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1.
Carbohydr Polym ; 289: 119430, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35483843

RESUMO

In this study, high-substituted hydroxypropyl cellulose (HHPC) and low-substituted hydroxypropyl cellulose (LHPC) were orally administered (150 or 300 mg/kg) to investigate the inflammation inhibitory effects on DSS-induced colitis mice. In addition, the anti-inflammatory potential of HHPC in-vitro (RAW 264.7 cells) was evaluated. The result showed that HHPC could inhibit the excessive secretion of TNF-α, IL-6, and NO in RAW 264.7 cells induced by lipopolysaccharide. Oral administration of HHPC and LHPC could dose-dependently mitigate the pathological damage of colon tissue, suppressed spleen edema, preserved thymus index, reduced the serum level of inflammatory mediators (TNF-α, IL-6, IL-1ß, and MPO), increased the secretion of sIgA in the colon, and restored the balance of the intestinal flora such as Rikenellaceae_RC9_gut_group, Lachnospiraceae_UCG-006, and Blautia. Overall, this study elucidated the therapeutic potential of LHPC and HHPC as a prebiotic to treat acute ulcerative colitis.


Assuntos
Colite , Fator de Necrose Tumoral alfa , Animais , Celulose/análogos & derivados , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Sulfato de Dextrana/toxicidade , Interleucina-6 , Camundongos , Fator de Necrose Tumoral alfa/efeitos adversos
2.
Nutrients ; 14(7)2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35406093

RESUMO

The bioactive peptides hydrolyzed from bone collagen have been found to possess health-promoting effects by regulating chronic diseases such as arthritis and hypertension. In the current study, the anti-inflammatory effect of bovine bone gelatin peptides (GP) was evaluated in 264.7 macrophages cells and followed by animal trials to investigate their interference on inflammatory cytokines and gut microbiota compositions in dextran sodium sulfate (DSS)-induced C57BL/6 mice. The GP was demonstrated to alleviate the extra secretion of interleukin-6 (IL-6), nitric oxide (NO) and tumor necrosis factor-α(TNF-α) in lipopolysaccharide (LPS)-induced RAW264.7 cells. In DSS-induced colitis mice, the gavage of GP was demonstrated to ameliorate the IBD symptoms of weight loss, hematochezia and inflammatory infiltration in intestinal tissues. In serum, the proinflammatory cytokines (TNF-α,IL-6, MCP-1, IL-1ß) were suppressed along with the decreasing effect on toll-like receptor 4 and cyclooxygenase-2 by GP treatment. In the analysis of gut microbiota, the GP was checked to modulate the abundance of Akkermansia, Parasutterella, Peptococcus, Bifidobacterium and Saccharibacteria. The above results imply that GP could attenuate DSS-induced colitis by suppressing the inflammatory cytokines and regulating the gut microbiota.


Assuntos
Colite , Lipopolissacarídeos , Animais , Anti-Inflamatórios/uso terapêutico , Bovinos , Colite/tratamento farmacológico , Citocinas , Sulfato de Dextrana/efeitos adversos , Gelatina/farmacologia , Interleucina-6 , Lipopolissacarídeos/efeitos adversos , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Fator de Necrose Tumoral alfa/efeitos adversos
3.
Acta Neurobiol Exp (Wars) ; 82(1): 35-51, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35451422

RESUMO

Hyperserotonemia, during the early developmental phase, generates behavioral and biochemical phenotypes associated with autism spectrum disorder (ASD) in rats. Phosphodiesterase­1 (PDE1) inhibitors are known to provide benefits in various brain conditions. We investigated the role of a selective PDE1 inhibitor, vinpocetine on ASD­related behavioral phenotypes (social behavioral deficits, repetitive behavior, anxiety, and hyperlocomotion) in a developmental hyperserotonemia (DHS) rat model. Also, effects on biochemical markers related with neuronal function brain derived neurotrophic factor (BDNF) and phosphorylated cAMP response element binding protein (pCREB), inflammation interleukins (IL­6 and IL­10) and tumor necrosis factor-alpha (TNF­α), and oxidative stress (TBARS and GSH) were studied in important brain areas (frontal cortex, cerebellum, hippocampus, and striatum). Administration of 5­methoxytryptamine (5­MT) to rats prenatally (gestational day 12) and in early developmental stages postnatal day (PND 0 - PND 20), resulted in impaired behavior and brain biochemistry. Administration of vinpocetine daily (10 and 20 mg/kg) to 5­MT rats from PND 21 to PND 48 resulted in an improvement of behavioral deficits. Also, vinpocetine administration significantly increased the levels of BDNF, ratio of pCREB/ CREB, IL­10, and GSH, and significantly decreased TNF­α, IL­6, and TBARS levels in different brain areas. Finally, our correlation analysis indicated that behavioral outcomes were significantly associated with the biochemical outcome. Vinpocetine, a selective PDE1 inhibitor, rectified important behavioral phenotypes related with ASD, possibly by improving markers of neuronal function, brain inflammation, and brain oxidative stress. Thus, PDE1 could be a potential target for pharmacological interventions and furthering our understanding of ASD pathogenesis.


Assuntos
Transtorno do Espectro Autista , Animais , Biomarcadores , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Inflamação/tratamento farmacológico , Interleucina-10/efeitos adversos , Interleucina-6 , Estresse Oxidativo , Inibidores de Fosfodiesterase/efeitos adversos , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico , Fator de Necrose Tumoral alfa/efeitos adversos , Alcaloides de Vinca
4.
J Healthc Eng ; 2022: 4185195, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35449859

RESUMO

Background: To investigate the effect of dexmedetomidine (Dex) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats and its mechanism. Methods: Eighteen SD rats were randomly divided into 3 groups (6 rats in each group): control group (intratracheal instillation of saline), ALI group (intratracheal instillation of 5 mg/kg LPS), and ALI-Dex group (tail vein injection of 50 µg/kg/h Dex + intratracheal instillation of LPS). Subsequently, the water content of lung tissues was assessed using the wet-dry (W/D) ratio and the histopathological changes of lung tissues using H&E staining. Further activities of ROS, SOD, and GSH-Px in lung tissues of rats were measured by an automatic biochemistry analyzer. ELISA was performed to detect TNF-α, IL-1ß, and IL-6 expression in alveolar lavage fluid (BALF) and Western blot to detect the expression of Nrf2/ARE pathway-related proteins. Results: After Dex treatment, a reduction in water content in lung tissue and an improvement of lung injury were found in the ALI rats. Compared with the ALI group, rats in the ALI-Dex group had decreased ROS activity and increased activities of SOD and GSH-Px in lung tissues. Dex-treated rats were also associated with a decrease in TNF-α, IL-1ß, and IL-6 expression in alveolar lavage fluid (BALF). Additionally, increased expression levels of HO-1 and NQO1 in lung tissues and elevated expression of Nrf2 in the nucleus were shown in the ALI-Dex group compared with the ALI group. Conclusion: Dex alleviates LPS-induced ALI by activating the Nrf2/ARE signaling pathway.


Assuntos
Lesão Pulmonar Aguda , Dexmedetomidina , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Animais , Dexmedetomidina/efeitos adversos , Humanos , Interleucina-6/efeitos adversos , Lipopolissacarídeos/efeitos adversos , Fator 2 Relacionado a NF-E2 , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/efeitos adversos , Superóxido Dismutase/efeitos adversos , Fator de Necrose Tumoral alfa/efeitos adversos , Água
5.
J Healthc Eng ; 2022: 5635063, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35392150

RESUMO

Objective: To investigate the effect and mechanism of combined stellate ganglion block (SGB) and dexmedetomidine (Dex) in obesity-related acute lung injury. Methods: Thirty-six 4-week-old male Wistar rats were randomly divided into 6 groups, each with 6 rats: blank group (Control), high-fat diet group (HFD), high-fat + lipopolysaccharide (LPS)-induced acute lung injury group (HFD + LPS), SGB group, Dex group, and SGB + Dex group. H&E staining detected the pathological structure of rat lung tissue. TUNEL staining was used to examine cell apoptosis in lung tissue. Oxidative factors were accessed by biochemical reagents. ELISA was employed to measure the levels of TNF-α, IL-1ß, and MCP1 in rat alveolar lavage fluid. Western blot detected the protein expression of glucose-regulated Protein 78 (GRP78), C/EBP homologous protein (CHOP), protein kinase R-like endoplasmic reticulum kinase (PERK), and p-PERK in lung tissue. Results: The body weight of rats in the HFD group was higher than that in the control group. The use of SGB or Dex alone could significantly reduce the rate of pulmonary edema and lung cell apoptosis in HFD-induced obese rats and reduce MPO, TNF-α, IL-1ß, and MCP1 levels, increasing the activity of SOD and GSH-Px. In addition, using SGB or Dex alone can also significantly reduce the protein expression levels of GRP78, CHOP, and p-PERK. The combined use of SGB and Dex can enhance the above effects. Conclusion: The combined use of SGB and Dex can protect against obesity-related acute lung injury and is more effective than using SGB or Dex alone.


Assuntos
Lesão Pulmonar Aguda , Dexmedetomidina , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Dexmedetomidina/efeitos adversos , Humanos , Lipopolissacarídeos/efeitos adversos , Masculino , Obesidade/complicações , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Transdução de Sinais , Gânglio Estrelado , Fator de Necrose Tumoral alfa/efeitos adversos
6.
Int J Mol Sci ; 23(5)2022 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-35269654

RESUMO

A chronic kidney disease (CKD) causes uremic toxin accumulation and gut dysbiosis, which further induces gut leakage and worsening CKD. Lipopolysaccharide (LPS) of Gram-negative bacteria and (1➔3)-ß-D-glucan (BG) of fungi are the two most abundant gut microbial molecules. Due to limited data on the impact of intestinal fungi in CKD mouse models, the influences of gut fungi and Lacticaseibacillus rhamnosus L34 (L34) on CKD were investigated using oral C. albicans-administered 5/6 nephrectomy (5/6Nx) mice. At 16 weeks post-5/6Nx, Candida-5/6Nx mice demonstrated an increase in proteinuria, serum BG, serum cytokines (tumor necrotic factor-α; TNF-α and interleukin-6), alanine transaminase (ALT), and level of fecal dysbiosis (Proteobacteria on fecal microbiome) when compared to non-Candida-5/6Nx. However, serum creatinine, renal fibrosis, or gut barrier defect (FITC-dextran assay and endotoxemia) remained comparable between Candida- versus non-Candida-5/6Nx. The probiotics L34 attenuated several parameters in Candida-5/6Nx mice, including fecal dysbiosis (Proteobacteria and Bacteroides), gut leakage (fluorescein isothiocyanate (FITC)-dextran), gut-derived uremic toxin (trimethylamine-N-oxide; TMAO) and indoxyl sulfate; IS), cytokines, and ALT. In vitro, IS combined with LPS with or without BG enhanced the injury on Caco-2 enterocytes (transepithelial electrical resistance and FITC-dextran permeability) and bone marrow-derived macrophages (supernatant cytokines (TNF-α and interleukin-1 ß; IL-1ß) and inflammatory genes (TNF-α, IL-1ß, aryl hydrocarbon receptor, and nuclear factor-κB)), compared with non-IS activation. These injuries were attenuated by the probiotics condition media. In conclusion, Candida administration worsens kidney damage in 5/6Nx mice through systemic inflammation, partly from gut dysbiosis-induced uremic toxins, which were attenuated by the probiotics. The additive effects on cell injury from uremic toxin (IS) and microbial molecules (LPS and BG) on enterocytes and macrophages might be an important underlying mechanism.


Assuntos
Lactobacillus rhamnosus , Insuficiência Renal Crônica , Uremia , Animais , Células CACO-2 , Candida , Citocinas , Disbiose/microbiologia , Glucanos , Humanos , Lactobacillus rhamnosus/fisiologia , Lipopolissacarídeos/toxicidade , Camundongos , Fator de Necrose Tumoral alfa/efeitos adversos
7.
PLoS One ; 17(2): e0263254, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35148358

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammatory bone destruction in which tumor necrosis factor alpha (TNF-α) plays a key role. Bovine lactoferrin (bLF) is a multifunctional protein with anti-inflammatory and immunomodulatory properties. This study aimed to clarify the inhibitory effects of bLF on the pathological progression of RA. The mannan-induced arthritis model in SKG mice (genetic RA model) was used. Orally applied liposomal bLF (LbLF) markedly reduced ankle joint swelling and bone destruction. Histologically, pannus formation and osteoclastic bone destruction were prevented in the LbLF-treated animals. Moreover, orally administered LbLF improved the balance between Th17 cells and regulatory T cells isolated from the spleen of mannan-treated SKG mice. In an in vitro study, the anti-inflammatory effects of bLF on TNF-α-induced TNF-α production and downstream signaling pathways were analyzed in human synovial fibroblasts from RA patients (RASFs). bLF suppressed TNF-α production from RASFs by inhibiting the nuclear factor kappa B and mitogen-activated protein kinase pathways. The intracellular accumulation of bLF in RASFs increased in an applied bLF dose-dependent manner. Knockdown of the lipoprotein receptor-related protein-1 (LRP1) siRNA gene reduced bLF expression in RASFs, indicating that exogenously applied bLF was mainly internalized through LRP-1. Immunoprecipitated proteins with anti-TNF receptor-associated factor 2 (TRAF2; an adapter protein/ubiquitin ligase) included bLF, indicating that bLF binds directly to the TRAF2-TRADD-RIP complex. This indicates that LbLF may effectively prevent the pathological progression of RA by suppressing TNF-α production by binding to the TRAF2-TRADD-RIP complex from the RASFs in the pannus. Therefore, supplemental administration of LbLF may have a beneficial effect on preventive/therapeutic reagents for RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Lactoferrina/administração & dosagem , Osteogênese/efeitos dos fármacos , Membrana Sinovial/citologia , Fator de Necrose Tumoral alfa/efeitos adversos , Administração Oral , Animais , Artrite Reumatoide/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Lactoferrina/farmacologia , Masculino , Camundongos , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Células Th17/metabolismo
8.
Bioengineered ; 13(1): 1198-1208, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35000533

RESUMO

Taxifolin (TXL), also known as dihydroquercetin, is one of the most important flavonoids prevalent across the plant kingdom. Increasing evidence has demonstrated its critical role in respiratory diseases. The present study aims to reveal the detailed mechanism in TNF-α-stimulated BEAS-2B cells by which TXL might exert effects on the development of asthma. Cell viability detection of BEAS-2B treated with TXL before and after TNF-α induction employed MMT. The expressions of inflammatory cytokines, MUC5AC and ICAM-1 were determined by quantitative reverse transcription PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA) and Western blot after TXL was exposed to an in vitro asthma model. Then, light transmittance and apoptosis were then measured employing fluorescein transmittance, TUNEL and Western blot. After overexpressing MMP10, the abovementioned assays were performed again. Finally, the association between Wnt/ß-catenin pathway and MMP10 was confirmed by detecting the proteins in this pathway. TXL increases the cell viability of TNF-induced BEAS-2B cells. TXL suppressed the inflammation, mucus formation, and apoptosis in TNF-α-induced BEAS-2B cells. Furthermore, after the prediction of binding sites between TXL and MMP10, it was found that overexpression of MMP10 reversed the effects of TXL on suppressing the progression of TNF-α-induced BEAS-2B cells. Finally, TXL blocked Wnt/ß-catenin pathway by inhibiting MMP10 expression.TXL can be a promising drug for the treatment of asthma due to its inhibition of MMP10 expression by blocking Wnt/ß-catenin pathway. Future experimental in vivo studies of asthma on this commonly used bioactive flavonoid could open new avenues for the therapies of asthma.


Assuntos
Anti-Inflamatórios/farmacologia , Asma/metabolismo , Brônquios/citologia , Metaloproteinase 10 da Matriz/metabolismo , Quercetina/análogos & derivados , Fator de Necrose Tumoral alfa/efeitos adversos , Asma/induzido quimicamente , Asma/tratamento farmacológico , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Metaloproteinase 10 da Matriz/genética , Modelos Biológicos , Quercetina/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
9.
Hematol Oncol ; 40(1): 63-71, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34606093

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy has shown excellent clinical efficacy in patients with hematologic malignancies. However, severe bleeding after this treatment is a life-threatening complication for most patients. This study evaluated the risk factors associated with bleeding in CAR T treatment and developed a predictive model for this complication. Analysis performed in the First Affiliated Hospital of Suzhou University and external validation launched in Suzhou Hongci Hematology Hospital (Jiangsu, China). We conducted a real-world study incorporating data from 400 patients with hematologic malignancies treated with CAR T between 1 November 2015 and 1 September 2019. Also, 39 patients from another hospital were selected for external validation. Patients with severe bleeding (hazard ratio [HR] 13.04, 95% confidence interval 5.82-29.18; p < 0.001) had a higher risk of death after CAR T. Stage III and IV cytokine release syndrome (CRS) (odds ratio [OR] 6.07, 95% CI 2.35-16.76; p < 0.001) and higher tumor necrosis factor-α (TNF-α) levels (OR 4.00, 95% CI 1.53-11.35; p < 0.001) were independent factors of bleeding in patients after CAR-T treatment. The predictive model developed by Lasso regression, which selected factors such as CRS period, transfusion volume, platelet percentage, platelet count, thrombinogen time, interleukin 6, and TNF-α levels, and showed Nomogram, yielded excellent agreement (C-statistics = 0.905) with the calibration curve, which improved clinical benefit with respect to established bleeding scores such as outpatient bleeding risk index (MOBRI). External validation was performed using 39 patients from another hospital with an AUC of 0.700. Patients with severe bleeding after Car-T therapy had increased the risk of death. A cross-validated bleeding risk score based on CRS stages and TNF-α level show significant prognostic value in patients undergoing CAR-T treatment.


Assuntos
Neoplasias Hematológicas/terapia , Hemorragia/patologia , Imunoterapia Adotiva/efeitos adversos , Fator de Necrose Tumoral alfa/efeitos adversos , Adulto , Feminino , Seguimentos , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco
10.
J Appl Biomed ; 19(3): 142-148, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34907757

RESUMO

To study the effect of sinomenine (Sin) on isoproterenol (Iso, ß-agonist)-induced cardiac hypertrophy (CH), we set up four mouse groups: control, Iso model, Iso+metoprolol (Met, ß blocker) 60 mg/kg and Iso+Sin 120 mg/kg. CH was induced by Iso (s.c. for 28 days) in mice, and Sin or Met were orally administered by gavage for 28 days in total. Left ventricular diastolic anterior wall thickness (LVAWd), left ventricular diastolic posterior wall thickness (LVPWd), left ventricular ejection fraction (LVEF), and short axis shortening (FS) were measured by echocardiography. Malondialdehyde (MDA) and total superoxide dismutase (T-SOD) were measured by commercial kits. Lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1ß) were measured by ELISA kits. Histological changes were observed using hematoxylin-eosin (HE) and Masson staining. Protein level of nuclear transcription factor-kappa B (NF-κB) was detected by immunohistochemistry. Compared with the control group, LVAWd, Left ventricular weight index (LVWI) and myocardial fibrosis of the Iso model group significantly increased, as well as NF-κB, LDH, MDA, TNF-α, and IL-1ß levels. However, the activity of T-SOD decreased. Compared with the Iso model group, LVWI of Iso model+Sin or Iso model+Met group was improved, LVAWd, LVPWd and myocardial fibrosis decreased, and NF-κB, LDH, MDA, TNF-α and IL-1ß levels decreased. T-SOD activity also increased. This study reveals that Sin inhibits the activation of NF-κB, lowers the levels of TNF-α and IL-1ß, has anti-oxidative stress effect and inhibits myocardial inflammation in mouse heart, thereby demonstrating its efficacy in preventing Iso induced CH.


Assuntos
NF-kappa B , Fator de Necrose Tumoral alfa , Animais , Cardiomegalia/induzido quimicamente , Fibrose , Isoproterenol/toxicidade , Camundongos , Morfinanos , NF-kappa B/metabolismo , Volume Sistólico , Superóxido Dismutase/efeitos adversos , Fator de Necrose Tumoral alfa/efeitos adversos , Função Ventricular Esquerda
11.
Nutrients ; 13(12)2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34959939

RESUMO

Plants of the genus Wikstroemia are traditionally used in China to treat various inflammatory diseases. The purpose of this study was to isolate the components of Wikstroemia ganpi (Siebold & Zucc.) Maxim., to evaluate their anti-atopic activities and to identify candidates with anti-atopic therapeutics. A total of 24 compounds were isolated by bioassay-guided separation, including one novel compound, which was tilianin 5-methyl ether. The anti-atopic activities of the isolated compounds were determined using TNF-α-treated RBL-2H3 cells and HaCaT cells. The mRNA expressions of IL-4, IL-6, GM-CSF, G-CSF and TRPV1 were reduced by luteolin 7-methyl ether. The study shows that the luteolin 7-methyl ether isolated from W. ganpi is a potential therapeutic agent for the treatment of atopic dermatitis.


Assuntos
Dermatite Atópica/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Queratinócitos/metabolismo , Luteolina/farmacologia , Éteres Metílicos/farmacologia , Fitoterapia , Fator de Necrose Tumoral alfa/efeitos adversos , Wikstroemia/química , Animais , Linhagem Celular , Dermatite Atópica/etiologia , Células HaCaT , Humanos , Inflamação , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Luteolina/isolamento & purificação , Éteres Metílicos/isolamento & purificação , Ratos
12.
Bioengineered ; 12(2): 11784-11796, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34699329

RESUMO

Obesity significantly impacts living a normal life by increasing morbidity. Additionally, obesity has been shown to be closely associated with severe inflammation in adipocytes. It is widely reported that berberine (BBR) has an anti-inflammatory effect and can reduce glucose and lipid accumulation, whereas ginsenoside Rb1 (Rb1) has been shown to have a significant inhibitory effect on insulin resistance and lipid peroxidation. In this study, we aimed to explore the synergetic effect of BBR and Rb1 on tumor necrosis factor alpha (TNF-α)-treated adipocytes and the mechanisms underlying it. We found that TNF-α reduced cell viability, facilitated the production of inflammatory factors, induced adipogenesis, activated the nuclear factor kappa B (NF-κB) pathway, and increased the expression of peroxisome proliferator-activated receptor gamma, CCAAT enhancer-binding protein alpha, and sterol regulatory element-binding protein-1 c in adipocytes. However, these effects were significantly alleviated by BBR or Rb1. Additionally, a synergetic effect was observed when BBR and Rb1 were used in combination. The effects of BBR in combination with Rb1 on cell proliferation, inflammation, adipogenesis, and the NF-κB pathway in TNF-α-treated adipocytes were significantly abolished by receptor activator of nuclear factor kappa-Β ligand, which is an activator of the NF-κB pathway. Collectively, the results revealed that BBR and Rb1 have a synergetic protective effect against TNF-α-induced inflammation in adipocytes. The mechanism underlying this synergetic effect was found to be inhibition of the NF-κB signaling pathway.


Assuntos
Adipócitos/patologia , Berberina/farmacologia , Ginsenosídeos/farmacologia , Inflamação/patologia , Substâncias Protetoras/farmacologia , Fator de Necrose Tumoral alfa/efeitos adversos , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Resistência à Insulina , Camundongos , NF-kappa B/metabolismo , Ligante RANK/farmacologia , Transdução de Sinais/efeitos dos fármacos
13.
Molecules ; 26(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34361563

RESUMO

The consumption of plant-based food is important for health promotion, especially regarding the prevention and management of chronic diseases such as diabetes. We investigated the effects of a lemon extract (LE), containing ≥20.0% total flavanones and ≥1.0% total hydroxycinnamic acids, on insulin signaling in murine 3T3-L1 adipocytes treated with TNF-α, which was used to mimic in vitro the insulin resistance condition that characterizes diabetes mellitus. Our results showed LE increased PPARγ, GLUT4 and DGAT-1 levels, demonstrating the potential of this lemon extract in the management of insulin resistance conditions associated with TNF-α pathway activation. LE treatment further decreased the release of interleukin 6 (IL-6) and restored triglyceride synthesis, which is the main feature of a healthy adipocyte.


Assuntos
Adipócitos/metabolismo , Citrus/química , Resistência à Insulina , Compostos Fitoquímicos , Extratos Vegetais , Fator de Necrose Tumoral alfa/efeitos adversos , Células 3T3-L1 , Animais , Camundongos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Fator de Necrose Tumoral alfa/farmacologia
14.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201546

RESUMO

Tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) are two cytokines involved in the perpetuation of the chronic inflammation state characterizing rheumatoid arthritis (RA). Significant advances in the treatment of this pathology have been made over the past ten years, partially through the development of anti-TNF and anti-IL-1 therapies. However, major side effects still persist and new alternative therapies should be considered. The formulation of the micro-immunotherapy medicine (MIM) 2LARTH® uses ultra-low doses (ULD) of TNF-α, IL-1ß, and IL-2, in association with other immune factors, to gently restore the body's homeostasis. The first part of this review aims at delineating the pivotal roles played by IL-1ß and TNF-α in RA physiopathology, leading to the development of anti-TNF and anti-IL-1 therapeutic agents. In a second part, an emphasis will be made on explaining the rationale of using multiple therapeutic targets, including both IL-1ß and TNF-α in 2LARTH® medicine. Particular attention will be paid to the ULD of those two main pro-inflammatory factors in order to counteract their overexpression through the lens of their molecular implication in RA pathogenesis.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Citocinas/administração & dosagem , Imunoterapia/métodos , Interleucina-1beta/administração & dosagem , Fator de Necrose Tumoral alfa/administração & dosagem , Administração Oral , Animais , Artrite Reumatoide/fisiopatologia , Relação Dose-Resposta a Droga , Humanos , Interleucina-1beta/efeitos adversos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/fisiologia , Interleucina-2/administração & dosagem , Interleucina-2/efeitos adversos , Terapia de Alvo Molecular/métodos , Medicina de Precisão , Fator de Necrose Tumoral alfa/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/fisiologia
15.
Sci Rep ; 11(1): 14811, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285296

RESUMO

Clodronate is a bisphosphonate agent commonly used as anti-osteoporotic drug. Throughout its use, additional anti-inflammatory and analgesic properties have been reported, although the benefits described in the literature could not solely relate to their inhibition of bone resorption. Thus, the purpose of our in vitro study is to investigate whether there are underlying mechanisms explaining the anti-inflammatory effect of clodronate and possibly involving hydrogen sulphide (H2S). Immortalised fibroblast-like synoviocyte cells (K4IM) were cultured and treated with clodronate in presence of TNF-α. Clodronate significantly modulated iNOS expression elicited by TNF-α. Inflammatory markers induced by TNF-α, including IL-1, IL-6, MCP-1 and RANTES, were also suppressed following administration of clodronate. Furthermore, the reduction in enzymatic biosynthesis of CSE-derived H2S, together with the reduction in CSE expression associated with TNF-α treatment, was reverted by clodronate, thus rescuing endogenous H2S pathway activity. Clodronate displays antinflammatory properties through the modulation of H2S pathway and cytokines levels, thus assuring the control of the inflammatory state. Although further investigation is needed to stress out how clodronate exerts its control on H2S pathway, here we showed for the first the involvement of H2S in the additive beneficial effects observed following clodronate therapy.


Assuntos
Anti-Inflamatórios/farmacologia , Ácido Clodrônico/farmacologia , Sulfeto de Hidrogênio/metabolismo , Sinoviócitos/citologia , Fator de Necrose Tumoral alfa/efeitos adversos , Linhagem Celular , Citocinas/metabolismo , Regulação para Baixo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Óxido Nítrico Sintase Tipo II/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo
16.
Mol Cell Endocrinol ; 535: 111390, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34224803

RESUMO

Somatostatin receptor 5 (SSTR5) is involved in intestinal barrier protection during colitis through modulating tight junction (TJ) proteins, but the mechanisms of SSTR5 in TJ regulation are largely unknown. Therefore, the present study was designed to illuminate how SSTR5 modulated intestinal barrier function and TJ proteins. In this study, activation of SSTR5 by its special agonist L817,818 effectively ameliorated impaired intestinal barrier function in TNF-α-pretreated cells and mice with colitis. Restoration of intestinal barrier function was dependent on upregulation of claudin-4 and ZO-1. Suppression of SSTR5 signaling through specific siRNA or the antagonist BIM23056 markedly exacerbated TNF-α-induced claudin-4 and ZO-1 damage. L817,818 treatment markedly suppressed TNF-α-induced NF-κB p65 phosphorylation, myosin light chain kinase (MLCK) upregulation and myosin light chain (MLC) phosphorylation. Exposure to a NF-κB inhibitor (QNZ) or MLCK inhibitor (ML-7) effectively inhibited compromised claudin-4 and ZO-1 induced by BIM23056/TNF-α. These observations indicate that activation of SSTR5 protects intestinal barrier function by upregulating claudin-4 and ZO-1 expression, which is mediated by NF-κB-MLCK-MLC signaling. Taken together, our findings suggest that SSTR5 might represent a promising target for colitis therapy.


Assuntos
Amidas/farmacologia , Colite/metabolismo , Naftalenos/farmacologia , Oligopeptídeos/farmacologia , Receptores de Somatostatina/metabolismo , Fator de Necrose Tumoral alfa/efeitos adversos , Animais , Células CACO-2 , Claudina-4/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Camundongos , Transdução de Sinais/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/metabolismo
17.
Sci Rep ; 11(1): 8259, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859296

RESUMO

Ceramide kinase (CERK) phosphorylates ceramide to produce ceramide-1-phosphate (C1P), which is involved in the development of metabolic inflammation. TNF-α modulates inflammatory responses in monocytes associated with various inflammatory disorders; however, the underlying mechanisms remain not fully understood. Here, we investigated the role of CERK in TNF-α-induced inflammatory responses in monocytes. Our results show that disruption of CERK activity in monocytes, either by chemical inhibitor NVP-231 or by small interfering RNA (siRNA), results in the defective expression of inflammatory markers including CD11c, CD11b and HLA-DR in response to TNF-α. Our data show that TNF-α upregulates ceramide phosphorylation. Inhibition of CERK in monocytes significantly reduced the secretion of IL-1ß and MCP-1. Similar results were observed in CERK-downregulated cells. TNF-α-induced phosphorylation of JNK, p38 and NF-κB was reduced by inhibition of CERK. Additionally, NF-κB/AP-1 activity was suppressed by the inhibition of CERK. Clinically, obese individuals had higher levels of CERK expression in PBMCs compared to lean individuals, which correlated with their TNF-α levels. Taken together, these results suggest that CERK plays a key role in regulating inflammatory responses in human monocytes during TNF-α stimulation. CERK may be a relevant target for developing novel therapies for chronic inflammatory diseases.


Assuntos
Inflamação/imunologia , Monócitos/imunologia , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Fator de Necrose Tumoral alfa/efeitos adversos , Ceramidas/metabolismo , Humanos , Inflamação/terapia , Terapia de Alvo Molecular , Monócitos/enzimologia , Fosforilação/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Células THP-1
18.
Mol Nutr Food Res ; 65(7): e2000425, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33465830

RESUMO

SCOPE: Human milk oligosaccharides (hMOs) can attenuate inflammation by modulating intestinal epithelial cells, but the mechanisms of action are not well-understood. Here, the effects of hMOs on tumor necrosis factor-α (TNF-α) induced inflammatory events in gut epithelial cells are studied. METHODS AND RESULTS: The modulatory effects of 2'-fucosyllactose, 3-fucosyllactose (3-FL), 6'-sialyllactose, lacto-N-tetraose, lacto-N-neotetraose (LNnT), lactodifucotetraose (LDFT), and lacto-N-triaose (LNT2) on immature (FHs 74 Int) and adult (T84) intestinal epithelial cells with or without TNF-α are determined. Interleukin-8 (IL-8) secretion in FHs 74 Int and T84 are quantified to determine hMO induced attenuation of inflammatory events by ELISA. 3-FL, LNnT, and LDFT significantly attenuate TNF-α induced inflammation in FHs 74 Int, while LNT2 induces IL-8 secretion in T84. In addition, microscale thermophoresis assays and ELISA are used to study the possible mechanisms of interaction between effective hMOs and tumor necrosis factor receptor 1 (TNFR1). 3-FL, LNnT, and LDFT exert TNFR1 ectodomain shedding while LNnT also shows binding affinity to TNFR1 with a Kd of 900 ± 660 nM. CONCLUSION: The findings indicate that specific hMO types attenuate TNF-α induced inflammation in fetal gut epithelial cells through TNFR1 in a hMO structure-dependent fashion suggest possibilities to apply hMOs in management of TNF-α dependent diseases.


Assuntos
Mucosa Intestinal/citologia , Leite Humano/química , Oligossacarídeos/farmacologia , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Linhagem Celular , Sobrevivência Celular , Gastroenterite/tratamento farmacológico , Humanos , Hidrólise , Interleucina-8/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/embriologia , Oligossacarídeos/química , Domínios Proteicos , Receptores Tipo I de Fatores de Necrose Tumoral/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/efeitos adversos
19.
Sci Rep ; 11(1): 565, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436852

RESUMO

Increasing evidence suggests that circular RNAs (circRNAs) play critical roles in various pathophysiological activities. However, the role of circRNAs in inflammatory bowel disease (IBD) remains unclear. Here we report the potential roles of hsa_circRNA_103765 in regulating cell apoptosis induced by TNF-α in Crohn's disease (CD). We identify that CircRNA_103765 expression was significantly upregulated in peripheral blood mononuclear cells (PBMCs) of patients with active IBD. A positive correlation with TNF-α significantly enhanced circRNA_103765 expression in CD, which was significantly reversed by anti-TNF-α mAb (infliximab) treatment. In vitro experiments showed that TNF-α could induce the expression of circRNA_103765, which was cell apoptosis dependent, while silencing of circRNA_103765 could protect human intestinal epithelial cells (IECs) from TNF-α-induced apoptosis. In addition, circRNA_103765 acted as a molecular sponge to adsorb the miR-30 family and impair the negative regulation of Delta-like ligand 4 (DLL4). Collectively, CircRNA_103765 is a novel important regulator of the pathogenesis of IBD via sponging miR-30 family-mediated DLL4 expression changes. Blockade of circRNA_103765 could serve as a novel approach for the treatment of IBD patients.


Assuntos
Doença de Crohn/genética , RNA Circular/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Células Epiteliais/patologia , Expressão Gênica/genética , Humanos , Mediadores da Inflamação , Infliximab/farmacologia , Intestinos/citologia , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Fator de Necrose Tumoral alfa/efeitos adversos , Fator de Necrose Tumoral alfa/imunologia , Regulação para Cima/genética
20.
Gut ; 70(6): 1023-1036, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33037057

RESUMO

OBJECTIVE: Dysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for selective IL-23 targeting therapies as part of personalised medicine. DESIGN: We performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA sequencing to derive a transcriptomic signature of hyperinflammatory monocytes. Using gene network correlation analysis, we deconvolved this signature into components associated with homeostasis and inflammation in patient biopsy samples. RESULTS: We characterised monocyte subsets of healthy individuals and patients with IBD that express IL-23. We identified autosensing and paracrine sensing of IL-1α/IL-1ß and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion after lipopolysaccharide stimulation, whole bacteria exposure induced IL-23 production in controls via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to antitumour necrosis factor (TNF) therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease. CONCLUSION: Our work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyperinflammation-associated IL-23 production in patients with severe ulcerating active Crohn's disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with IBD that might benefit from IL-23p19 and/or IL-1α/IL-1ß-targeting therapies upstream of IL-23.


Assuntos
Resistência a Medicamentos/genética , Doenças Inflamatórias Intestinais/genética , Interleucina-10/genética , Subunidade p19 da Interleucina-23/biossíntese , Subunidade p19 da Interleucina-23/genética , Monócitos/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Comunicação Autócrina , Células Cultivadas , Feminino , Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Homeostase/genética , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Interleucina-10/metabolismo , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Comunicação Parácrina , Receptores de Interleucina-10/antagonistas & inibidores , Receptores de Interleucina-10/metabolismo , Transdução de Sinais/genética , Transcriptoma , Fator de Necrose Tumoral alfa/efeitos adversos , Adulto Jovem
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