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1.
Gene ; 766: 145153, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32950633

RESUMO

AIM: Acute lung injury (ALI) is the mild form of acute respiratory distress syndrome (ARDS) which is a common lung disease with a high incidence and mortality rate. Recent studies manifested that some circular RNAs were associated with ALI. In this study, we aimed to uncover the effect of circular RNA circ_0054633 on ALI initiation and progression and proposed a new mechanism related to ALI. METHODS: The lipopolysaccharides (LPS)-induced acute lung injury model were build both in vivo of rat and in vitro of primary murine pulmonary microvascular endothelial cells (MPVECs). Hematoxylin and eosin (H&E) was employed to observe the tissue morphology and estimate the degree of lung damage. We used real-time quantitative polymerase chain reaction (RT-qPCR) to measure the expression level of circ_0054633. The expression levels of inflammatory cytokines IL-17A and tumor necrosis factor-α (TNF-α) were detected by ELISA. The effects of circ_0054633 on MPVECs proliferation and apoptosis were detected with the help of CCK-8 and apoptosis assay, separately. The expression level of NF-κB p65 protein was measured by Western blot. RESULTS: circ_0054633, IL-17A, TNF-α and NF-κB p65 were all overexpressed in LPS-treated rat and MPVECs, and LPS enhanced the proliferation and apoptosis of MPVECs. While circ_0054633 silencing reversed the above promotion effects of LPS on IL-17A, TNF-α expression and MPVECs proliferation and apoptosis. CONCLUSIONS: Quietness of circ_0054633 alleviated LPS-induced ALI via NF-κB signaling pathway, implicating circ_0054633 may be a potential biomarker for diagnose and therapy of ALI.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Proliferação de Células/fisiologia , Células Endoteliais/metabolismo , Inflamação/metabolismo , NF-kappa B/metabolismo , RNA Circular/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Inflamação/induzido quimicamente , Interleucina-17/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
2.
J Biol Regul Homeost Agents ; 34(5): 1699-1708, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33148374

RESUMO

Osteosarcoma is the most prevailing malignant bone tumor among adolescents. Punicalagin, a polyphenolic compound extracted from pomegranate, possesses many functions such as anti-oxidation, anti-bacterial, anti-virus, and immunosuppression, which can counter the aggressiveness of a variety of cancers such cervical, ovarian and prostate. This study aimed to investigate the inhibitory effect of punicalagin on the proliferation and metastasis of osteosarcoma cells and its potential regulatory mechanisms. Osteosarcoma cell lines (HOS cells, U2OS cells and MG63 cells) were treated with different doses of punicalagin, and the effects on osteosarcoma cell activity were examined in vitro using cell counting kit-8 (CCK-8), colony formation and apoptosis assays. The mobility, migration and invasion abilities of osteosarcoma cells were detected by wound healing and Transwell assays. NF-κB activity was explored by the NF-κB p65 luciferase reporter assay. Western blot was used to investigate the expressions of downstream proteins. We found that punicalagin inhibited the viability of osteosarcoma cells in vitro in dose-dependent and time-dependent manners and promoted apoptosis. In addition, punicalagin could significantly impede the mobility, migration and invasion abilities of osteosarcoma cells. In terms of mechanism, punicalagin down-regulated the expressions of p65, survivin, XIAP, CIAP2 and other proteins, and suppressed the proliferation and metastasis of osteosarcoma cells by repressing NF-κB signaling pathway. In conclusion, it is concluded that punicalagin restrains the growth and metastasis of osteosarcoma by obstructing the NF-κB signal transduction pathway.


Assuntos
Neoplasias Ósseas/patologia , Taninos Hidrolisáveis/uso terapêutico , NF-kappa B/antagonistas & inibidores , Osteossarcoma/patologia , Transdução de Sinais/efeitos dos fármacos , Apoptose , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , NF-kappa B/genética , Osteossarcoma/tratamento farmacológico
3.
In Vivo ; 34(6): 3723-3730, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33144490

RESUMO

BACKGROUND/AIM: Influenza viruses, corona viruses and related pneumotropic viruses cause sickness and death partly by inducing cytokine storm, a hyper-proinflammatory host response by immune cells and cytokines in the host airway. Based on our in vivo experience with digitoxin as an inhibitor of TNFα-driven NFĸB signaling for cytokine expression in prostate cancer in rats and in cystic fibrosis in humans, we hypothesize that this drug will also block a virally-activated cytokine storm. Materials Methods: Digitoxin was administered intraperitoneally to cotton rats, followed by intranasal infection with 107TCID50/100 g of cotton rat with influenza strain A/Wuhan/H3N2/359/95. Daily digitoxin treatment continued until harvest on day 4 of the experiment. RESULTS: The cardiac glycoside digitoxin significantly and differentially suppressed levels of the cytokines TNFα, GRO/KC, MIP2, MCP1, and IFNγ, in the cotton rat lung in the presence of influenza virus. CONCLUSION: Since cytokine storm is a host response, we suggest that digitoxin may have a therapeutic potential not only for influenza and but also for coronavirus infections.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Digitoxina/farmacologia , Pulmão/virologia , Pneumonia Viral/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Animais , Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/biossíntese , Citocinas/genética , Modelos Animais de Doenças , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/metabolismo , Influenza Humana/virologia , Pulmão/patologia , Masculino , NF-kappa B/genética , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Neoplasias da Próstata/complicações , Neoplasias da Próstata/patologia , Neoplasias da Próstata/virologia , Ratos , Fator de Necrose Tumoral alfa/genética
4.
Zhongguo Zhong Yao Za Zhi ; 45(19): 4686-4691, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33164433

RESUMO

In this study, the oxygen-glucose deprivation(OGD) model in the human brain microvascular endothelial cell(HBMEC) was used to simulate the ischemic neuronal damage and observe the inflammatory response, explore the possible mechanisms for treating cerebral ischemia/reperfusion and improving memory impairment from the view point of inhibiting inflammatory response, which is of great reference significance for related Chinese medicine treatment of ischemic diseases. HBMECs were given with drugs at the same time of OGD injury, and reoxygenated for 2 h after 4 h treatment. Cell supernatant was then collected, and the inflammatory factors in cell supernatant were detected. Immunofluorescence assay was used to detect HBMECs morphology and expression of p-nuclear factor kappa-light-chain-enhancer of activated B(p-NF-κB); Western blot was used to detect expression changes of Toll like receptor 4(TLR4), myeloid differentiation primary response 88(MYD88) and p-NF-κB. The results showed that, after OGD modeling, the levels of interleukin 6(IL-6), IL-1α, IL-1ß and tumor necrosis factor-α(TNF-α) were significantly increased; baicalin protected HBMEC, inhibited intranuclear transcription of p-NF-κB, significantly decreased HBMEC release of inflammatory factors caused by OGD injury, and inhibited the expression of TLR4, MYD88, and p-NF-κB. The studies suggested that baicalin had obvious protective effect on HBMECs damaged by OGD, and could inhibit inflammatory response. Its protection mechanism may be related to inhibiting TLR4 signaling pathways.


Assuntos
NF-kappa B , Receptor 4 Toll-Like , Encéfalo/metabolismo , Células Endoteliais/metabolismo , Flavonoides , Humanos , Hipóxia , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
5.
Nat Commun ; 11(1): 5666, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168815

RESUMO

Aquaporin 3 (AQP3) is a transporter of water, glycerol and hydrogen peroxide (H2O2) that is expressed in various epithelial cells and in macrophages. Here, we developed an anti-AQP3 monoclonal antibody (mAb) that inhibited AQP3-facilitated H2O2 and glycerol transport, and prevented liver injury in experimental animal models. Using AQP3 knockout mice in a model of liver injury and fibrosis produced by CCl4, we obtained evidence for involvement of AQP3 expression in nuclear factor-κB (NF-κB) cell signaling, hepatic oxidative stress and inflammation in macrophages during liver injury. The activated macrophages caused stellate cell activation, leading to liver injury, by a mechanism involving AQP3-mediated H2O2 transport. Administration of an anti-AQP3 mAb, which targeted an extracellular epitope on AQP3, prevented liver injury by inhibition of AQP3-mediated H2O2 transport and macrophage activation. These findings implicate the involvement of macrophage AQP3 in liver injury, and provide evidence for mAb inhibition of AQP3-mediated H2O2 transport as therapy for macrophage-dependent liver injury.


Assuntos
Anticorpos Monoclonais/farmacologia , Aquaporina 3/antagonistas & inibidores , Aquaporina 3/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Animais , Aquaporina 3/genética , Células CHO , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Quimiocina CCL4/efeitos adversos , Cricetulus , Modelos Animais de Doenças , Descoberta de Drogas , Glicerol/metabolismo , Peróxido de Hidrogênio/metabolismo , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Medicina Molecular , NF-kappa B/metabolismo , Estresse Oxidativo , Transdução de Sinais , Transcriptoma
6.
Yakugaku Zasshi ; 140(11): 1351-1363, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33132271

RESUMO

Epidemiological studies have shown that coffee consumption may be associated with a lower risk of developing several chronic disorders. To elucidate the molecular mechanism of the effects of coffee, we analyzed molecular response upon exposure to coffee extract using cellular and animal models of these diseases. As obesity is recognized as a major risk factor for these chronic diseases, we investigated the effect of coffee on adipogenesis using mouse preadipocyte 3T3-L1 cells. We found that coffee induced proteasomal degradation of IRS-1, leading to reduction of PPARγ expression, a master transcription factor for adipogenesis. Reduction in weight as well as in IRS-1 expression was detected in the fat tissues of the high fat-diet-fed mice when reared with 60% coffee for 7 weeks. As for Alzheimer's disease, we analyzed the effect of coffee on amyloid ß (Aß) production in human neuronal SH-SY5Y cells. We found a 20% reduction in Aß production when treated with 2.5% coffee for 2 d. This reduction was due to proteasomal degradation of BACE1 (ß-secretase), which was activated by protein kinase A. In addition, coffee ameliorates LPS-induced inflammatory responses in RAW264.7 macrophages by reducing NFκB activity and Nrf2 activation. Roasted coffee prevents selenite-induced cataractogenesis by ameliorating antioxidant loss. Pyrocatechol, a component of roasted coffee, also reduced Aß production and exhibits anti-inflammatory effects by a similar mechanism as coffee. Our results suggest that roasting coffee beans to generate pyrocatechol is necessary for the preventive effects of coffee intake on the chronic diseases.


Assuntos
Doença de Alzheimer/prevenção & controle , Catarata/prevenção & controle , Doença Crônica/prevenção & controle , Café , Ingestão de Líquidos/fisiologia , Adipogenia , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Catecóis , Células Cultivadas , Café/química , Modelos Animais de Doenças , Manipulação de Alimentos , Temperatura Alta , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , PPAR gama/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Células RAW 264.7
7.
Chem Biol Interact ; 331: 109276, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33002459

RESUMO

Ulcerative colitis (UC) is a chronic disease driven primarily by uncontrolled pervasive inflammatory responses affecting the colon and rectum. Currently available medications carry multiple detrimental adverse effects, which have emphasized the mandatory need for safer and more efficient novel therapeutic alternatives. Melittin is the main constituent of bee venom and exhibits potent anti-inflammatory properties. The antiulcerogenic effect of oral melittin (40 µg/kg) was explored in the current study using the acetic acid-induced colitis model. Increase in body weight and decrease in colon mass index were observed in the melittin group. Microscopically, melittin ameliorated acetic acid-induced histological damage. Melittin administration has efficiently amended the elevated levels of the cytokines, tumor necrosis factor (TNF-α) and interleukin 6 (IL-6) seen in the colitis group. This was accompanied by inhibition of the upstream signaling molecules, Toll-like receptor 4 (TLR4), tumor necrosis factor receptor (TNF-R)-associated factor (TRAF6), mitogen-activated protein kinase 38 (p38 MAPK), and nuclear factor kappaB (NF-κB) in the melittin group. Moreover, treatment with melittin resulted in marked decrease in colonic level of prostaglandin E2 (PGE2) together with the enzymes involved in its synthesis, secretory phospholipase A2 (sPLA2) and cyclooxygenase 2 (COX-2). Additionally, melittin has attenuated acetic acid-induced oxidative stress as manifested by the significant diminishment in malondialdehyde (MDA) as well as the increase in superoxide dismutase (SOD) and reduced glutathione (GSH) levels. Therefore, melittin mitigated UC pathogenesis and could be considered as a potent and promising therapeutic alternative for UC treatment.


Assuntos
Antiulcerosos/farmacologia , Meliteno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor 4 Toll-Like/metabolismo , Ácido Acético/toxicidade , Administração Oral , Animais , Antiulcerosos/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo/metabolismo , Colo/patologia , Ciclo-Oxigenase 2/metabolismo , Interleucina-6/metabolismo , Malondialdeído/metabolismo , Meliteno/uso terapêutico , Camundongos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Med Hypotheses ; 143: 110185, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33017914

RESUMO

COVID-19 pandemic is spreading rapidly worldwide, and drug selection can affect the morbidity and mortality of the disease positively or negatively. Alpha-lipoic acid (ALA) is a potent antioxidant and reduces oxidative stress and inhibits activation of nuclear factor-kappa B (NF-kB). ALA reduces ADAM17 activity and ACE2 upregulation. ALA is known to have antiviral effects against some viruses. ALA may show antiviral effect by reducing NF-kB activation and alleviating redox reactions. ALA increases the intracellular glutathione strengthens the human host defense. ALA activates ATP dependent K+ channels (Na+, K+-ATPase). Increased K+ in the cell raises the intracellular pH. As the intracellular pH increases, the entry of the virus into the cell decreases. ALA can increase human host defense against SARS-CoV-2 by increasing intracellular pH. ALA treatment increases antioxidant levels and reduces oxidative stress. Thus, ALA may strengthen the human host defense against SARS-CoV-2 and can play a vital role in the treatment of patients with critically ill COVID-19. It can prevent cell damage by decreasing lactate production in patients with COVID-19. Using ALA with insulin in patients with diabetes can show a synergistic effect against SARS-CoV-2. We think ALA treatment will be beneficial against COVID-19 in patients with diabetes.


Assuntos
Proteína ADAM17/metabolismo , Infecções por Coronavirus/prevenção & controle , Complicações do Diabetes/prevenção & controle , NF-kappa B/metabolismo , Pandemias/prevenção & controle , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/prevenção & controle , Ácido Tióctico/uso terapêutico , Antioxidantes/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/complicações , Complicações do Diabetes/virologia , Diabetes Mellitus/tratamento farmacológico , Humanos , Concentração de Íons de Hidrogênio , Insulina/metabolismo , Oxirredução , Estresse Oxidativo , Pneumonia Viral/complicações
9.
J Toxicol Sci ; 45(10): 651-660, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33012733

RESUMO

Inhalation of silica particles leads to pulmonary inflammatory responses. Clara cell protein 16 (CC16) has been reported to played a protective role in inflammatory lung diseases. However, its role on silica particles-induced inflammation has not been fully clarified. In this study, THP-1 macrophages were exposed to 75 µg/cm2 silica particles with or without 2 µg/mL exogenous CC16 (recombinant CC16, rCC16) for 24 hr. The production of inflammatory cytokines, including interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and IL-6, in the cell supernatants of different groups was detected through ELISA kits and real-time RT-PCR, respectively. The nuclear translocation of nuclear factor (NF)-κB, protein levels of pro-IL-1ß, the nucleotide-binding domain-like receptor protein 3 (NLRP3) and caspase-1 were evaluated via immunofluorescence or western blot. Results showed that, at 75 µg/cm2 silica particle concentration, the treatment of rCC16 significantly decreased IL-1ß, TNF-α and IL-6 protein release and mRNA levels in THP-1 macrophages. Compared to those only exposed to silica particles, THP-1 macrophages exposed to both silica particles and rCC16 showed significantly lower nuclear levels and higher cytosol levels of NF-κB p65, as well as lower co-localization coefficients through immunofluorescence. Additionally, the administration of rCC16 significantly attenuated the increase of pro-IL-1ß, NLRP3 and caspase-1 levels induced by silica particle exposure. Our results suggested that exogenous CC16 could inhibit silica particles-induced inflammation in THP-1 macrophages, mainly through suppressing NF-κB pathway and caspase-1 activation.


Assuntos
Caspase 1/metabolismo , Expressão Gênica/efeitos dos fármacos , Inflamação/genética , Macrófagos Alveolares/imunologia , Macrófagos/imunologia , NF-kappa B/metabolismo , Dióxido de Silício/toxicidade , Caspase 1/genética , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Humanos , NF-kappa B/genética , Tamanho da Partícula , Proteínas Recombinantes/farmacologia , Células THP-1 , Uteroglobina/farmacologia
10.
PLoS One ; 15(10): e0235803, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33031374

RESUMO

Cystic Fibrosis (CF), caused by mutations affecting the CFTR gene, is characterised by viscid secretions in multiple organ systems. CF airways contain thick mucus, creating a gradient of hypoxia, which promotes the establishment of polymicrobial infection. Such inflammation predisposes to further infection, a self-perpetuating cycle in mediated by NF-κB. Anaerobic Gram-negative Prevotella spp. are found in sputum from healthy volunteers and CF patients and in CF lungs correlate with reduced levels of inflammation. Prevotella histicola (P. histicola) can suppress murine lung inflammation, however, no studies have examined the role of P. histicola in modulating infection and inflammation in the CF airways. We investigated innate immune signalling and NF-kB activation in CF epithelial cells CFBE41o- in response to clinical stains of P. histicola and Pseudomonas aeruginosa (P. aeruginosa). Toll-Like Receptor (TLR) expressing HEK-293 cells and siRNA assays for TLRs and IKKα were used to confirm signalling pathways. We show that P. histicola infection activated the alternative NF-kB signalling pathway in CF bronchial epithelial cells inducing HIF-1α protein. TLR5 signalling was responsible for the induction of the alternative NF-kB pathway through phosphorylation of IKKα. The induction of transcription factor HIF-1α was inversely associated with the induction of the alternative NF-kB pathway and knockdown of IKKα partially restored canonical NF-kB activation in response to P. histicola. This study demonstrates that different bacterial species in the respiratory microbiome can contribute differently to inflammation, either by activating inflammatory cascades (P. aeruginosa) or by muting the inflammatory response by modulating similar or related pathways (P. histicola). Further work is required to assess the complex interactions of the lung microbiome in response to mixed bacterial infections and their effects in people with CF.


Assuntos
Brônquios/imunologia , Fibrose Cística/imunologia , NF-kappa B/metabolismo , Prevotella/imunologia , Infecções por Pseudomonas/complicações , Pseudomonas aeruginosa/imunologia , Receptores Toll-Like/metabolismo , Brônquios/metabolismo , Brônquios/microbiologia , Brônquios/patologia , Fibrose Cística/metabolismo , Fibrose Cística/microbiologia , Fibrose Cística/patologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Humanos , Interleucina-8/metabolismo , NF-kappa B/genética , Prevotella/isolamento & purificação , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/isolamento & purificação , Transdução de Sinais , Receptores Toll-Like/imunologia
11.
Int J Nanomedicine ; 15: 7143-7153, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33061372

RESUMO

Introduction: Tobacco mosaic virus-based nanoparticles (TMV VNPs) were previously shown to promote osteogenic differentiation in vitro. This study aims to investigate whether and how TMV VNPs impact on osteoclastogenesis in vitro and bone injury healing in vivo. Methods: Raw264.7 cells were cultured in osteoclastogenic medium in culture plates coated with or without TMV and TMV-RGD1 VNPs, followed by TRAP staining, RT-qPCR and WB assessing expression of osteoclastogenic marker genes, and immunofluorescence assessing NF-κB activation. TMV and TMV-RGD1-modified hyaluronic acid hydrogel were used to treat mouse tibial bone injury. Bone injury healing was checked by micro-CT and Masson staining. Results: TMV and TMV-RGD1 VNPs significantly inhibited osteoclast differentiation and downregulated the expression of osteoclastogenic marker genes Ctr, Ctsk, Mmp-9, Rank, and Trap. Moreover, TMV and TMV-RGD1 VNPs inhibited NF-κB p65 phosphorylation and nuclear translocation, as well as activation of mTOR/AKT signaling pathway. TMV and TMV-RGD1-modified HA hydrogel strongly promoted mouse tibial bone injury with increased bone mass compared to plain HA hydrogel. The amount of osteoclasts was significantly reduced in TMV and TMV-RGD1 treated mice. TMV-RGD1 was more effective than TMV in inhibiting osteoclast differentiation and promoting bone injury repair. Discussion: These data demonstrated the great potential of TMV VNPs to be developed into biomaterial for bone injury repair or replacement.


Assuntos
Nanopartículas/química , Osteogênese , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Vírus do Mosaico do Tabaco/fisiologia , Animais , Osso e Ossos/patologia , Diferenciação Celular/efeitos dos fármacos , Camundongos , NF-kappa B/metabolismo , Nanopartículas/ultraestrutura , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células RAW 264.7 , Ratos , Transdução de Sinais/efeitos dos fármacos , Tíbia/patologia , Cicatrização
12.
Sheng Li Xue Bao ; 72(5): 541-550, 2020 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-33106824

RESUMO

The occurrence and development of pulmonary arterial hypertension (PAH) is closely related to the genetic mutation of bone morphogenetic protein receptor type II (BMPRII) encoding gene and the inflammatory response mediated by nuclear factor κB (NF-κB) pathway. This paper was aimed to investigate the effect of NF-κB pathway inhibitors on lipopolysaccharide (LPS)-induced pulmonary artery endothelial cell injury. Human pulmonary artery endothelial cells were treated with 1 µg/mL of LPS. The expression levels of BMPRII and interleukin-8 (IL-8) were detected by Western blot and qPCR. The rat PAH model was established by intraperitoneal (i.p.) injection of monocrotaline (MCT). The expression levels of BMPRII and IL-8 in pulmonary artery endothelial cells were detected by immunofluorescence staining. Cardiac hemodynamic changes and pulmonary vascular remodeling were detected in the MCT-PAH model rats. The results showed that LPS caused down-regulation of BMPRII expression and up-regulation of IL-8 expression in human pulmonary artery endothelial cells. NF-κB inhibitor BAY11-7082 (10 µmol/L) reversed the effect of LPS. In the pulmonary artery endothelial cells of MCT-PAH model, BMPRII expression was down-regulated, IL-8 expression was up-regulated, weight ratio of right ventricle to left ventricle plus septum [RV/(LV+S)] and right ventricular systolic pressure (RVSP) were significantly increased, cardiac output (CO) and tricuspid annular plane systolic excursion (TAPSE) were significantly reduced, and pulmonary vessel wall was significantly thickened. BAY11-7082 (5 mg/kg, i.p., 21 consecutive days) reversed the above changes in the MCT-PAH model rats. These results suggest that LPS down-regulates the expression level of BMPRII through NF-κB signaling pathway, promoting the occurrence and development of PAH. Therefore, the NF-κB pathway can be used as a potential therapeutic target for PAH.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II , Hipertensão Pulmonar , Animais , Regulação para Baixo , Células Endoteliais/metabolismo , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Lipopolissacarídeos , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Remodelação Vascular
13.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1534-1538, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067950

RESUMO

OBJECTIVE: To explore the effect of nuclear factor kappa-B (NF-κB) inhibitor pyrrolidine dithiocarbamate (PDTC) on the proliferation and apoptosis of acute leukemia cell HL-60. METHODS: HL-60 cells were cultured with PDTC of 0, 25, 50, 100 µmol/L for 24, 48, 72 h. The inhibition rate of cell proliferation was detected by CCK-8 assay. Cell apoptosis was detected by Hoechst staining. Cell cycle was detected by flow cytometry. The expression of B-cell lymphoma-2 (BCL-2), BCL-2 associated X protein (BAX), cyclinD1, activated cysteinyl aspartate specific proteinase (cleaved caspase 3), cleaved caspase 8 and activation of NF-κB signal pathway related protein was detected by Western blot. RESULTS: After the HL-60 cells were cultured with PDTC of 25, 50, 100 µmol/L for 24, 48, 72 h, the inhibition rate of cell proliferation increased with the enhancement of PDTC concentration at the same time point (r=0.924, P<0.01). At the same PDTC concentration, the inhibition rate of cell proliferation increased with prolonging of time (r=0.952, P<0.01). After HL-60 cell was cultured with PDTC of 25, 50, 100 µmol/L for 48 h, compared with control group, PDTC of 25, 50, 100 µmol/L increased the cell apoptotic rate, arrested cell cycle at G1 phase (P<0.01), the expression of BCL-2, cyclinD1 and p-NF-κB p65 was down-regulated(P<0.05), the expression of BAX, cleaved caspase 3, cleaved caspase 8 was up-regulated(P<0.01). PDTC of 50, 100 µmol/L down-regulated the expression of p-inhibitor of NF-κB (p-IκBα)(P<0.01). CONCLUSION: PDTC can inhibit acute leukemia HL-60 cell proliferation and induce cell apoptosis.


Assuntos
Apoptose , Leucemia , Proliferação de Células , Células HL-60 , Humanos , NF-kappa B , Pirrolidinas , Tiocarbamatos
14.
Wei Sheng Yan Jiu ; 49(5): 775-801, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33070823

RESUMO

OBJECTIVE: To study the anti-apoptotic effect of cyanidin-3-O-glucoside(C3 G) on H_2O_2-induced injury in human embryonic kidney(HEK)-293 cells. METHODS: Hydrogen peroxide induced injury of HEK-293 cell was used as the research object. HEK-293 cells were pretreated with different concentrations of C3 G(1. 25, 5, 20 µmol/L). The anti-apoptotic effects of C3 G on injured cells were examined by the release rates of LDH and mitochondrial membrane potential(MMP). Western blot and qRT-PCR were used to detect the protein expression and mRNA expression of NF-κB P65. RESULTS: The result showed that the release rate of LDH was increased, MMP was decreased, the protein and mRNA of P65 was increased after H_2O_2 inducing. Whereas, the release rates of LDH were significantly lower than that of the injured group after 1. 25, 5, 20 µmol/L C3 G pretreatment of injured cells(P<0. 05). The MMP of C3 G group was significantly higher than injured group with concentration-dependent increases. The proteins and mRNA of P65 were also significantly lower than that of injured group(P<0. 05). CONCLUSION: Cyanidin-3-O-glucoside shows anti-apoptotic effect on H_2O_2-induced injury in HEK-293 cell. The mechanisms of anti-apoptotic effects may be to achieve by protecting cell biofilms, and inhibiting the activity of NF-κB signaling pathway.


Assuntos
Apoptose , NF-kappa B , Glucosídeos/farmacologia , Células HEK293 , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais
15.
Signal Transduct Target Ther ; 5(1): 240, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060566

RESUMO

The COVID-19 pandemic has emerged as a global health emergency due to its association with severe pneumonia and relative high mortality. However, the molecular characteristics and pathological features underlying COVID-19 pneumonia remain largely unknown. To characterize molecular mechanisms underlying COVID-19 pathogenesis in the lung tissue using a proteomic approach, fresh lung tissues were obtained from newly deceased patients with COVID-19 pneumonia. After virus inactivation, a quantitative proteomic approach combined with bioinformatics analysis was used to detect proteomic changes in the SARS-CoV-2-infected lung tissues. We identified significant differentially expressed proteins involved in a variety of fundamental biological processes including cellular metabolism, blood coagulation, immune response, angiogenesis, and cell microenvironment regulation. Several inflammatory factors were upregulated, which was possibly caused by the activation of NF-κB signaling. Extensive dysregulation of the lung proteome in response to SARS-CoV-2 infection was discovered. Our results systematically outlined the molecular pathological features in terms of the lung response to SARS-CoV-2 infection, and provided the scientific basis for the therapeutic target that is urgently needed to control the COVID-19 pandemic.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/genética , Lesão Pulmonar/genética , Pneumonia Viral/genética , Proteoma/genética , Proteômica/métodos , Síndrome Respiratória Aguda Grave/genética , Idoso , Autopsia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Lesão Pulmonar/virologia , Masculino , Redes e Vias Metabólicas , Anotação de Sequência Molecular , NF-kappa B/genética , NF-kappa B/metabolismo , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Proteoma/metabolismo , Síndrome Respiratória Aguda Grave/metabolismo , Síndrome Respiratória Aguda Grave/patologia , Síndrome Respiratória Aguda Grave/virologia , Índice de Gravidade de Doença , Transdução de Sinais
16.
Nat Commun ; 11(1): 5117, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037203

RESUMO

Exposure of gastric epithelial cells to the bacterial carcinogen Helicobacter pylori causes DNA double strand breaks. Here, we show that H. pylori-induced DNA damage occurs co-transcriptionally in S-phase cells that activate NF-κB signaling upon innate immune recognition of the lipopolysaccharide biosynthetic intermediate ß-ADP-heptose by the ALPK1/TIFA signaling pathway. DNA damage depends on the bi-functional RfaE enzyme and the Cag pathogenicity island of H. pylori, is accompanied by replication fork stalling and can be observed also in primary cells derived from gastric organoids. Importantly, H. pylori-induced replication stress and DNA damage depend on the presence of co-transcriptional RNA/DNA hybrids (R-loops) that form in infected cells during S-phase as a consequence of ß-ADP-heptose/ ALPK1/TIFA/NF-κB signaling. H. pylori resides in close proximity to S-phase cells in the gastric mucosa of gastritis patients. Taken together, our results link bacterial infection and NF-κB-driven innate immune responses to R-loop-dependent replication stress and DNA damage.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Helicobacter pylori/patogenicidade , NF-kappa B/metabolismo , Proteínas Quinases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Bactérias/metabolismo , Linhagem Celular Tumoral , DNA/química , DNA/genética , Dano ao DNA , Replicação do DNA/efeitos dos fármacos , Floxuridina , Glicosiltransferases/metabolismo , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/metabolismo , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Lipopolissacarídeos/metabolismo , Mutação , NF-kappa B/genética , Proteínas Quinases/genética , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia
17.
J Pharmacol Sci ; 144(4): 189-196, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070837

RESUMO

Pneumonia is a common illness that continues to be the major killer of remaining to be a significant source of morbidity and mortality in the patient population. Many microorganisms cause pneumonia, and now concern is turning to the importance of the cause the new therapies for viral pneumonia. In the current study, we report the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on poly I: C-induced pneumonia. Andrographolide sulfonate was administrated through intraperitoneal injection to mice with poly I: C-induced pneumonia. Recruitment of airway inflammatory cells, alteration of lung histological induced by Poly I: C were significantly ameliorated by andrographolide sulfonate. The protein levels of pro-inflammatory cytokines in bronchoalveolar fluid (BALF) and serum were reduced by andrographolide sulfonate treatment. The levels of MUC5AC and MUC5B in lung tissue were also suppressed. These results reveal that andrographolide sulfate remarkably alleviated pneumonia induced by poly I:C in mice. Moreover, andrographolide sulfonate markedly inhibited the activation of nuclear factor-κB (NF-κB). Taken together, we demonstrated that andrographolide sulfonate ameliorated poly I: C-induced pneumonia in mice, suggesting the possible use of andrographolide sulfonate for virus-induced pneumonia in clinical.


Assuntos
Diterpenos/administração & dosagem , Diterpenos/farmacologia , NF-kappa B/metabolismo , Fitoterapia , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Poli I-C/efeitos adversos , Animais , Citocinas/sangue , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos C57BL , Mucina-5AC/metabolismo , Mucina-5B/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/patologia , Pneumonia Viral/tratamento farmacológico
18.
J Pharmacol Sci ; 144(4): 204-211, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070839

RESUMO

The deficiency of survival motor neuron (SMN) protein can result in the onset of spinal muscular atrophy (SMA), an autosomal recessive disorder characterized by a progressive loss of motor neurons and skeletal muscle atrophy. The mechanism underlying SMA pathology remains unclear. Here, we demonstrate that SMN protein regulates oxidative stress and inflammatory response in microglia. Antisense oligonucleotide, which increases SMN protein expression (SMN-ASO), attenuated SMA model mice phenotypes and suppressed the activation of microglia in the spinal cord. The expression of oxidative stress marker in microglia was decreased by SMN-ASO injection in SMA model mice. Increased reactive oxygen species production and subsequent antioxidative stress reaction was observed in SMN protein-depleted RAW264.7. Furthermore, nuclear factor kappa B (NFκB) and c-Jun amino terminal kinase (JNK) signaling, which mainly mediate the inflammatory response, are activated in SMN protein-depleted RAW264.7. Tumor necrosis factor-α (TNF-α) production is also increased in SMN protein-depleted RAW264.7. These findings suggest that SMN protein regulates oxidative stress and inflammatory response in microglia, supporting current claims that microglia can be an effective target for SMA therapy.


Assuntos
Inflamação/genética , Microglia/metabolismo , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/genética , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/farmacologia , Oligonucleotídeos/uso terapêutico , Estresse Oxidativo/genética , Medula Espinal/citologia , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo , Proteína 1 de Sobrevivência do Neurônio Motor/fisiologia , Animais , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Terapia de Alvo Molecular , Atrofia Muscular Espinal/metabolismo , NF-kappa B/metabolismo , Células RAW 264.7 , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Fator de Necrose Tumoral alfa/metabolismo
19.
Signal Transduct Target Ther ; 5(1): 218, 2020 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-33011739

Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Glicosídeos Cardíacos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Animais , Antivirais/química , Betacoronavirus/patogenicidade , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Bufanolídeos/química , Bufanolídeos/farmacologia , Glicosídeos Cardíacos/química , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cloroquina/química , Cloroquina/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Digoxina/química , Digoxina/farmacologia , Ensaios de Triagem em Larga Escala , Interações Hospedeiro-Patógeno/genética , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Janus Quinases/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Pandemias , Fenantrenos/química , Fenantrenos/farmacologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Transdução de Sinais , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos
20.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(8): 704-711, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32958127

RESUMO

Objective To elucidate the mechanisms by which elongation factor Tu GTP binding domain containing 2 (Eftud2) enhances the immune function of murine macrophages by bioinformatics analysis. Methods The bone marrow-derived macrophages (BMDMs) of Eftud2 myeloid cell-specific knockout (MKO) mice (n=10) and wild-type (WT) littermates (n=10) were collected and stimulated by lipopolysaccharide (LPS) (100 ng/mL) for 2 hours. Bioinformatics analysis was conducted to examine the differences in gene expression and mRNA transcription levels. The the differences in gene expression and alternative splicing of mRNA transcription in BMDMs were analyzed by DEGseq and rMATS, respectively. The signaling pathways affected were clarified by Kyoto Encyclopedia of Genes and Genomes (KEGG) classification and enrichment methods. Results Compared with WT counterparts, the expression levels of IL-6, IL-1ß, TNF-α, and the genes related to immune response in MKO BMDMs were down-regulated following LPS stimulation. KEGG pathway analysis showed that the differently expressed genes in BMDMs and alternative splicing mainly affected the signal transduction and immune system-related metabolic pathways, and had a strong correlation with PI3K-AKT signaling pathway. The difference in alternative splicing also existed in ubiquitination and endocytosis. Compared with WT counterparts, there were 232 differences in alternative splicing in MKO BMDMs, among which 125 were skipping exons, accounting for the largest proportion. In addition, the analysis of alternative splicing differences also confirmed the previous experimental results, that is, Eftud2 could participate in the activation of inflammatory signaling pathways by enhancing the alternative splicing of key molecules such as MyD88 in TLR4-NF-κB signaling pathway, thereby augmenting the function of macrophages. Conclusion Eftud2 can promote the release of inflammatory cytokines in BMDMs by regulating gene expression and alternative splicing, and consequently enhance the immune function of macrophages.


Assuntos
Biologia Computacional , Expressão Gênica , Macrófagos , Animais , Citocinas/genética , Citocinas/imunologia , Expressão Gênica/genética , Expressão Gênica/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Camundongos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo
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