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1.
Zhongguo Zhong Yao Za Zhi ; 47(16): 4454-4461, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-36046875

RESUMO

This study aimed to further explore the relevant mechanism of action by network pharmacology integrated with animal experimental verification based on previous proven effective treatment of vertebral artery type of cervical spondylosis(CSA) by Panlongqi Tablets. Bionetwork analysis was performed to establish drug-disease interaction network, and it was found that the key candidate targets of Panlongqi Tablets were enriched in multiple signaling pathways related to CSA pathological links, among which phosphatidylinositol 3-kinase(PI3 K)/serine-threonine kinase(AKT/PKB) signaling pathway was the most significant. Further, mixed modeling method was used to build the CSA rat model, and the rats were divided into normal, model, Panlongqi Tablets low-, medium-and high-dose(0.16, 0.32, 0.64 g·kg~(-1)) and Jingfukang Granules(positive drug, 1.35 g·kg~(-1)) groups. After successful modeling, the rats were administered for 8 consecutive weeks. Pathological changes of rat cervical muscle tissues were detected by hematoxylin-eosin(HE) staining, and the content of interleukin-1ß(IL-1ß), tumor necrosis factor-α(TNF-α), vascular endothelial cell growth factor(VEGF) and chemokine(C-C motif) ligand 2(CCL2) in rat serum and/or cervical tissues was determined by enzyme-linked immunosorbent assay(ELISA). Western blot was employed to detect the protein expression levels of chemokine(C-C motif) receptor 2(CCR2), PI3 K, AKT, phosphorylated AKT(p-AKT), I-kappa-B-kinase beta(IKK-beta/IKKß), nuclear factor kappa B(NF-κB P65) and phosphorylated nuclear factor kappa B(NF-κB p-P65) in rat cervical tissues, and positive expression of p-NF-κB P65 in rat cervical muscle tissues was detected by immunofluorescence. The results showed that Panlongqi Tablets at different doses improved the degree of muscle fibrosis and inflammation in cervical muscle tissues of CSA rats, and reduced the content of inflammatory factors IL-1ß, TNF-α, VEGF, CCL2 and CCR2 in serum and/or cervical tissues. The protein expression levels of PI3 K, p-AKT, IKKß and p-NF-κB P65 as well as the nuclear entry of p-NF-κB P65 in cervical tissues were down-regulated. These findings suggest that Panlongqi Tablets can significantly inhibit the inflammatory response of CSA rats, and the mechanism of action may be related to the down-regulation of the activation of PI3 K/AKT signaling pathway.


Assuntos
NF-kappa B , Espondilose , Animais , Medicamentos de Ervas Chinesas , Quinase I-kappa B/metabolismo , Quinase I-kappa B/farmacologia , NF-kappa B/metabolismo , Farmacologia em Rede , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais , Espondilose/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Artéria Vertebral/metabolismo
2.
Tumour Biol ; 44(1): 187-203, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36093651

RESUMO

BACKGROUND: The alternative NF-κB pathway is activated by the NF-κB-inducing kinase (NIK) mediated phosphorylation of the inhibitor of κ-B kinase α (IKKα). IKKα then phosphorylates p100/NFKB2 to result in its processing to the active p52 subunit. Evidence suggests that basal breast cancers originate within a subpopulation of luminal progenitor cells which is expanded by signaling to IKKα. OBJECTIVE: To determine the role of IKKα in the development of basal tumors. METHODS: Kinase dead IkkαAA/AA mice were crossed with the C3(1)-TAg mouse model of basal mammary cancer. Tumor growth and tumor numbers in WT and IkkαAA/AA mice were assessed and immunopathology, p52 expression and stem/progenitor 3D colony forming assays were performed. Nik-/- mammary glands were isolated and mammary colonies were characterized. RESULTS: While tumor growth was slower than in WT mice, IkkαAA/AA tumor numbers and pathology were indistinguishable from WT tumors. Both WT and IkkαAA/AA tumors expressed p52 except those IkkαAA/AA tumors where NIK, IKKαAA/AA and ErbB2 were undetectable. Colonies formed by WT and IkkαAA/AA mammary cells were nearly all luminal/acinar however, colony numbers and sizes derived from IkkαAA/AA cells were reduced. In contrast to IkkαAA/AA mice, virgin Nik-/- mammary glands were poorly developed and colonies were primarily derived from undifferentiated bipotent progenitor cells. CONCLUSIONS: C3(1)-TAg induced mammary tumors express p100/p52 even without functional IKKα. Therefore the development of basal-like mammary cancer does not strictly rely on IKKα activation. Signal-induced stabilization of NIK may be sufficient to mediate processing of p100NFKB2 which can then support basal-like mammary tumor formation. Lastly, in contrast to the pregnancy specific role of IKKα in lobuloalveogenesis, NIK is obligatory for normal mammary gland development.


Assuntos
Quinase I-kappa B , Neoplasias Mamárias Animais , Animais , Feminino , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Neoplasias Mamárias Animais/genética , Camundongos , NF-kappa B/metabolismo , Fosforilação , Gravidez , Transdução de Sinais
3.
Biomed Pharmacother ; 154: 113529, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36030586

RESUMO

Osteoporosis a common disease in postmenopausal women which contains significant impact on the living quality of women. With the aging of the population, the number of patients suffer from osteoporosis has shown a significant increase. Given the limitations of clinical drugs for the treatment of osteoporosis, natural extracts with small side effects have a great application prospect in the treatment of osteoporosis. Praeruptorin B (Pra-B), is one of the main components found in the roots of Peucedanum praeruptorum Dunn and exhibits anti-inflammatory effects. However, there is no research on the influence of Pra-B on osteoporosis. Here, we showed that Pra-B can dose-dependently suppress osteoclastogenesis without cytotoxicity. Receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL)-induced the nuclear import of P65 was inhibited by Pra-B, which indicated the suppressive effect of Pra-B on NF-κB signaling. Further, Pra-B enhanced the expression of Glutathione S-transferase Pi 1 (GSTP1) and promoted the S-glutathionylation of IKKß to inhibit the nuclear translocation of P65. Moreover, in vivo experiments showed that Pra-B considerably attenuated the bone loss in ovariectomy (OVX)-induced mice. Collectively, our studies revealed that Pra-B suppress the NF-κB signaling targeting GSTP1 to rescued RANKL-induced osteoclastogenesis in vitro and OVX-induced bone loss in vivo, supporting the potential of Pra-B for treating osteoporosis in the future.


Assuntos
Quinase I-kappa B , Osteoporose , Animais , Diferenciação Celular , Cumarínicos , Feminino , Glutationa S-Transferase pi/metabolismo , Humanos , Quinase I-kappa B/metabolismo , Camundongos , NF-kappa B/metabolismo , Osteoclastos , Osteogênese , Osteoporose/metabolismo , Ovariectomia/efeitos adversos , Ligante RANK/metabolismo , Ligante RANK/farmacologia
4.
Signal Transduct Target Ther ; 7(1): 264, 2022 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-35918322

RESUMO

Metastasis is the leading cause of cancer-related death. The interactions between circulating tumor cells and endothelial adhesion molecules in distant organs is a key step during extravasation in hematogenous metastasis. Surgery is a common intervention for most primary solid tumors. However, surgical trauma-related systemic inflammation facilitates distant tumor metastasis by increasing the spread and adhesion of tumor cells to vascular endothelial cells (ECs). Currently, there are no effective interventions to prevent distant metastasis. Here, we show that HECTD3 deficiency in ECs significantly reduces tumor metastasis in multiple mouse models. HECTD3 depletion downregulates expression of adhesion molecules, such as VCAM-1, ICAM-1 and E-selectin, in mouse primary ECs and HUVECs stimulated by inflammatory factors and inhibits adhesion of tumor cells to ECs both in vitro and in vivo. We demonstrate that HECTD3 promotes stabilization, nuclear localization and kinase activity of IKKα by ubiquitinating IKKα with K27- and K63-linked polyubiquitin chains at K296, increasing phosphorylation of histone H3 to promote NF-κB target gene transcription. Knockout of HECTD3 in endothelium significantly inhibits tumor cells lung colonization, while conditional knockin promotes that. IKKα kinase inhibitors prevented LPS-induced pulmonary metastasis. These findings reveal the promotional role of the HECTD3-IKKα axis in tumor hematogenous metastasis and provide a potential strategy for tumor metastasis prevention.


Assuntos
Células Endoteliais , Neoplasias , Animais , Células Endoteliais/metabolismo , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Inflamação/genética , Inflamação/metabolismo , Camundongos , Camundongos Knockout , Neoplasias/genética , Neoplasias/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
5.
Int J Mol Sci ; 23(16)2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-36012250

RESUMO

The preclinical research conducted so far suggest that depression development may be influenced by the inflammatory pathways both at the periphery and within the central nervous system. Furthermore, inflammation is considered to be strongly connected with antidepressant treatment resistance. Thus, this study explores whether the chronic mild stress (CMS) procedure and agomelatine treatment induce changes in TGFA, TGFB, IRF1, PTGS2 and IKBKB expression and methylation status in peripheral blood mononuclear cells (PBMCs) and in the brain structures of rats. Adult male Wistar rats were subjected to the CMS and further divided into matched subgroups to receive vehicle or agomelatine. TaqMan gene expression assay and methylation-sensitive high-resolution melting (MS-HRM) were used to evaluate the expression of the genes and the methylation status of their promoters, respectively. Our findings confirm that both CMS and antidepressant agomelatine treatment influenced the expression level and methylation status of the promoter region of investigated genes in PBMCs and the brain. What is more, the present study showed that response to either stress stimuli or agomelatine differed between brain structures. Concluding, our results indicate that TGFA, TGFB, PTGS2, IRF1 and IKBKB could be associated with depression and its treatment.


Assuntos
Acetamidas , Encéfalo , Leucócitos Mononucleares , Naftalenos , Acetamidas/farmacologia , Animais , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Metilação de DNA , Modelos Animais de Doenças , Quinase I-kappa B/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Naftalenos/farmacologia , Regiões Promotoras Genéticas , Ratos , Ratos Wistar , Estresse Psicológico
6.
FASEB J ; 36(9): e22512, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36001064

RESUMO

The kinase IKKß controls pro-inflammatory gene expression, and its activity in the liver and leukocytes was shown to drive metabolic inflammation and insulin resistance in obesity. However, it was also proposed that liver IKKß signaling protects obese mice from insulin resistance and endoplasmic reticulum (ER) stress by increasing XBP1s protein stability. Furthermore, mice lacking IKKß in leukocytes display increased lethality to lipopolysaccharides. This study aims at improving our understanding of the role of IKKß signaling in obesity. We induced IKKß deletion in hematopoietic cells and liver of obese mice by Cre-LoxP recombination, using an INF-inducible system, or a liver-specific IKKß deletion in obese mice by adenovirus delivery of the Cre recombinase. The histopathological, immune, and metabolic phenotype of the mice was characterized. IKKß deletion in the liver and hematopoietic cells was not tolerated in mice with established obesity exposed to the TLR3 agonist poly(I:C) and exacerbated liver damage and ER-stress despite elevated XBP1s. By contrast, liver-specific ablation of IKKß in obese mice reduced steatosis and improved insulin sensitivity in association with increased XBP1s protein abundance and reduced expression of de-novo lipogenesis genes. We conclude that IKKß blockage in liver and leukocytes is not tolerated in obese mice exposed to TLR3 agonists. However, selective hepatic IKKß ablation improves fatty liver and insulin sensitivity in association with increased XBP1s protein abundance and reduced expression of lipogenic genes.


Assuntos
Fígado Gorduroso , Resistência à Insulina , Animais , Fígado Gorduroso/metabolismo , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Leucócitos/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Receptor 3 Toll-Like/metabolismo
7.
JCI Insight ; 7(17)2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-35917178

RESUMO

Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition of the noncanonical IκB kinases TANK-binding kinase 1 and IKKε with amlexanox restores insulin sensitivity and glucose homeostasis in diabetic mice and human patients. Here we report that amlexanox improves diet-induced hypertriglyceridemia and hypercholesterolemia in Western diet-fed (WD-fed) Ldlr-/- mice and protects against atherogenesis. Amlexanox ameliorated dyslipidemia, inflammation, and vascular dysfunction through synergistic actions that involve upregulation of bile acid synthesis to increase cholesterol excretion. Transcriptomic profiling demonstrated an elevated expression of key bile acid synthesis genes. Furthermore, we found that amlexanox attenuated monocytosis, eosinophilia, and vascular dysfunction during WD-induced atherosclerosis. These findings demonstrate the potential of amlexanox as a therapy for hypercholesterolemia and atherosclerosis.


Assuntos
Aterosclerose , Diabetes Mellitus Experimental , Hipercolesterolemia , Aminopiridinas , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Ácidos e Sais Biliares , Humanos , Hipercolesterolemia/tratamento farmacológico , Quinase I-kappa B/metabolismo , Camundongos , Proteínas Serina-Treonina Quinases
8.
Int J Mol Sci ; 23(15)2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35955463

RESUMO

Angiogenesis is a process that drives breast cancer (BC) progression and metastasis, which is linked to the altered inflammatory process, particularly in triple-negative breast cancer (TNBC). In targeting inflammatory angiogenesis, natural compounds are a promising option for managing BC. Thus, this study was designed to determine the natural alkaloid sanguinarine (SANG) potential for its antiangiogenic and antimetastatic properties in triple-negative breast cancer (TNBC) cells. The cytotoxic effect of SANG was examined in MDA-MB-231 and MDA-MB-468 cell models at a low molecular level. In this study, SANG remarkably inhibited the inflammatory mediator chemokine CCL2 in MDA-MB-231 and MDA-MB-468 cells. Furthermore, qRT-PCR confirmed with Western analysis studies showed that mRNA CCL2 repression was concurrent with reducing its main regulator IKBKE and NF-κB signaling pathway proteins in both TNBC cell lines. The total ERK1/2 protein was inhibited in the more responsive MDA-MB-231 cells. SANG exhibited a higher potential to inhibit cell migration in MDA-MB-231 cells compared to MDA-MB-468 cells. Data obtained in this study suggest a unique antiangiogenic and antimetastatic effect of SANG in the MDA-MB-231 cell model. These effects are related to the compound's ability to inhibit the angiogenic CCL2 and impact the ERK1/2 pathway. Therefore, SANG use may be recommended as a component of the therapeutic strategy for TNBC.


Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Antineoplásicos/farmacologia , Benzofenantridinas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Quimiocina CCL2/metabolismo , Humanos , Quinase I-kappa B/metabolismo , Isoquinolinas , Sistema de Sinalização das MAP Quinases , NF-kappa B/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/patologia , Fator de Necrose Tumoral alfa/metabolismo
9.
Mol Neurobiol ; 59(10): 6141-6157, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35871708

RESUMO

Class IIa histone deacetylases (HDAC) have been shown to drive innate immune cell-mediated inflammation in the peripheral system, but their roles in cerebral inflammatory responses remain largely unknown. Here, we elucidate that HDAC7 is selectively elevated in lipopolysaccharide (LPS)-challenged astrocytes both in vivo and in vitro. We identify that HDAC7 binds to the inhibitory kappa B kinase (IKK) to promote IKKα and IKKß deacetylation and subsequent activation, leading to the activation of nuclear factor κB (NF-κB). Astrocyte-specific overexpression of HDAC7 results in NF-κB activation, pro-inflammatory gene upregulation and anxiety-like behaviors in mice, while downregulating HDAC7 reserves LPS-induced NF-κB activation and inflammatory responses. Furthermore, pharmacological inhibition of HDAC7 by a class IIa HDAC inhibitor attenuates LPS-induced NF-κB activation, inflammatory responses and anxiety-like behaviors both in vivo and in vitro. Together, our data reveal a novel mechanism of HDAC7 in astrocyte-mediated inflammation and suggest that targeting HDAC7 could be a potential therapeutic strategy for the treatment of anxiety and other inflammation-related diseases.


Assuntos
Astrócitos , Histona Desacetilases , NF-kappa B , Animais , Astrócitos/metabolismo , Linhagem Celular , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/metabolismo
10.
Cell Signal ; 98: 110403, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35835332

RESUMO

IKKγ prototypically promotes NFκBp65 activity by regulating the assembly of the IKK holocomplex. In hypertrophied cardiomyocytes, the p65-p300 complex-induced regenerative efforts are neutralized by the p53-p300 complex-mediated apoptotic load resulting in compromised cardiac function. The present study reports that nitrosative stress leads to S-Nitrosylation of IKKγ in hypertrophied cardiomyocytes in a pre-clinical model. Using a cardiomyocyte-targeted nanoconjugate, IKKγ S-Nitrosylation-resistant mutant plasmids were delivered to the pathologically hypertrophied heart that resulted in improved cardiac function by amelioration of cardiomyocyte apoptosis and simultaneous induction of their cell cycle re-entry machinery. Mechanistically, in IKKγ S-Nitrosyl mutant-transfected hypertrophied cells, increased IKKγ-p300 binding downregulated the binding of p53 and p65 with p300. This shifted the binding preference of p65 from p300 to HDAC1 resulting in upregulated expression of cyclin D1 and CDK2 via the p27/pRb pathway. This approach has therapeutic advantage over mainstream anti-hypertrophic remedies which concomitantly reduce the regenerative prowess of resident cardiomyocytes during hypertrophy upon downregulation of myocyte apoptosis. Therefore, cardiomyocyte-targeted delivery of IKKγ S-Nitrosyl mutants during hypertrophy can be exploited as a novel strategy to re-muscularize the diseased heart.


Assuntos
Quinase I-kappa B , Miócitos Cardíacos , Cardiomegalia/patologia , Humanos , Quinase I-kappa B/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Nitrosativo , Proteína Supressora de Tumor p53/metabolismo
11.
Front Immunol ; 13: 941579, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844609

RESUMO

African swine fever virus (ASFV) encodes more than 150 proteins, which establish complex interactions with the host for the benefit of the virus in order to evade the host's defenses. However, currently, there is still a lack of information regarding the roles of the viral proteins in host cells. Here, our data demonstrated that ASFV structural protein p17 exerts a negative regulatory effect on cGAS-STING signaling pathway and the STING signaling dependent anti-HSV1 and anti-VSV functions. Further, the results indicated that ASFV p17 was located in ER and Golgi apparatus, and interacted with STING. ASFV p17 could interfere the STING to recruit TBK1 and IKKϵ through its interaction with STING. It was also suggested that the transmembrane domain (amino acids 39-59) of p17 is required for interacting with STING and inhibiting cGAS-STING pathway. Additionally, with the p17 specific siRNA, the ASFV induced IFN-ß, ISG15, ISG56, IL-6 and IL-8 gene transcriptions were upregulated in ASFV infected primary porcine alveolar macrophages (PAMs). Taken together, ASFV p17 can inhibit the cGAS-STING pathway through its interaction with STING and interference of the recruitment of TBK1 and IKKϵ. Our work establishes the role of p17 in the immune evasion and thus provides insights on ASFV pathogenesis.


Assuntos
Vírus da Febre Suína Africana , Animais , Quinase I-kappa B/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Transdução de Sinais , Suínos
12.
Biochem Biophys Res Commun ; 621: 46-52, 2022 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-35810590

RESUMO

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and play critical roles in tumorigenesis. CAFs consists of multiple subpopulations, which have diverse functions. The detailed mechanism, including the role of NF-κB, a critical transcription factor for inflammation and cell survival, in CAFs has not been adequately explored. In this study, we examined the roles of IKKß, a key kinase for NF-κB activation, in activated CAFs by using mice (KO mice) with deletion of IKKß in activated fibroblasts (aFbs). We found that melanoma cells implanted in KO mice showed significantly more growth than those implanted in control mice. To exclude the effects of deletion of IKKß in cells other than aFbs, we implanted a mixture of melanoma cells and IKKß-deleted aFbs in wild-type mice and observed that the mixture showed greater growth than a mixture of melanoma cells and normal aFbs. In exploring the mechanisms, we found that conditioned medium from IKKß-deleted aFbs promotes the proliferation of melanoma cells, and the expression of growth arrest-specific 6 (GAS6) and hepatocyte growth factor (HGF), which are major tumor-promoting factors, was upregulated in IKKß-deleted aFbs. These results indicated the tumor-suppressing function of IKKß in activated CAFs.


Assuntos
Fibroblastos Associados a Câncer , Melanoma , Animais , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos/metabolismo , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Melanoma/patologia , Camundongos , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases , Microambiente Tumoral
13.
Clin Exp Pharmacol Physiol ; 49(10): 1072-1081, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35690890

RESUMO

Obesity is associated with low-grade inflammation and disturbances in hepatic metabolism. This study aimed to investigate the effects of resistance exercise on inflammatory signalling related to IκB kinase (IKK) ɛ protein (IKKɛ) and on hepatic fat accumulation in obese mice. Male Swiss mice were distributed into three groups: control (CTL) fed with standard chow; obese (OB) mice induced by a high-fat diet (HFD); obese exercised (OB + RE) mice fed with HFD and submitted to a resistance exercise training. The resistance exercise training protocol consisted of 20 sets/3 ladder climbs for 8 weeks, three times/week on alternate days. The training overload was equivalent to 70% of the maximum load supported by the rodent. Assays were performed to evaluate weight gain, hepatic fat content, fasting glucose, insulin sensitivity, IKKɛ phosphorylation and proteins related to insulin signalling and lipogenesis in the liver. Mice that received the high-fat diet showed greater adiposity, impaired insulin sensitivity, increased fasting glucose and increased hepatic fat accumulation. These results were accompanied by an increase in IKKɛ phosphorylation and lipogenesis-related proteins such as cluster of differentiation 36 (CD36) and fatty acid synthase (FAS) in the liver of obese mice. In contrast, exercised mice showed lower body weight and adiposity evolution throughout the experiment. In addition, resistance exercise suppressed the effects of the high-fat diet by reducing IKKɛ phosphorylation and hepatic fat content. In conclusion, resistance exercise training improves hepatic fat metabolism and glycaemic homeostasis, which are, at least in part, linked to the anti-inflammatory effect of reduced IKKɛ phosphorylation in the liver of obese mice.


Assuntos
Adiposidade , Quinase I-kappa B , Fígado , Obesidade , Treinamento de Força , Animais , Dieta Hiperlipídica/efeitos adversos , Glucose/metabolismo , Humanos , Quinase I-kappa B/metabolismo , Resistência à Insulina , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Fosforilação
14.
Front Immunol ; 13: 860327, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35769477

RESUMO

Endothelial cells (ECs) are important contributors to inflammation in immune-mediated inflammatory diseases (IMIDs). In this study, we examined whether CD4+ memory T (Tm) cells can drive EC inflammatory responses. Human Tm cells produced ligands that induced inflammatory responses in human umbilical vein EC as exemplified by increased expression of inflammatory mediators including chemokines and adhesion molecules. NF-κB, a key regulator of EC activation, was induced by Tm cell ligands. We dissected the relative contribution of canonical and non-canonical NF-κB signaling to Tm induced EC responses using pharmacological small molecule inhibitors of IKKß (iIKKß) or NF-κB inducing kinase (iNIK). RNA sequencing revealed substantial overlap in IKKß and NIK regulated genes (n=549) that were involved in inflammatory and immune responses, including cytokines (IL-1ß, IL-6, GM-CSF) and chemokines (CXCL5, CXCL1). NIK regulated genes were more restricted, as 332 genes were uniquely affected by iNIK versus 749 genes by iIKKß, the latter including genes involved in metabolism, proliferation and leukocyte adhesion (VCAM-1, ICAM-1). The functional importance of NIK and IKKß in EC activation was confirmed by transendothelial migration assays with neutrophils, demonstrating stronger inhibitory effects of iIKKß compared to iNIK. Importantly, iIKKß - and to some extent iNIK - potentiated the effects of currently employed therapies for IMIDs, like JAK inhibitors and anti-IL-17 antibodies, on EC inflammatory responses. These data demonstrate that inhibition of NF-κB signaling results in modulation of Tm cell-induced EC responses and highlight the potential of small molecule NF-κB inhibitors as a novel treatment strategy to target EC inflammatory responses in IMIDs.


Assuntos
Células Endoteliais , NF-kappa B , Linfócitos T CD4-Positivos/metabolismo , Quimiocinas/metabolismo , Células Endoteliais/metabolismo , Humanos , Quinase I-kappa B/metabolismo , Células T de Memória , NF-kappa B/metabolismo , Transdução de Sinais
16.
Zhen Ci Yan Jiu ; 47(6): 504-9, 2022 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-35764517

RESUMO

OBJECTIVE: To investigate the effect of electroacupuncture (EA) on the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) inflammatory pathway in the liver of obese rats with insulin resistance, and explore its mechanism. METHODS: Male Wistar rats were randomly divided into a normal group (n=15) and an experimental group (n=30). The obesity-induced insulin resistance model was induced by the high-fat diet (HFD) in rats of the experimental group for 8 weeks. Subsequently, the model rats were further divided into a model group (n=15) and an EA group (n=15). EA was applied at "Zhongwan "(CV12), "Guanyuan" (CV4), "Zusanli "(ST36) and "Fenglong "(ST40) in the EA group for 10 min, three times a week for 8 weeks. The body weight of rats in each group was measured before intervention and at the 2nd, 4th, 6th, and 8th weeks during the intervention. Glucose infusion rate (GIR) was measured by glucose clamp test before and after treatment. After treatment, fast blood glucose (FBG) was detected by the glucometer, and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. The contents of fasting insulin (FINS), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were determined by ELISA. The protein expressions of TLR4, IκB kinase ß (IKKß), phosphorylated IKKß (p-IKKß), NF-κB p65, and TNF-α related to the TLR4/NF-κB signaling pathway in the liver of rats were detected by Western blot. RESULTS: Compared with the normal group, the body weight, HOMA-IR levels, serum levels of FINS, TNF-α, and IL-6 were up-regulated (P<0.01), and the GIR level was down-regulated (P<0.01), the protein expressions of TLR4, IKKß, p-IKKß, NF-κB p65 and TNF-α in liver tissues were increased(P<0.05) in the model group. Compared with the model group, the EA group showed weight loss from the 6th week, and the HOMA-IR levels,serum levels of FINS, TNF-α, and IL-6 were decreased(P<0.01, P<0.05), the GIR level was up-regulated (P<0.01), the protein expressions of TLR4, IKKß, p-IKKß, NF-κB p65 and TNF-α in liver tissues were down-regulated (P<0.05). CONCLUSION: EA can reduce the inflammatory response and improve peripheral insulin sensitivity by inhibiting the TLR4/NF-κB pathway in liver tissues of obese rats with insulin resistance, showing a good regulatory effect on insulin resistance induced by obesity.


Assuntos
Eletroacupuntura , Resistência à Insulina , Animais , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Resistência à Insulina/genética , Interleucina-6/genética , Fígado , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Obesidade/genética , Obesidade/terapia , Proteínas Serina-Treonina Quinases , Ratos , Ratos Wistar , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
17.
Biochem J ; 479(11): 1121-1126, 2022 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-35647902

RESUMO

Numerous studies, published over many years, have established the key role that the IκB kinase (IKK) subunits, α and ß, play in regulating the Nuclear Factor κB (NF-κB) pathway. This research generally concluded that their functions can be separated, with IKKß being the critical regulator of the canonical NF-κB pathway, while IKKα functions as the key activating kinase for the non-canonical pathway. However, other roles for these kinases have been described and several reports concluded that this separation of their functions may not always be the case. This commentary discusses the recent report by Biochem J. 479, 305-325, who elegantly demonstrate that in KRAS driven colorectal cancer cell lines, IKKα is an important regulator of the canonical NF-κB pathway. As is so often the case with trying to understand the complexity of NF-κB signalling, cellular context is everything.


Assuntos
Quinase I-kappa B , NF-kappa B , Linhagem Celular , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases , Transdução de Sinais
18.
Nat Commun ; 13(1): 3426, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35701499

RESUMO

Regulation of endosomal Toll-like receptor (TLR) responses by the chemokine CXCL4 is implicated in inflammatory and fibrotic diseases, with CXCL4 proposed to potentiate TLR responses by binding to nucleic acid TLR ligands and facilitating their endosomal delivery. Here we report that in human monocytes/macrophages, CXCL4 initiates signaling cascades and downstream epigenomic reprogramming that change the profile of the TLR8 response by selectively amplifying inflammatory gene transcription and interleukin (IL)-1ß production, while partially attenuating the interferon response. Mechanistically, costimulation by CXCL4 and TLR8 synergistically activates TBK1 and IKKε, repurposes these kinases towards an inflammatory response via coupling with IRF5, and activates the NLRP3 inflammasome. CXCL4 signaling, in a cooperative and synergistic manner with TLR8, induces chromatin remodeling and activates de novo enhancers associated with inflammatory genes. Our findings thus identify new regulatory mechanisms of TLR responses relevant for cytokine storm, and suggest targeting the TBK1-IKKε-IRF5 axis may be beneficial in inflammatory diseases.


Assuntos
Quinase I-kappa B , Fatores Reguladores de Interferon , Monócitos , Fator Plaquetário 4 , Proteínas Serina-Treonina Quinases , Receptor 8 Toll-Like , Epigênese Genética , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/imunologia , Quinase I-kappa B/metabolismo , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Fatores Reguladores de Interferon/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Fator Plaquetário 4/imunologia , Fator Plaquetário 4/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptor 8 Toll-Like/genética , Receptor 8 Toll-Like/imunologia , Receptor 8 Toll-Like/metabolismo
19.
Int J Mol Sci ; 23(12)2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35743220

RESUMO

The NF-κB pathway is central pathway for inflammatory and immune responses, and IKKγ/NEMO is essential for NF-κB activation. In a previous report, we identified the role of glycogen synthase kinase-3ß (GSK-3ß) in NF-κB activation by regulating IKKγ/NEMO. Here, we show that NEMO phosphorylation by GSK-3ß leads to NEMO localization into multivesicular bodies (MVBs). Using the endosome marker Rab5, we observed localization into endosomes. Using siRNA, we identified the AAA-ATPase Vps4A, which is involved in recycling the ESCRT machinery by facilitating its dissociation from endosomal membranes, which is necessary for NEMO stability and NF-κB activation. Co-immunoprecipitation studies of NEMO and mutated NEMO demonstrated its direct interaction with Vps4A, which requires NEMO phosphorylation. The transfection of cells by a mutated and constitutively active form of Vps4A, Vps4A-E233Q, resulted in the formation of large vacuoles and strong augmentation in NEMO expression compared to GFP-Vps4-WT. In addition, the overexpression of the mutated form of Vps4A led to increased NF-κB activation. The treatment of cells with the pharmacologic V-ATPase inhibitor bafilomycin A led to a dramatic downregulation of NEMO and, in this way, inhibited NF-κB signal transduction. These results reveal an unexpected role for GSK-3ß and V-ATPase in NF-κB signaling activation.


Assuntos
Quinase I-kappa B , NF-kappa B , Adenosina Trifosfatases , Glicogênio Sintase Quinase 3 beta/genética , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Corpos Multivesiculares/metabolismo , NF-kappa B/metabolismo
20.
Int Immunopharmacol ; 110: 108944, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35728304

RESUMO

ACT001 has been shown to exhibit excellent antitumor and anti-fibrosis activities. However, the role of ACT001 in acute lung injury (ALI) and the underlying mechanism remains largely unclear. The present study aimed to investigate the protective effects of ACT001 on ALI and explore the potential mechanisms. Herein, we firstly established the ALI mouse model induced by intratracheal instillation of lipopolysaccharide (LPS). ACT001 treatment significantly alleviated histopathological changes of lung tissues with lower infiltration of pulmonary M1 macrophages in ALI mice. Then, we performed in vitro experiment and found that ACT001 treatment effectively inhibited the M1 phenotype of RAW264.7 and THP-1.. Next, we performed pull-down and mass spectrometry analysis to screen the interacting proteins of ACT001, identifying IKKß and STAT1 as the critical target proteins of ACT001. And ACT001 treatment significantly suppressed the NF-κB and STAT1 pathways, thereby inhibiting the M1 polarization against inflammation in vivo and in vitro. Finally, we used IMD 0354 (IMD) and Fludarabine (Flud) to specifically block the activity of IKKß and STAT1, and stimulated macrophages through IKKß and STAT1 overexpression. Our data clearly showed that ACT001-induced decrease of the M1 polarization was blocked by IMD and Flud treatment, and reversed by IKKß and STAT1 overexpression in RAW264.7 cells. In conclusion, we discovered that ACT001 significantly alleviates inflammation and limits M1 phenotype of pulmonary macrophages via suppressing NF-κB and STAT1 signaling pathways, providing new insights for the development of drugs to treat ALI/ARDS.


Assuntos
Lesão Pulmonar Aguda , NF-kappa B , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Furanos , Quinase I-kappa B/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais
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