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1.
Zhongguo Zhong Yao Za Zhi ; 46(16): 4193-4200, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34467732

RESUMO

As a dangerous disease with rapid progression, endotoxemia is easy to induce the damage to multiple organs. However, its specific and efficient treatment methods are still lacking at present. Both Qingkailing Injection(QKLI) and Shengmai Injection(SMI) have been proved effective in anti-inflammation, anti-endotoxin and organ protection. In this study, carrageenan and endotoxin were injected successively into rats to establish an endotoxemia model. Different doses of QKLI and SMI were administered to the endotoxemia rats by intraperitoneal injection separately or in combination. Then the count of white blood cells, the number of platelets, the content of cytokines, biochemical indexes, organ coefficient and pathological changes of main organs in the rats were detected. The results showed that the rats in the model group had obvious symptoms of endotoxemia, i.e., leucopenia, thrombocytopenia, increase in cytokines(IL-6 and TNF-α) and biochemical indexes of liver and kidney function as well as pathological damage to liver, kidney and lung. QKLI alone can alleviate the above symptoms of endotoxemia and the organ injury. SMI alone is less effective in improving disseminated intravascular coagulation(DIC) and cytokine secretion complicated with endotoxemia, but capable of reducing the inflammation degree of the lung, liver and kidney. The combination of QKLI and SMI remarkably increased the number of platelets in the peripheral blood, improved the liver and kidney function and reduced inflammatory factors, with lung, liver, kidney and other organ structures protected well. Moreover, the improvement effect of the combination of QKLI and SMI was stronger than those of the two injections alone at fixed doses, indicative of a synergistic effect.


Assuntos
Medicamentos de Ervas Chinesas , Endotoxemia , Animais , Combinação de Medicamentos , Endotoxemia/tratamento farmacológico , Ratos
2.
Nutrients ; 13(8)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34444753

RESUMO

Plant-based diets are becoming more popular for many reasons, and epidemiological as well as clinical data also suggest that a well-balanced vegan diet can be adopted for the prevention, and in some cases, in the treatment of many diseases. In this narrative review, we provide an overview of the relationships between these diets and various conditions and their potential biochemical background. As whole plant foods are very rich in food-derived antioxidants and other phytochemicals, they have many positive physiological effects on different aspects of health. In the background of the beneficial health effects, several biochemical processes could stand, including the reduced formation of trimethylamine oxide (TMAO) or decreased serum insulin-like growth factor 1 (IGF-1) levels and altered signaling pathways such as mechanistic target of rapamycin (mTOR). In addition, the composition of plant-based diets may play a role in preventing lipotoxicity, avoiding N-glycolylneuraminic acid (Neu5Gc), and reducing foodborne endotoxin intake. In this article, we attempt to draw attention to the growing knowledge about these diets and provide starting points for further research.


Assuntos
Fenômenos Bioquímicos , Dieta , Animais , Antioxidantes , Dieta Vegana , Endotoxemia , Humanos , Fator de Crescimento Insulin-Like I , Metilaminas , Neoplasias , Sirolimo , Serina-Treonina Quinases TOR , Veganos
3.
Nutrients ; 13(8)2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34444955

RESUMO

Diet and dietary components have profound effects on the composition of the gut microbiota and are among the most important contributors to the alteration in bacterial flora. This review examines the effects the "Western", "plant-based", "high-fat", "medical ketogenic", and "Mediterranean" diets have on the composition of the gut microbiota in both mice and human subjects. We show that specific dietary components that are commonly found in the "plant-based" and "Mediterranean" diet play a role in shifting the microbial composition. This review further evaluates the bacterial metabolites that are associated with diet, and their role in systemic inflammation and metabolic endotoxemia. Furthermore, the associations between diet/dietary components and altering bacterial composition, may lead to potential therapeutic targets for type II diabetes, obesity, and inflammatory diseases.


Assuntos
Dieta/efeitos adversos , Microbioma Gastrointestinal/fisiologia , Fenômenos Fisiológicos da Nutrição , Animais , Dieta/métodos , Dieta Hiperlipídica/efeitos adversos , Dieta Cetogênica/efeitos adversos , Dieta Mediterrânea/efeitos adversos , Dieta Vegetariana/efeitos adversos , Dieta Ocidental/efeitos adversos , Endotoxemia/etiologia , Endotoxemia/microbiologia , Humanos , Inflamação/etiologia , Inflamação/microbiologia , Camundongos
4.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445223

RESUMO

Increasing evidence suggests that systemic inflammation triggers a neuroinflammatory response that involves sustained microglia activation. This response has deleterious consequences on memory and learning capability in experimental animal models and in patients. However, the mechanisms connecting systemic inflammation and microglia activation remain poorly understood. Here, we identify the autotaxin (ATX)/lysophosphatidic acid (LPA)/LPA-receptor axis as a potential pharmacological target to modulate the LPS-mediated neuroinflammatory response in vitro (the murine BV-2 microglia cell line) and in vivo (C57BL/6J mice receiving a single i.p. LPS injection). In LPS-stimulated (20 ng/mL) BV-2 cells, we observed increased phosphorylation of transcription factors (STAT1, p65, and c-Jun) that are known to induce a proinflammatory microglia phenotype. LPS upregulated ATX, TLR4, and COX2 expression, amplified NO production, increased neurotoxicity of microglia conditioned medium, and augmented cyto-/chemokine concentrations in the cellular supernatants. PF8380 (a type I ATX inhibitor, used at 10 and 1 µM) and AS2717638 (an LPA5 antagonist, used at 1 and 0.1 µM) attenuated these proinflammatory responses, at non-toxic concentrations, in BV-2 cells. In vivo, we demonstrate accumulation of PF8380 in the mouse brain and an accompanying decrease in LPA concentrations. In vivo, co-injection of LPS (5 mg/kg body weight) and PF8380 (30 mg/kg body weight), or LPS/AS2717638 (10 mg/kg body weight), significantly attenuated LPS-induced iNOS, TNFα, IL-1ß, IL-6, and CXCL2 mRNA expression in the mouse brain. On the protein level, PF8380 and AS2717638 significantly reduced TLR4, Iba1, GFAP and COX2 expression, as compared to LPS-only injected animals. In terms of the communication between systemic inflammation and neuroinflammation, both inhibitors significantly attenuated LPS-mediated systemic TNFα and IL-6 synthesis, while IL-1ß was only reduced by PF8380. Inhibition of ATX and LPA5 may thus provide an opportunity to protect the brain from the toxic effects that are provoked by systemic endotoxemia.


Assuntos
Benzoxazóis/farmacologia , Encéfalo/metabolismo , Endotoxemia , Isoquinolinas/farmacologia , Lipopolissacarídeos/toxicidade , Microglia/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Piperazinas/farmacologia , Piperidinas/farmacologia , Receptores de Ácidos Lisofosfatídicos , Animais , Encéfalo/patologia , Linhagem Celular , Modelos Animais de Doenças , Endotoxemia/induzido quimicamente , Endotoxemia/metabolismo , Endotoxemia/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Microglia/patologia , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/metabolismo
5.
Molecules ; 26(16)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34443679

RESUMO

Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a "two-bottle" as well as a "drinking in the dark" paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.


Assuntos
Consumo de Bebidas Alcoólicas/patologia , Antagonistas de Receptores de Canabinoides/farmacologia , Endotoxemia/patologia , Etanol/efeitos adversos , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Receptor CB1 de Canabinoide/antagonistas & inibidores , Consumo de Bebidas Alcoólicas/sangue , Animais , Ansiedade/sangue , Ansiedade/complicações , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/complicações , Cicloexanóis/administração & dosagem , Teste de Labirinto em Cruz Elevado , Endotoxemia/sangue , Endotoxemia/complicações , Endotoxinas/sangue , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Hipotermia Induzida , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Pirazóis/administração & dosagem , Receptor CB1 de Canabinoide/metabolismo , Rimonabanto/administração & dosagem , Rimonabanto/farmacologia , Estereoisomerismo , Sulfonamidas/administração & dosagem
6.
Biomed Res Int ; 2021: 5554991, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34337024

RESUMO

Background: Obesity is a main contributing factor for the development of glucose intolerance and type 2 diabetes mellitus (T2D). Roux-en-Y gastric bypass (RYGB) is believed to be one of the most effective treatments to reduce body weight and improve glucose metabolism. In this study, we sought to explore the underlying mechanisms of weight reduction and insulin resistance improvement after RYGB. Methods: This was a prospective observational study using consecutive samples of 14 obese subjects undergoing bariatric surgery. Main assessments were serum indexes (blood metabolites, glucose-lipid regulating hormones, trimethylamine-N-oxide (TMAO), and lipopolysaccharide-binding protein (LBP), fecal short-chain fatty acids (SCFAs), and gut microbiota. Correlation analysis of the factors changed by RYGB was used to indicate the potential mechanism by which surgery improves insulin resistance. Results: The subjects showed significant improvement on indices of obesity and insulin resistance and a correlated change of gut microbiota components at 1 month, 3 months, and 6 months post-RYGB operation. In particular, the abundance of a counterobese strain, Akkemansia muciniphila, had gradually increased with the postoperative time. Moreover, these changes were negatively correlated to serum levels of LBP and positively correlated to serum TMAO and fecal SCFAs. Conclusions: Our findings uncovered links between intestinal microbiota alterations, circulating endotoxemia, and insulin resistance. This suggests that the underlying mechanism of protection of the intestine by RYGB in obesity may be through changing the gut microbiota.


Assuntos
Endotoxemia/microbiologia , Endotoxemia/cirurgia , Derivação Gástrica , Microbioma Gastrointestinal , Resistência à Insulina , Proteínas de Fase Aguda/metabolismo , Proteínas de Transporte/metabolismo , Regulação para Baixo , Humanos , Glicoproteínas de Membrana/metabolismo , Metaboloma , Metilaminas/metabolismo , Obesidade/microbiologia , Obesidade/cirurgia
7.
Rev. ecuat. pediatr ; 22(2): 1-6, 31 de agosto del 2021.
Artigo em Espanhol | LILACS | ID: biblio-1284490

RESUMO

Propósito de la revisión: el objetivo de la revisión es delinear la fisiopatología de la Entero Colitis Necrotizante (ECN) clásica del recién nacido, proponer un listado de antecedentes perinatales que definan un grupo de riesgo y establecer parámetros simples y objetivos, que ayuden a establecer un diagnóstico clínico precoz. Recientes hallazgos: La mortalidad de la Entero Colitis Necrotizante clásica del recién nacido sigue siendo elevada. Aunque la enfermedad tiene varias presentaciones, es única con una única vía de instalación, la hipoperfusión intestinal como agente agresor inicial. Extracto: La falta de estrategias de prevención y el diagnóstico clínico muy tardío explican la mortalidad elevada de la ECN. Existe una gran confusión sobre el origen de la enferme-dad, dando a entender que existen diferentes tipos de ECN, aunque la enfermedad es única, tiene diferentes manifestaciones según las condiciones del recién nacido con una vía común de instalación, la hipoperfusión intestinal como agente agresor inicial. En este artículo se postula que reconocer a la hipoperfusión intestinal como agente agresor inicial, es "encontrar el hilo perdido", que permitirá desarrollar estrategias de prevención y tratamiento, al identificar los pacientes en riesgo de ECN y lograr el diagnóstico de manera precoz.


Purpose of the review: The objective of the review is to delineate the pathophysiology of the classic Entero Necrotizing Colitis (NEC) of the newborn, propose a list of perinatal ante-cedents that define a risk group and establish simple and objective parameters that help to establish an early clinical diagnosis. Recent findings: The mortality of the classic Necrotizing Entero Colitis of the newborn is still high. Although the disease has several presentations, it is unique with a single installation route, intestinal hypoperfusion as the initial offending agent. Excerpt: The lack of prevention strategies and very late clinical diagnosis explain the high mortality of NEC. There is great confusion about the origin of the disease, giving to under-stand that there are different types of NEC, although the disease is unique, it has different manifestations according to the conditions of the newborn with a common route of installation, intestinal hypoperfusion as an initial assailant agent. This article postulates that recog-nizing intestinal hypoperfusion as the initial offending agent is "finding the lost thread", that developing prevention and treatment strategies, by identifying patients at risk of NEC and achieving a diagnosis in a way early.


Objetivo da revisão: O objetivo da revisão é delinear a fisiopatologia da Entero Colite Necrosante (NEC) clássica do recém-nascido, propor uma lista de antecedentes perinatais que definem um grupo de risco e estabelecer parâmetros simples e objetivos que auxiliem no diagnóstico clínico precoce. Descobertas recentes: A mortalidade da Entero Colite Necrosante clássica do recém-nascido ainda é alta. Embora a doença tenha várias apresentações, é única com uma única via de instalação, a hipoperfusão intestinal como agente agressor inicial. Resumo: A falta de estratégias de prevenção e o diagnóstico clínico muito tardio explicam a alta mortalidade da NEC. Há grande confusão sobre a origem da doença, sugerindo que existem diferentes tipos de NEC, embora a doença seja única, ela tem diferentes manifestações dependendo das condições do recém-nascido com uma via comum de instalação, a hipoperfusão intestinal como agente. assaltante inicial. Este artigo postula que reconhecer a hipoperfusão intestinal como agente agressor inicial é "encontrar o fio condutor", o que permitirá o desenvolvimento de estratégias de prevenção e tratamento, por meio da identificação de pacientes em risco de NEC e do diagnóstico precoce.


Assuntos
Humanos , Recém-Nascido , Enterocolite Necrosante , Reflexo de Mergulho , Hemorragia Gastrointestinal , Recém-Nascido , Recém-Nascido Prematuro , Endotoxemia , Enterocolite
8.
Front Immunol ; 12: 674079, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248955

RESUMO

At homeostasis the vast majority of neutrophils in the circulation expresses CD16 and CD62L within a narrow expression range, but this quickly changes in disease. Little is known regarding the changes in kinetics of neutrophils phenotypes in inflammatory conditions. During acute inflammation more heterogeneity was found, characterized by an increase in CD16dim banded neutrophils. These cells were probably released from the bone marrow (left shift). Acute inflammation induced by human experimental endotoxemia (LPS model) was additionally accompanied by an immediate increase in a CD62Llow neutrophil population, which was not as explicit after injury/trauma induced acute inflammation. The situation in sub-acute inflammation was more complex. CD62Llow neutrophils appeared in the peripheral blood several days (>3 days) after trauma with a peak after 10 days. A similar situation was found in the blood of COVID-19 patients returning from the ICU. Sorted CD16low and CD62Llow subsets from trauma and COVID-19 patients displayed the same nuclear characteristics as found after experimental endotoxemia. In diseases associated with chronic inflammation (stable COPD and treatment naive HIV) no increases in CD16low or CD62Llow neutrophils were found in the peripheral blood. All neutrophil subsets were present in the bone marrow during homeostasis. After LPS rechallenge, these subsets failed to appear in the circulation, but continued to be present in the bone marrow, suggesting the absence of recruitment signals. Because the subsets were reported to have different functionalities, these results on the kinetics of neutrophil subsets in a range of inflammatory conditions contribute to our understanding on the role of neutrophils in health and disease.


Assuntos
COVID-19/imunologia , Endotoxemia/imunologia , Inflamação/imunologia , Neutrófilos/imunologia , SARS-CoV-2/fisiologia , Ferimentos e Lesões/imunologia , Doença Aguda , Adulto , Idoso , Movimento Celular , Células Cultivadas , Doença Crônica , Feminino , Humanos , Selectina L/metabolismo , Lipopolissacarídeos/imunologia , Masculino , Pessoa de Meia-Idade , Receptores de IgG/metabolismo , Adulto Jovem
9.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200709

RESUMO

Sepsis is characterized by multiple-organ dysfunction caused by the dysregulated host response to infection. Until now, however, the role of the Wnt signaling has not been fully characterized in multiple organs during sepsis. This study assessed the suppressive effect of a Wnt signaling inhibitor, Wnt-C59, in the kidney, lung, and liver of lipopolysaccharide-induced endotoxemic mice, serving as an animal model of sepsis. We found that Wnt-C59 elevated the survival rate of these mice and decreased their plasma levels of proinflammatory cytokines and organ-damage biomarkers, such as BUN, ALT, and AST. The Wnt/ß-catenin and NF-κB pathways were stimulated and proinflammatory cytokines were upregulated in the kidney, lung, and liver of endotoxemic mice. Wnt-C59, as a Wnt signaling inhibitor, inhibited the Wnt/ß-catenin pathway, and its interaction with the NF-κB pathway, which resulted in the inhibition of NF-κB activity and proinflammatory cytokine expression. In multiple organs of endotoxemic mice, Wnt-C59 significantly reduced the ß-catenin level and interaction with NF-κB. Our findings suggest that the anti-endotoxemic effect of Wnt-C59 is mediated via reducing the interaction between ß-catenin and NF-κB, consequently suppressing the associated cytokine upregulation in multiple organs. Thus, Wnt-C59 may be useful for the suppression of the multiple-organ dysfunction during sepsis.


Assuntos
Benzenoacetamidas/farmacologia , Citocinas/metabolismo , Endotoxemia/tratamento farmacológico , Lipopolissacarídeos/toxicidade , NF-kappa B/antagonistas & inibidores , Piridinas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , Animais , Citocinas/genética , Endotoxemia/induzido quimicamente , Endotoxemia/metabolismo , Endotoxemia/patologia , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Domínios e Motivos de Interação entre Proteínas , beta Catenina/metabolismo
10.
Nutr J ; 20(1): 47, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34074289

RESUMO

PURPOSE: Alterations in the gut microbiome (dysbiosis) has been associated with increased microbial translocation, leading to chronic inflammation in coronary artery disease (CAD). It has been proposed that modulation of gut microbiota by probiotic might modify metabolic endotoxemia. Therefore, the purpose of this study was to examine the effects of Lactobacillus rhamnosus GG (LGG) on endotoxin level, and biomarkers of inflammation in CAD participants. METHODS: This study was a 12-weeks randomized, double-blind, and intervention on 44 patients with CAD. Patients were randomly allocated to receive either one LGG capsule 1.6 × 109 colony-forming unit (CFU) or the placebo capsules for 12 weeks. In addition, all the participants were also prescribed a calorie-restricted diet. Serum levels of interleukin-1ß (IL-1ß), Toll-like receptor 4 (TLR4), interleukin-10 (IL-10), and lipopolysaccharide (LPS), were assessed before and after the intervention. RESULTS: A significant decrease in IL1-Beta concentration (- 1.88 ± 2.25, vs. 0.50 ± 1.58 mmol/L, P = 0.027), and LPS levels (- 5.88 ± 2.70 vs. 2.96+ 5.27 mg/L, P = 0.016), was observed after the probiotic supplementation compared with the placebo. Participants who had ≥2.5 kg weight loss showed significantly improved cardiovascular-related factors, compared to patients with < 2.5 kg weight reduction, regardless of the supplement they took. CONCLUSION: These data provide preliminary evidence that probiotic supplementation has beneficial effects on metabolic endotoxemia, and mega inflammation in participants with CAD.


Assuntos
Doença da Artéria Coronariana , Endotoxemia , Probióticos , Biomarcadores , Restrição Calórica , Suplementos Nutricionais , Método Duplo-Cego , Endotoxemia/terapia , Humanos , Inflamação
11.
Front Immunol ; 12: 658404, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163471

RESUMO

Chronic kidney disease induces disruption of the intestinal epithelial barrier, leading to gut bacterial translocation. Here, we appreciated bacterial translocation by analyzing circulating lipopolysaccharides (LPS) using two methods, one measuring only active free LPS, and the other quantifying total LPS as well as LPS lipid A carbon chain length. This was done in end-stage renal disease (ESRD) patients and healthy volunteers (HV). We observed both higher LPS concentration in healthy volunteers and significant differences in composition of translocated LPS based on lipid A carbon chain length. Lower LPS activity to mass ratio and higher concentration of high-density lipoproteins were found in HV, suggesting a better plasma capacity to neutralize LPS activity. Higher serum concentrations of soluble CD14 and pro-inflammatory cytokines in ESRD patients confirmed this hypothesis. To further explore whether chronic inflammation in ESRD patients could be more related to LPS composition rather than its quantity, we tested the effect of HV and patient sera on cytokine secretion in monocyte cultures. Sera with predominance of 14-carbon chain lipid A-LPS induced higher secretion of pro-inflammatory cytokines than those with predominance of 18-carbon chain lipid A-LPS. TLR4 or LPS antagonists decreased LPS-induced cytokine production by monocytes, demonstrating an LPS-specific effect. Thereby, septic inflammation observed in ESRD patients may be not related to higher bacterial translocation, but to reduced LPS neutralization capacity and differences in translocated LPS subtypes.


Assuntos
Translocação Bacteriana , Suscetibilidade a Doenças , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Falência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Adulto , Idoso , Biomarcadores , Estudos de Casos e Controles , Comorbidade , Citocinas/sangue , Gerenciamento Clínico , Suscetibilidade a Doenças/imunologia , Endotoxemia/diagnóstico , Endotoxemia/etiologia , Feminino , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Falência Renal Crônica/complicações , Falência Renal Crônica/diagnóstico , Transplante de Rim , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo
12.
J Food Biochem ; 45(7): e13805, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34096077

RESUMO

High mobility group box 1 (HMGB1) is a well-defined mediator involved in the pathophysiologic response to endotoxemia and sepsis. However, the mechanisms and therapeutic agents that could prevent its release are not fully elucidated. Here, the present study demonstrates that the ginseng leaf extract (GLE) regulates lipopolysaccharide (LPS)-triggered release of HMGB1 in macrophages and endotoxemic animal model. Treatment of RAW264.7 macrophages with GLE significantly inhibited the release of HMGB1 stimulated by LPS. GLE also suppressed the generation of nitric oxide (NO) and expression of inducible NO synthase (iNOS) in a dose-dependent manner. These effects of GLE were accompanied by inhibition of HMGB1 release stimulated by LPS, indicating a potential mechanism by which GLE regulates HMGB1 release through NO signaling. Furthermore, induction of suppressor of cytokine signaling 1 by GLE-mediated GLE-dependent suppression of HMGB1 release and NO/iNOS induction by inhibiting Janus kinase 2/signal transducer and activator of transcription 1 signal in RAW 264.7 cells exposed to LPS. Finally, administration of the GLE ameliorated the survival rate of LPS-injected endotoxemic mice in a NO-dependent manner. Thus, GLE may block the LPS-stimulated release of HMGB1 by regulating cellular signal networks, thereby providing a therapeutic strategy for endotoxemia as a functional food. PRACTICAL APPLICATIONS: High mobility group box 1 (HMGB1) is released into the extracellular milieu when immune cells are exposed to pathogen-related molecules such as lipopolysaccharide (LPS), in which it acts as a critical mediator of lethality in sepsis and endotoxemia. The extract of ginseng leaf, which is a part that can be easily thrown away, ameliorated the survival rate of endotoxemic mice by inhibiting HMGB1 secretion in a NO-dependent manner. Thus, this study suggests that ginseng leaf can be used as a functional food by resolving the immune responses in the pathology of endotoxemia.


Assuntos
Endotoxemia , Proteína HMGB1 , Panax , Animais , Endotoxemia/induzido quimicamente , Endotoxemia/tratamento farmacológico , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Células RAW 264.7
13.
Am J Pathol ; 191(9): 1526-1536, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34116023

RESUMO

Sepsis-induced endothelial acute respiratory distress syndrome is related to microvascular endothelial dysfunction caused by endothelial glycocalyx disruption. Recently, recombinant antithrombin (rAT) was reported to protect the endothelial glycocalyx from septic vasculitis; however, the underlying mechanism remains unknown. Here, we investigated the effect of rAT administration on vascular endothelial injury under endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 10-week-old male C57BL/6 mice, and saline or rAT was administered intraperitoneally at 3 and 24 hours after LPS administration. Subsequently, serum and/or pulmonary tissues were examined for inflammation and cell proliferation and differentiation by histologic, ultrastructural, and microarray analyses. The survival rate was significantly higher in rAT-treated mice than in control mice 48 hours after LPS injection (75% versus 20%; P < 0.05). Serum interleukin-1ß was increased but to a lesser extent in response to LPS injection in rAT-treated mice than in control mice. Lectin staining and ultrastructural studies showed a notable attenuation of injury to the endothelial glycocalyx after rAT treatment. Microarray analysis further showed an up-regulation of gene sets corresponding to DNA repair, such as genes involved in DNA helicase activity, regulation of telomere maintenance, DNA-dependent ATPase activity, and ciliary plasm, after rAT treatment. Thus, rAT treatment may promote DNA repair, attenuate inflammation, and promote ciliogenesis, thereby attenuating the acute respiratory distress syndrome caused by endothelial injury.


Assuntos
Antitrombinas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotoxemia/complicações , Pulmão/efeitos dos fármacos , Síndrome do Desconforto Respiratório , Animais , Modelos Animais de Doenças , Endotélio Vascular/patologia , Glicocálix/efeitos dos fármacos , Glicocálix/patologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/farmacologia , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/fisiopatologia
14.
Clin Transl Gastroenterol ; 12(6): e00348, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34092777

RESUMO

INTRODUCTION: Patients with community-acquired pneumonia display enhanced levels of lipopolysaccharides (LPS) compared with controls, suggesting that low-grade endotoxemia may be implicated in vascular disturbances. It is unknown whether this occurs in patients with coronavirus 2019 (COVID-19) and its impact on thrombotic complications. METHODS: We measured serum levels of zonulin, a marker of gut permeability, LPS, and D-dimer in 81 patients with COVID-19 and 81 healthy subjects; the occurrence of thrombotic events in COVID-19 during the intrahospital stay was registered. RESULTS: Serum LPS and zonulin were higher in patients with COVID-19 than in control subjects and, in COVID-19, significantly correlated (R = 0.513; P < 0.001). Among the 81 patients with COVID-19, 11 (14%) experienced thrombotic events in the arterial (n = 5) and venous circulation (n = 6) during a median follow-up of 18 days (interquartile range 11-27 days). A logistic regression analysis showed that LPS (P = 0.024) and D-dimer (P = 0.041) independently predicted thrombotic events. DISCUSSION: The study reports that low-grade endotoxemia is detectable in patients with COVID-19 and is associated with thrombotic events. The coexistence of low-grade endotoxemia with enhanced levels of zonulin may suggest enhanced gut permeability as an underlying mechanism.


Assuntos
COVID-19 , Endotoxemia , Haptoglobinas/metabolismo , Mucosa Intestinal , Precursores de Proteínas/metabolismo , SARS-CoV-2 , Trombose , Biomarcadores/sangue , COVID-19/sangue , COVID-19/complicações , COVID-19/fisiopatologia , Correlação de Dados , Endotoxemia/diagnóstico , Endotoxemia/metabolismo , Endotoxemia/virologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/virologia , Lipopolissacarídeos/análise , Masculino , Pessoa de Meia-Idade , Permeabilidade , Pneumonia Viral/diagnóstico , Pneumonia Viral/etiologia , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Trombose/sangue , Trombose/diagnóstico , Trombose/etiologia
15.
Clin Transl Gastroenterol ; 12(6): e00367, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34092778

RESUMO

Severe acute respiratory syndrome coronavirus 2 infection has been associated with both endotoxemia and thrombosis of small and large vessels, but the relationship between these 2 phenomena has not been pursued. Oliva et al. in this issue of Clinical and Translational Gastroenterology demonstrate an association between the 2 findings and suggest that increased intestinal permeability is a possible mechanism to explain the endotoxemia. Although the evidence to support this hypothesis is only suggestive, the role of the small intestine in the illness produced by the virus needs to be further explored.


Assuntos
COVID-19 , Endotoxemia , Intestino Delgado , SARS-CoV-2 , Trombose , COVID-19/sangue , COVID-19/complicações , COVID-19/fisiopatologia , Correlação de Dados , Endotoxemia/diagnóstico , Endotoxemia/metabolismo , Endotoxemia/virologia , Humanos , Intestino Delgado/metabolismo , Intestino Delgado/virologia , Permeabilidade , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Trombose/sangue , Trombose/diagnóstico , Trombose/etiologia
16.
J Zoo Wildl Med ; 52(2): 755-762, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34130423

RESUMO

A multiparous pygmy hippopotamus (Choeropsis liberiensis) dam produced three consecutive calves that died acutely at 13-15 wk of age from bacterial sepsis, for which diagnostic and therapeutic intervention was not possible. Streptococcus iniae (Cases 1 and 3), Escherichia coli (Case 2), and an unidentified member of the family Pasteurellaceae (Case 1) were identified in postmortem tissues through bacterial culture followed by standard and molecular identification methods. After the loss of two calves, a series of vaccinations were administered to the dam during the third pregnancy to enhance transplacental and colostral transfer of antibodies to the calf. The third calf did not survive, and the source of the bacterial infection in these three calves was undetermined. Prior to and after the birth of the fourth calf, nutritional and nutraceutical supplements were provided to the dam and calf. Additionally, pest control around the barn was enhanced. The fourth calf survived. Pygmy hippopotamus calves at the age of 13-15 wk may have increased susceptibility to bacterial infection, possibly due to waning maternally derived immunity. The findings in these cases, combined with a previous association of S. iniae in pygmy hippopotamus deaths, suggest that this bacterium is an especially important pathogen of the endangered pygmy hippopotamus.


Assuntos
Artiodáctilos , Infecções Bacterianas/veterinária , Endotoxemia/veterinária , Infecções por Escherichia coli/veterinária , Sepse/veterinária , Infecções Estreptocócicas/veterinária , Criação de Animais Domésticos , Animais , Animais de Zoológico , Infecções Bacterianas/prevenção & controle , Vacinas Bacterianas/imunologia , Endotoxemia/microbiologia , Escherichia coli , Infecções por Escherichia coli/patologia , Feminino , Masculino , Sepse/microbiologia , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/patologia , Streptococcus iniae
17.
Front Immunol ; 12: 637845, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995355

RESUMO

Baroreflex and chemoreflex act through the autonomic nervous system, which is involved with the neural regulation of inflammation. The present study reports the effects of reflex physiological sympathetic activation in endotoxemic rats using bilateral carotid occlusion (BCO), a physiological approach involving the baroreflex and chemoreflex mechanisms and the influence of the baroreceptors and peripheral chemoreceptors in the cardiovascular and systemic inflammatory responses. After lipopolysaccharide (LPS) administration, the arterial pressure was recorded during 360 min in unanesthetized rats, and serial blood samples were collected to analyze the plasma cytokine levels. BCO elicited the reflex activation of the sympathetic nervous system, providing the following outcomes: (I) increased the power of the low-frequency band in the spectrum of the systolic arterial pressure during the BCO period; (II) reduced the levels of pro-inflammatory cytokines in plasma, including the tumor necrosis factor (TNF) and the interleukin (IL)-1ß; (III) increased the plasma levels of anti-inflammatory cytokine IL-10, 90 min after LPS administration. Moreover, selective baroreceptor or chemoreceptor denervation deactivated mechanosensitive and chemical sensors, respectively, and decreased the release of the LPS-induced cytokine but did not alter the BCO modulatory effects. These results show, for the first time, that physiological reflex activation of the sympathetic circuit decreases the inflammatory response in endotoxemic rats and suggest a novel function for the baroreceptors as immunosensors during the systemic inflammation.


Assuntos
Barorreflexo/fisiologia , Endotoxemia/patologia , Inflamação/fisiopatologia , Pressorreceptores/fisiologia , Sistema Nervoso Simpático/fisiologia , Animais , Sistema Nervoso Autônomo/fisiologia , Pressão Sanguínea/fisiologia , Células Quimiorreceptoras/fisiologia , Interleucina-10/sangue , Interleucina-1beta/sangue , Lipopolissacarídeos , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/sangue
18.
Vet Immunol Immunopathol ; 237: 110267, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33993048

RESUMO

In veterinary medicine, inflammation in swine is evaluated principally by clinical signs. This method is often unreliable when assessing large animal populations because of inconsistent interpretations of clinical observations. This study examined whether changes in miRNA expression can predict the severity of the inflammatory response in swine after administration of Escherichia coli lipopolysaccharide (LPS). Whole blood from swine challenged with LPS at 0.125 µg/kg to 2.0 µg/kg body weight was collected at 0, 1, 3, and 8 h post LPS-challenge. Mature miRNAs were extracted from plasma and quantitative real-time-PCR (qRT-PCR) was used to evaluate the 84 most abundant swine miRNAs found in plasma. The miRNA changes in expression were assessed using the comparative CT Method (ΔΔCT method) for normalization with an exogenous control. The results revealed that expression of ssc-let-7e-5p, ssc-mir-22-3p, and ssc-miR-146a-5p were the most significantly changed miRNA over the time course. At 1 h post-LPS, ssc-let-7e-5p decreased as the LPS dosage levels increased from 0.125 to 1.0 µg/kg. Similarly, as the LPS doses increased from 0.125 to 0.5 µg/kg, ssc-miR-22-3p levels significantly decreased at 1 h post-LPS. In the 2.0 µg/kg LPS, ssc-miR-146a-5p levels increased between 0 and 3 h post-LPS; however, expression was downregulated with a 145 % decrease from 3 to 8 h. The three miRNA biomarkers suggest potentially useful surrogate endpoints for the evaluation of inflammatory and endotoxemia responses in swine.


Assuntos
Inflamação/veterinária , Lipopolissacarídeos/farmacologia , MicroRNAs/sangue , Doenças dos Suínos/genética , Transcriptoma/efeitos dos fármacos , Animais , Biomarcadores/sangue , Endotoxemia/sangue , Endotoxemia/diagnóstico , Endotoxemia/veterinária , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/genética , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Suínos , Doenças dos Suínos/sangue
19.
Arch Biochem Biophys ; 705: 108900, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33964247

RESUMO

Mitochondria play an essential role in inflammatory processes such as sepsis or endotoxemia, contributing to organ-cellular redox metabolism, emerging as the energy hub of the cell, and as an important center of action of second messengers. In this work, we aimed to elucidate the energy state, redox balance, and mitochondrial remodeling status in cerebral cortex in an experimental model of endotoxemia. Female Sprague-Dawley rats were subjected to a single dose of LPS (ip 8 mg kg-1 body weight) for 6 h. State 3 O2 consumption was observed increased, ATP production and P/O ratio were observed decreased, probably indicating an inefficient oxidative phosphorylation process. O2- production and both systemic and tissue NO markers were observed increased in treated animals. The existence of nitrated proteins suggests an alteration in the local redox balance and possible harmful effects over energetic processes. Increases in PGC-1α and mtTFA expression, and in OPA-1 expression, suggest an increase in de novo formation of mitochondria and fusion of pre-existing mitochondria. The observed elongation of mitochondria correlates with the occurrence of mild mitochondrial dysfunction and increased levels of systemic NO. Our work presents novel results that contribute to unravel the mechanism by which the triad endotoxemia-redox homeostasis-energy management interact in the cerebral cortex, leading to propose a relevant mechanism for future developing therapeutics with the aim of preserving this organ from inflammatory and oxidative damage.


Assuntos
Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Endotoxemia/metabolismo , Endotoxemia/patologia , Metabolismo Energético , Dinâmica Mitocondrial , Animais , Feminino , Fosforilação Oxidativa , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
20.
Epilepsia ; 62(6): 1472-1481, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33893636

RESUMO

OBJECTIVE: Traumatic brain injury (TBI) may lead to the disruption of the intestinal barrier (IB), and to the escape of products of commensal gut bacteria, including lipopolysaccharide (LPS), into the bloodstream. We examined whether lateral fluid percussion injury (LFPI) and post-traumatic epilepsy (PTE) are associated with the increased intestinal permeability and endotoxemia, and whether these events in turn are associated with PTE. METHODS: LFPI was delivered to adult male Sprague-Dawley rats. Before, 1 week, and 7 months after LFPI, the IB permeability was examined by measuring plasma concentration of fluorescein isothiocyanate-labeled dextran (FD4) upon its enteral administration. Plasma LPS concentration was measured in the same animals, using enzyme-linked immunosorbent assay. PTE was examined 7 months after LFPI, with use of video-EEG (electroencephalography) monitoring. RESULTS: One week after LFPI, the IB disruption was detected in 14 of 17 and endotoxemia - in 10 of 17 rats, with a strong positive correlation between FD4 and LPS levels, and between plasma levels of each of the analytes and the severity of neuromotor deficit. Seven months after LFPI, IB disruption was detected in 13 of 15 and endotoxemia in 8 of 15 rats, with a strong positive correlation between plasma levels of the two analytes. Five of 15 LFPI rats developed PTE. Plasma levels of both FD4 and LPS were significantly higher in animals with PTE than among the animals without PTE. The analysis of seven rats, which were examined repeatedly at 1 week and at 7 months, confirmed that late IB disruption and endotoxemia were not due to lingering of impairments occurring shortly after LFPI. SIGNIFICANCE: LFPI leads to early and remote disruption of IB and a secondary endotoxemia. Early and late perturbations may occur in different subjects. Early changes reflect the severity of acute post-traumatic motor dysfunction, whereas late changes are associated with PTE.


Assuntos
Lesões Encefálicas Traumáticas/fisiopatologia , Endotoxemia/fisiopatologia , Epilepsia Pós-Traumática/fisiopatologia , Intestinos/fisiopatologia , Animais , Lesões Encefálicas Traumáticas/complicações , Dextranos , Eletroencefalografia , Endotoxemia/etiologia , Epilepsia Pós-Traumática/complicações , Fluoresceína-5-Isotiocianato/análogos & derivados , Lipopolissacarídeos/sangue , Masculino , Permeabilidade , Ratos , Ratos Sprague-Dawley
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