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1.
Life Sci ; 253: 117606, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32320707

RESUMO

BACKGROUND/AIMS: In cirrhosis, the levels of proinflammatory cytokines are high in the liver and blood. Endotoxin decreases level of consciousness in cirrhotic rats. Phosphatidylserine exists in the cell membrane structure and is essential for the survival of neurons. Phosphatidylserine receptor is found in phagocytic cells and also activates the signaling of membrane proteins in apoptotic process. Therefore this study was aimed to explore the hypothesis that hepatic encephalopathy is prevented by phosphatidylserine treatment and if so, whether this is associated with altered level of proinflammatory cytokines in the brain. METHODS: Cirrhosis was induced by surgical ligation of the bile duct in male Wister rats. The groups were treated with phosphatidylserine and saline for 4 weeks. Brain IL6, TNFα and the expression of phosphatidylserine receptor were assessed. Intraperitoneal injections of either saline or lipopolysaccharide (0.1 mg/kg) were administered to each group. Finally, animal behavior, blood ammonia and the expression of toll like receptor 4 were examined in the brain. RESULTS: Cirrhosis in rats was associated with altered expression of toll-like receptor4 in brain cortex and phosphatidylserine treatment increases toll-like receptor4 receptor expression. Phosphatidylserine had anti-inflammatory effect in healthy rats but no effect in cirrhotic rats. Chronic phosphatidylserine treatment decreased blood ammonia in BDL cirrhotic rats treated with lipopolysaccharide. CONCLUSION: The brain of cirrhotic rat is more susceptible to acute endotoxemia and chronic phosphatidylserine treatment decreases blood ammonia and encephalopathy in cirrhotic rats by encountering endotoxin. Phosphatidylserine may boost immune system against endotoxin.


Assuntos
Anti-Inflamatórios/farmacologia , Endotoxemia/tratamento farmacológico , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/prevenção & controle , Cirrose Hepática/metabolismo , Fosfatidilserinas/farmacologia , Animais , Anti-Inflamatórios/metabolismo , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Ductos Biliares/metabolismo , Encéfalo , Citocinas/metabolismo , Endotoxinas/metabolismo , Encefalopatia Hepática/complicações , Lipopolissacarídeos/metabolismo , Fígado , Cirrose Hepática Experimental , Masculino , Fagócitos/efeitos dos fármacos , Fosfatidilserinas/metabolismo , Ratos , Ratos Wistar , Receptores de Superfície Celular/metabolismo , Receptor 4 Toll-Like/metabolismo , Resultado do Tratamento
2.
Med Sci Monit ; 25: 8472-8481, 2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31707400

RESUMO

BACKGROUND Cardiac dysfunction during endotoxemia is a major cause of cardiovascular disease with high morbidity and mortality. Alisol B 23-acetate (AB23A) is a triterpenoid extracted from the Rhizoma Alismatis, a kind of traditional Chinese medicine, exhibits anti-inflammatory activity on endotoxemia. This investigation aimed to uncover the protective effects of AB23A against sepsis-induced cardiac dysfunction. MATERIAL AND METHODS Adult male C57BL/6 mice received lipopolysaccharide (LPS) (20 mg/kg intravenous) stimulation, with or without pre-treatment of AB23A (10 mg/kg, 20 mg/kg, or 40 mg/kg). Histopathological staining and cardiac function were performed 4 hours after LPS stimulation. Then the levels of interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-alpha were monitored with enzyme-linked immunosorbent assay (ELISA). In addition, H9C2 cells were treated with LPS (5 µg/mL) with or without pre-treated with AB23A (0.1 µM, 1 µM, or 10 µM), and the production of reactive oxygen species (ROS) was detected by DCFH-DA combined with flow cytometry. The expression of Toll-like receptor 4 (TLR4), NADPH oxidase 2 (NOX2), NOX4, P38, p-P38, extracellular-signal-regulated kinase (ERK), and p-ERK were assessed by western blotting. RESULTS AB23A improved the survival rate and ameliorated myocardial injury, decreased inflammatory infiltration and the level of IL-6, IL-1ß, and TNF-alpha in the LPS-stimulated mouse model. Moreover, AB23A inhibited the ROS production in LPS-treated H9C2 cells. In addition, AB23A suppressed the levels of TLR4 and NOX2 as well as the activation levels of P38 and ERK both in vivo and in vitro. CONCLUSIONS AB23A reduced LPS-induced myocardial dysfunction by inhibiting inflammation and ROS production through the TLR4/NOX2 pathway.


Assuntos
Colestenonas/farmacologia , Endotoxemia/tratamento farmacológico , Cardiopatias/tratamento farmacológico , Animais , China , Medicamentos de Ervas Chinesas/farmacologia , Cardiopatias/induzido quimicamente , Cardiopatias/fisiopatologia , Inflamação , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Medicina Tradicional Chinesa/métodos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NADPH Oxidase 2/metabolismo , NADPH Oxidases/metabolismo , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Sepse , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Triterpenos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Pharmacol Rep ; 71(6): 1281-1288, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31683199

RESUMO

BACKGROUND: Sepsis initiates an inflammatory response that causes widespread injury, and candidates for related myocardial depressant factors include cytokines and nitric oxide (NO). Nuclear factor kappa-B (NF-κB) stimulated by toll-like receptor 4 activation in sepsis mediates the transcription of multiple proinflammatory genes. These inflammatory mediators can cause myocardial dysfunction, which may deteriorate sepsis outcomes. To address this risk, we investigated the potential beneficial effects of a novel isoquinolines derivative, CYY054c, in LPS-induced inflammatory response leading to endotoxemia. METHODS: The effects of CYY054c on cytokine and inflammatory-related protein production were evaluated in lipopolysaccharide (LPS)-stimulated macrophages. To determine whether CYY054c alleviates inflammatory storm-induced myocardial dysfunction in vivo, LPS was injected in rats, and cardiac function was measured by a pressure-volume loop. RESULTS: CYY054c inhibited LPS-induced NF-κB expression in macrophages and reduced the release of tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6), as well as the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In the animal studies, CYY054c alleviated LPS-upregulated plasma TNF-α, IL-1ß, IL-6, and NO concentrations, as well as cardiac monocyte chemotactic protein-1, iNOS, and COX-2 expression in rats, contributing to the improvement of cardiac function during endotoxemia. CONCLUSIONS: The reduction of NF-κB-mediated inflammatory mediators and the maintenance of hemodynamic performance by CYY054c improved the outcomes during endotoxemia. CYY054c may be a potential therapeutic agent for sepsis.


Assuntos
Anti-Inflamatórios/farmacologia , Endotoxemia/tratamento farmacológico , Isoquinolinas/farmacologia , Animais , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Endotoxemia/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
4.
J Biochem Mol Toxicol ; 33(12): e22406, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31593353

RESUMO

Soybean Bowman-Birk protease inhibitor (BBI) and genistein, two biological compounds from soybean, are well-known for their anti-inflammatory, antioxidant, and anticancer activities. The aim of this study was designing a BBI-genistein conjugate and then investigating its protective effect on lipopolysaccharide (LPS)-induced inflammation in BALB/c mice, compared with the effects of combination of BBI and genistein. BBI was purified from soybean and the BBI-genistein conjugate was synthesized. The BALB/c mice were intraperitoneally treated 2 hours before LPS induction. Our results showed that treatment with the combination of BBI and genistein greatly led to more reduced serum levels of tumor necrosis factor (TNF)-α and interferon (IFN)-γ compared with the treatments of BBI alone, the BBI-genistein conjugate, and genistein alone, respectively. Moreover, the expression of TNF-α and IFN-γ in the splenocytes was significantly downregulated along with improving host survival against the LPS-induced lethal endotoxemia in the same way. Our data support a new combined therapy using BBI and genistein, as natural anti-inflammatory agents, to develop a new drug for inflammatory diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Endotoxemia/tratamento farmacológico , Genisteína/uso terapêutico , Extratos Vegetais/uso terapêutico , Soja/química , Inibidor da Tripsina de Soja de Bowman-Birk/uso terapêutico , Animais , Combinação de Medicamentos , Endotoxemia/induzido quimicamente , Genisteína/administração & dosagem , Inflamação/metabolismo , Injeções Intraperitoneais , Interferon gama/antagonistas & inibidores , Interferon gama/sangue , Estimativa de Kaplan-Meier , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/antagonistas & inibidores , Baço/patologia , Taxa de Sobrevida , Resultado do Tratamento , Inibidor da Tripsina de Soja de Bowman-Birk/administração & dosagem , Inibidor da Tripsina de Soja de Bowman-Birk/isolamento & purificação , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/sangue
5.
Pak J Pharm Sci ; 32(4): 1467-1475, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31608864

RESUMO

Recently, several studies have demonstrated that reactive oxygen species are responsible for inducing multiple organ failure and septic shock. Particularly, mitochondrial dysfunction has been demonstrated in the pathogenesis of multiple organ dysfunction syndrome (MODS). In cytopathic hypoxia, impairment of mitochondrial oxidative phosphorylation decreases aerobic adenosine triphosphate (ATP) production and potentially induces MODS. Shen-Fu (SF) injections are widely used in the treatment of various diseases. SF exhibits cardiovascular protective effects. For example, it can stretch the coronary artery, stabilize blood pressure, regulate IRI, and improve the overall heart function. Clinical studies have demonstrated that SF injections have notable therapeutic effects on septic and hemorrhagic shocks. In the present study, the effects of SF injection on mitochondrial function in the intestinal epithelial cells of rats with endotoxemia were analyzed.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Endotoxemia/tratamento farmacológico , Intestino Delgado/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Animais , Citocromos c/metabolismo , Citocinas/sangue , Medicamentos de Ervas Chinesas/administração & dosagem , Endotoxemia/metabolismo , Endotoxemia/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Injeções Intravenosas , Intestino Delgado/patologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/patologia , Ratos Sprague-Dawley
6.
Int J Mol Sci ; 20(19)2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31581682

RESUMO

Recently, bioactive peptides have attracted attention for their therapeutic applications in the pharmaceutical industry. Among them, antimicrobial peptides are candidates for new antibiotic drugs. Since pseudin-2 (Ps), isolated from the skin of the paradoxical frog Pseudis paradoxa, shows broad-spectrum antibacterial activity with high cytotoxicity, we previously designed Ps-K18 with a Lys substitution for Leu18 in Ps, which showed high antibacterial activity and low toxicity. Here, we examined the potency of Ps-K18, aiming to develop antibiotics derived from bioactive peptides for the treatment of Gram-negative sepsis. We first investigated the antibacterial mechanism of Ps-K18 based on confocal micrographs and field emission scanning electron microscopy, confirming that Ps-K18 targets the bacterial membrane. Anti-inflammatory mechanism of Ps-K18 was investigated by secreted alkaline phosphatase reporter gene assays and RT-PCR, which revealed that Ps-K18 activates innate defense via Toll-like receptor 4-mediated nuclear factor-kappa B signaling pathways. Moreover, we investigated the antiseptic effect of Ps-K18 using a lipopolysaccharide or Escherichia coli K1-induced septic shock mouse model. Ps-K18 significantly reduced bacterial growth and inflammatory responses in the septic shock model. Ps-K18 showed low renal and liver toxicity and attenuated lung damage effectively. This study suggests that Ps-K18 is a potent peptide antibiotic that could be applied therapeutically to Gram-negative sepsis.


Assuntos
Proteínas de Anfíbios/química , Anti-Infecciosos Locais/farmacologia , Anti-Inflamatórios/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Animais , Peptídeos Catiônicos Antimicrobianos/química , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Endotoxemia/tratamento farmacológico , Endotoxemia/microbiologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/ultraestrutura , Humanos , Macrófagos , Camundongos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
7.
Growth Horm IGF Res ; 48-49: 36-44, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31494533

RESUMO

OBJECTIVE: To investigate the anti-inflammatory property of ghrelin treatment on the Growth Hormone (GH)/Insulin-like Growth Factor-I (IGF-1) axis in Wistar rats that have undergone endotoxemia. DESIGN: In this randomized animal study, lipopolysaccharide (LPS) (5 mg/kg; intraperitoneal) was administered to induce endotoxemia, and ghrelin (15 nmol/kg; endovenous) was injected simultaneously. Blood and liver samples were collected 2 h, 6 h and 12 h after LPS administration for analysis. MEASUREMENTS: Tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, beta (IL-1ß), and IL-6 from both blood and liver were determined by ELISA assay. Serum nitrate was determined by chemiluminescense. Growth hormone receptor (GHR) and growth hormone secretagogue receptor 1a (GHSR-1a) were determined by western blotting. GHR mRNA and IGF-1 mRNA were determined by RT-PCR. RESULTS: LPS administration induced a decrease in IGF-1 and GH serum levels, characterizing GH/IGF-1 axis disruption. Ghrelin treatment attenuated the decrease of serum levels of IGF-1 as well as the increase of TNF-α, IL-1ß, IL-6 and nitrate induced by LPS. The increase of induced GHSR-1a protein expression seen in the LPS group after 2 h remained until 6 h after ghrelin treatment. However, attenuation of the circulating IGF-1 decrease by ghrelin treatment was not accompanied by changes in GHR protein expression nor GHR and IGF-1 gene expression. CONCLUSION: Ghrelin was able to attenuate changes in the GH/IGF-1 axis observed during systemic inflammation, which may be due to the modulation of pro-inflammatory mediators release.


Assuntos
Endotoxemia/metabolismo , Grelina/farmacologia , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Receptores da Somatotropina/metabolismo , Animais , Citocinas/metabolismo , Endotoxemia/tratamento farmacológico , Endotoxemia/patologia , Lipopolissacarídeos/farmacologia , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar
8.
Adv Exp Med Biol ; 1145: 321-341, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31364085

RESUMO

Polymyxin B is an antibiotic that shows strong bactericidal activity against Gram-negative bacteria, by binding to and inactivating endotoxin. Systemic administration of polymyxin B in humans is restricted because of its nephrotoxicity and neurotoxicity, and this compound was therefore considered a strong candidate ligand for the extracorporeal selective adsorption of circulating endotoxin in the blood. Toraymyxin® is a direct hemoperfusion column that uses polymyxin B attached to an insoluble carrier to bind endotoxin in the blood. In 1994, the Japanese National Health Insurance system approved the use of Toraymyxin for the treatment of endotoxemia and septic shock.In this chapter, we will review the development, clinical use, and efficacy of Toraymyxin, examine the structure of the Toraymyxin column, and comment on the current position of Toraymyxin in the treatment of severe sepsis and septic shock. We will also highlight some potential new applications of Toraymyxin for pulmonary diseases.


Assuntos
Antibacterianos/farmacologia , Endotoxinas/isolamento & purificação , Hemoperfusão , Polimixina B/farmacologia , Endotoxemia/tratamento farmacológico , Endotoxinas/sangue , Humanos , Sepse/tratamento farmacológico , Choque Séptico/tratamento farmacológico
9.
PLoS One ; 14(8): e0221392, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31449541

RESUMO

The prevalence of metabolic syndrome (MetSyn) has risen 35% since 2012 and over two-thirds of Americans exhibit features characterizing this condition (obesity, dyslipidemia, hyperglycemia, insulin resistance and/or endothelial dysfunction). The aim of this study was to evaluate the effects of a novel dietary supplemental organic mineral complex (OMC) on these risk factors in a rodent model of MetSyn. Six-week old male Sprague-Dawley rats were fed either standard chow or a high-fat diet (HFD) composed of 60% kcal from fat for 10 weeks. Rats were also treated with OMC in their drinking water at either 0 mg/mL (control), 0.6 mg/mL, or 3.0 mg/mL. The HFD-treated rats exhibited significantly increased body mass (p<0.05), epididymal fat pad mass (p<0.001), waist circumference (p = 0.010), in addition to elevations in plasma endotoxins (p<0.001), ALT activity (p<0.001), fasting serum glucose (p = 0.025) and insulin concentrations (p = 0.009). OMC did not affect body weight or adiposity induced by the HFD. At the higher dose OMC significantly blunted HFD-induced hyperglycemia (p = 0.021), whereas both low and high doses of OMC prevented HFD-induced endotoxemia (p = 0.002 and <0.001, respectively) and hepatocyte injury (ALT activity, p<0.01). Despite evidence of oxidative stress (elevated urinary H2O2 p = 0.032) in HFD-fed rats, OMC exhibited no demonstrable antioxidative effect. Consistent with prior studies, mesenteric arteries from HFD rats had more uncoupled eNOS (p = 0.006) and iNOS protein expression (p = 0.027) in addition to impaired endothelium-dependent vasodilation that was abrogated by the high dose of OMC (p<0.05). This effect of OMC may be attributed to the high nitrate content of the supplement. These findings suggest that the OMC supplement, particularly at the higher dose, ameliorated several risk factors associated with MetSyn via a non-antioxidant-dependent mechanism.


Assuntos
Endotoxemia/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Minerais/farmacologia , Compostos Orgânicos/farmacologia , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Endotoxemia/etiologia , Endotoxemia/patologia , Humanos , Hiperglicemia/etiologia , Hiperglicemia/patologia , Resistência à Insulina/fisiologia , Fígado/efeitos dos fármacos , Fígado/lesões , Fígado/patologia , Minerais/química , Compostos Orgânicos/química , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
10.
Exp Anim ; 68(4): 559-568, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31292306

RESUMO

An uncontrolled inflammation induced critical health problems with serious morbidity and death, which namely acute lung injury (ALI). Recently researchs have found the anti-inflammatory effects of emodin. Here, we investigated the potential effects of emodin on a mouse model with a lethal dose of the potential mechanisms and lipopolysaccharide (LPS)-induced inflammatory lung injury in mice. The pulmonary histological abnormalities, the Evans blue's leakage, the myeloperoxidase (MPO) activity, the grades of TNF-α, IL-6, nitric oxide (NO), lactic acid (LA) in lung tissues were determined 18 h post exposure of LPS. Based on the expression of LC3-II with BECN1 was determined using Western blotting. Besides, the LPS-exposed mice for survival rate was monitored. The results indicated that intervention with emodin was important for mitigating LPS-induced pulmonary histological change and LPS-induced leakage of Evans blue, which were associated with suppressed elevation of MPO activity and inhibited up-regulation of TNF-α, IL-6, NO with LA in lung tissues. Moreover, intervention with emodin enhanced the survival rate of LPS-exposed mice. Finally, therapy with emodin increased the LC3 and BECN1 in lungs of LPS-exposed mice. Treatment with 3-MA (the autophagy inhibitor) reversed the beneficial effects of emodin. In conclusion, emodin might provide pharmacological benefits in LPS-induced inflammatory lung injury, and the mechanisms might be related to the restoration of autophagy.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Autofagia , Emodina/uso terapêutico , Endotoxemia/tratamento farmacológico , Inflamação/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/mortalidade , Animais , Autofagia/efeitos dos fármacos , Modelos Animais de Doenças , Endotoxemia/induzido quimicamente , Endotoxemia/mortalidade , Inflamação/induzido quimicamente , Inflamação/mortalidade , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
11.
Redox Biol ; 26: 101269, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31330482

RESUMO

The gastrointestinal (GI) tract can play a critical role in the development of pathologies associated with overeating, overweight and obesity. We previously observed that supplementation with anthocyanins (AC) (particularly glycosides of cyanidin and delphinidin) mitigated high fat diet (HFD)-induced development of obesity, dyslipidemia, insulin resistance and steatosis in C57BL/6J mice. This paper investigated whether these beneficial effects could be related to AC capacity to sustain intestinal monolayer integrity, prevent endotoxemia, and HFD-associated dysbiosis. The involvement of redox-related mechanisms were further investigated in Caco-2 cell monolayers. Consumption of a HFD for 14 weeks caused intestinal permeabilization and endotoxemia, which were associated with a decreased ileum expression of tight junction (TJ) proteins (occludin, ZO-1 and claudin-1), increased expression of NADPH oxidase (NOX1 and NOX4) and NOS2 and oxidative stress, and activation of redox sensitive signals (NF-κB and ERK1/2) that regulate TJ dynamics. AC supplementation mitigated all these events and increased GLP-2 levels, the intestinal hormone that upregulates TJ protein expression. AC also prevented, in vitro, tumor necrosis factor alpha-induced Caco-2 monolayer permeabilization, NOX1/4 upregulation, oxidative stress, and NF-κB and ERK activation. HFD-induced obesity in mice caused dysbiosis and affected the levels and secretion of MUC2, a mucin that participates in intestinal cell barrier protection and immune response. AC supplementation restored microbiota composition and MUC2 levels and distribution in HFD-fed mice. Thus, AC, particularly delphinidin and cyanidin, can preserve GI physiology in HFD-induced obesity in part through redox-regulated mechanisms. This can in part explain AC capacity to mitigate pathologies, i.e. insulin resistance and steatosis, associated with HFD-associated obesity.


Assuntos
Antocianinas/farmacologia , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Oxirredução , Substâncias Protetoras/farmacologia , Células CACO-2 , Disbiose , Endotoxemia/tratamento farmacológico , Endotoxemia/etiologia , Endotoxemia/metabolismo , Células Caliciformes/metabolismo , Humanos , Mucina-2/genética , Mucina-2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Transdução de Sinais
12.
Res Vet Sci ; 125: 290-297, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31349186

RESUMO

Endotoxemia treatment options are still of interest due to high mortality and choline treatment is one of them because of its role in the cholinergic anti-inflammatory pathway. This study investigated serum choline and butyrylcholinesterase (BChE) responses, and their correlations with inflammatory, oxidative stress and tissue damage biomarkers, including paraoxanase-1 (PON1), and clinical signs in calves with endotoxemia and the effect of choline treatment in these responses. Healthy calves (n = 20) were divided equally into 4 groups: Control (0.9% NaCl, iv), Choline (C; 1 mg/kg/iv,once), Lipopolysaccharide (LPS; 2 µg/kg/iv,once) and LPS + C. Clinical and laboratory examinations were performed before and 0.5-48 h (hrs) after treatments. Following LPS administration, serum choline level increased at 0.5-24 h (P < .01), whereas serum BChE and PON1 level decreased at 48 h (P < .01) compared to their baselines. In LPS + C group, the increase in serum choline level was significantly higher (P < .01) than that of C and LPS groups. LPS did not decrease serum BChE levels significantly in calves treated with choline. Serum choline and BChE results correlated negatively with white blood cell count and positively (P < .001) with PON1 levels, oxidative stress index, inflammation and hepato-muscular injury markers. In conclusion serum choline and BChE may have a role in the pathophysiology of endotoxemia in calves. High serum choline concentration is associated with an improvement in response to LPS administration in calves treated with choline, probably by preventing the imbalances between oxidative stress and anti-oxidant capacity, preventing the serum BChE and PON1 decreases, and inhibition/attenuation of acute phase reaction and hepato-muscular injury in calves with endotoxemia.


Assuntos
Butirilcolinesterase/sangue , Doenças dos Bovinos/induzido quimicamente , Colina/sangue , Endotoxemia/veterinária , Lipopolissacarídeos/toxicidade , Reação de Fase Aguda/tratamento farmacológico , Administração Intravenosa , Animais , Biomarcadores/sangue , Butirilcolinesterase/metabolismo , Bovinos , Doenças dos Bovinos/sangue , Doenças dos Bovinos/tratamento farmacológico , Endotoxemia/tratamento farmacológico , Endotoxemia/fisiopatologia , Inflamação/tratamento farmacológico , Contagem de Leucócitos , Lipopolissacarídeos/administração & dosagem , Masculino , Estresse Oxidativo , Distribuição Aleatória
13.
J Immunol ; 203(2): 453-464, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31160535

RESUMO

Sepsis has a well-studied inflammatory phase, with a less-understood secondary immunosuppressive phase. Elevated blood lactate and slow lactate clearance are associated with mortality; however, regulatory roles are unknown. We hypothesized that lactic acid (LA) contributes to the late phase and is not solely a consequence of bacterial infection. No studies have examined LA effects in sepsis models in vivo or a mechanism by which it suppresses LPS-induced activation in vitro. Because mast cells can be activated systemically and contribute to sepsis, we examined LA effects on the mast cell response to LPS. LA significantly suppressed LPS-induced cytokine production and NF-κB transcriptional activity in mouse bone marrow-derived mast cells and cytokine production in peritoneal mast cells. Suppression was MCT-1 dependent and reproducible with sodium lactate or formic acid. Further, LA significantly suppressed cytokine induction following LPS-induced endotoxemia in mice. Because glycolysis is linked to inflammation and LA is a byproduct of this process, we examined changes in glucose metabolism. LA treatment reduced glucose uptake and lactate export during LPS stimulation. LA effects were mimicked by glycolytic inhibitors and reversed by increasing ATP availability. These results indicate that glycolytic suppression and ATP production are necessary and sufficient for LA effects. Our work suggests that enhancing glycolysis and ATP production could improve immune function, counteracting LA suppressive effects in the immunosuppressive phase of sepsis.


Assuntos
Trifosfato de Adenosina/metabolismo , Glicólise/efeitos dos fármacos , Ácido Láctico/farmacologia , Lipopolissacarídeos/farmacologia , Mastócitos/efeitos dos fármacos , Animais , Citocinas/metabolismo , Endotoxemia/tratamento farmacológico , Endotoxemia/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Sepse/tratamento farmacológico , Sepse/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Oxid Med Cell Longev ; 2019: 7136585, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31182997

RESUMO

Ouabain, a steroid binding to the Na+/K+-ATPase, has several pharmacological effects. In addition to the recognized effects of blood pressure, there is more convincing evidence suggesting that ouabain is involved in immunologic functions and inflammation. Hypoxia-inducible factor 1α (HIF-1α) is a metabolic regulator which plays a considerable role in immune responses. Previous studies had shown that HIF-1α-induced glycolysis results in functional reshaping in macrophages. In this study, we investigated the role of glycolytic pathway activation in the anti-inflammatory effect of ouabain. We found that ouabain is involved in anti-inflammatory effects both in vivo and in vitro. Additionally, ouabain can inhibit LPS-induced upregulation of GLUT1 and HK2 at the transcriptional level. GM-CSF pretreatment almost completely reversed the inhibitory effect of ouabain on LPS-induced release of proinflammatory cytokines. Alterations in glycolytic pathway activation were required for the anti-inflammatory effect of ouabain. Ouabain can significantly inhibit the upregulation of HIF-1α at the protein level. Our results also revealed that the overexpression of HIF-1α can reverse the anti-inflammatory effect of ouabain. Thus, we conclude that the HIF-1α-dependent glycolytic pathway is essential for the anti-inflammatory effect of ouabain.


Assuntos
Endotoxemia/tratamento farmacológico , Endotoxemia/metabolismo , Fator 1 Induzível por Hipóxia/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Ouabaína/uso terapêutico , Animais , Endotoxemia/induzido quimicamente , Glicólise/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , ATPase Trocadora de Sódio-Potássio/metabolismo
15.
Int Immunopharmacol ; 73: 482-490, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173970

RESUMO

There is currently no specific drug for the treatment of sepsis and antibiotic administration is considered the best option, despite numerous issues. Therefore, the development of drugs to control the pathogen-induced inflammatory responses associated with sepsis is essential. To address this, our study examined the transcriptomes of lipopolysaccharide (LPS)-induced dendritic cells (DCs), identifying TANK-binding kinase1 (Tbk1) as a key factor involved in the inflammatory response. These data suggested drug repositioning of the Tbk1 inhibitor CYT387, currently used for the treatment of myelofibrosis and some cancers, as a candidate for regulating the LPS-induced inflammatory response. CYT387 also inhibited pro-inflammatory cytokine and surface molecule expression by mature DCs after LPS exposure. These effects correlated with both Akt phosphorylation and IκBα degradation. Finally, CYT387 demonstrated therapeutic effects in LPS-induced endotoxemia and Escherichia coli K1-induced mouse models of sepsis and decreased the expression of pro-inflammatory cytokines. In conclusion, our study suggests that drug repositioning of CYT387 may serve as a potential therapeutic for sepsis.


Assuntos
Benzamidas/uso terapêutico , Endotoxemia/tratamento farmacológico , Infecções por Escherichia coli/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Sepse/tratamento farmacológico , Animais , Benzamidas/farmacologia , Citocinas/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Reposicionamento de Medicamentos , Endotoxemia/imunologia , Infecções por Escherichia coli/imunologia , Feminino , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Inibidor de NF-kappaB alfa/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/farmacologia , Sepse/imunologia , Transcriptoma/efeitos dos fármacos
16.
Nutrients ; 11(5)2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035432

RESUMO

We evaluated the effectiveness of pharmacological doses of grape-seed proanthocyanidin extract (GSPE) in reversing intestinal barrier alterations and local inflammation in female Wistar rats fed a long-term obesogenic diet. Animals were fed a 17-week cafeteria diet (CAF diet), supplemented with daily GSPE doses (100 or 500 mg kg-1 body weight) during the final two weeks. CAF diet enhanced the intestinal permeation of an orally administered marker (ovalbumin, OVA) and increased the plasma levels of tumor necrosis factor-α (TNF-α) and lipopolysaccharides (LPS) in 2-3-fold. Ex vivo Ussing chamber assays showed a 55-70% reduction in transepithelial electrical resistance (TEER) and increased the TNF-α secretions in both small and large intestinal sections with a 25-fold increment in the ileum. Ileal tissues also presented a 4-fold increase of myeloperoxidase (MPO) activity. Both GSPE-treatments were able to restitute TEER values in the ileum and colon and to reduce plasma LPS to basal levels without a dose-dependent effect. However, effects on the OVA permeation and TNF-α secretion were dose and section-specific. GSPE also reduced ileal MPO activity and upregulated claudin 1 gene expression. This study provides evidence of the efficacy of GSPE-supplementation ameliorating diet-induced intestinal dysfunction and metabolic endotoxemia when administered at the end of a long-term obesogenic diet.


Assuntos
Endotoxemia/induzido quimicamente , Enteropatias/induzido quimicamente , Proantocianidinas/farmacologia , Sementes/química , Vitis/química , Animais , Dieta , Relação Dose-Resposta a Droga , Endotoxemia/tratamento farmacológico , Feminino , Enteropatias/tratamento farmacológico , Proantocianidinas/administração & dosagem , Proantocianidinas/química , Ratos , Ratos Wistar
17.
Drugs ; 79(8): 855-862, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31062264

RESUMO

BACKGROUND: Hyperphosphatemia control is a major issue in hemodialysis patients. Both sevelamer and nicotinamide are prescribed for this purpose. In addition, they exert pleiotropic effects such as an improvement of inflammatory status and potentially enhanced clearance of uremic toxins. In the present secondary analysis of the NICOREN trial, we investigated the impact of sevelamer and nicotinamide on uremic toxins, toxin precursors, and endotoxemia in chronic hemodialysis patients. METHODS: Circulating uremic toxins (including phenylacetylglutamine, trimethylamine-N-oxide, p-cresyl sulfate, indoxyl sulfate, kynurenine, hippuric acid, indole-3-acetic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, kynurenic acid, and p-cresyl glucuronide) and precursors were measured by ultra-performance liquid chromatography-tandem mass spectrometry, and urea, uric acid, phosphate, C-reactive protein, and intact parathyroid hormone by routine biochemistry methods. Serum endotoxin (evaluated by lipopolysaccharide levels) and C-terminal fibroblast growth factor-23 levels were measured using enzyme-linked immunosorbent assay kits. RESULTS: One hundred hemodialysis patients were randomized to receive either nicotinamide or sevelamer treatment. Among them, 63% were male, mean (± standard deviation) age was 65 ± 14 years, 47% had diabetes mellitus, and 51% had a history of cardiovascular disease. In the sevelamer group, but not the nicotinamide group, serum levels of urea, uric acid, and fibroblast growth factor-23 were significantly reduced after 6 months of treatment. The other circulating uremic toxins and toxin precursors remained unchanged in response to either phosphate-lowering agent. Sevelamer treatment led to a marked decrease in serum lipopolysaccharide (p < 0.001) whereas nicotinamide treatment induced an only modest decrease of borderline significance (p = 0.057). There was no change in C-reactive protein levels. CONCLUSION: In contrast to sevelamer, nicotinamide did not reduce circulating levels of low-molecular-weight uremic toxins other than phosphate, and neither agent reduced circulating uremic toxins of high-molecular-weight or protein-bound toxins. Sevelamer, but not nicotinamide, reduced serum endotoxin levels. Despite no change in serum C-reactive protein, the endotoxin-lowering effect of sevelamer may help to attenuate the inflammatory status of patients with chronic kidney disease.


Assuntos
Endotoxemia/tratamento farmacológico , Endotoxinas/sangue , Niacinamida/administração & dosagem , Insuficiência Renal Crônica/tratamento farmacológico , Sevelamer/administração & dosagem , Idoso , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Hiperfosfatemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Fosfatos/sangue , Diálise Renal , Ácido Úrico/sangue
18.
J Med Food ; 22(6): 594-601, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30874461

RESUMO

Liver plays a pivotal role in host defense mechanisms related to endotoxemia. However, liver dysfunction often occurs in early sepsis. This study investigated the hepatoprotective potential of natural stilbenoid piceatannol (PIC) in lipopolysaccharide (LPS)-induced endotoxemic mice. Swiss Albino mice were divided into four groups: Control (C), LPS administrated (LPS), PIC administrated (PIC), and LPS administrated/PIC preadministrated (LPS+PIC) animals. PIC was administrated intraperitoneally (i.p.) at the dose of 4 mg/kg/day during 7 days. Endotoxemia was induced with a single i.p. administration of LPS at the dose of 4 mg/kg. Superoxide dismutase (SOD), catalase (CAT) and lipid peroxidation (LP) levels, light microscopic pathology, and genotoxicity were investigated. Proliferating cell nuclear antigen and SQSTM1/p62 immunofluorescence were measured. PIC preadministration restored SOD activity, reduced LP and genotoxicity. However, moderate level of oxidative stress (OS) had been progressed in PIC preadministrated animals depending upon prolonged autophagic response and selective degradation of CAT. Positive OS stimulated liver regeneration by upregulating oval cells' and downregulating hepatocytes' proliferation and resulted in the maintanence of hepatic tissue integrity in PIC preadministrated animals. These results suggested that PIC may be a useful hepatoprotective agent in LPS-induced endotoxemia as a modulator of OS and genotoxicity, as an inducer of autophagy, and as a promoter of liver regeneration.


Assuntos
Endotoxemia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Estilbenos/administração & dosagem , Animais , Catalase/metabolismo , Endotoxemia/metabolismo , Endotoxemia/fisiopatologia , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Regeneração , Superóxido Dismutase/metabolismo
19.
Int J Mol Sci ; 20(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897706

RESUMO

Although dexamethasone (DEX) is a widely used immunoregulatory agent, knowledge about its pharmacological properties in farm animals, especially pigs, is insufficient. Previous studies suggest that compared to other species, pigs are less sensitive to the immunosuppression conferred by DEX and more sensitive to the threat of bacterial endotoxins. However, there is a paucity of studies examining DEX immunomodulation in endotoxemia in this species. In this study, a porcine endotoxemia model was established by lipopolysaccharide (LPS) and the effect of DEX-pretreatment on the magnitude and kinetics of neuroendocrine, metabolic, hematologic, inflammatory, and behavioural responses were examined. DEX decreased cortisol, adrenocorticotropic hormone (ACTH), red blood cell, hemoglobin, hematocrit, and lymphocyte whereas glucose concentration was increased under both normal and endotoxemic conditions. By contrast, DEX decreased triglyceride, lactate, and IL-6 concentrations and increased platelet count only under an endotoxemic condition. DEX also reduced the frequency of sickness behaviour following LPS challenge. PCA showed that glucose and triglyceride metabolism together with red blood cell count mainly contributed to the separation of clusters during DEX treatment. Our study demonstrates that DEX protects pigs from inflammation and morbidity in endotoxemia, in spite of their less sensitivity to DEX. Moreover, its considerable role in the regulation of the metabolic and hematologic responses in endotoxemic pigs is revealed for the first time.


Assuntos
Dexametasona/uso terapêutico , Endotoxemia/tratamento farmacológico , Hormônio Adrenocorticotrópico/sangue , Animais , Citocinas/sangue , Endotoxemia/sangue , Feminino , Glucose/metabolismo , Hidrocortisona/sangue , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/sangue , Masculino , Suínos , Triglicerídeos/sangue
20.
Braz J Med Biol Res ; 52(3): e7905, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30810621

RESUMO

Dexmedetomidine (DEX), a selective agonist of α2-adrenergic receptors, has anti-inflammation properties and potential beneficial effects against trauma, shock, or infection. Therefore, this study aimed to investigate whether DEX might protect against multiple-organ dysfunction in a two-hit model of hemorrhage/resuscitation (HS) and subsequent endotoxemia. Eighty Wistar rats were randomized into four groups: NS (normal saline), HS/L (HS plus lipopolysaccharide), HS/L+D (HS/L plus dexmedetomidine), and HS/L+D+Y (HS/L+D plus yohimbine). Six hours after resuscitation, blood gas (PaO2) and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urine nitrogen (BUN), creatinine (Cr), TNF-α, IL-ß, IL-6, IL-8, IL-10, and nitric oxide (NO) were measured. The histopathology was assayed by staining. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels and heme oxygenase-1 (HO-1) were assayed. The PaO2 levels in HS/L rats were lower whereas the ALT, AST, BUN, Cr, TNF-α, IL-ß, IL-6, IL-8, IL-10, and NO levels were higher compared to the control group. The HS/L+D increased PaO2 and further increased IL-10 and decreased ALT, AST, BUN, Cr, TNF-α, IL-ß, IL-6, IL-8, and NO levels of the HS/L groups. In addition, the MDA in the HS/L groups increased whereas SOD activity decreased compared to the control group. Moreover, the HO-1 expression levels were increased by DEX administration in lung, liver, and kidney tissues. Lungs, livers, and kidneys of the HS/L group displayed significant damage, but such damage was attenuated in the HS/L+D group. All of the above-mentioned effects of DEX were partly reversed by yohimbine. DEX reduced multiple organ injury caused by HS/L in rats, which may be mediated, at least in part, by α2-adrenergic receptors.


Assuntos
Dexmedetomidina/uso terapêutico , Endotoxemia/tratamento farmacológico , Hemorragia/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Ressuscitação , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Endotoxemia/patologia , Hemorragia/patologia , Masculino , Insuficiência de Múltiplos Órgãos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Fatores de Tempo
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