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1.
Zhongguo Zhong Yao Za Zhi ; 46(1): 146-154, 2021 Jan.
Artículo en Chino | MEDLINE | ID: mdl-33645064

RESUMEN

This study aimed to assess whether chrysin(ChR) can inhibit epithelial-mesenchymal transition(EMT) of type Ⅱ alveolar epithelial cell and produce anti-pulmonary fibrosis effect by regulating the NF-κB/Twist 1 signaling pathway. Sixty rats were randomly divided into the control group, the bleomycin(BLC) group, BLC+ChR(50 mg·kg~(-1)) group and BLC+ChR(100 mg·kg~(-1)) group, with 15 rats in each group. The pulmonary fibrosis model was induced by intratracheal injection of BLC(7 500 U·kg~(-1)). Rats were orally administered with different doses of ChR after BLC injection for 28 days. The cells were divided into control group, TGF-ß1 group(5 ng·mL~(-1)), and TGF-ß1+ChR(1, 10, 100 µmol·L~(-1)) groups. The type Ⅱ alveolar epithelial cells were treated with TGF-ß1 for 24 h, and then treated with TGF-ß1 for 48 h in the presence or absence of different doses of ChR(1, 10 and 100 µmol·L~(-1)). The morphological changes and collagen deposition in lung tissues were analyzed by HE staining, Masson staining and immunohistochemistry. The mRNA and protein expression levels of collagen Ⅰ, E-cadherin, zonula occludens-1(ZO-1), vimentin, alpha smooth muscle actin(α-SMA), inhibitor of nuclear factor kappa B alpha(IκBα), nuclear factor-kappa B p65(NF-κB p65), phospho-NF-κB p65(p-p65) and Twist 1 in lung tissues and cells were detected by qPCR and Western blot, respectively. The animal experiment results showed that as compared with the BLC group, after administration of ChR for 28 days, bleomycin-induced pulmonary fibrosis in rats was significantly relieved, collagen Ⅰ expression in lung tissues was significantly reduced(P<0.05 or P<0.01), and EMT of alveolar epithelial cells was obviously inhibited [the expression levels of E-cadherin and ZO-1 were increased and the expression levels of vimentin and α-SMA were decreased(P<0.05 or P<0.01)], concomitantly with significantly reduced IκBα and p65 phosphorylation level in cytoplasm and decreased NF-κB p65 and Twist 1 expression in nucleus(P<0.05 or P<0.01). The cell experiment results showed that different doses of ChR(1, 10 and 100 µmol·L~(-1)) significantly reduced TGF-ß1-induced collagen Ⅰ expression(P<0.05 or P<0.01), significantly inhibited EMT of type Ⅱ alveolar epithelial cells[the expression levels of E-cadherin and ZO-1 were increased and the expression levels of vimentin and α-SMA were decreased(P<0.05 or P<0.01)], and inhibited IκBα and p65 phosphorylation in cytoplasm and down-regulated NF-κB p65 and Twist 1 expression in nucleus induced by TGF-ß1(P<0.05 or P<0.01). The results suggest that ChR can reverse EMT of type Ⅱ alveolar epithelial cell and alleviate pulmonary fibrosis in rats, and its mechanism may be associated with reducing IκBα phosphorylation and inhibiting NF-κB p65 phosphorylation and nuclear transfer, thus down-regulating Twist 1 expression.


Asunto(s)
Transición Epitelial-Mesenquimal , FN-kappa B , Células Epiteliales Alveolares/metabolismo , Animales , Flavonoides , FN-kappa B/genética , FN-kappa B/metabolismo , Ratas , Transducción de Señal , Factor de Crecimiento Transformador beta1/genética
2.
Zhongguo Zhong Yao Za Zhi ; 46(4): 845-854, 2021 Feb.
Artículo en Chino | MEDLINE | ID: mdl-33645089

RESUMEN

Network pharmacology and liver fibrosis(LF) model in vitro were used to analyze the underly mechanism of anti-liver fibrosis effect that induced by Piperis Longi Fructus and its major active compounds. TCMSP and TCMIP were used to search for the chemical constituents of Piperis Longi Fructus, as well as the oral bioavailability(OB), drug-likeness(DL), intercellular permeability of intestinal epithelial cells(Caco-2) and Drug-likeness grading were set as limiting conditions. The related target genes of Piperis Longi Fructus were queried by TCMSP database, while related targets of LF were screened by GeneCards databases. Interaction network was constructed using Cytoscape 3.7.1. These above data were imported into STRING database for PPI network analysis. Enrichment of gene ontology(GO) and pathway analysis(KEGG) within Bioconductor database were utilized to note functions of related targets of Piperis Longi Fructus. Finally, the core targets and pathways were preliminarily verified by in vitro experiments. The effects of piperlongumine(PL), the major active component of Piperis Longi Fructus, on proliferation of rat liver stellate cells(HSC-T6) and expression of α smooth muscle actin(α-SMA) and collagen Ⅰ were investigated. The major factors TNF-α of tumor necrosis factor(TNF) pathway and NF-κB p65, IL-6 protein expressions of LF process were examined. A total of 12 active compounds such as PL were obtained by analyzing the bioavailability and drug-like properties, which inferred to 48 targets. The functional enrichment analysis of GO obtained 1 240 GO items, mainly involving in process of biology and molecular function. A total of 99 signaling pathways were enriched in the KEGG pathway enrichment analysis, including TNF signaling pathway, cGMP-PKG signaling pathway, calcium signaling pathways. CCK-8 assay showed that PL inhibited proliferation of HSC-T6 induced by transforming growth factor-ß1(TGF-ß1). Western blot analysis found that treated with PL suppressed the protein expressions of α-SMA, collagen Ⅰ, TNF-α and p65 in HSC-T6. Enzyme linked immunosorbent assay(ELISA) showed that PL inhibited the expressions of TNF-α and IL-6 in the cluture supertant of HSC-T6 cells. In conclusion, PL could play an anti-liver fibrosis role by regulating TNF/NF-κB signaling pathway. This study provided the mechanism basis of anti-LF effects induced by Piperis Longi Fructus and its major active compounds, which might help for the further study of the mechanism and key targets of Piperis Longi Fructus.


Asunto(s)
Células Estrelladas Hepáticas , Cirrosis Hepática , Animales , Células CACO-2 , Células Estrelladas Hepáticas/metabolismo , Humanos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/genética , FN-kappa B/metabolismo , Ratas , Transducción de Señal
3.
Int J Mol Med ; 47(4): 1, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33537804

RESUMEN

Quercetin (Quer) is a typical antioxidant flavonoid from plants that is involved in bone metabolism, as well as in the progression of inflammatory diseases. Elevated levels of tumor necrosis factor­α (TNF­α), a typical pro­inflammatory cytokine, can affect osteogenesis. In the present study, TNF­α was used to establish an in vitro model of periodontitis. The effects of Quer on, as well as its potential role in the osteogenic response of human periodontal ligament stem cells (hPDLSCs) under TNF­α­induced inflammatory conditions and the underlying mechanisms were then investigated. Within the appropriate concentration range, Quer did not exhibit any cytotoxicity. More importantly, Quer significantly attenuated the TNF­α induced the suppression of osteogenesis­related genes and proteins, alkaline phosphatase (ALP) activity and mineralized matrix in the hPDLSCs. These findings were associated with the fact that Quer inhibited the activation of the NF­κB signaling pathway, as well as the expression of NLRP3 inflammation­associated proteins in the inflammatory microenvironment. Moreover, the silencing of NLRP3 by small interfering RNA (siRNA) was found to protect the hPDLSCs against TNF­α­induced osteogenic damage, which was in accordance with the effects of Quer. On the whole, the present study demonstrates that Quer reduces the impaired osteogenesis of hPDLSCs under TNF­α­induced inflammatory conditions by inhibiting the NF­κB/NLRP3 inflammasome pathway. Thus, Quer may prove to be a potential remedy against periodontal bone defects.


Asunto(s)
Inflamasomas/metabolismo , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Osteogénesis/efectos de los fármacos , Ligamento Periodontal/patología , Quercetina/farmacología , Células Madre/patología , Factor de Necrosis Tumoral alfa/toxicidad , Adolescente , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Humanos , Mediadores de Inflamación/metabolismo , Sustancias Protectoras/farmacología , Transducción de Señal/efectos de los fármacos , Células Madre/efectos de los fármacos , Adulto Joven
4.
Med Sci Monit ; 27: e926492, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33563887

RESUMEN

BACKGROUND The aim of this study was to evaluate the potential role of dual oxidase 1 (DUOX1) in wound healing. MATERIAL AND METHODS Primary fibroblasts were isolated from wound granulation tissue. Fibroblasts cell lines were established using DUOX1 overexpression and interference. Cell proliferation and reactive oxygen species (ROS) production were measured and compared among the groups. RESULTS DUOX1 expression was highest in the slow-healing tissues (P<0.05). Knockdown of DUOX1 significantly increased cell proliferation and inhibited ROS production and cell apoptosis (P<0.01). Moreover, expression of malondialdehyde (MDA) was significantly reduced, while expression of superoxide dismutase (SOD) expression was significantly increased (P<0.01). In addition, DUOX1 silencing significantly upregulated collagen I, collagen III, and NF-kappaB protein levels in the cytoplasm, and inhibited the protein levels of P21, P16, and NF-kappaB in the nucleus (P<0.01). Overexpression of DUOX1 caused a reverse reaction mediated by knockdown of DUOX1. When DUOX1-overexpressing cells were treated with the ROS inhibitor N-acetyl-L-cysteine (NAC), the protein levels that were increased by DUOX1 overexpression were reversed. CONCLUSIONS These results suggest that knockdown of DUOX1 significantly benefits wound healing, likely by the regulation of oxidative stress via NF-kappaB pathway activation.


Asunto(s)
Oxidasas Duales/metabolismo , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Cicatrización de Heridas/fisiología , Acetilcisteína/farmacología , Adulto , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Células Cultivadas , Oxidasas Duales/genética , Femenino , Fibroblastos , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Malondialdehído/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Cultivo Primario de Células , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Superóxido Dismutasa/metabolismo , Cicatrización de Heridas/efectos de los fármacos
5.
Cell Rep ; 34(7): 108761, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33567255

RESUMEN

Coronavirus disease 2019 (COVID-19) is a current global health threat caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Emerging evidence indicates that SARS-CoV-2 elicits a dysregulated immune response and a delayed interferon (IFN) expression in patients, which contribute largely to the viral pathogenesis and development of COVID-19. However, underlying mechanisms remain to be elucidated. Here, we report the activation and repression of the innate immune response by SARS-CoV-2. We show that SARS-CoV-2 RNA activates the RIG-I-MAVS-dependent IFN signaling pathway. We further uncover that ORF9b immediately accumulates and antagonizes the antiviral type I IFN response during SARS-CoV-2 infection on primary human pulmonary alveolar epithelial cells. ORF9b targets the nuclear factor κB (NF-κB) essential modulator NEMO and interrupts its K63-linked polyubiquitination upon viral stimulation, thereby inhibiting the canonical IκB kinase alpha (IKKα)/ß/γ-NF-κB signaling and subsequent IFN production. Our findings thus unveil the innate immunosuppression by ORF9b and provide insights into the host-virus interplay during the early stage of SARS-CoV-2 infection.


Asunto(s)
/genética , Quinasa I-kappa B/metabolismo , /metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/virología , /metabolismo , Células HEK293 , Humanos , Inmunidad Innata/inmunología , Interferón Tipo I/metabolismo , Interferones/metabolismo , FN-kappa B/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Cultivo Primario de Células , Receptores de Ácido Retinoico/metabolismo , /inmunología , Transducción de Señal , Ubiquitinación
6.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(1): 306-310, 2021 Feb.
Artículo en Chino | MEDLINE | ID: mdl-33554840

RESUMEN

In recent years, it is found that the classical IKKα and IKKß pathway were closely relates with hematological tumors, except the classical pathogenesis, moreover the classical IKKß pathway is deeply studied. The studies indicated that the IKKßis activated to phosphorylate the NF-κB through multiple cascades under the effect of extracellular IL-6, TNF-α and other stimulating factors. At the cellular level, the classical IKKßcan promote the tumor cell survival and proliferation, reduce the cell apoptosis, and promote the angiogenesis and cell transfer. Although the classical IKKα plays a role in regulating IKKß activity, but its role in non-classical pathway is more prominent. This review briefly summarizes the latest advance of researches on the pathogenesis of hematological malignancies in term of IKKα and IKKßpathway, so as to provide the theoretic basis for deeply understanding and studying the pathogenesis of hematologic tumors. At present, blocking the classical IKKα and IKKß pathway has become a new target for treatment of hematological tumors, moreover, some specific inhibitor for IKKα and IKKßpathway have been developed, for example, LY2409881, BMS 345541 and so on. Most of these drugs are in clinical trials and display some good anti-tumor effects.


Asunto(s)
Neoplasias Hematológicas , Transducción de Señal , Supervivencia Celular , Humanos , Quinasa I-kappa B/metabolismo , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa
7.
Adv Exp Med Biol ; 1275: 1-33, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33539010

RESUMEN

Protein kinases are intracellular signaling enzymes that catalyze the phosphorylation of specific residues in their target substrate proteins. They play important role for regulation of life and death decisions. The complexity of the relationship between death receptors and protein kinases' cell death decision-making mechanisms create many difficulties in the treatment of various diseases. The most of fifteen different cell death pathways, which are reported by Nomenclature Committee on Cell Death (NCCD) are protein kinase signal transduction-mediated negative or positive selections. Tumor necrosis factor (TNF) as a main player of death pathways is a dual-functioning molecule in that it can promote both cell survival or cell death. All apoptotic and necrotic signal transductions are conveyed through death domain-containing death receptors, which are expressed on the surface of nearly all human cells. In humans, eight members of the death receptor family have been identified. While the interaction of TNF with TNF Receptor 1 (TNFR1) activates various signal transduction pathways, different death receptors activate three main signal transduction pathways: nuclear factor kappa B (NF-ĸB)-mediated differentiation or pro-inflammatory cytokine synthesis, mitogen-activated protein kinase (MAPK)-mediated stress response and caspase-mediated apoptosis. The link between the NF-ĸB and the c-Jun NH2-terminal kinase (JNK) pathways comprise another check-point to regulate cell death. TNF-α also promotes the "receptor-interacting serine/threonine protein kinase 1" (RIPK1)/RIPK3/ mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necrosis. Thus, necrosome is mainly comprised of MLKL, RIPK3 and, in some cases, RIPK1. In fact, RIPK1 is at the crossroad between life and death, downstream of various receptors as a regulator of endoplasmic reticulum stress-induced death. TNFR1 signaling complex (TNF-RSC), which contains multiple kinase activities, promotes phosphorylation of transforming growth factor ß-activated kinase 1 (TAK1), inhibitor of nuclear transcription factor κB (IκB) kinase (IKK) α/IKKß, IκBα, and NF-κB. IKKs affect cell-survival pathways in NF-κB-independent manner. Toll-like receptor (TLR) stimulation triggers various signaling pathways dependent on myeloid differentiation factor-88 (MyD88), Interleukin-1 receptor (IL-1R)-associated kinase (IRAK1), IRAK2 and IRAK4, lead to post-translational activation of nucleotide and oligomerization domain (NLRP3). Thereby, cell fate decisions following TLR signaling is parallel with death receptor signaling. Inhibition of IKKα/IKKß or its upstream activators sensitize cells to death by inducing RIPK1-dependent apoptosis or necroptosis. During apoptosis, several kinases of the NF-κB pathway, including IKK1 and NF-κB essential modulator (NEMO), are cleaved by cellular caspases. This event can terminate the NF-κB-derived survival signals. In both canonical and non-canonical pathways, IKK is key to NF-κB activation. Whereas, the activation process of IKK, the functions of NEMO ubiquitination, IKK-related non-canonical pathway and the nuclear transportation of NEMO and functions of IKKα are still debated in cell death. In addition, cluster of differentiation 95 (CD95)-mediated non-apoptotic signaling and CD95- death-inducing signaling complex (DISC) interactions are waiting for clarification.


Asunto(s)
Quinasa I-kappa B , Proteínas Quinasas , Apoptosis , Humanos , Quinasa I-kappa B/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Fosforilación , Proteínas Quinasas/genética , Transducción de Señal , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
8.
Zhen Ci Yan Jiu ; 46(1): 33-8, 2021 Jan 25.
Artículo en Chino | MEDLINE | ID: mdl-33559423

RESUMEN

OBJECTIVE: To observe the effects of electroacupuncture on the hypothalamic Toll-like receptor 4 (TLR4)/ inhibitor nuclear factor kappa-B α(IκBα)/nuclear factor-κB (NF-κB) signaling pathway in obese insulin resistance (OIR) rats,so as to explore the mechanism of EA underlying improving of insulin resistance. METHODS: Rats were randomly divided into normal, model and EA groups, with 8 rats in each group. The rat model of OIR was established by feeding with high-fat diet for 8 weeks. EA(2 Hz,1 mA)was applied to unilateral"Zusanli"(ST36),"Fenglong"(ST40),"Zhongwan"(CV12)and"Guanyuan"(CV4)for 10 min, 3 times a week for 8 weeks. The body mass, fasting blood glucose(FBG) and postprandial blood glucose (PBG) were measured before and after 2、4、6、8 weeks' intervention. An intraperitoneal injection glucose tolerance test and hyperglycemic clamps were applied to test insulin resistance. The expression of TLR4、p-IκBα、NF-κB p65、TNF-α、IL-1ß mRNA and protein in hypothalamus was detected by quantitative real-time PCR and Western blot, separately. RESULTS: Compared with the normal group, the body mass and PBG of the model group were significantly increased (P<0.01); glucose infusion rate(GIR) was significantly reduced (P<0.01); in the IPGTT test, the increase in blood glucose was significantly greater after 90 and 120 min of glucose injection(P<0.01); the hypothalamus TLR4, NF-κB p65,p-IκBα, TNF-α, IL-1ß mRNA and protein expressions were all significantly increased (P<0.01). After EA intervention, the body weight and PBG were significantly down-regulated after 6 weeks and 2 weeks of intervention (P<0.05, P<0.01); GIR were significantly up-regulated after 8 weeks of intervention (P<0.05); In the IPGTT test, the increase in blood glucose 60 min after glucose injection was significantly down-regulated (P<0.05); hypothalamus TLR4, NF-κB p65,p-IκBα, TNF-α, IL -1ß mRNA and protein expression were significantly down-regulated (P<0.01). CONCLUSION: EA can reduce the body weight of OIR rats and improve IR, which may be related to down-regulating the hypothalamic TLR4/IκBα/NF-κB signaling pathway.


Asunto(s)
Electroacupuntura , Resistencia a la Insulina , Puntos de Acupuntura , Animales , Hipotálamo/metabolismo , Resistencia a la Insulina/genética , Inhibidor NF-kappaB alfa/genética , FN-kappa B/genética , FN-kappa B/metabolismo , Obesidad/genética , Obesidad/terapia , Ratas , Ratas Wistar , Transducción de Señal , Receptor Toll-Like 4/genética
9.
Biomed Environ Sci ; 34(1): 29-39, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33531105

RESUMEN

Objective: Antimony (Sb) has recently been identified as a novel nerve poison, although the cellular and molecular mechanisms underlying its neurotoxicity remain unclear. This study aimed to assess the effects of the nuclear factor kappa B (NF-κB) signaling pathway on antimony-induced astrocyte activation. Methods: Protein expression levels were detected by Western blotting. Immunofluorescence, cytoplasmic and nuclear fractions separation were used to assess the distribution of p65. The expression of protein in brain tissue sections was detected by immunohistochemistry. The levels of mRNAs were detected by Quantitative real-time polymerase chain reaction (qRT-PCR) and reverse transcription-polymerase chain reaction (RT-PCR). Results: Antimony exposure triggered astrocyte proliferation and increased the expression of two critical protein markers of reactive astrogliosis, inducible nitric oxide synthase (iNOS) and glial fibrillary acidic protein (GFAP), indicating that antimony induced astrocyte activation in vivo and in vitro. Antimony exposure consistently upregulated the expression of inflammatory factors. Moreover, it induced the NF-κB signaling, indicated by increased p65 phosphorylation and translocation to the nucleus. NF-κB inhibition effectively attenuated antimony-induced astrocyte activation. Furthermore, antimony phosphorylated TGF-ß-activated kinase 1 (TAK1), while TAK1 inhibition alleviated antimony-induced p65 phosphorylation and subsequent astrocyte activation. Conclusion: Antimony activated astrocytes by activating the NF-κB signaling pathway.


Asunto(s)
Antimonio/toxicidad , Astrocitos/efectos de los fármacos , FN-kappa B/metabolismo , Animales , Astrocitos/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Quinasas Quinasa Quinasa PAM , Masculino , Ratones Endogámicos ICR , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos
10.
Chem Biol Interact ; 335: 109368, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33412153

RESUMEN

Dapagliflozin, a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has featured marked anti-inflammatory effects in murine models of myocardial infarction, renal injury, and neuroinflammation. Yet, its potential impact on the pathogenesis of inflammatory bowel diseases (IBD) has not been previously investigated. The presented study aimed to explore the prospect of dapagliflozin to mitigate 2,4,6 trinitrobenzene sulfonic acid (TNBS)-induced rat colitis model which recapitulates several features of the human IBD. The molecular mechanisms pertaining to the dynamic balance between autophagy/apoptosis and colon injury were delineated, particularly, AMPK/mTOR, HMGB1/RAGE/NF-κB and Nrf2/HO-1 pathways. The colon tissues were examined using immunoblotting, ELISA, and histopathology. Dapagliflozin (0.1, 1 and 5 mg/kg; p.o.) dose-dependently mitigated colitis severity as manifested by suppression of the disease activity scores, macroscopic damage scores, colon weight/length ratio, histopathologic perturbations, and inflammatory markers. More important, dapagliflozin enhanced colonic autophagy via upregulating Beclin 1 and downregulating p62 SQSTM1 protein expression. In this context, dapagliflozin activated the AMPK/mTOR pathway by increasing the p-AMPK/AMPK and lowering the p-mTOR/mTOR ratios, thereby, favoring autophagy. Moreover, dapagliflozin dampened the colonic apoptosis via lowering the caspase-3 activity, cleaved caspase-3 expression, and Bax/Bcl-2 ratio. Furthermore, dapagliflozin attenuated the HMGB1/RAGE/NF-κB pathway via lowering HMGB1, RAGE, and p-NF-κBp65 protein expression. Regarding oxidative stress, dapagliflozin lowered the oxidative stress markers and augmented the Nrf2/HO-1 pathway. Together, the present study reveals, for the first time, the ameliorative effect of dapagliflozin against experimental colitis via augmenting colonic autophagy and curbing apoptosis through activation of AMPK/mTOR and Nrf2/HO-1 pathways and suppression of HMGB1/RAGE/NF-κB cascade.


Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Compuestos de Bencidrilo/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Glucósidos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/patología , Colon/patología , Factor de Transcripción de la Proteína de Unión a GA/metabolismo , Proteína HMGB1 , Hemo Oxigenasa (Desciclizante)/metabolismo , Masculino , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Ácido Trinitrobencenosulfónico
11.
Int J Nanomedicine ; 16: 133-145, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33447032

RESUMEN

Background: Rheumatoid arthritis (RA) is an autoimmune disease that underlies chronic inflammation of the synovial membrane. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat RA. However, a long list of adverse events associated with long-term treatment regimens with NSAIDs negatively influences patient compliance and therapeutic outcomes. Aim: The aim of this work was to achieve site-specific delivery of celecoxib-loaded spanlastic nano-vesicle-based delivery system to the inflamed joints, avoiding systemic administration of large doses. Methodology: To develop spanlastic nanovesicles for transdermal delivery of celecoxib, modified injection method was adopted using Tween 80 or Brij as edge activators. Entrapment efficiency, vesicle size, ex vivo permeation, and morphology of the prepared nano-vesicles were characterized. Carbopol-based gels containing the selected formulations were prepared, and their clarity, pH, rheological performance, and ex vivo permeation were characterized. Celecoxib-loaded niosomes and noisome-containing gels were developed for comparison. The in vivo efficacy of the selected formulations was evaluated in a rat model of Freund's complete adjuvant-induced arthritis. Different inflammatory markers including TNF-α, NF-кB and COX-2 were assessed in paw tissue before and after treatment. Results: The size and entrapment efficiency of the selected spanlastic nano-vesicle formulation were 112.5 ± 3.6 nm, and 83.6 ± 2.3%, respectively. This formulation has shown the highest transdermal flux and permeability coefficient compared to the other investigated formulations. The spanlastics-containing gel of celecoxib has shown transdermal flux of 6.9 ± 0.25 µg/cm2/hr while the celecoxib niosomes-containing gel and unprocessed celecoxib-loaded gel have shown 5.2 ± 0.12 µg/cm2/hr and 0.64 ± 0.09 µg/cm2/hr, respectively. In the animal model of RA, the celecoxib-loaded spanlastics-containing gel significantly reduced edema circumference and significantly suppressed TNF-α, NF-кB and COX-2 levels compared to the niosomes-containing gel, the marketed diclofenac sodium gel, and unprocessed celecoxib-loaded gel. Conclusion: The spanlastic nano-vesicle-containing gel represents a more efficient site-specific treatment for topical treatment of chronic inflammation like RA, compared to commercial and other conventional alternatives.


Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Celecoxib/uso terapéutico , Ciclooxigenasa 2/metabolismo , Regulación hacia Abajo , FN-kappa B/metabolismo , Nanopartículas/química , Factor de Necrosis Tumoral alfa/metabolismo , Administración Cutánea , Administración Tópica , Animales , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/genética , Celecoxib/farmacología , Ciclooxigenasa 2/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Adyuvante de Freund , Regulación de la Expresión Génica/efectos de los fármacos , Cinética , Liposomas , Masculino , Ratones , FN-kappa B/genética , Tamaño de la Partícula , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Wistar , Reología , Absorción Cutánea/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genética
12.
Nat Commun ; 12(1): 95, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33398028

RESUMEN

Microtubule-associated protein Tau can form protein aggregates transmissible within the brain, correlating with the progression of tauopathies in humans. The transmission of aggregates requires neuron-released Tau to interact with surface receptors on target cells. However, the underlying molecular mechanisms in astrocytes and downstream effects are unclear. Here, using a spatially resolved proteomic mapping strategy, we show that integrin αV/ß1 receptor binds recombinant human Tau, mediating the entry of Tau fibrils in astrocytes. The binding of distinct Tau species to the astrocytic αV/ß1 receptor differentially activate integrin signaling. Furthermore, Tau-mediated activation of integrin signaling results in NFκB activation, causing upregulation of pro-inflammatory cytokines and chemokines, induction of a sub-group of neurotoxic astrocytic markers, and release of neurotoxic factors. Our findings suggest that filamentous recombinant human Tau-mediated activation of integrin signaling induces astrocyte conversion towards a neurotoxic state, providing a mechanistic insight into tauopathies.


Asunto(s)
Astrocitos/metabolismo , Receptores de Vitronectina/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas tau/metabolismo , Animales , Astrocitos/patología , Células Cultivadas , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Células HEK293 , Proteoglicanos de Heparán Sulfato/metabolismo , Humanos , Inflamación/patología , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Neuronas/metabolismo , Neuronas/patología , Unión Proteica , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Talina/metabolismo , Proteínas tau/ultraestructura
13.
Ecotoxicol Environ Saf ; 208: 111609, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396129

RESUMEN

With the wide application of neodymium oxide nanoparticles (NPs-Nd2O3) in various fields, their health hazards have aroused public concern in recent years. However, data regarding the cytotoxicity of NPs-Nd2O3 is limited. In this study, we investigated the function and mechanism of long-chain non-coding RNAs (lncRNAs) in NPs-Nd2O3-induced airway inflammation. Treatment with NPs-Nd2O3 induced an inflammatory response in human bronchial epithelial cells (16HBE) by upregulating the expression of interleukin-6 (IL-6) and interleukin-8 (IL-8). The levels of LDH and intracellular ROS in the cells treated by various doses of NPs-Nd2O3 also increased significantly. After treatment with 10 µg/ml NPs-Nd2O3, RNA microarray and real-time quantitative polymerase chain reaction (qRT-PCR) showed a significant upregulation of lncRNA loc105377478. Functional experiments suggested lncRNA loc105377478 enhanced the expression of IL-6, IL-8 and ROS in NPs-Nd2O3-treated 16HBE cells, and it was further demonstrated that lncRNA loc105377478 promoted the activation of NF-κB by negatively regulating ADIPOR1 expression. Moreover, the expression of IL-6 and IL-8 in NPs-Nd2O3-treated 16HBE cells was regulated by lncRNA loc105377478, which was mediated by the NF-κB signaling pathway. In conclusion, lncRNA loc105377478 promotes NF-κB activation by negatively regulating ADIPOR1 expression, thereby upregulating the expression of IL-6 and IL-8 in 16HBE cells treated with NPs-Nd2O3.


Asunto(s)
Células Epiteliales/efectos de los fármacos , FN-kappa B/metabolismo , Nanopartículas/química , Nanopartículas/toxicidad , Neodimio/toxicidad , Óxidos/toxicidad , ARN Largo no Codificante/genética , Receptores de Adiponectina/metabolismo , Bronquios/efectos de los fármacos , Bronquios/inmunología , Bronquios/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/inmunología , Relación Dosis-Respuesta a Droga , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Humanos , Inflamación , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Neodimio/química , Óxidos/química , Transducción de Señal , Regulación hacia Arriba
14.
Nat Commun ; 12(1): 117, 2021 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-33402692

RESUMEN

Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-κB pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding 68Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival.


Asunto(s)
Infecciones por Virus de Epstein-Barr/genética , Regulación Neoplásica de la Expresión Génica , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Recurrencia Local de Neoplasia/genética , Receptores de Somatostatina/genética , Proteínas de la Matriz Viral/genética , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/mortalidad , Infecciones por Virus de Epstein-Barr/virología , Femenino , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/crecimiento & desarrollo , Herpesvirus Humano 4/patogenicidad , Interacciones Huésped-Patógeno/genética , Humanos , Metástasis Linfática , Masculino , Ratones , Ratones Desnudos , Terapia Molecular Dirigida , FN-kappa B/genética , FN-kappa B/metabolismo , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/mortalidad , Carcinoma Nasofaríngeo/virología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/virología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/virología , Octreótido/farmacología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Receptores de Somatostatina/antagonistas & inhibidores , Receptores de Somatostatina/metabolismo , Transducción de Señal , Análisis de Supervivencia , Proteínas de la Matriz Viral/antagonistas & inhibidores , Proteínas de la Matriz Viral/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Life Sci ; 267: 118934, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33385405

RESUMEN

The biological functions of melatonin range beyond the regulation of the circadian rhythm. With regard to cancer, melatonin's potential to suppress cancer initiation, progression, angiogenesis and metastasis as well as sensitizing malignant cells to conventional chemo- and radiotherapy are among its most interesting effects. The targets at which melatonin initiates its anti-cancer effects are in common with those of a majority of existing anti-cancer agents, giving rise to the notion that this molecule is a pleiotropic agent sharing many features with other antineoplastic drugs in terms of their mechanisms of action. Among these common mechanisms of action are the regulation of several major intracellular pathways including mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) and protein kinase B (AKT/PKB) signaling. The important mediators affected by melatonin include cyclins, nuclear factor-κB (NF-κB), heat shock proteins (HSPs) and c-Myc, all of which can serve as potential targets for cancer drugs. Melatonin also exerts some of its anti-cancer effects via inducing epigenetic modifications, DNA damage and mitochondrial disruption in malignant cells. The regulation of these mediators by melatonin mitigates tumor growth and invasiveness via modulating their downstream responsive genes, housekeeping enzymes, telomerase reverse transcriptase, apoptotic gene expression, angiogenic factors and structural proteins involved in metastasis. Increasing our knowledge on how melatonin affects its target sites will help find ways of exploiting the beneficial effects of this ubiquitously-acting molecule in cancer therapy. Acknowledging this, here we reviewed the most studied target pathways attributed to the anti-cancer effects of melatonin, highlighting their therapeutic potential.


Asunto(s)
Melatonina/metabolismo , Melatonina/farmacología , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Ritmo Circadiano/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Melatonina/fisiología , FN-kappa B/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal/efectos de los fármacos , Telomerasa/metabolismo
16.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(1): 55-63, 2021 Jan 30.
Artículo en Chino | MEDLINE | ID: mdl-33509753

RESUMEN

OBJECTIVE: To investigate the role of NDUFA13 inactivation in the pathogenesis of spontaneous hepatitis in mice and explore the possible mechanisms. METHODS: Hepatocyte-specific NDUFA13 knockout (NDUFA13fl/-) mice were generated by intercrossing NDUFA13fl/fl and Alb-Cre mice based on Cre/loxP transgenic technology, and tail and liver DNA of the mice was genotyped by PCR analysis. Ten NDUFA13fl/- mice and 10 littermate control NDUFA13fl/fl mice were housed, and in each group, 5 mice were euthanized at the age of 4 weeks and the other 5 at two years for pathological examination of the liver tissues with HE staining. Immunohistochemistry was used to verify the expression levels of NDUFA13, NF-κB/p65, NF-κB/p-p65 and inflammasome NLRP3. The total intracellular ROS and mitochondrial ROS levels were measured with a ROS staining kit. The expressions of the inflammatory cell markers (CD45, MPO, and F4/80) and inflammatory cytokines (IL1ß and IL33) in the liver were detected with immunohistochemistry and immunofluorescence assay. RESULTS: Liver-specific NDUFA13 heterozygous knockout mice were successfully constructed as verified by PCR results. HE staining revealed severe liver damage in both 4- week-old and 2-year-old NDUFA13fl/- mice as compared with their littermate controls. Immunohistochemistry showed a significant decrease of NDUFA13 expression in both 4-week-old and 2-year-old NDUFA13fl/- mice (P < 0.05). The expression levels of NF-κB signals p65, p-p65 and NLRP3 inflammasomes were all significantly increased in NDUFA13fl/- mice (P < 0.05). The total intracellular ROS and mitochondrial ROS levels in NDUFA13fl/- mice were also significantly increased. NDUFA13 knockout obviously promoted the expression of the inflammatory cell markers (CD45, MPO and F4/80) and the secretion of IL-1ß and IL-33 in the liver tissue of the mice (P < 0.05). CONCLUSIONS: Hepatocytes-specific NDUFA13 ablation can trigger spontaneous hepatitis in mice possibly mediated by the activation of ROS/NF-κB/NLRP3 signaling.


Asunto(s)
Hepatitis , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Inflamasomas , Ratones , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Transducción de Señal
17.
J Med Chem ; 64(1): 768-781, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-33440945

RESUMEN

Berberine (BBR), a traditional Chinese medicine, has therapeutic effects on a variety of inflammation-related diseases, but its direct proteomic targets remain unknown. Using activity-based protein profiling, we first demonstrated that BBR directly targets the NEK7 protein via the hydrogen bond between the 2,3-methylenedioxy and 121-arginine (R121) residues. The fact that R121 is located precisely within the key domain involved in the NEK7-NLRP3 interaction allows BBR to specifically block the NEK7-NLRP3 interaction and successively inhibit IL-1ß release, independent of the NF-κB and TLR4 signaling pathways. Moreover, BBR displays in vivo anti-inflammatory efficacy in a NEK7-dependent manner. Therefore, we consider NEK7 to be a key target of BBR in the treatment of NLRP3-related inflammatory diseases, and the development of novel NEK7-NLRP3 interaction inhibitors might be easily achieved using NEK7 as a target.


Asunto(s)
Antiinflamatorios/química , Berberina/química , Quinasas Relacionadas con NIMA/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Berberina/metabolismo , Berberina/farmacología , Sitios de Unión , Humanos , Enlace de Hidrógeno , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Monocitos/citología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , FN-kappa B/metabolismo , Quinasas Relacionadas con NIMA/antagonistas & inhibidores , Quinasas Relacionadas con NIMA/genética , Proteína con Dominio Pirina 3 de la Familia NLR/química , Dominios y Motivos de Interacción de Proteínas/efectos de los fármacos , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad
18.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(1): 31-38, 2021 Jan.
Artículo en Chino | MEDLINE | ID: mdl-33441226

RESUMEN

Objective To investigate the effect of ephrin type-A receptor 2 (EphA2) on the expression of inflammatory cytokines in airway epithelial cells induced by house dust mite extract (HDM) and the underlying mechanism. Methods The cell model of EphA2 knockdown was established by transfection of EphA2 siRNA into airway cell line 16HBE cells. After the 16HBE cells were stimulated with HDM, the mRNA levels of EphA2, interleukin 6 (IL-6) and IL-8 were determined by real-time quantitative PCR (qPCR), and the protein levels of IL-6, IL-8, IL-17A, IL-17F and tumor necrosis factor-α (TNF-α) were measured by cytometric bead array (CBA). Western blotting was used to analyze the protein expression of EphA2, phosphorylated EphA2 (p-EphA2), signal transducer and activator of transcription (STAT3), phosphorylated STAT3 (p-STAT3), p38 mitogen-activated protein kinases (p38 MAPK), phosphorylated p38 MAPK (p-p38 MAPK), nuclear factor κ-B p65 (NF-κB p65) and phosphorylated NF-κB p65 (p-NF-κB p65). Then, in the 16HEB cells stimulated by STAT3 inhibitor Stattic or p38 MAPK inhibitor SB203580 in combination with HDM, the mRNA and protein expression levels of IL-6 and IL-8 were detected by qPCR and CBA. Results Knockdown of EphA2 significantly inhibited the expression of IL-6 and IL-8 in HDM-induced 16HBE, and reduced the total protein and phosphorylated levels of STAT3 and p38 MAPK, but had no significant effect on the total protein and phosphorylated levels of NF-κB p65. After stattic inhibited the expression and activation of STAT3, the mRNA and protein levels of IL-6 and IL-8 significantly decreased in HDM-induced 16HBE cells. Interestingly, while SB203580 inhibited the activation of p38 MAPK signaling pathway, it only inhibited the mRNA levels of IL-6 and IL-8 in HDM-induced 16HBE cells, but had no effect on their protein levels. Conclusion HDM can induce the expression of IL-6 and IL-8 in 16HBE cells to participate in airway inflammation by activating the EphA2-STAT3/p38 MAPK pathway.


Asunto(s)
FN-kappa B , Transducción de Señal , Animales , Células Epiteliales/metabolismo , Humanos , Inflamación , FN-kappa B/metabolismo , Pyroglyphidae , Factor de Transcripción STAT3/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
19.
Zhonghua Zhong Liu Za Zhi ; 43(1): 118-125, 2021 Jan 23.
Artículo en Chino | MEDLINE | ID: mdl-33472324

RESUMEN

Objective: To investigate the effect of pentraxin 3 (PTX3) on the proliferation, invasion and drug resistance of pediatric neuroblastoma cells and its mechanism. Methods: si-RNA (si-RNA group), si-PTX3 (si-PTX3 group), siRNA+ pcDNA3.1 (siRNA+ pcDNA3.1 group), si-PTX3+ pcDNA3.1 (si-PTX3+ pcDNA3.1 group), siRNA+ pcDNA3.1-Toll-like receptor 4 (siRNA+ pcDNA3.1-TLR4 group) and si-PTX3+ pcDNA3.1-TLR4 (si-PTX3+ pcDNA3.1-TLR4 group) were transfected into SH-SY5Y cells. Collected 32 cases of tumor tissue and cancerous tissue in children with childhood neuromaternal cells who were treated at Zhumadian center hospital from July 2016 to August 2019. Real-time fluorescent quantitative polymerase chain (RT-qPCR) reaction and immunohistochemistry experiments were used to detect the protein expressions of PTX3 in neuroblastoma tissues and normal tissues. 5-Ethynyl-2'-deoxyuridine (EdU) was used to detect the proliferation effect of PTX3 on neuroblastoma cell SH-SY5Y. Western blot experiment was used to detect the protein expression levels of vascular endothelial growth factor (VEGF), resistance-related proteins including P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP-1), and invasion-related protein matrix metalloproteinase-1 (MMP-1). Results: PTX3 mRNA expressions in neuroblastoma tissues were 0.87±0.07, higher than 0.13±0.06 of normal tissues, and the differences were statistically significant (P<0.05), The expression of the immunohistochemistry test PTX3 protein was consistent with the qRT-PCR results. Compared with the si-RNA group (0.95±0.08; 1.02±0.10), the mRNA and protein expressions of PTX3 in the si-PTX3 group (0.25±0.05; 0.45±0.66) decreased, the differences were statistically significant (all P<0.05). The number of EdU positive cells, invasion rate, VEGF, MMP-1, P-gp and MRP-1 protein expressions in si-RNA group were (31.86±1.86)%, (28.12±2.96)%, (0.58±0.07), (0.44±0.06), (0.46±0.08) and (0.51±0.05), respectively, higher than (19.73±1.22)%, (8.45±1.06)%, (0.25±0.05), (0.19±0.03), (0.19±0.06) and (0.16±0.07) in si-PTX3 group, and the differences were statistically significant (all P<0.05). The Number of EdU positive cells [(19.49±1.68)%], invasion rate [(8.48±1.36)%], VEGF protein expression (0.10±0.15), P-gp (0.18±0.07) , TLR4 (0.45±0.06), p-p65 (0.25±0.05) protein expressions in si-PTX3+ pcDNA3.1 group were relatively lower compared with siRNA+ pcDNA3.1 group [(38.21±2.67)%, (26.39±2.14)%, 0.49±0.05, 0.52±0.06, 0.93±0.14 and 0.82±0.06] (all P<0.05). The number of EdU-positive cells [(62.73±5.18)%], invasion rate [(50.45±3.25)%], VEGF protein expression (2.17±0.17), P-gp (2.15±0.16), TLR4 (2.68±0.16), p-p65 (2.48±0.13) protein expressions in the siRNA+ pcDNA3.1-TLR4 group increased compared with siRNA+ pcDNA3.1 group (all P<0.05). Conclusions: Inhibition of PTX3 can inhibit the proliferation and invasion of neuroblastoma cells SH-SY5Y, and reduce drug resistance. Its mechanism may be achieved by regulating the TLR4/NF-κB signaling pathway. This result can provide a new perspective for pediatric neuroblasts tumor diagnosis and clinical treatment.


Asunto(s)
FN-kappa B , Neuroblastoma , Proteína C-Reactiva , Proliferación Celular , Niño , Resistencia a Medicamentos , Humanos , FN-kappa B/metabolismo , Neuroblastoma/genética , Componente Amiloide P Sérico , Transducción de Señal , Receptor Toll-Like 4/genética , Factor A de Crecimiento Endotelial Vascular/genética
20.
Nat Commun ; 12(1): 567, 2021 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-33495464

RESUMEN

The regulatory elements controlling gene expression during acute inflammation are not fully elucidated. Here we report the identification of a set of NF-κB-bound elements and common chromatin landscapes underlying the acute inflammatory response across cell-types and mammalian species. Using primary vascular endothelial cells (human/mouse/bovine) treated with the pro-inflammatory cytokine, Tumor Necrosis Factor-α, we identify extensive (~30%) conserved orthologous binding of NF-κB to accessible, as well as nucleosome-occluded chromatin. Regions with the highest NF-κB occupancy pre-stimulation show dramatic increases in NF-κB binding and chromatin accessibility post-stimulation. These 'pre-bound' regions are typically conserved (~56%), contain multiple NF-κB motifs, are utilized by diverse cell types, and overlap rare non-coding mutations and common genetic variation associated with both inflammatory and cardiovascular phenotypes. Genetic ablation of conserved, 'pre-bound' NF-κB regions within the super-enhancer associated with the chemokine-encoding CCL2 gene and elsewhere supports the functional relevance of these elements.


Asunto(s)
Cromatina/genética , Células Endoteliales/metabolismo , Regulación de la Expresión Génica/genética , Inflamación/genética , FN-kappa B/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos/genética , Enfermedad Aguda , Animales , Sitios de Unión/genética , Bovinos , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Cromatina/metabolismo , Secuencia Conservada/genética , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/metabolismo , Inflamación/patología , Lógica , Ratones , Modelos Genéticos , Unión Proteica , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/farmacología
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