTG) hyperplasia and parathyroid hormone (PTH) elevation. Previously, we demonstrated that NF-κB activation contributed to parathyroid cell proliferation in rats with chronic kidney disease. Although vitamin D inhibits inflammation and ameliorates SHPT, the contribution of vitamin D deficiency to SHPT via local NF-κB activation remains to be clarified. PTGs collected from 10 uremic patients with advanced SHPT were used to test the expressions of vitamin D receptor (VDR), NF-κB, and proliferating cell nuclear antigen (PCNA). Freshly excised PTG tissues were incubated for 24 hours in vitro with VDR activator (VDRA) calcitriol or NF-κB inhibitor pyrrolidine thiocarbamate (PDTC). Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to investigate the regulation of PTH transcription by NF-κB. We found higher levels of activated NF-κB and lower expression of VDR in nodular hyperplastic PTGs than in diffuse hyperplasia. In cultured PTG tissues, treatment with VDRA or PDTC inhibited NF-κB activation and PCNA expression, and downregulated preproPTH mRNA and intact PTH levels. ChIP assays demonstrated the presence of NF-κB binding sites in PTH promoter. Furthermore, in luciferase reporter assays, addition of exogenous p65 significantly increased PTH luciferase activity by 2.4-fold (P < 0.01), while mutation of NF-κB binding site at position -908 of the PTH promoter suppressed p65-induced PTH reporter activity (P < 0.01). In summary, local NF-κB activation contributes to SHPT and mediates the transcriptional activation of PTH directly in uremic patients. Vitamin D deficiency may be involved in SHPT via the activation of NF-κB pathway.


Assuntos
NF-kappa B/fisiologia , Glândulas Paratireoides/metabolismo , Hormônio Paratireóideo/metabolismo , Uremia/metabolismo , Calcitriol/administração & dosagem , Feminino , Humanos , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/metabolismo , Hiperparatireoidismo Secundário/patologia , Hiperplasia , Masculino , Pessoa de Meia-Idade , NF-kappa B/antagonistas & inibidores , Glândulas Paratireoides/química , Glândulas Paratireoides/patologia , Hormônio Paratireóideo/biossíntese , Hormônio Paratireóideo/genética , Antígeno Nuclear de Célula em Proliferação/análise , Pirrolidinas/administração & dosagem , Receptores de Calcitriol/análise , Receptores de Calcitriol/efeitos dos fármacos , Receptores de Calcitriol/metabolismo , Tiocarbamatos/administração & dosagem , Técnicas de Cultura de Tecidos , Fator de Transcrição RelA/análise , Transcrição Genética/efeitos dos fármacos , Uremia/complicações , Uremia/patologia
9.
Int Urol Nephrol ; 53(7): 1473-1482, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33763781

RESUMO

BACKGROUND/AIMS: Inflammation is well known to play a pivotal role in renal injury. Rhein is a major component of the medicinal Rhubarb. The aim of this study was to investigate whether Rhein protects against renal injury and explore its underlying mechanism. METHODS: 5/6 nephrectomization (5/6 Nx) was operated on Sprague-Dawley rats. Human kidney tubular epithelial (HK-2) cells were treated with lipopolysaccharide (LPS). The level of blood urea nitrogen (BUN) and serum creatinine (SCr) was examined. Kidney tissues were stained with hematoxylin and eosin to check the morphology. The cell viability was examined. The levels of cytokines and chemokines were measured by ELISA kit. The protein expression was determined by western blot. RESULTS: Rhein significantly decreased SCr and BUN levels in 5/6 Nx rat. The morphologic findings indicated noteworthy amelioration of the damaged renal tissue in Rhein-treated rats. Rhein significantly protects HK-2 cells from LPS-mediated apoptosis. The productions of inflammatory signaling molecules (TNF-α, IL-6 and MCP-1) were inhibited by Rhein. LPS-induced NF-κB activation was also attenuated by Rhein via blocking its nuclear translocation by inhibiting phosphorylation of IκBα. CONCLUSION: These findings provide evidence that Rhein protect against renal injury, and NF-κB signaling pathway is involved in this protective effect.


Assuntos
Antraquinonas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Inflamação/prevenção & controle , NF-kappa B/fisiologia , Nefrectomia , Complicações Pós-Operatórias/prevenção & controle , Insuficiência Renal Crônica/prevenção & controle , Transdução de Sinais/fisiologia , Animais , Masculino , Ratos , Ratos Sprague-Dawley
10.
Anticancer Res ; 41(3): 1251-1259, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33788716

RESUMO

BACKGROUND/AIM: Sorafenib, an oral multi-kinase inhibitor, has been shown to improve the outcome of patients with osteosarcoma (OS). However, the anti-OS effect and mechanism of sorafenib has not yet been fully understood. The main purpose of this study was to investigate the effect of sorafenib on apoptotic signaling and Nuclear Factor-κB (NF-κB)-mediated anti-apoptotic and metastatic potential in OS in vitro. MATERIALS AND METHODS: The effect of sorafenib on apoptotic signaling transduction, anti-apoptotic, and metastatic potential of OS U-2 cells was verified with flow cytometry, trans-well invasion/migration, and western blotting assay. RESULTS: Sorafenib induced the extrinsic and intrinsic apoptotic pathways. In addition, sorafenib reduced the invasion and migration ability of OS cells, induced NF-κB activation, and the expression of anti-apoptotic proteins and metastasis-associated proteins encoded by NF-κB target genes. CONCLUSION: Sorafenib led to stimulation of extrinsic/intrinsic apoptotic pathways and NF-κB inactivation in U-2 OS cells.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Osteossarcoma/tratamento farmacológico , Sorafenibe/farmacologia , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Humanos , NF-kappa B/fisiologia , Invasividade Neoplásica , Metástase Neoplásica , Osteossarcoma/patologia , Osteossarcoma/secundário
11.
Front Immunol ; 12: 630381, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763073

RESUMO

Aneurysmal subarachnoid hemorrhage (aSAH) is a highly fatal and morbid type of hemorrhagic strokes. Intracranial aneurysms (ICAs) rupture cause subarachnoid hemorrhage. ICAs formation, growth and rupture involves cellular and molecular inflammation. Macrophages orchestrate inflammation in the wall of ICAs. Macrophages generally polarize either into classical inflammatory (M1) or alternatively-activated anti-inflammatory (M2)-phenotype. Macrophage infiltration and polarization toward M1-phenotype increases the risk of aneurysm rupture. Strategies that deplete, inhibit infiltration, ameliorate macrophage inflammation or polarize to M2-type protect against ICAs rupture. However, clinical translational data is still lacking. This review summarizes the contribution of macrophage led inflammation in the aneurysm wall and discuss pharmacological strategies to modulate the macrophageal response during ICAs formation and rupture.


Assuntos
Aneurisma Roto/etiologia , Aneurisma Intracraniano/etiologia , Macrófagos/fisiologia , Polaridade Celular , Humanos , Inflamação/etiologia , Aneurisma Intracraniano/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Monócitos/fisiologia , NF-kappa B/fisiologia
12.
J Mol Med (Berl) ; 99(4): 517-530, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33538854

RESUMO

The human gastrointestinal tract is in constant contact with microbial stimuli. Its barriers have to ensure co-existence with the commensal bacteria, while enabling surveillance of intruding pathogens. At the centre of the interaction lies the epithelial layer, which marks the boundaries of the body. It is equipped with a multitude of different innate immune sensors, such as Toll-like receptors, to mount inflammatory responses to microbes. Dysfunction of this intricate system results in inflammation-associated pathologies, such as inflammatory bowel disease. However, the complexity of the cellular interactions, their molecular basis and their development remains poorly understood. In recent years, stem cell-derived organoids have gained increasing attention as promising models for both development and a broad range of pathologies, including infectious diseases. In addition, organoids enable the study of epithelial innate immunity in vitro. In this review, we focus on the gastrointestinal epithelial barrier and its regional organization to discuss innate immune sensing and development.


Assuntos
Células Epiteliais/imunologia , Trato Gastrointestinal/imunologia , Imunidade Inata , Organoides , Adulto , Animais , Bancos de Espécimes Biológicos , Polaridade Celular , Previsões , Microbioma Gastrointestinal/imunologia , Trato Gastrointestinal/citologia , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Perfilação da Expressão Gênica , Células Caliciformes/imunologia , Humanos , Tolerância Imunológica , Recém-Nascido , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/imunologia , Camundongos , Modelos Imunológicos , NF-kappa B/fisiologia , Especificidade de Órgãos , Organoides/citologia , Organoides/imunologia , Celulas de Paneth/imunologia , Nódulos Linfáticos Agregados/imunologia , Células-Tronco/imunologia , Receptores Toll-Like/imunologia
13.
FASEB J ; 35(3): e21375, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33559200

RESUMO

Host-pathogen interactions play an important role in defining the outcome of a disease. Recent studies have shown that the bacterial quorum sensing molecules (QSM) can interact with host cell membrane proteins, mainly G protein-coupled receptors (GPCRs), and induce innate immune responses. However, few studies have examined QSM-GPCR interactions and their influence on oral innate immune responses. In this study, we examined the role of bitter taste receptor T2R14 in sensing competence stimulating peptides (CSPs) secreted by cariogenic bacterium Streptococcus mutans and in mediating innate immune responses in gingival epithelial cells (GECs). Transcriptomic and western blot analyses identify T2R14 to be highly expressed in GECs. Our data show that only CSP-1 from S. mutans induces robust intracellular calcium mobilization compared to CSP-2 and CSP-3. By using CRISPR-Cas9, we demonstrate that CSP-1 induced calcium signaling and secretion of cytokines CXCL-8/IL-8, TNF-α, and IL-6 is mediated through T2R14 in GECs. Interestingly, the NF-kB signaling activated by CSP-1 in GECs was independent of T2R14. CSP-1-primed GECs attracted differentiated HL-60 immune cells (dHL-60) and this effect was abolished in T2R14 knock down GECs and also in cells primed with T2R14 antagonist 6-Methoxyflavone (6-MF). Our findings identify S. mutans CSP-1 as a peptide ligand for the T2R family. Our study establishes a novel host-pathogen interaction between cariogenic S. mutans CSP-1 and T2R14 in GECs leading to an innate immune response. Collectively, these findings suggest T2Rs as potential therapeutic targets to modulate innate immune responses upon oral bacterial infections.


Assuntos
Proteínas de Bactérias/fisiologia , Gengiva/imunologia , Interações Hospedeiro-Patógeno , Percepção de Quorum/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Streptococcus mutans/fisiologia , Cálcio/metabolismo , Linhagem Celular , Movimento Celular , Citocinas/biossíntese , Células Epiteliais/imunologia , Gengiva/citologia , Humanos , Imunidade Inata , NF-kappa B/fisiologia , Fosfolipase C beta/fisiologia
14.
FASEB J ; 35(3): e21283, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33617050

RESUMO

The pathological characteristics of osteoarthritis are cartilage matrix degradation, chondrocytes apoptosis, and low-grade inflammation of the joint. Recent studies have shown that blood vessels grow from the subchondral bone to the articular cartilage. However, the relationship among inflammation, angiogenesis, and chondrocyte apoptosis is still unclear. We found that chondrocytes could secrete chemokines and VEGF to promote the migration of vascular endothelial cells in response to TNF-α stimulation. The invasion of blood vessels leads to increased oxygen tension in the local environment, which increased the expression of SETD7 in chondrocytes by activating the JAK-STAT5 pathway. The bond of phosphorylated STAT5 and the specific locus in the promoter of SETD7 directly increased the transcription of SETD7. On the one hand, SETD7-regulated chemokine expression by forming a positive loop; on the other hand, SETD7-mediated chondrocyte apoptosis by inhibiting the nuclear localization of HIF-1α. In this study, we discovered a novel function of chondrocytes as mediators of inflammation and angiogenesis. Our study demonstrates that SETD7 is a potential molecular target to prevent OA development and progression.


Assuntos
Apoptose , Cartilagem Articular/patologia , Condrócitos/patologia , Histona-Lisina N-Metiltransferase/fisiologia , Osteoartrite/patologia , Animais , Movimento Celular , Células Cultivadas , Condrócitos/fisiologia , Células Endoteliais/fisiologia , Feminino , Histona-Lisina N-Metiltransferase/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/fisiologia , Neovascularização Patológica/etiologia , Osteoartrite/etiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Fator de Transcrição STAT5/fisiologia
15.
FASEB J ; 35(3): e21383, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33629796

RESUMO

Breast cancer is a malignancy arising in the mammary epithelial tissues. Recent studies have indicated the abundance of microRNAs (miRNAs) in extracellular vesicles (EVs), and their interactions have been illustrated to exert crucial roles in the cell-to-cell communication. The present study focused on investigating whether EV-delivered miR-370-3p affects breast cancer. Initially, the miR-370-3p expression pattern was examined in the cancer-associated fibroblasts (CAFs), normal fibroblasts (NFs), and cancerous cells-derived EVs. The relation of miR-370-3p to CYLD was assessed using luciferase activity assay. Afterwards, based on ectopic expression and depletion experiments in the MCF-7 breast cancer cells, we evaluated stemness, migration, invasion, and sphere formation ability, and EMT, accompanied with measurement on the expression patterns of pro-inflammatory factors and nuclear factor-kappa B (NF-κB) signaling-related genes. Finally, tumorigenesis and proliferation were analyzed in vivo using a nude mouse xenograft model. The in vitro experiments revealed that breast cancer cell-derived EVs promoted NF activation, while activated fibroblasts contributed to enhanced stemness, migration, invasion, as well as EMT of cancerous cells. In addition, EVs could transfer miR-370-3p from breast cancer cells to NFs, and EV-encapsulated miR-370-3p was also found to facilitate fibroblast activation. Mechanistically, EV-encapsulated miR-370-3p downregulated the expression of CYLD through binding to its 3'UTR and activated the NF-κB signaling pathway, thereby promoting the cellular functions in vitro and in vivo in breast cancer. Taken together, EVs secreted by breast cancer cells could carry miR-370-3p to aggravate breast cancer through downregulating CYLD expression and activating the NF-κB signaling pathway.


Assuntos
Neoplasias da Mama/patologia , Enzima Desubiquitinante CYLD/fisiologia , Vesículas Extracelulares/fisiologia , Fibroblastos/fisiologia , MicroRNAs/fisiologia , NF-kappa B/fisiologia , Animais , Linhagem Celular Tumoral , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Humanos , Neoplasias Pulmonares/secundário , Camundongos , Transdução de Sinais/fisiologia
16.
J Surg Res ; 262: 212-223, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33610056

RESUMO

BACKGROUND: Intestinal ischemia-reperfusion (I/R) injury constitutes a severe disorder, in great part resulting from oxidative stress. Because sulforaphane and albumin were shown to increase antioxidant defenses, we evaluated the therapeutic potential of these agents in an experimental model of I/R injury. METHODS: Wistar rats were used to establish a model of intestinal I/R (35 min of ischemia, followed by 45 min of reperfusion) and were treated with albumin (5 mL/kg), sulforaphane (500 µg/kg), or saline intravenously before reperfusion. Animals that were not subjected to I/R served as the sham (laparotomy only) and control groups. Blood samples were analyzed for arterial gas, reactive oxygen species, and reactive nitrogen species using different molecular fluorescent probes. After euthanasia, ileal samples were collected for analysis, including histopathology, immunohistochemistry, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling assays, and lactic dehydrogenase measurement. RESULTS: Oxygenation status and hemodynamic parameters were uniform during the experiment. The sulforaphane- or albumin-treated groups showed reduced concentrations of reactive oxygen species (P < 0.04), nitric oxide (P < 0.001), and peroxynitrite (P = 0.001), compared with I/R injury untreated animals. Treatment with sulforaphane or albumin resulted in the preservation of goblet cells (P < 0.03), reductions in histopathologic scores (P < 0.01), macrophage density (P < 0.01), iNOS expression (P < 0.004), NF-kappa B activation (P < 0.05), and apoptotic rates (P < 0.04) in the mucosa and a reduction in the concentration of lactic dehydrogenase (P < 0.04), more pronounced with sulforaphane. CONCLUSIONS: Attenuation of intestinal I/R injury in this model probably reflects the antioxidative effects of systemic administration of both sulforaphane and albumin and reinforces their use in future translational research.


Assuntos
Albuminas/uso terapêutico , Antioxidantes/uso terapêutico , Intestinos/irrigação sanguínea , Isotiocianatos/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Sulfóxidos/uso terapêutico , Animais , Modelos Animais de Doenças , Masculino , NF-kappa B/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
17.
J Mol Neurosci ; 71(1): 28-41, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32567007

RESUMO

This study was designed to test whether the Cronobacter sakazakii infection-impaired contextual learning and memory are mediated by the activation of the complement system; subsequent activation of inflammatory signals leads to alternations in serotonin transporter (SERT). To test this, rat pups (postnatal day, PND 15) were treated with either C. sakazakii (107 CFU) or Escherichia coli OP50 (107 CFU) or Luria bertani broth (100 µL) through oral gavage and allowed to stay with their mothers until PND 24. Experimental groups' rats were allowed to explore (PNDs 31-35) and then trained in contextual learning task (PNDs 36-43). Five days after training, individuals were tested for memory retention (PNDs 49-56). Observed behavioural data showed that C. sakazakii infection impaired contextual-associative learning and memory. Furthermore, our analysis showed that C. sakazakii infection activates complement system complement anaphylatoxin (C5a) (a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1)) and mitogen-activated protein kinase kinase1 (MEKK1). Subsequently, MEKK1 induces pro-inflammatory signals possibly through apoptosis signal-regulating kinase-1 (ASK-1), c-Jun N-terminal kinase (JNK1/3) and protein kinase B gamma (AKT-3). In parallel, activated nuclear factor kappa-light-chain-enhancer B cells (NF-κB) induces interleukin-6 (IL-6) and IFNα-1, which may alter the level of serotonin transporter (SERT). Observed results suggest that impaired contextual learning and memory could be correlated with C5a-mediated NF-κß and ASK1 pathways.


Assuntos
Aprendizagem por Associação/fisiologia , Ativação do Complemento , Complemento C5a/fisiologia , Cronobacter sakazakii/patogenicidade , Infecções por Enterobacteriaceae/complicações , Deficiências da Aprendizagem/etiologia , MAP Quinase Quinase Quinase 5/fisiologia , Transtornos da Memória/etiologia , NF-kappa B/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Serotonina/metabolismo , Transdução de Sinais/fisiologia , Proteína ADAMTS1/metabolismo , Animais , Animais Lactentes , Córtex Cerebral/metabolismo , Infecções por Enterobacteriaceae/imunologia , Infecções por Escherichia coli/complicações , Infecções por Escherichia coli/imunologia , Regulação da Expressão Gênica/imunologia , Inflamação , Interferon-alfa/metabolismo , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Deficiências da Aprendizagem/imunologia , Deficiências da Aprendizagem/microbiologia , MAP Quinase Quinase Quinase 1/metabolismo , Transtornos da Memória/imunologia , Transtornos da Memória/microbiologia , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
18.
Int J Cancer ; 148(5): 1233-1244, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33205453

RESUMO

Tumor-associated macrophages (TAMs) are crucial components of the tumor microenvironment. They play vital roles in hepatocellular carcinoma (HCC) progression. However, the interactions between TAMs and HCC cells have not been fully characterized. In this study, TAMs were induced using human monocytic cell line THP-1 cells in vitro to investigate their functions in HCC progression. S100 calcium-binding protein A9 (S100A9), an inflammatory microenvironment-related secreted protein, was identified to be significantly upregulated in TAMs. S100A9 expression in tumor tissues was associated with poor survival of HCC patients. It could enhance the stem cell-like properties of HepG2 and MHCC-97H cells by activating nuclear factor-kappa B signaling pathway through advanced glycosylation end product-specific receptor in a Ca2+ -dependent manner. Furthermore, we found that, after treatment with S100A9, HepG2 and MHCC-97H cells recruited more macrophages via chemokine (CC motif) ligand 2, which suggests a positive feedback between TAMs and HCC cells. Taken together, our findings reveal that TAMs could upregulate secreted protein S100A9 and enhance the stem cell-like properties of HCC cells and provide a potential therapeutic target for combating HCC.


Assuntos
Calgranulina B/fisiologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/fisiologia , Macrófagos Associados a Tumor/fisiologia , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/fisiologia , Receptor para Produtos Finais de Glicação Avançada/fisiologia
19.
J Ethnopharmacol ; 264: 112800, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32224195

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The San Wu Huangqin Decoction (SWHD), which is made from the dried root of Sophora flavescens Aiton (Kushen in Chinese), the dried root of Scutellaria baicalensis Georgi (Huangqin in Chinese), and the dried root tuber of Rehmannia glutinosa (Gaertn.) DC. (Dihuang in Chinese), is a traditional Chinese formula used to treat prolonged fever and inflammatory diseases in clinics and proven to inhibit influenza virus effectively in our previous study. AIM OF THE STUDY: This work was performed to study the regulation of SWHD on inflammation and immune dysfunction induced by the influenza virus and the underlying mechanism in the treatment of SWHD. METHODS: In this study, the influenza virus A/PR/8/34 (H1N1)-infected mouse model was used to investigate the regulation of SWHD on inflammation and immune dysfunction induced by H1N1. The pathological changes, the capacity of proliferation of T and B lymphocytes, the cytotoxicity of natural killer (NK) cells, and the levels of IL-6, TNF-α, IL-1ß, IL-4, and IFN-γ in the serum, bronchoalveolar lavage fluid (BALF), and lung were analyzed. The effects of type 1 T helper cell (Th1) and type 2 T helper cell (Th2) immune responses were discussed indirectly. In addition, the expression levels of p-p65, p65, IKKα/ß, p-IκBα, and IκBα in relation to the NF-κB pathway were measured using Western blot analysis, or immunohistochemical assay. RESULTS: SWHD decreased the pathological changes in lung tissues, promoted the proliferation of T and B lymphocytes, enhanced NK cell activity, and accelerated the phagocytic function of macrophages in H1N1-infected mice. At the same time, SWHD decreased the levels of IL-6, TNF-α, IL-1ß, IFN-γ, and increased the level of IL-4 in the serum, BALF, and lung of model mice. Moreover, the p-p65, p65, and IκBα protein expression levels were inhibited, whereas the p-IκBα protein expression levels were improved in the lungs of H1N1-infected mice. CONCLUSIONS: SWHD can inhibit the replication of the H1N1 virus and reduced the excessive inflammation and immune dysfunction induced by the H1N1 virus in the body. This work provides rich experimental basis for further anti-inflammation research of SWHD and sets the foundation for the development of a viral inflammation drug of traditional Chinese medicine.


Assuntos
Antivirais/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Imunidade Celular/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , NF-kappa B/fisiologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Animais , Antivirais/farmacologia , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Imunidade Celular/fisiologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
20.
Domest Anim Endocrinol ; 74: 106508, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32861957

RESUMO

In this study, a rabbit endometritis model was developed to study cow endometritis. In addition, the protective effects of baicalin (a flavonoid) against endometritis were investigated. Clinical symptoms, differential leukocyte counting, uterine secretion smear microscopy and chemical examination, urine testing, and signs of necropsy showed abnormal changes and inflammatory responses in the uterus of rabbits. Histopathological results revealed visible inflammatory exudates and blood spots between intercellular spaces which confirmed that the rabbit endometritis model was successfully developed. Most importantly, these inflammatory signs were partially attenuated with baicalin treatment. The data revealed that the increased body temperature and leukocyte cells, pus, and the detachment of epithelial cells were alleviated with baicalin administration in a dose-dependent manner. Histopathological tissue changes such as inflammatory cells infiltrates, hyperemia, hemorrhages, and shedding of epithelial cells were partially attenuated with baicalin treatment. In addition, the mRNA expression of inflammation-related genes (iNOS, IL-1ß, TNF-α, IL-10, IL-4, and IL-6) was significantly altered in RAW264.7 cells after LPS treatment. Further, the phosphorylated protein expression of JNK, p65, and IκBα were significantly reduced with LPS treatment. Intriguingly, baicalin pretreatment reversed the alteration in mRNA expression of inflammation-related genes and significantly reduced the phosphorylation of JNK, p65, and IκBα. In summary, our results suggest that baicalin has protective effects on bacterial-induced endometritis in rabbits that involve the suppression of NF-κB and JNK signaling pathways and pro-inflammatory cytokines.


Assuntos
Endometrite/microbiologia , Infecções por Escherichia coli/tratamento farmacológico , Flavonoides/uso terapêutico , Sistema de Sinalização das MAP Quinases/fisiologia , NF-kappa B/fisiologia , Infecções Estafilocócicas/tratamento farmacológico , Animais , Anti-Infecciosos , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Doenças dos Bovinos/microbiologia , Citocinas/análise , Citocinas/genética , Modelos Animais de Doenças , Endometrite/tratamento farmacológico , Endometrite/veterinária , Feminino , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , NF-kappa B/efeitos dos fármacos , Células RAW 264.7 , RNA Mensageiro/análise , Coelhos , Útero/química , Útero/patologia
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