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1.
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
2.
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
3.
Allergol. immunopatol ; 50(5): 121-128, sept. 2022. ilus, graf
Artigo em Inglês | IBECS | ID: ibc-ADZ-13

RESUMO

Background: Sepsis-induced acute lung injury (ALI) is a syndrome associated with inflamma-tion. Cornus iridoid glycoside (CIG), a bioactive component isolated from Corni Fructus, exhibits anti-inflammatory activities. However, the function and underlying mechanisms of CIG in mice with sepsis-induced ALI remain elusive.Methods: The sepsis-elicited ALI model of mice was established by the induction of cecal ligation and puncture (CLP). The wet/dry (W/D) ratio of lung tissues was examined, and the pathological alterations were determined by hematoxylin and eosin staining. The messenger RNA (mRNA) expressions and serum levels of Interleukin (IL)-1Beta IL-6, and tumor necrosis factor-alfa(TNF-alpha) were measured by reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent serologic assay, respectively. The concentrations of malondial-dehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were assessed by biochemical kits. In addition, the relative protein levels of p-p65, p65, phosphorylated-nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (p-IκBalpha), IκBalpha, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) gene were analyzed by Western blotting analysis.Results: CLP enhanced W/D ratio and aggravated pathological changes and scores in mice, which were obviously alleviated by the two concentrations of CIG treatment. CIG treatment notably decreased the CLP-induced mRNA expressions and serum levels of IL-1Beta, IL-6, TNF-alpha, and MDA, but enhanced the decreased concentrations (caused by CLP) of SOD and GSH-Px. Moreover, CIG treatment significantly decreased the ratios of p65/p-p65 and IκBα/p-IκBalpha caused by CLP, but...(AU)


Assuntos
Animais , Masculino , Camundongos , Lesão Pulmonar Aguda , Cornus , Sepse , Modelos Animais , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/etiologia , Cornus/genética , Cornus/metabolismo , Inflamação/complicações , Interleucina-6 , Glucosídeos Iridoides/efeitos adversos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , RNA Mensageiro , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/patologia , Superóxido Dismutase/efeitos adversos
4.
Food Funct ; 13(18): 9459-9469, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-35979800

RESUMO

This study aimed to identify and prepare peptides from selenium (Se)-enriched soybeans and determine whether dietary Se-enriched soybean peptides (Se-SPep) could inhibit lung injury in mice induced by fine particulate matter 2.5 (PM2.5). BALB/c mice were randomly divided into six groups. The mice in the prevention groups were pretreated with 378 mg kg-1 of Se-SPep, soybean peptides (SPep), and Se-enriched soybean protein (Se-SPro), respectively, for four weeks. The mice in the PM2.5 exposure group received concentrated PM2.5 (15 µg per day mice) for 1 h daily from the third week for two weeks. The results showed that the leukocyte and cytokine (IL-1ß, IL-6, TNF-α) levels in the bronchoalveolar lavage fluid (BALF) of the PM2.5 exposure group were higher than those in the control group. Se-SPep pretreatment decreased the IL-1ß, IL-6, and TNF-α levels compared with the PM2.5 exposure group. Additionally, Se-SPep pretreatment inhibited TLR4/NF-κB/IκBα and NLRP3/ASC/caspase-1 protein expression in the lungs. In conclusion, Se-SPep pretreatment may protect the lungs of the mice against PM2.5-induced inflammation, suggesting that Se-SPep represents a potential preventative agent to inhibit PM2.5-induced lung injury.


Assuntos
Lesão Pulmonar , Selênio , Animais , Caspase 1/metabolismo , Citocinas/metabolismo , Inflamassomos/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Pulmão/metabolismo , Lesão Pulmonar/induzido quimicamente , Camundongos , Camundongos Endogâmicos BALB C , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/genética , 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 , Material Particulado/toxicidade , Selênio/farmacologia , Transdução de Sinais , Proteínas de Soja/metabolismo , Soja/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
5.
Cell Metab ; 34(9): 1312-1324.e6, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36007522

RESUMO

High expression of PD-L1 in tumor cells contributes to tumor immune evasion. However, whether PD-L1 expression in tumor cells is regulated by the availability of nutrients is unknown. Here, we show that in human glioblastoma cells, high glucose promotes hexokinase (HK) 2 dissociation from mitochondria and its subsequent binding and phosphorylation of IκBα at T291. This leads to increased interaction between IκBα and µ-calpain protease and subsequent µ-calpain-mediated IκBα degradation and NF-κB activation-dependent transcriptional upregulation of PD-L1 expression. Expression of IκBα T291A in glioblastoma cells blocked high glucose-induced PD-L1 expression and promoted CD8+ T cell activation and infiltration into the tumor tissue, reducing brain tumor growth. Combined treatment with an HK inhibitor and an anti-PD-1 antibody eliminates tumor immune evasion and remarkably enhances the anti-tumor effect of immune checkpoint blockade. These findings elucidate a novel mechanism underlying the upregulation of PD-L1 expression mediated by aerobic glycolysis and underscore the roles of HK2 as a glucose sensor and a protein kinase in regulation of tumor immune evasion.


Assuntos
Antígeno B7-H1 , Glioblastoma , Linhagem Celular Tumoral , Glucose , Glicólise , Humanos , Inibidor de NF-kappaB alfa/metabolismo , Fosforilação , Evasão Tumoral
6.
Ecotoxicol Environ Saf ; 243: 114019, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36030685

RESUMO

Patients with trichloroethene-induced Trichloroethylene hypersensitivity syndrome (THS) often present kidney injury. However, the role of Wnt 5a/Ca2+ pathway in renal tubular injury in Trichloroethylene (TCE) sensitized mice remains unclear. This study aimed to investigate how Wnt 5a/Ca2+ pathway induced renal tubular epithelial cell injury in TCE sensitized mice. A total of 84 female BALB/c Specific Pathogen Free mice aged 6-8 weeks were used to establish TCE sensitized mouse models. Renal histology and serum levels of α1-MG and ß2-MG were used to assess the renal injury. The renal protein levels of Wnt 5a, ROR2, FZD5, PLC, p-CaMKII, IκB α, p-IκB α, NF-κB(p65), TNF α, IL 6 and IL 1ß were measured. The levels of serum α1-MG and ß2-MG and TNF α, IL 6 and IL 1ß levels in the kidney tissue were significantly increased in TCE sensitized positive group. However, Box5 pretreatment inhibited the expression of PLC, p-CaMKII, p65 and attenuated the injury of renal tubular epithelial cells and suppressed the upregulated expression of the above cytokines. In addition, KN93 also reduced nuclear translocation of p65 and renal injury as well as the elevated cytokines by inhibiting CaMKII. These data identify Wnt 5a binding to ROR2 and FZD5, p65 nuclear translocation, and inflammatory cytokine release as a novel mechanism for renal tubular epithelial cells injury by sensitization with TCE. Box5 or KN93 pretreatment can block the expression of inflammatory cytokines and reduce the injury of renal tubular epithelial cells.


Assuntos
Sinalização do Cálcio , Rim , Proteína Wnt-5a , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Citocinas/metabolismo , Células Epiteliais/metabolismo , Feminino , Inflamação , Interleucina-6/metabolismo , Rim/patologia , Camundongos , Camundongos Endogâmicos BALB C , Inibidor de NF-kappaB alfa/metabolismo , Tricloroetileno/toxicidade , Fator de Necrose Tumoral alfa/metabolismo , Proteína Wnt-5a/metabolismo
7.
Nutrients ; 14(16)2022 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-36014933

RESUMO

Helicobacter pylori (H. pylori) increases production of reactive oxygen species (ROS) and activates signaling pathways associated with gastric cell invasion, which are mediated by matrix metalloproteinases (MMPs). We previously demonstrated that H. pylori activated mitogen-activated protein kinase (MAPK) and increased expression of MMP-10 in gastric epithelial cells. MMPs degrade the extracellular matrix, enhancing tumor invasion and cancer progression. The signaling pathway of phosphatidylinositol 3-kinase (PI3K)/serine/threonine protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is associated with MMP expression. ROS activates PIK3/AKT/mTOR signaling in cancer. Astaxanthin, a xanthophyll carotenoid, shows antioxidant activity by reducing ROS levels in gastric epithelial cells infected with H. pylori. This study aimed to determine whether astaxanthin inhibits MMP expression, cell invasion, and migration by reducing the PI3K/AKT/mTOR signaling in H. pylori-infected gastric epithelial AGS cells. H. pylori induced PIK3/AKT/mTOR and NF-κB activation, decreased IκBα, and induced MMP (MMP-7 and -10) expression, the invasive phenotype, and migration in AGS cells. Astaxanthin suppressed these H. pylori-induced alterations in AGS cells. Specific inhibitors of PI3K, AKT, and mTOR reversed the H. pylori-stimulated NF-κB activation and decreased IκBα levels in the cells. In conclusion, astaxanthin suppressed MMP expression, cell invasion, and migration via inhibition of PI3K/AKT/mTOR/NF-κB signaling in H. pylori-stimulated gastric epithelial AGS cells.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Células Epiteliais/metabolismo , Mucosa Gástrica/metabolismo , Infecções por Helicobacter/patologia , Helicobacter pylori/genética , Humanos , Metaloproteinases da Matriz/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirolimo , Serina-Treonina Quinases TOR/metabolismo , Xantofilas/metabolismo , Xantofilas/farmacologia
8.
Psychopharmacology (Berl) ; 239(10): 3133-3143, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35882635

RESUMO

RATIONALE: It is known that both selective serotonin and serotonin noradrenaline reuptake inhibitors (SSRI, SNRI) are first-line drugs for the treatment of major depressive disorder. It has also been considered that both SSRI and SNRI can improve the symptoms of major depressive disorder by increasing the concentration of monoamine in the synaptic cleft based on the monoamine hypothesis. However, accumulating evidence has indicated that inflammation in the brain may be a key factor in the pathophysiological mechanisms that underlie the development of major depressive disorder. OBJECTIVES: It has been advocated that microglial cells may regulate the inflammatory response under pathological conditions such as major depressive disorder. In this study, we focused on whether duloxetine can ameliorate the inflammatory response induced by lipopolysaccharide (LPS) in BV-2 microglial cells. RESULTS: Our results indicated that duloxetine significantly decreased the NO production induced by LPS. The increase in the protein expression level of iNOS induced by LPS was significantly decreased by treatment with duloxetine. Moreover, the increases in the protein expression levels of phosphorylated-IκBα, phosphorylated-Akt and Akt induced by LPS were also significantly decreased. Unexpectedly, the protein expression levels of other pro-inflammatory factors such as COX-2 and the phosphorylation ratios for various molecules including IκBα and Akt were not changed by treatment with duloxetine. CONCLUSIONS: These findings suggest that duloxetine may have an anti-inflammatory effect, which could contribute to its therapeutic effectiveness for major depressive disorder.


Assuntos
Transtorno Depressivo Maior , Inibidores da Recaptação de Serotonina e Norepinefrina , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/metabolismo , Transtorno Depressivo Maior/metabolismo , Cloridrato de Duloxetina/farmacologia , Humanos , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo II/farmacologia , Norepinefrina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serotonina/metabolismo , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia
9.
Mediators Inflamm ; 2022: 6367264, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35784173

RESUMO

Background: Preeclampsia (PE) is the main reason of maternal and perinatal morbidity and mortality. Gut microbiota imbalance in PE patients is accompanied by elevated serum lipopolysaccharide (LPS) levels, but whether it affects the occurrence and development of PE, the underlying mechanism is not clear. This paper intends to investigate the relationship between lncRNA BC030099, inflammation, and gut microbiota in PE. Methods: The feces of the patients were collected, and gut microbiota changes were assessed by 16S rRNA sequencing and pathway analysis by PICRUSt. Next, we examined LPS and lncRNA BC030099 levels in feces or placenta of PE patients. Then, we knocked down lncRNA BC030099 in HTR-8/SVneo cells and added the NF-κB pathway inhibitor JSH-23. CCK-8 and Transwell assays were performed to determine cell proliferation, migration, and invasion. Western blot was utilized to evaluate MMP2, MMP9, snail, and E-cadherin, p-IκBα, IκBα, and nuclear NF-κB p65 levels. IL-6, IL-1ß, and TNF-α levels were examined by ELISA. Results: Gut microbiota was altered in PE patients, and microbial genes associated with LPS biosynthesis were significantly elevated in gut microbiota in the PE group. LPS level in feces and placenta of PE group was significantly elevated. lncRNA BC030099 level in placenta of PE group was also notably promoted. Knockdown of lncRNA BC030099 promoted HTR-8/SVneo cell proliferation, migration, and invasion. Knockdown of lncRNA BC030099 also elevated MMP2, MMP9, and snail levels and repressed E-cadherin level. In addition, lncRNA BC030099 affected NF-κB pathway. Furthermore, NF-κB inhibitor reversed HTR-8/SVneo cell proliferation, invasion, and migration induced by LPS. Conclusions: The gut microbiota dysbiosis in PE contributed to HTR-8/SVneo cell proliferation, invasion, and migration via lncRNA BC030099/NF-κB pathway.


Assuntos
Microbioma Gastrointestinal , Pré-Eclâmpsia , RNA Longo não Codificante , Caderinas/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Disbiose/metabolismo , Feminino , Humanos , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Gravidez , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Ribossômico 16S/metabolismo , Trofoblastos/metabolismo
10.
Neurochem Res ; 47(10): 3063-3075, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35809188

RESUMO

Neuroinflammation plays an important role in brain tissue injury during intracerebral hemorrhage. Gabapentin can reduce inflammation and oxidative stress through inhibiting nuclear factor κB (NFκB) signals. Here, we showed that gabapentin reduced brain tissue injury in ICH through suppressing NFκB-mediated neuroinflammation. ICH was induced by injecting collagenase IV into the right striatum of Sprague-Dawley rats. PC12 and BV2 cells injury induced by Hemin were used to simulate ICH in vitro. Inflammation and apoptosis were assessed in rat brain tissue and in vitro cells. The neurobehavioral scores were significantly decreased in ICH rats compared with sham rats. Phosphorylated IκB-α and cleaved caspase3, and apoptosis rate were significantly higher in tissue surrounding the hematoma than in brain tissues from rats subjected to sham surgery. Furthermore, serum IL-6 levels in ICH rats were higher than in sham rats. Gabapentin treatment significantly improved the behavioral scores, decreased levels of phosphorylated IκB-α and cleaved caspase3, apoptosis rate, and serum IL-6 level in ICH rats. Hemin-treated BV2 cells displayed higher levels of phosphorylated IκB-α, cleaved caspase3, and IL-6 in the supernatant compared with vehicle-treated cells. Hemin treatment induced a significantly lower level of peroxisome proliferator-activated receptor γ (PPARγ) in BV2 cells. BV2-PC12 co-culture cells treated by hemin displayed higher levels of cleaved caspase3 in PC12 cells. Furthermore, gabapentin treatment could reduce these effects induced by hemin and the protective effects of gabapentin were significantly attenuated by PPARγ inhibitor. Therefore, gabapentin may reduce inflammation and apoptosis induced by the ICH through PPARγ-NFκB pathway.


Assuntos
Lesões Encefálicas , Hemina , Animais , Apoptose , Encéfalo/metabolismo , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Gabapentina/uso terapêutico , Hemina/farmacologia , Inflamação/tratamento farmacológico , Interleucina-6/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Doenças Neuroinflamatórias , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley , Salicilamidas
11.
J Agric Food Chem ; 70(28): 8662-8671, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35797440

RESUMO

Oyster polysaccharides (OPS) have a variety of biological activities. In this study, we aimed to investigate the potential mechanisms of OPS to ameliorate hepatic oxidative stress and inflammation in mice induced by a high-fat diet (HFD). The results showed that OPS reduced the HFD-induced increases in serum transaminase levels and alleviated hepatic oxidative stress and inflammation. Moreover, OPS regulated bile acid metabolism and increased bile acid content in the liver, serum, and feces. Serum bile acid profile results indicated that OPS reduced levels of chenodeoxycholic acid, deoxycholic acid, and lithocholic acid associated with high-affinity agonists of Farnesol X receptor (FXR). Western blot analysis showed that OPS accelerated bile acid metabolism by downregulating hepatic FXR expression and promoting its downstream CYP7A1, CYP27A1, and CYP8B1 protein expression. Meanwhile, OPS ameliorated oxidative stress and inflammation in the liver by modulating FXR-AMPKα-Nrf2/NF-κB signaling to reduce p-IκBα/IκBα, p-NF-κB p65/NF-κB p65, IL-1ß, and TNF-α expression and increase p-Nrf2/Nrf2, HO-1, and NQO-1 expression. This study was the first to explore the possible mechanism of OPS in improving liver oxidative stress and inflammation from the perspective of bile acid metabolism, providing a theoretical basis for OPS as a new source of functional food.


Assuntos
Ácidos e Sais Biliares , Crassostrea , Animais , Ácidos e Sais Biliares/metabolismo , Crassostrea/metabolismo , Dieta Hiperlipídica/efeitos adversos , Farneseno Álcool/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fígado/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Polissacarídeos/metabolismo
12.
Front Immunol ; 13: 901566, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35874667

RESUMO

Acute liver injury (ALI) is a disease that seriously threatens human health and life, and a dysregulated inflammation response is one of the main mechanisms of ALI induced by various factors. Phosphatidylethanolamine binding protein 4 (PEBP4) is a secreted protein with multiple biological functions. At present, studies on PEBP4 exist mainly in the field of tumors and rarely in inflammation. This study aimed to explore the potential roles and mechanisms of PEBP4 on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced ALI. PEBP4 was downregulated after treatment with LPS/D-GalN in wild-type mice. PEBP4 hepatocyte-conditional knockout (CKO) aggravated liver damage and repressed liver functions, including hepatocellular edema, red blood cell infiltration, and increased aspartate aminotransferase (AST)/alanine aminotrans-ferase (ALT) activities. The inflammatory response was promoted through increased neutrophil infiltration, myeloperoxidase (MPO) activities, and cytokine secretions (interleukin-1ß, IL-1ß; tumor necrosis factor alpha, TNF-α; and cyclooxygenase-2, COX-2) in PEBP4 CKO mice. PEBP4 CKO also induced an apoptotic effect, including increasing the degree of apoptotic hepatocytes, the expressions and activities of caspases, and pro-apoptotic factor Bax while decreasing anti-apoptotic factor Bcl-2. Furthermore, the data demonstrated the levels of Toll-like receptor 4 (TLR4), phosphorylation-inhibitor of nuclear factor kappaB Alpha (p-IκB-α), and nuclear factor kappaB (NF-κB) p65 were upregulated, while the expressions of cytoplasmic IκB-α and NF-κB p65 were downregulated after PEBP4 CKO. More importantly, both the NF-κB inhibitor (Ammonium pyrrolidinedithiocarbamate, PDTC) and a small-molecule inhibitor of TLR4 (TAK-242) could inhibit TLR4/NF-κB signaling activation and reverse the effects of PEBP4 CKO. In summary, the data suggested that hepatocyte-conditional knockout of PEBP4 aggravated LPS/D-GalN-induced ALI, and the effect is partly mediated by activation of the TLR4/NF-κB signaling pathway.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , NF-kappa B , Proteína de Ligação a Fosfatidiletanolamina , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Galactosamina/toxicidade , Hepatócitos/metabolismo , Humanos , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Fígado/patologia , Camundongos , Camundongos Knockout , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Proteína de Ligação a Fosfatidiletanolamina/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
13.
Pharm Biol ; 60(1): 1077-1087, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35645173

RESUMO

CONTEXT: Deer antler based active ingredients are known to have certain anti-inflammatory and antioxidant activities. However, its potential hepatoprotective effect remains unclear. OBJECTIVE: This article reports the hepatoprotective effect of protein components in deer antler bases (R1) on lipopolysaccharide/d-galactosamine (LPS/d-GalN)-induced acute liver injury (ALI) in mice, and explores its possible mechanism. MATERIALS AND METHODS: The four separated and purified protein components of deer antler bases were screened and verified by the RAW264.7 cell inflammation model. In the in vivo experiment of LPS/d-GalN-induced ALI in mice, ALT, AST, SOD, CAT, GSH and MDA were detected. The liver histopathology was analysed, the COX-2 and iNOS proteins were analysed by immunohistochemistry, and 4-HNE was analysed by immunofluorescence staining. In addition, the effects on the MAPK pathway and NF-κB/IκB-α pathway in liver proteins were explored. RESULTS: With isolated RA protein fraction pre-treated RAW264.7 cells, NO production decreased by 35.3% compared with the model group. The experimental results of ALI in mice induced by LPS/d-GalN show that R1 protein components can protect mice from ALI through anti-inflammatory and anti-oxidative stress effects and reduce liver pathological damage in mice. The results also indicate that the R1 protein component may protect the liver by inhibiting the activation of the MAPK pathway and the NF-κB/IκB-α pathway induced by LPS/d-GalN. CONCLUSIONS: The separated and purified R1 protein component of deer antler base has a good protective effect on LPS/d-GalN-induced liver injury, and may become a potential material for protecting against liver injury.


Assuntos
Chifres de Veado , Doença Hepática Induzida por Substâncias e Drogas , Cervos , Animais , Anti-Inflamatórios/farmacologia , Chifres de Veado/química , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Galactosamina/toxicidade , Lipopolissacarídeos/toxicidade , Camundongos , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo
14.
J Cell Physiol ; 237(9): 3554-3564, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35696549

RESUMO

Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by fat accumulation and chronic inflammation in the liver. Dynein light chain of 8 kDa (LC8) was identified previously as an inhibitor of nuclear factor kappa B (NF-κB), a key regulator of inflammation, however, its role in NASH remains unknown. In this study, we investigated whether LC8 can alleviate NASH using a mouse model of methionine and choline-deficient (MCD) diet-induced NASH and examined the underlying mechanism. LC8 transgenic (Tg) mice showed lower hepatic steatosis and less progression of NASH, including hepatic inflammation and fibrosis, compared to wild-type (WT) mice after consuming an MCD diet. The hepatic expression of lipogenic genes was lower, while that of lipolytic genes was greater in LC8 Tg mice than WT mice, which might be associated with resistance of LC8 Tg mice to hepatic steatosis. Consumption of an MCD diet caused oxidative stress, IκBα phosphorylation, and subsequent p65 liberation from IκBα and nuclear translocation, resulting in induction of proinflammatory cytokines and chemokines. However, these effects of MCD diet were reduced by LC8 overexpression. Collectively, these results suggest that LC8 alleviates MCD diet-induced NASH by inhibiting NF-κB through binding to IκBα to interfere with IκBα phosphorylation and by reducing oxidative stress via scavenging reactive oxygen species. Thus, boosting intracellular LC8 could be a potential therapeutic strategy for patients with NASH.


Assuntos
Deficiência de Colina , Hepatopatia Gordurosa não Alcoólica , Animais , Colina/metabolismo , Deficiência de Colina/metabolismo , Modelos Animais de Doenças , Dineínas/metabolismo , Inflamação/metabolismo , Fígado/metabolismo , Metionina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Estresse Oxidativo
15.
Gene ; 837: 146703, 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-35772653

RESUMO

A high-concentrate diet has been reported to promote an inflammatory response in dairy cows. The purpose of this study was to clarify the effect of the high-concentrate (HC) diet on hepatic Forkhead box protein A2 (FOXA2) expression and uncover the molecular mechanisms in inflammatory responses in the liver. The results showed that the HC diet reduced the ruminal fluid pH and elevated the secretion of SAA3, IL-1α, and IL-8 and reduced that of IL-10 in peripheral blood plasma. Compared with the low-concentrate (LC) group, the concentration of myeloperoxidase (MPO) was higher in the liver of dairy cows in the HC group. In addition, the relative mRNA expression of acute phase proteins (HP, SAA3, and LBP), proinflammatory cytokines (TNFα, IL-1α, IL-1ß, IL-8), TLR4, MyD88, TRAF6, TRIF, IκBα, p65, p38 and JNK1 was upregulated and that of IL-10 was downregulated in the liver of the HC group. Consistently, the protein abundance of TLR4, TNFα and phosphorylation of proteins involved in NF-κB (IκBα and p65) and MAPK (p38 and JNK) pathways were significantly increased in the HC group compared with the LC group. And both the mRNA and protein abundance of FOXA2 were downregulated in the HC group. Further epigenetic analysis results demonstrated that chromatin compaction and DNA hypermethylation contributed to inhibiting FOXA2 expression, in which the demethylase ten-eleven translocation 1 (TET1) and histone deacetylase 3 (HDAC3) might participate. Overall, these findings demonstrated that the high-concentrate diet triggered inflammatory cascades and downregulated FOXA2 by epigenetic modifications in the liver of dairy cows.


Assuntos
Rúmen , Fator de Necrose Tumoral alfa , Animais , Bovinos , Dieta , Epigênese Genética , Feminino , Fatores de Transcrição Forkhead/genética , Interleucina-10/genética , Interleucina-8/genética , Fígado/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , RNA Mensageiro/metabolismo , Rúmen/metabolismo , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética
16.
J Invest Surg ; 35(8): 1648-1659, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35732295

RESUMO

BACKGROUND: Hepatic ischemia/reperfusion injury (HIRI) is an unavoidable complication in liver surgery, however its pathological process is still unclear. Therefore, in this study, the role and mechanism of peroxisome proliferator-activated receptor gamma (PPARγ) was investigated in HIRI. MATERIALS AND METHODS: We constructed mice models with HIRI and L02 cell models insulted hypoxia/re-oxygenation (H/R). PPARγ agonist rosiglitazone was administered prior to HIRI in mice and PPARγ-siRNA was to H/R treatment in L02 cells. Liver injury was measured by serum ALT, AST and LDH levels and performing H&E staining; the inflammatory injury was reflected by inflammatory markers IL-1ß, IL-6 and TNF-α, which were assayed by Real-time PCR and Western blotting, MPO activity was determined using commercial kits; oxidative stress injury was evaluated by iNOS, MDA, SOD and GSH-PX levels; apoptosis was detected by cleaved-Caspase-3, TUNEL staining and flow cytometry; NF-κB signaling activation was reflected by phosphorylation of IκBα (p-IκBα) and nuclear translocation of NF-κB p65. RESULTS: The level of PPARγ expression was obviously down-regulated both in mice liver subjected to IRI and in L02 cells to H/R. Overexpression of PPARγ presented protective effect on HIRI by reducing serum levels of aminotransferase and hepatic necrosis, inhibiting inflammation and apoptosis and alleviating oxidative stress in vivo. But PPARγ-siRNA aggravate H/R insult by promoting inflammation and apoptosis in vitro. Mechanistically, the NF-κB pathway activity was increased with PPARγ down-regulation by PPARγ-siRNA. Importantly, inhibition of NF-κB signaling abolished PPARγ knockdown-mediated hepatic injury. CONCLUSIONS: PPARγ present protective effects on HIRI by attenuating liver injury, inflammatory response, oxidative stress and apoptosis in vivo and in vitro, and its mechanism may be related to down-regulation of NF-κB signaling.


Assuntos
NF-kappa B , Traumatismo por Reperfusão , Animais , Apoptose , Inflamação , Isquemia/metabolismo , Fígado/patologia , Camundongos , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , PPAR gama/metabolismo , PPAR gama/farmacologia , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia
17.
Ecotoxicol Environ Saf ; 241: 113811, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35772362

RESUMO

Deoxynivalenol (DON) is one of the mycotoxins that contaminate cereals and feed, thereby endangering human and animal health. Dihydroartemisinin (DHA), a derivative of artemisinin, has anti-inflammatory and antioxidant functions in addition to anti-malaria and anti-cancer. The purpose of this study was to investigate the effects of DHA on alleviating liver apoptosis and inflammation induced by DON in piglets. The experimental design followed a 2 (normal diet and DON-contaminated diet) × 2 (with and without supplementation of DHA) factorial arrangement. 36 weaned piglets were subjected to a 21-day experiment. Results showed that DON increased ALT activity, the levels of TNF-α, IL-1ß and IL-2, and reduced the levels of total protein (TP) and albumin (ALB) in the serum. However, DHA decreased the levels of TNF-α, IL-1ß and IL-2, and increased the levels of TP and ALB. Also, DON decreased glutathione (GSH) content and catalase (CAT) activity, and increased methane dicarboxylic aldehyde (MDA) content. But GSH content was increased by DHA. In addition, DHA decreased DON-induced increase in apoptosis rate of hepatocytes. Furthermore, DON activated death receptor pathway to promote apoptosis by up-regulating the protein expression of FasL and caspase-3, and the mRNA expression of FasL, TNFR1, caspase-8, Bid, Bax, CYC and caspase-3. However, DHA reduced caspase-3 protein expression, as well as the mRNA expression of FADD, Bid, Bax, CYC and caspase-3. Besides, DON also activated TNF/NF-κB pathway to induce an inflammatory response by up-regulating TNF-α protein expression, and the mRNA expression of TNFR1, RIP1, IKKß, IκBα, IL-1ß and IL-8. Nevertheless, DHA reduced the mRNA expression of RIP1, IκBα, NF-κB, IL-1ß and IL-6, and the protein expression of TNF-α and NF-κB. In conclusion, DHA improved DON-induced negative effects on serum biochemical parameters and inflammatory cytokine levels, hepatic antioxidant capacity, hepatic apoptosis and inflammation.


Assuntos
Artemisininas , NF-kappa B , Animais , Antioxidantes/metabolismo , Apoptose , Artemisininas/toxicidade , Caspase 3/genética , Caspase 3/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-2/metabolismo , Fígado , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , RNA Mensageiro/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Suínos , Tricotecenos , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo
18.
Poult Sci ; 101(8): 101962, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35690001

RESUMO

The aim of this study was to investigate the protective effect of trans-anethole (TA) on lipopolysaccharide-induced acute liver inflammation model of chickens by determining the levels of inflammatory mediators in serum and liver, relative mRNA expression and protein expression of inflammation-related genes in NF-κB signaling pathway. A total of 160 one-day-old male chickens (Arbor Acres) were assigned into 4 treatments with 8 replicates of 5 birds each. On d 20, the control group was intraperitoneally injected with sterile saline and the other groups were injected with lipopolysaccharide (LPS; 5 mg/kg body weight). There were no significant differences in average daily gain (ADG), average daily feed intake (ADFI) and feed conversion ratio (FCR) among groups. However, compared with the control group, the LPS group significantly increased (P < 0.01) the serum levels of interleukin-6 (IL-6), interleukin-1beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and decreased (P < 0.01) the interleukin-10 (IL-10) level. TA attenuated (P < 0.01) these increases in IL-1ß, TNF-α, ALT, and AST levels and improved (P < 0.01) the IL-10 level. In liver, the groups fed with TA had lower (P < 0.01) concentrations of IL-6 and TNF-α as well as higher (P < 0.05) concentration of IL-10. Furthermore, TA downregulated (P < 0.05) the mRNA expression levels of nuclear factor kappa B p65 (NF-κB p65) and TNF-α, also upregulated (P < 0.05) IL-10 and inhibitor of NF-κB alpha (IκBα) upon LPS challenge. In protein level, supplementation of 600 mg/kg of TA downregulated (P < 0.05) and upregulated (P < 0.05) the protein expression of NF-κB p65 and IκBα, respectively. The present findings suggest that TA could alleviate the acute liver inflammation induced by LPS via blocking the activation of NF-κB and the 600 mg/kg of TA plays more fruitful role in protecting broilers against LPS stimulus.


Assuntos
Lipopolissacarídeos , NF-kappa B , Derivados de Alilbenzenos , Animais , Anisóis , Galinhas/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/veterinária , Interleucina-10/farmacologia , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/metabolismo , Masculino , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa
19.
Aquat Toxicol ; 249: 106211, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35667248

RESUMO

4-octylphenol (4-OP), a toxic estrogenic environmental pollutant, can threaten aquatic animal and human health. However, toxic effect of 4-OP on fish has not been reported. To investigate molecular mechanism of gill poisoning caused by 4-OP exposure, a carp 4-OP poisoning model was established, and then blood and gills were collected on day 60. The results demonstrated that gill was a target organ attacked by 4-OP, and exposure to 4-OP caused carp gill inflammatory injury. There were 1605 differentially expressed genes (DEGs, including 898 up-regulated DEGs and 707 down-regulated DEGs). KEGG and GO were used to further analyze obtained 1605 DEGs, indicating that complement activation, immune response, and inflammatory response participated in the mechanism of 4-OP-caused carp gill inflammatory injury. Our data at transcription level further revealed that 4-OP caused complement activation through triggering complement component 3a/complement component 3a receptor (C3a/C3aR) axis and complement component 5a/complement component 5a receptor 1 (C5a/C5aR1) axis, induced immunosuppression through the imbalances of T helper (Th) 1/Th2 cells and regulatory T (Treg)/Th17 cells, as well as caused inflammatory injury via toll like receptor 7/inhibitor kappa B alpha/nuclear factor-kappa B (TLR7/IκBα/NF-κB) pathway. Taken together, immunosuppression participated in complement activation-mediated inflammatory damage in carp gills after 4-OP treatment. The findings of this study will provide pioneering information and theoretical support for the mechanism of 4-OP poisoning, and will provide reference for the assessment of estrogenic environmental pollution risk.


Assuntos
Carpas , Ativação do Complemento , Fenóis , Poluentes Químicos da Água , Animais , Carpas/metabolismo , Complemento C3a/metabolismo , Complemento C5a/metabolismo , Proteínas de Peixes/genética , Brânquias/metabolismo , Terapia de Imunossupressão , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Fenóis/toxicidade , Receptor 7 Toll-Like/metabolismo , Poluentes Químicos da Água/toxicidade
20.
J Pineal Res ; 73(2): e12812, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35652241

RESUMO

Aflatoxin B1 (AFB1) is a widespread contaminant in foods and feedstuffs, and its target organ is the liver. Melatonin (MT) has been shown to alleviate inflammation in organs and remodel gut microbiota in animals and humans. However, the underlying mechanism by which MT alleviates AFB1-induced liver injury remains unclear. In the present study, MT pretreatment markedly increased the expression of intestinal tight junction proteins (ZO-1, Occludin, and Claudin-1), decreased intestinal permeability, reduced production of gut-derived Lipopolysaccharide (LPS) and remodeled gut microbiota, ultimately alleviated AFB1-induced liver injury in mice. Interestingly, MT pretreatment failed to exert beneficial effects on the intestine and liver in antibiotic-treated mice. Meanwhile, MT pretreatment significantly increased the farnesoid X receptor (FXR) protein expression of ileum, and decreased the TLR4/NF-κB signaling pathway-related messenger RNA (mRNA) and proteins (TLR4, MyD88, p-p65, and p-IκBα) expression in livers of AFB1-exposed mice. Subsequently, pretreatment by Gly-ß-MCA, an intestine-selective FXR inhibitor, blocked the alleviating effect of MT on liver injury through increasing the liver-specific expression of TLR4/NF-κB signaling pathway-related mRNA and proteins (TLR4, MyD88, p-p65, and p-IκBα). In conclusion, MT pretreatment ameliorated AFB1-induced liver injury and the potential mechanism may be related to regulate gut microbiota/intestinal FXR/liver TLR4 signaling axis, which provides a strong evidence for the protection of gut-derived liver inflammation.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Microbioma Gastrointestinal , Melatonina , Aflatoxina B1/toxicidade , Animais , Humanos , Inflamação , Fígado/metabolismo , Melatonina/farmacologia , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , RNA Mensageiro , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
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