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1.
J Immunol Res ; 2022: 9166370, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35340587

RESUMO

Tumor necrosis factor-α (TNF-α) lies at the apex of signal transduction cascades that results in induced destruction of joints in rheumatoid arthritis. It is therefore of great medicinal interest to modulate the cellular responses to TNF-α. Ebosin, a novel exopolysaccharide derived from Streptomyces sp, has been demonstrated to have remarkable therapeutic actions on collagen-induced arthritis in rats, while it also suppressed the production of IL-1ß, TNF-α, and IL-6 at both mRNA and protein levels in cultured fibroblast-like synoviocytes. In order to further understand the potential mechanisms involved in the anti-inflammatory effects of ebosin at molecular level, we investigated the impact of it on the activation of MAPK and NF-κB pathways following TNF-α induced in fibroblast-like synoviocytes (FLS). The results showed that the phosphorylation levels of TNF-α-induced p38, JNK1, JNK2, IKKα, IKKß, and IκB, as well as NF-κB nuclear translocation, were reduced significantly in FLS cells in response to ebosin. Furthermore, we proved that ebosin decreased the level of NF-κB in the nucleus and blocked the DNA-binding ability of NF-κB using electrophoresis mobility gel shift assay. Besides, low levels of matrix metalloproteinases (MMP-1 and MMP-3) and chemokines (interleukin-8 and RANTES) were found in TNF-α-stimulated fibroblast-like synoviocytes treated with ebosin. These results indicate that ebosin can suppress a range of activities in both MAPK and NF-κB pathways induced by TNF-α in rat fibroblast-like synoviocytes, which provides a rationale for examining the use of ebosin as a potential therapeutic candidate for rheumatic arthritis.


Assuntos
NF-kappa B , Sinoviócitos , Animais , Fibroblastos , NF-kappa B/metabolismo , Polissacarídeos Bacterianos , Ratos , Sinoviócitos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
2.
Nat Commun ; 13(1): 5506, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127339

RESUMO

Chemoresistance limits its clinical implementation for pancreatic ductal adenocarcinoma (PDAC). We previously generated an EGFR/HER2 targeted conjugate, dual-targeting ligand-based lidamycin (DTLL), which shows a highly potent antitumor effect. To overcome chemoresistance in PDAC, we aim to study DTLL efficacy when combined with gemcitabine and explore its mechanisms of action. DTLL in combination with gemcitabine show a superior inhibitory effect on the growth of gemcitabine-resistant/sensitive tumors. DTLL sensitizes gemcitabine efficacy via distinct action mechanisms mediated by mothers against decapentaplegic homolog 4 (SMAD4). It not only prevents neoplastic proliferation via ATK/mTOR blockade and NF-κB impaired function in SMAD4-sufficient PDACs, but also restores SMAD4 bioactivity to trigger downstream NF-κB-regulated signaling in SMAD4-deficient tumors and to overcome chemoresistance. DTLL seems to act as a SMAD4 module that normalizes its function in PDAC, having a synergistic effect in combination with gemcitabine. Our findings provide insight into a rational SMAD4-directed precision therapy in PDAC.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Aminoglicosídeos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Enedi-Inos , Receptores ErbB , Humanos , Ligantes , NF-kappa B/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Proteína Smad4/genética , Serina-Treonina Quinases TOR
3.
Sci Rep ; 12(1): 15685, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127495

RESUMO

Mast cells (MC) play a central role in the early containment of bacterial infections, such as that caused by Listeria monocytogenes (L.m). The mechanisms of MC activation induced by L.m infection are well known, so it is possible to evaluate whether they are susceptible to targeting and modulation by different drugs. Recent evidence indicates that valproic acid (VPA) inhibits the immune response which favors L.m pathogenesis in vivo. Herein, we examined the immunomodulatory effect of VPA on L.m-mediated MC activation. To this end, bone marrow-derived mast cells (BMMC) were pre-incubated with VPA and then stimulated with L.m. We found that VPA reduced MC degranulation and cytokine release induced by L.m. MC activation during L.m infection relies on Toll-Like Receptor 2 (TLR2) engagement, however VPA treatment did not affect MC TLR2 cell surface expression. Moreover, VPA was able to decrease MC activation by the classic TLR2 ligands, peptidoglycan and lipopeptide Pam3CSK4. VPA also reduced cytokine production in response to Listeriolysin O (LLO), which activates MC by a TLR2-independent mechanism. In addition, VPA decreased the activation of critical events on MC signaling cascades, such as the increase on intracellular Ca2+ and phosphorylation of p38, ERK1/2 and -p65 subunit of NF-κB. Altogether, our data demonstrate that VPA affects key cell signaling events that regulate MC activation following L.m infection. These results indicate that VPA can modulate the functional activity of different immune cells that participate in the control of L.m infection.


Assuntos
Listeria monocytogenes , Listeriose , Citocinas/metabolismo , Humanos , Lipopeptídeos/metabolismo , Listeriose/tratamento farmacológico , Listeriose/metabolismo , Mastócitos/metabolismo , NF-kappa B/metabolismo , Peptidoglicano/metabolismo , Receptor 2 Toll-Like/metabolismo , Ácido Valproico/metabolismo , Ácido Valproico/farmacologia
4.
J Neuroinflammation ; 19(1): 231, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36131309

RESUMO

BACKGROUND: Radiation-induced brain injury (RIBI) is the most serious complication of radiotherapy in patients with head and neck tumors, which seriously affects the quality of life. Currently, there is no effective treatment for patients with RIBI, and identifying new treatment that targets the pathological mechanisms of RIBI is urgently needed. METHODS: Immunofluorescence staining, western blotting, quantitative real-time polymerase chain reaction (Q-PCR), co-culture of primary neurons and microglia, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, enzyme-linked immunosorbent assay (ELISA), and CRISPR-Cas9-mediated gene editing techniques were employed to investigate the protective effects and underlying mechanisms of pregabalin that ameliorate microglial activation and neuronal injury in the RIBI mouse model. RESULTS: Our findings showed that pregabalin effectively repressed microglial activation, thereby reducing neuronal damage in the RIBI mouse model. Pregabalin mitigated inflammatory responses by directly inhibiting cytoplasmic translocation of high-mobility group box 1 (HMGB1), a pivotal protein released by irradiated neurons which induced subsequent activation of microglia and inflammatory cytokine expression. Knocking out neuronal HMGB1 or microglial TLR2/TLR4/RAGE by CRISPR/Cas9 technique significantly inhibited radiation-induced NF-κB activation and pro-inflammatory transition of microglia. CONCLUSIONS: Our findings indicate the protective mechanism of pregabalin in mitigating microglial activation and neuronal injury in RIBI. It also provides a therapeutic strategy by targeting HMGB1-TLR2/TLR4/RAGE signaling pathway in the microglia for the treatment of RIBI.


Assuntos
Lesões Encefálicas , Proteína HMGB1 , Animais , Lesões Encefálicas/metabolismo , Citocinas/metabolismo , DNA Nucleotidilexotransferase/metabolismo , DNA Nucleotidilexotransferase/farmacologia , Proteína HMGB1/metabolismo , Camundongos , Microglia/metabolismo , NF-kappa B/metabolismo , Neurônios/metabolismo , Pregabalina/metabolismo , Pregabalina/farmacologia , Pregabalina/uso terapêutico , Qualidade de Vida , Transdução de Sinais , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo
5.
Mediators Inflamm ; 2022: 1870579, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36133743

RESUMO

Osteoarthritis (OA), a chronic degenerative joint disease, always occurred in the aging population. There is evidence suggests that chondrocytes' survival, inflammation, and apoptosis play critical roles in OA pathogenesis. LMX1B has been shown to be involved in antiosteogenic function in early patterning of the calvaria. However, the role and mechanism of LMX1B in OA is not unknown. The present study observed that LMX1B was highly expressed in OA patients compared with normal patients. Besides, we found that IL-1ß increased LMX1B mRNA and protein expression in SW1353 and C28/I2 chondrocytes. LMX1B knockdown increased IL-1ß-induced cell viability and proliferation and suppressed cell apoptosis and inflammation response, including IFN-γ, TNF-α, IL-6, prostaglandin E2 (PGE2), and NO both in SW1353 and C28/I2. Furthermore, LMX1B silence inhibited MMP-3 and MMP-13 expression both in SW1353 and C28/I2 cells. Also, the activation of the NF-κB and NLRP3 signaling pathway was suppressed in LMX1B silence cells by decreasing the p-p65 and NLRP3 protein expressions. Additionally, inhibition of NF-κB by PDTC suppressed NLRP3 expression. Moreover, NLRP3 overexpression reversed the effects of LMX1B silence on chondrocytes' survival, proliferation, apoptosis, and inflammation. Finally, we confirmed that LMX1B depletion had protective effects in OA rats in vivo.


Assuntos
Condrócitos , Osteoartrite , Idoso , Animais , Apoptose/genética , Células Cultivadas , Dinoprostona/metabolismo , Humanos , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Osteoartrite/metabolismo , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/metabolismo
6.
Contrast Media Mol Imaging ; 2022: 6056829, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36134116

RESUMO

In order to investigate the effects of different doses of Dahuang Zhechong pills on the ubiquitin proteasome pathway/nuclear factor-κB (UPP-NF-κB) in rats with atherosclerosis (AS), 58-week-old male Wistar rats were selected and randomly divided into the normal group, model group, control group, low-dose group, and high-dose group. The model group and the drug group are given intraperitoneal injections of vitamins, and the model group and the drug group are given a high-fat diet. Rats in the low-dose group and high-dose group are given low-dose and high-dose Dahuang Zhechong pill lavage solution, respectively. Besides, the control group is given simvastatin solution by gavage, and intervention is performed once a day for 12 weeks. Ubiquitin (Ub) protein expression, ubiquitin activase (UBE1), nuclear factor-κB, nuclear inhibitory factor-κB (IκB) gene expression, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and serum tumor necrosis factor-α (TNF-α) are compared. The experimental result shows that Dahuang Zhechong pills can reduce inflammation and prevent and treat AS by blocking the activation of the UPP/NF-κB signaling pathway and can be used as a proteasome inhibitor in the clinical treatment of AS.


Assuntos
Aterosclerose , NF-kappa B , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , LDL-Colesterol/uso terapêutico , Medicamentos de Ervas Chinesas , Masculino , NF-kappa B/metabolismo , NF-kappa B/uso terapêutico , Complexo de Endopeptidases do Proteassoma/uso terapêutico , Inibidores de Proteassoma/uso terapêutico , Ratos , Ratos Wistar , Sinvastatina/uso terapêutico , Ativador de Plasminogênio Tecidual/uso terapêutico , Triglicerídeos , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/uso terapêutico , Ubiquitinas/uso terapêutico , Vitaminas/uso terapêutico
7.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(8): 1119-1125, 2022 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-36073209

RESUMO

OBJECTIVE: To explore the effect of WDSUB1 on dextran sulfate sodium (DSS)-induced inflammatory colon injury in mice and the underlying mechanism. METHODS: Different WDSUB1 siRNA sequences were transfected into mouse fibroblast L929 cells and the optimal sequence was selected by Western blotting. Twelve male C57BL/6 mice were randomized into two groups for injection of siWDSUB1 or siControl via the caudal vein, followed by treatment with 2.5% DSS in drinking water to establish mouse models of DSS- induced colitis (n=6). The expression level of WDSUB1 in the colon tissue of the mice was detected with Western blotting and RT-PCR, the changes in body weight and fecal condition were recorded, and the clinical symptoms of the mice were evaluated. The mRNA expression levels of IL-6, COX-2 and TNF-α and the protein expression of IκBα and P65 in the colon tissues were detected with RT- PCR and Western blotting, respectively. RESULTS: The mRNA and protein expressions of WDSUB1 in the colon tissues were significantly lower in colitis mice with WDSUB1 knock-down than in the control mice. Compared with the control mice, the mice receiving siWDSUB1 injection showed obviously milder weight loss, diarrhea and hematochezia with significantly lower mRNA expressions of COX2, IL-6 and TNFα (P < 0.05) and protein expression of IκBα but without obvious changes in P65 expression in the colon tissue. CONCLUSION: WDSUB1 knockdown can alleviate DSS- induced colitis in mice possibly by inhibiting the NF-κB signaling pathway and decreasing the expression of inflammatory factors in the colon tissues.


Assuntos
Colite , NF-kappa B , Animais , Colite/induzido quimicamente , Ciclo-Oxigenase 2/metabolismo , Sulfato de Dextrana/efeitos adversos , Interleucina-6/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , RNA Mensageiro , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
8.
PLoS Comput Biol ; 18(9): e1010152, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36084132

RESUMO

Activation of gene expression in response to environmental cues results in substantial phenotypic heterogeneity between cells that can impact a wide range of outcomes including differentiation, viral activation, and drug resistance. An important source of gene expression noise is transcriptional bursting, or the process by which transcripts are produced during infrequent bursts of promoter activity. Chromatin accessibility impacts transcriptional bursting by regulating the assembly of transcription factor and polymerase complexes on promoters, suggesting that the effect of an activating signal on transcriptional noise will depend on the initial chromatin state at the promoter. To explore this possibility, we simulated transcriptional activation using a transcriptional cycling model with three promoter states that represent chromatin remodeling, polymerase binding and pause release. We initiated this model over a large parameter range representing target genes with different chromatin environments, and found that, upon increasing the polymerase pause release rate to activate transcription, changes in gene expression noise varied significantly across initial promoter states. This model captured phenotypic differences in activation of latent HIV viruses integrated at different chromatin locations and mediated by the transcription factor NF-κB. Activating transcription in the model via increasing one or more of the transcript production rates, as occurs following NF-κB activation, reproduced experimentally measured transcript distributions for four different latent HIV viruses, as well as the bimodal pattern of HIV protein expression that leads to a subset of reactivated virus. Importantly, the parameter 'activation path' differentially affected gene expression noise, and ultimately viral activation, in line with experimental observations. This work demonstrates how upstream signaling pathways can be connected to biological processes that underlie transcriptional bursting, resulting in target gene-specific noise profiles following stimulation of a single upstream pathway.


Assuntos
Infecções por HIV , HIV-1 , Cromatina/genética , HIV-1/genética , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Transcrição Genética/genética , Ativação Transcricional/genética , Latência Viral
9.
Sci Rep ; 12(1): 15490, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109620

RESUMO

Probiotics are considered to play an crucial role in the treatment of high-fat diet (HFD)-induced lipid metabolic diseases, including metabolic syndrome (MS). This study aimed to investigate the effects of Lactobacillus plantarum S9 on MS in HFD-fed rats, and to explore the underlying role of probiotics in the treatment of MS. Sprague-Dawley rats were fed with HFD for 8 weeks, followed by the treatment of L. plantarum S9 for 6 weeks, and The body weight and blood glucose level of rats were detected on time. The results showed that L. plantarum S9 significantly decreased the body weight gain, Lee's index, and liver index. Additionally, L. plantarum S9 reduced the levels of serum lipids and insulin resistance. L. plantarum S9 also decreased the levels of alanine aminotransferase (ALT) and aspartate transaminase (AST) in liver. Moreover, the serum levels of MS-related inflammatory signaling molecules, including lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α), were significantly elevated. Western blot analysis showed that L. plantarum S9 inhibited the activation of nuclear factor-κB (NF-κB) pathway, decreased the expression level of Toll-like receptor 4 (TLR4), suppressed the activation of inflammatory signaling pathways, and reduced the expression levels of inflammatory factors in HFD-fed rats. Moreover, it further decreased the ratios of p-IκBα/IκBα, p-p65/NF-κB p65, and p-p38/p38. In summary, L. plantarum S9, as a potential functional strain, prevents or can prevent onset of MS.


Assuntos
Resistência à Insulina , Lactobacillus plantarum , Síndrome Metabólica , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Glicemia/metabolismo , Peso Corporal , Dieta Hiperlipídica/efeitos adversos , Inflamação/metabolismo , Lactobacillus plantarum/metabolismo , Lipopolissacarídeos/metabolismo , Síndrome Metabólica/etiologia , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
10.
Mediators Inflamm ; 2022: 5978271, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36110097

RESUMO

Psoriasis is a chronic inflammatory skin disease, and elevation of proinflammatory cytokine levels is a critical driver of the pathogenesis of psoriasis. Extracellular cold-inducible RNA-binding protein (eCIRP) has been shown to play a role in various acute and chronic inflammatory diseases. C23, a short peptide derived from CIRP, competitively binds CIRP receptors and reduces damage in inflammatory diseases. However, the effect of eCIRP in psoriasis has not been studied. In the present study, we investigated the role of eCIRP in the expression of proinflammatory cytokines in keratinocytes. Our data show that eCIRP expression was increased in the sera of psoriasis patients and imiquimod- (IMQ-) induced psoriatic mice and cells stimulated with proinflammatory cytokines (IL-1α, IL-17A, IL-22, oncostatin M, and TNF-α; mix M5). Recombinant human CIRP (rhCIRP) promoted the expression of the proinflammatory cytokines TNF-α, IL-6, and IL-8 and the activation of NF-kappaB (NF-κB) and ERK1/2 in cultured keratinocytes. We then found that the above effects of eCIRP could be blocked by C23 in both normal keratinocytes and M5-stimulated psoriatic keratinocytes. In addition, in vivo experiments revealed that C23 could effectively ameliorate IMQ-induced psoriatic dermatitis. TNF-α and IL-6 mRNA expressions were reduced in the skin lesions of mice with C23-treated IMQ-induced psoriasis, and this effect was accompanied by inhibition of the NF-κB and ERK1/2 signaling pathways. In summary, eCIRP plays an important role in the pathogenesis of psoriasis and may become a new target for psoriasis treatment.


Assuntos
NF-kappa B , Psoríase , Animais , Humanos , Imiquimode , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Queratinócitos/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , NF-kappa B/metabolismo , Oncostatina M/metabolismo , Psoríase/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
11.
PLoS One ; 17(9): e0271950, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36048826

RESUMO

Proliferative vitreoretinopathy (PVR) is characterized by the growth and contraction of cellular membranes within the vitreous cavity and on both surfaces of the retina, resulting in recurrent retinal detachments and poor visual outcomes. Proinflammatory cytokines like tumor necrosis factor alpha (TNFα) have been associated with PVR and the epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells. Cigarette smoke is the only known modifiable risk factor for PVR, but the mechanisms are unclear. The purpose of this study was to examine the impact of cigarette smoke on the proinflammatory TNFα/NF-κB/Snail pathway in RPE cells to better understand the mechanisms through which cigarette smoke increases the risk of PVR. Human ARPE-19 cells were exposed to cigarette smoke extract (CSE), for 4 to 24-hours and TNFα, Snail, IL-6, IL-8, and α-SMA levels were analyzed by qPCR and/or Western blot. The severity of PVR formation was assessed in a murine model of PVR after intravitreal injection of ARPE-19 cells pre-treated with CSE or not. Fundus imaging, OCT imaging, and histologic analysis 4 weeks after injection were used to examine PVR severity. ARPE-19 cells exposed to CSE expressed higher levels of TNFα, SNAIL, IL6 and IL8 mRNA as well as SNAIL, Vimentin and α-SMA protein. Inhibition of TNFα and NF-κB pathways blocked the effect of CSE. In vivo, intravitreal injection of ARPE-19 cells treated with CSE resulted in more severe PVR compared to mice injected with untreated RPE cells. These studies suggest that the TNFα pathway is involved in the mechanism whereby cigarette smoke increases PVR. Further investigation into the role of TNFα/NF-κB/Snail in driving PVR and pharmacological targeting of these pathways in disease are warranted.


Assuntos
Fumar Cigarros , NF-kappa B , Fator de Necrose Tumoral alfa , Vitreorretinopatia Proliferativa , Animais , Fumar Cigarros/efeitos adversos , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal , Humanos , Camundongos , NF-kappa B/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Tabaco/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismo , Vitreorretinopatia Proliferativa/metabolismo
12.
Cytokine ; 159: 156018, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36054965

RESUMO

An increase in the number of mast cells could contribute to inflammatory diseases and pathologic conditions. A receptor activator of NF-κB ligand (RANKL)/RANK system is one of the key signaling pathways accelerating mast cell-mediated allergic inflammatory reactions. However, the biological functions of RANKL in mast cell proliferation remains to be clarified. The aim of the present study is to clarify the role of RANKL in mast cell proliferation. Surprisingly, RANKL remarkably reduced the proliferation of human mast cell line, HMC-1 cells through the inhibition of murine double minute 2 (MDM2) and Ki-67 mRNA expressions in a dose-dependent manner. RANKL significantly reduced cell viability, whereas it increased cellular senescence via increasing levels of p53, phosphorylated(p)-p53, p21, and p16 and decreasing levels of retinoblastoma protein (pRb) and p-pRb in HMC-1 cells. Even in rat peritoneal mast cells, RANKL induced cellular senescence by increasing filamentous-actin polymerization. In addition, RANKL remarkably reduced thymic stromal lymphopoietin (TSLP)-induced mast cell proliferation via the downregulation of MDM2 and Ki-67. RANKL decreased levels of p-signal transducer and activator of transcription 6 in TSLP-stimulated HMC-1 cells. The mast cell growth factor, interleukin-13 was remarkably down-regulated by treatment with RANKL in TSLP-stimulated HMC-1 cells. Furthermore, RANKL increased the number of senescence-associated ß-galactosidase-stained cells and protein levels of p53, p-p53, and p21 in TSLP-stimulated HMC-1 cells. These data suggest that RANKL down-regulates mast cell proliferation by inducing senescence.


Assuntos
Interleucina-13 , Proteínas Proto-Oncogênicas c-mdm2 , Actinas/metabolismo , Animais , Proliferação de Células , Citocinas/metabolismo , Humanos , Interleucina-13/metabolismo , Antígeno Ki-67/metabolismo , Ligantes , Mastócitos/metabolismo , Camundongos , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , RNA Mensageiro/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Proteína do Retinoblastoma , Fator de Transcrição STAT6/metabolismo , Fator de Células-Tronco , Proteína Supressora de Tumor p53/metabolismo , beta-Galactosidase/metabolismo
13.
Proc Natl Acad Sci U S A ; 119(37): e2121385119, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36067309

RESUMO

Interferon (IFN) regulatory factor 3 (IRF3) is a transcription factor activated by phosphorylation in the cytoplasm of a virus-infected cell; by translocating to the nucleus, it induces transcription of IFN-ß and other antiviral genes. We have previously reported IRF3 can also be activated, as a proapoptotic factor, by its linear polyubiquitination mediated by the RIG-I pathway. Both transcriptional and apoptotic functions of IRF3 contribute to its antiviral effect. Here, we report a nontranscriptional function of IRF3, namely, the repression of IRF3-mediated NF-κB activity (RIKA), which attenuated viral activation of NF-κB and the resultant inflammatory gene induction. In Irf3-/- mice, consequently, Sendai virus infection caused enhanced inflammation in the lungs. Mechanistically, RIKA was mediated by the direct binding of IRF3 to the p65 subunit of NF-κB in the cytoplasm, which prevented its nuclear import. A mutant IRF3 defective in both the transcriptional and the apoptotic activities was active in RIKA and inhibited virus replication. Our results demonstrated IRF3 deployed a three-pronged attack on virus replication and the accompanying inflammation.


Assuntos
Imunidade Inata , Fator Regulador 3 de Interferon , NF-kappa B , Pneumonia Viral , Transporte Ativo do Núcleo Celular , Animais , Núcleo Celular/metabolismo , Expressão Gênica , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/genética , Camundongos , NF-kappa B/metabolismo , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Vírus Sendai
14.
Biomed Pharmacother ; 153: 113407, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076533

RESUMO

Hypertension has become one of the important diseases harmful to human health. In China, Qingda granule (QDG) has been used to treat hypertension for decades. Previous studies by our team have shown that oxidative stress may be one of the pathways through which QDG inhibits hypertension-induced organs injury. However, the specific molecular mechanism of its anti-hypotension and renal oxidative stress response were unclearly. This study investigated QDG's potential protective mechanism against hypertension-induced renal injury. Mice were infused with Angiotensin Ⅱ (Ang Ⅱ, 500 ng/kg/min) or equivalent saline solution (Control) and administered oral QDG (1.145 g/kg/day) or saline for four weeks. QDG treatment mitigated the elevated blood pressure and reduced renal pathological changes induced by Ang Ⅱ. As per the RNA sequencing results, QDG affects oxidative stress signaling. In agreement with these findings, QDG significantly attenuated the Ang Ⅱ-induced increase in Nitrogen oxides 1 (NOX1) and reactive oxygen species and the decrease in superoxide dismutase in renal tissue. Additionally, QDG significantly inhibited Interleukin 6 (IL-6), Tumor necrosis factor α (TNF-α), and Interleukin 1ß (IL-1ß) expression in renal tissues and blocked the phosphorylation of P65 (NF-κB subunit) and IκB. These results were confirmed in vitro. Overall, QDG reduced Ang Ⅱ-induced elevated blood pressure and renal injury by inhibiting oxidative stress and inflammation caused by NOX1 and NF-κB pathways. The results of this study provide an experimental basis for the clinical application of QDG, and to open up a new direction for the clinical treatment of hypertension.


Assuntos
Angiotensina II , Hipertensão , Angiotensina II/efeitos adversos , Angiotensina II/toxicidade , Animais , Medicamentos de Ervas Chinesas , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Inflamação/metabolismo , Rim/patologia , Camundongos , NF-kappa B/metabolismo , Óxidos de Nitrogênio/metabolismo , Óxidos de Nitrogênio/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos
15.
Biomed Pharmacother ; 153: 113409, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076534

RESUMO

Ulcerative colitis is an idiopathic disease that is widely incident worldwide. Canagliflozin, antidiabetic agent, exhibited significant anti-inflammatory effects in a variety of animal models. Additionally, hyaluronic acid is considered one of the key players in the tissue regeneration process. It has been proven to modulate inflammation and cellular migration, which are the main phases of wound healing. The combination of hyaluronic acid with chitosan in microsphere fabrication was anticipated to reveal a synergistic muco-adhesiveness potential with additional advantage of the chitosan penetration enhancing effect. The current study aimed to explore the potential of canagliflozin-loaded chitosan-hyaluronic acid microspheres intrarectal administration to mitigate acetic acid-induced colitis in rats. Colon tissues were examined for macroscopic and microscopic pathological changes. ELISA and qRT-PCR techniques were applied for the detection of cytokines involved in the AMPK/NF-κB/NLRP3 axis. Intrarectal administration of this formula alleviated colitis severity, which was reflected by the reduced DAI, MES, colonic weight/length ratio and histopathological scoring values. Interestingly, canagliflozin-loaded chitosan-hyaluronic acid microspheres significantly enhanced AMPK phosphorylation and depressed NF-κB and NLRP3 expression leading to a subsequent reduction in caspase-1 cleavage and the inhibition of several inflammatory cytokines, including IL-1ß, and IL-18. Overall, the current study revealed that the protective effects of the formula against acetic acid-induced colitis are primarily mediated via augmenting AMPK phosphorylation and its consequences of NF-κB inactivation. Since canagliflozin is not associated with hypoglycemic effects, clinical application of canagliflozin-loaded chitosan-hyaluronic acid microspheres represent a novel therapeutic option for the treatment of patients with ulcerative colitis.


Assuntos
Quitosana , Colite Ulcerativa , Colite , Proteínas Quinases Ativadas por AMP/metabolismo , Ácido Acético/farmacologia , Animais , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Quitosana/farmacologia , Colite/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo , Citocinas/metabolismo , Ácido Hialurônico/metabolismo , Microesferas , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Transdução de Sinais
16.
Biomed Pharmacother ; 153: 113444, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076559

RESUMO

Liver fibrosis is an important pathologic process in response to chronic or repetitive liver injury. It can advance to liver cirrhosis. Both peroxisome proliferator-activated receptor gamma (PPARγ) and Nogo-B play critical roles in fibrogenesis, while PPARγ is essential for the development. However, the effect of Nogo-B deficiency on the development of liver fibrosis in cell-specific PPARγ deficient mice remains unknown. In this study, hepatocyte or macrophage PPARγ deficient (hPPARγ KO or mPPARγ KO) mice, Nogo-B deficient mice, and cell-specific PPARγ plus Nogo-B double deficient (hPPARγ/Nogo-B DKO or mPPARγ/Nogo-B DKO) mice were induced liver fibrosis by CCl4 injection. We found hPPARγ KO mice showed enhanced liver fibrotic signatures compared to mPPARγ KO mice after CCl4 administration. Hepatocyte or macrophage PPARγ deficiency further enhanced CCl4-induced severe inflammation infiltration, apoptosis and M1 macrophage polarization in the liver. In contrast, Nogo-B deficiency effectively ameliorated PPARγ deficiency-aggravated liver injury and fibrosis. It ameliorated PPARγ deficiency-aggravated liver inflammation and fibrosis by suppressing hepatic stellate cell activation, TLR4-NF-κB/TNF-α signaling and M1 macrophage polarization. In conclusion, our study demonstrates that PPARγ deficiency increases susceptibility of mice to develop CCl4-induced liver injury/fibrosis, which is potently reduced by Nogo-B deficiency, indicating Nogo-B inhibition might be a therapeutic approach for liver fibrosis treatment.


Assuntos
NF-kappa B , PPAR gama , Animais , Fibrose , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Cirrose Hepática/metabolismo , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Proteínas Nogo , PPAR gama/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
17.
Nutrients ; 14(17)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36079919

RESUMO

Hawk tea (Litsea coreana Levl. var. lanuginosa) is a traditional herbal tea in southwestern China, and was found to possess hepatoprotective effects in our previous study. However, it is unclear whether hawk tea flavonoids (HTF) can alleviate alcoholic liver damage (ALD). Firstly, we extracted and identified the presence of 191 molecules categorized as HTFs, with reynoutrin, avicularin, guaijaverin, cynaroside, and kaempferol-7-O-glucoside being the most prevalent. After taking bioavailability into consideration and conducting comprehensive sorting, the contribution of guaijaverin was the highest (0.016 mg/mice). Then, by daily intragastric administration of HTF (100 mg/kg/day) to the ALD mice, we found that HTF alleviated liver lipid deposition (inhibition of TG, TC, LDL-C) by reducing liver oxidative-stress-mediated inflammation (up-regulation NRF2/HO-1 and down-regulation TLR4/MyD88/NF-κB pathway) and reshaping the gut microbiota (Lactobacillus, Bifidobacterium, Bacillus increased). Overall, we found HTF could be a potential protective natural compound for treating ALD via the gut-liver axis and guaijaverin might be the key substance involved.


Assuntos
Flavonoides , Microbioma Gastrointestinal , Hepatopatias Alcoólicas , Chás de Ervas , Animais , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Fígado/metabolismo , Hepatopatias Alcoólicas/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais
18.
Nutrients ; 14(17)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36079923

RESUMO

Piper longum linn has traditionally been used for the treatment of respiratory and gastrointestinal disorders in India. Although various pharmacological effects of P. longum have been studied, its effects on bone have not been clearly elucidated. Therefore, this study examined the inhibitory effect of the water extract of P. longum Linn (WEPL) on osteoclast differentiation. WEPL directly affected the osteoclast precursors and suppressed osteoclast differentiation in vitro. In addition, the expression levels of c-Fos and nuclear factor of activated T cells 1, a critical transcription factor for osteoclastogenesis, were significantly downregulated by WEPL via the suppression of the receptor activator of nuclear factor (NF)-κB ligand-induced mitogen-activated protein kinase and NF-κB signaling pathways. Consistent with the in vitro results, oral administration of WEPL (100 and 300 mpk) to ovariectomized mice for six weeks relieved the OVX-induced bone loss. We also identified phytochemicals in WEPL that are reported to exert inhibitory effects on osteoclastogenesis and/or bone loss. Collectively, the findings of our study indicate that WEPL has an anti-osteoporotic effect on OVX-induced bone loss by diminishing osteoclast differentiation, suggesting that it may be useful to treat several bone diseases caused by excessive bone resorption.


Assuntos
Doenças Ósseas Metabólicas , Reabsorção Óssea , Piper , Extratos Vegetais , Animais , Doenças Ósseas Metabólicas/metabolismo , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Reabsorção Óssea/prevenção & controle , Diferenciação Celular , Feminino , Camundongos , NF-kappa B/metabolismo , Osteoclastos , Osteogênese , Ovariectomia/efeitos adversos , Piper/química , Extratos Vegetais/farmacologia , Ligante RANK/metabolismo
19.
Molecules ; 27(17)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36080491

RESUMO

Inflammation is an immune response to cellular damage caused by various stimuli (internal or external) and is essential to human health. However, excessive inflammatory responses may be detrimental to the host. Considering that the existing drugs for the treatment of inflammatory diseases have various side effects, such as allergic reactions, stomach ulcers, and cardiovascular problems, there is a need for research on new anti-inflammatory agents with low toxicity and fewer side effects. As 4',6-dimethoxyisoflavone-7-O-ß-d-glucopyranoside (wistin) is a phytochemical that belongs to an isoflavonoid family, we investigated whether wistin could potentially serve as a novel anti-inflammatory agent. In this study, we found that wistin significantly reduced the production of nitric oxide and intracellular reactive oxygen species in lipopolysaccharide-stimulated RAW 264.7 cells. Moreover, wistin reduced the mRNA levels of pro-inflammatory enzymes (inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2)) and cytokines (interleukin (IL)-1ß and IL-6) and significantly reduced the protein expression of pro-inflammatory enzymes (iNOS and COX-2). Furthermore, wistin reduced the activation of the nuclear factor-κB and p38 signaling pathways. Together, these results suggest that wistin is a prospective candidate for the development of anti-inflammatory drugs.


Assuntos
Lipopolissacarídeos , NF-kappa B , Animais , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Transdução de Sinais
20.
J Immunol Res ; 2022: 6151847, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36081452

RESUMO

Diabetic nephropathy (DN) is a fatal complication of diabetes and the main cause of end-stage renal disease. Due to the suboptimal effects of current treatments, there is an urgent need to develop new therapeutic strategies for DN. Trametenolic acid (TA), a lanostane-type tetracyclic triterpenoid, is one of the main active ingredients extracted from the natural product Inonotus obliquus. Our study was aimed at clarifying the potential protective effects of TA on DN and its underlying mechanism. In this research, C57BLKS/db (db/db) mice were used as the spontaneous DN model, and TA (10 mg/kg/d) was intraperitoneally injected for 4 consecutive weeks. Ratio of right kidney weight/body weight was calculated, and the contents of serum creatinine (Scr), blood urea nitrogen (BUN), and urine albumin were detected. The activities of superoxide dismutase (SOD) and catalase (CAT) and the contents of reductive glutathione (GSH) and malondialdehyde (MDA) were measured. The histopathological changes of renal tissues were observed by hematoxylin and eosin (HE), periodic acid-Schiff (PAS), and Masson staining. The protein expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase-1 (NQO-1), nuclear factor kappa B (NF-κB), proinflammation cytokine tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), Nephrin, and Podocin were detected by western blot assay. Immunohistochemistry was utilized to detect expressions of collagen III (COL-III) and fibronectin (FN). Our results showed that TA administration significantly reduced the ratio of right kidney weight/body weight, BUN, Scr, and urine albumin levels and alleviated the histopathological changes of DN mice. Moreover, TA administration remarkably increased GSH content and SOD and CAT activities and decreased MDA content. Western blot assay demonstrated that TA activated Nrf2 signaling and increased the expression of downstream antioxidant enzymes HO-1 and NQO-1. Further studies illustrated that NF-κB signaling was inhibited, and downstream proinflammation cytokine expressions of TNF-α, IL-6, and IL-1ß were also downregulated. In addition, we also found that TA administration significantly increased the expression of nephrin and podocin proteins and reduced the protein expression of COL-III and FN. These findings suggested that TA exhibited a renoprotective effect by ameliorating oxidative stress and inflammation via Nrf2/HO-1 and NF-κB signaling pathways.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Triterpenos , Albuminas/metabolismo , Animais , Antioxidantes/metabolismo , Peso Corporal , Nefropatias Diabéticas/tratamento farmacológico , Glutationa/metabolismo , Heme Oxigenase-1/metabolismo , Interleucina-6/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Superóxido Dismutase/metabolismo , Triterpenos/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo
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