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1.
Front Immunol ; 14: 1224335, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37600769

RESUMO

Sepsis is a life-threatening organ dysfunction caused by abnormal host response to infection. Millions of people are affected annually worldwide. Derangement of the inflammatory response is crucial in sepsis pathogenesis. However, metabolic, coagulation, and thermoregulatory alterations also occur in patients with sepsis. Fatty acid mobilization and oxidation changes may assume the role of a protagonist in sepsis pathogenesis. Lipid oxidation and free fatty acids (FFAs) are potentially valuable markers for sepsis diagnosis and prognosis. Herein, we discuss inflammatory and metabolic dysfunction during sepsis, focusing on fatty acid oxidation (FAO) alterations in the liver and muscle (skeletal and cardiac) and their implications in sepsis development.


Assuntos
Ácidos Graxos , Fígado , Músculo Esquelético , Miocárdio , Sepse , Sepse/metabolismo , Oxirredução , Ácidos Graxos/metabolismo , Humanos , Fígado/metabolismo , Músculo Esquelético/metabolismo , Miocárdio/metabolismo
2.
J Endocrinol ; 259(1)2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37552528

RESUMO

Prior research demonstrated that glucagon has protective roles against inflammation, but its effect on the resolution of inflammation remains elusive. Using in vitro and in vivo approaches, this study aimed to investigate the pro-resolving potential of glucagon on pulmonary neutrophilic inflammation caused by lipopolysaccharide. Lipopolysaccharide induced an increase in the proportions of neutrophils positives to glucagon receptor (GcgR) in vitro. In addition, lipopolysaccharide induced an increase in the neutrophil accumulation and expression of GcgR by the inflammatory cells in the lungs, however, without altering glucagon levels. Intranasal treatment with glucagon, at the peak of neutrophilic inflammation, reduced the neutrophil number in the bronchoalveolar lavage (BAL), and lung tissue within 24 h. The reduction of neutrophilic inflammation provoked by glucagon was accompanied by neutrophilia in the blood, an increase in the apoptosis rate of neutrophils in the BAL, enhance in the pro-apoptotic Bax protein expression, and decrease in the anti-apoptotic Bcl-2 protein levels in the lung. Glucagon also induced a rise in the cleavage of caspase-3 in the lungs; however, it was not significant. Glucagon inhibited the levels of IL-1ß and TNF-α while increasing the content of pro-resolving mediators transforming growth factor (TGF-ß1) and PGE2 in the BAL and lung. Finally, glucagon inhibited lipopolysaccharide-induced airway hyper-reactivity, as evidenced by the reduction in lung elastance values in response to methacholine. In conclusion, glucagon-induced resolution of neutrophilic inflammation by promoting cessation of neutrophil migration and a rise of neutrophil apoptosis and the levels of pro-resolving mediators TGF-ß1 and PGE2.


Assuntos
Glucagon , Lipopolissacarídeos , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Glucagon/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Dinoprostona/farmacologia , Pulmão , Inflamação/metabolismo , Neutrófilos/metabolismo
3.
Foods ; 12(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36673347

RESUMO

The present study investigated the effects of murici and tapereba on improving hepatic and inflammatory biomarkers in high-fat-diet rats. Female Wistar rats were divided into five groups (n = 10/group): control (CON), high-fat diet (HF), murici drink + high-fat diet (Mu-HF), tapereba drink + high-fat diet (Tap-HF), and murici and tapereba blend drink + high-fat diet (MT-HF). Drinks were offered daily for 60 days, following which body and liver weights, hepatosomatic indexes, serum parameters, inflammatory profile, and antioxidant activity (DPPH and ORAC) were analyzed. The cell death of hepatic cells was evaluated using flow cytometry. It was observed that weight gain was similar among the groups, while glycemia was lower in the MT-HF group. A high-fat diet increased the concentration of cholesterol total, ALT, IL-1ß (in plasma and liver), and TNF-α (in the liver), and this was reduced by treatment with the fruit-based beverages. The other evaluated parameters showed no statistically significant difference. Compared to the CON and HF groups, the groups that received the drinks had higher cellular antioxidant activity and reduced oxidative stress, lipid oxidation, and development of pro-inflammatory cytokines, such as IL-1ß. A high-fat diet induced higher cell death in hepatic tissue, which was prevented by the murici, tapereba, and the fruit-blend drinks. The consumption of murici, tapereba, and fruit-blend-based beverages showed beneficial effects on liver metabolism; therefore, they may serve as a nutritional approach for preventing and treating non-alcoholic liver disease.

4.
Front Immunol ; 14: 1287512, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38299144

RESUMO

Acute respiratory distress syndrome (ARDS) is marked by damage to the capillary endothelium and alveolar epithelium following edema formation and cell infiltration. Currently, there are no effective treatments for severe ARDS. Pathologies such as sepsis, pneumonia, fat embolism, and severe trauma may cause ARDS with respiratory failure. The primary mechanism of edema clearance is the epithelial cells' Na/K-ATPase (NKA) activity. NKA is an enzyme that maintains the electrochemical gradient and cell homeostasis by transporting Na+ and K+ ions across the cell membrane. Direct injury on alveolar cells or changes in ion transport caused by infections decreases the NKA activity, loosening tight junctions in epithelial cells and causing edema formation. In addition, NKA acts as a receptor triggering signal transduction in response to the binding of cardiac glycosides. The ouabain (a cardiac glycoside) and oleic acid induce lung injury by targeting NKA. Besides enzymatic inhibition, the NKA triggers intracellular signal transduction, fostering proinflammatory cytokines production and contributing to lung injury. Herein, we reviewed and discussed the crucial role of NKA in edema clearance, lung injury, and intracellular signaling pathway activation leading to lung inflammation, thus putting the NKA as a protagonist in lung injury pathology.


Assuntos
Lesão Pulmonar , Pneumonia , Síndrome do Desconforto Respiratório , Humanos , ATPase Trocadora de Sódio-Potássio/metabolismo , Edema
5.
Front Pharmacol ; 13: 999300, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36386185

RESUMO

Malaria is caused by the protozoan Plasmodium sp and affects millions of people worldwide. Its clinical form ranges from asymptomatic to potentially fatal and severe. Current treatments include single drugs such as chloroquine, lumefantrine, primaquine, or in combination with artemisinin or its derivatives. Resistance to antimalarial drugs has increased; therefore, there is an urgent need to diversify therapeutic approaches. The disease cycle is influenced by biological, social, and anthropological factors. This longevity and complexity contributes to the records of drug resistance, where further studies and proposals for new therapeutic formulations are needed for successful treatment of malaria. Nanotechnology is promising for drug development. Preclinical formulations with antimalarial agents have shown positive results, but only a few have progressed to clinical phase. Therefore, studies focusing on the development and evaluation of antimalarial formulations should be encouraged because of their enormous therapeutic potential.

6.
J Vis Exp ; (184)2022 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-35723465

RESUMO

Acute respiratory distress syndrome (ARDS) is a significant threat to critically ill patients with a high fatality rate. Pollutant exposure, cigarette smoke, infectious agents, and fatty acids can induce ARDS. Animal models can mimic the complex pathomechanism of the ARDS. However, each of them has limitations. Notably, oleic acid (OA) is increased in critically ill patients with harmful effects on the lung. OA can induce lung injury by emboli, disrupting tissue, altering pH, and impairing edema clearance. OA-induced lung injury model resembles various features of ARDS with endothelial injury, increased alveolar permeability, inflammation, membrane hyaline formation, and cell death. Herein, induction of lung injury is described by injecting OA (in salt form) directly into the lung and intravenously in a mouse since it is the physiological form of OA at pH 7. Thus, the injection of OA in the salt form is a helpful animal model to study lung injury/ARDS without causing emboli or altering the pH, thereby getting close to what is happening in critically ill patients.


Assuntos
Lesão Pulmonar , Síndrome do Desconforto Respiratório , Animais , Estado Terminal , Modelos Animais de Doenças , Humanos , Camundongos , Ácido Oleico/toxicidade , Síndrome do Desconforto Respiratório/induzido quimicamente
7.
Pharmaceuticals (Basel) ; 14(10)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34681202

RESUMO

Chronic obstructive pulmonary disease (COPD) is one of the leading global causes of morbidity and mortality. A hallmark of COPD is progressive airflow obstruction primarily caused by cigarette smoke (CS). CS exposure causes an imbalance favoring pro- over antioxidants (oxidative stress), leading to transcription factor activation and increased expression of inflammatory mediators and proteases. Different cell types, including macrophages, epithelial cells, neutrophils, and T lymphocytes, contribute to COPD pathophysiology. Alteration in cell functions results in the generation of an oxidative and inflammatory microenvironment, which contributes to disease progression. Current treatments include inhaled corticosteroids and bronchodilator therapy. However, these therapies do not effectively halt disease progression. Due to the complexity of its pathophysiology, and the risk of exacerbating symptoms with existing therapies, other specific and effective treatment options are required. Therapies directly or indirectly targeting the oxidative imbalance may be promising alternatives. This review briefly discusses COPD pathophysiology, and provides an update on the development and clinical testing of novel COPD treatments.

8.
Front Immunol ; 12: 633540, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34295325

RESUMO

Sepsis is one of the most common comorbidities observed in diabetic patients, associated with a deficient innate immune response. Recently, we have shown that glucagon possesses anti-inflammatory properties. In this study, we investigated if hyperglucagonemia triggered by diabetes might reduce the migration of neutrophils, increasing sepsis susceptibility. 21 days after diabetes induction by intravenous injection of alloxan, we induced moderate sepsis in Swiss-Webster mice through cecum ligation and puncture (CLP). The glucagon receptor (GcgR) antagonist des-his1-[Glu9]-glucagon amide was injected intraperitoneally 24h and 1h before CLP. We also tested the effect of glucagon on CXCL1/KC-induced neutrophil migration to the peritoneal cavity in mice. Neutrophil chemotaxis in vitro was tested using transwell plates, and the expression of total PKA and phospho-PKA was evaluated by western blot. GcgR antagonist restored neutrophil migration, reduced CFU numbers in the peritoneal cavity and improved survival rate of diabetic mice after CLP procedure, however, the treatment did no alter hyperglycemia, CXCL1/KC plasma levels and blood neutrophilia. In addition, glucagon inhibited CXCL1/KC-induced neutrophil migration to the peritoneal cavity of non-diabetic mice. Glucagon also decreased the chemotaxis of neutrophils triggered by CXCL1/KC, PAF, or fMLP in vitro. The inhibitory action of glucagon occurred in parallel with the reduction of CXCL1/KC-induced actin polymerization in neutrophils in vitro, but not CD11a and CD11b translocation to cell surface. The suppressor effect of glucagon on CXCL1/KC-induced neutrophil chemotaxis in vitro was reversed by pre-treatment with GcgR antagonist and adenylyl cyclase or PKA inhibitors. Glucagon also increased PKA phosphorylation directly in neutrophils in vitro. Furthermore, glucagon impaired zymosan-A-induced ROS production by neutrophils in vitro. Human neutrophil chemotaxis and adherence to endothelial cells in vitro were inhibited by glucagon treatment. According to our results, this inhibition was independent of CD11a and CD11b translocation to neutrophil surface or neutrophil release of CXCL8/IL-8. Altogether, our results suggest that glucagon may be involved in the reduction of neutrophil migration and increased susceptibility to sepsis in diabetic mice. This work collaborates with better understanding of the increased susceptibility and worsening of sepsis in diabetics, which can contribute to the development of new effective therapeutic strategies for diabetic septic patients.


Assuntos
Movimento Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Suscetibilidade a Doenças/etiologia , Glucagon/administração & dosagem , Neutrófilos/efeitos dos fármacos , Sepse/etiologia , Sepse/imunologia , Adulto , Animais , Movimento Celular/imunologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/microbiologia , Feminino , Glucagon/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Neutrófilos/imunologia
9.
Front Pharmacol ; 12: 624704, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935717

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), identified for the first time in Wuhan, China, causes coronavirus disease 2019 (COVID-19), which moved from epidemic status to becoming a pandemic. Since its discovery in December 2019, there have been countless cases of mortality and morbidity due to this virus. Several compounds such as chloroquine, hydroxychloroquine, lopinavir-ritonavir, and remdesivir have been tested as potential therapies; however, no effective treatment is currently recommended by regulatory agencies. Some studies on respiratory non-enveloped viruses such as adenoviruses and rhinovirus and some respiratory enveloped viruses including human respiratory syncytial viruses, influenza A, parainfluenza, SARS-CoV, and SARS-CoV-2 have shown the antiviral activity of cardiac glycosides, correlating their effect with Na+/K+-ATPase (NKA) modulation. Cardiac glycosides are secondary metabolites used to treat patients with cardiac insufficiency because they are the most potent inotropic agents. The effects of cardiac glycosides on NKA are dependent on cell type, exposure time, and drug concentration. They may also cause blockage of Na+ and K+ ionic transport or trigger signaling pathways. The antiviral activity of cardiac glycosides is related to cell signaling activation through NKA inhibition. Nuclear factor kappa B (NFκB) seems to be an essential transcription factor for SARS-CoV-2 infection. NFκB inhibition by cardiac glycosides interferes directly with SARS-CoV-2 yield and inflammatory cytokine production. Interestingly, the antiviral effect of cardiac glycosides is associated with tyrosine kinase (Src) activation, and NFκB appears to be regulated by Src. Src is one of the main signaling targets of the NKA α-subunit, modulating other signaling factors that may also impair viral infection. These data suggest that Src-NFκB signaling modulated by NKA plays a crucial role in the inhibition of SARS-CoV-2 infection. Herein, we discuss the antiviral effects of cardiac glycosides on different respiratory viruses, SARS-CoV-2 pathology, cell signaling pathways, and NKA as a possible molecular target for the treatment of COVID-19.

10.
J Neuroinflammation ; 18(1): 60, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632243

RESUMO

BACKGROUND: The term sepsis is used to designate a systemic condition of infection and inflammation associated with hemodynamic changes that result in organic dysfunction. Gestational sepsis can impair the development of the central nervous system and may promote permanent behavior alterations in the offspring. The aim of our work was to evaluate the effects of maternal sepsis on inflammatory cytokine levels and synaptic proteins in the hippocampus, neocortex, frontal cortex, and cerebellum of neonatal, young, and adult mice. Additionally, we analyzed the motor development, behavioral features, and cognitive impairments in neonatal, young and adult offspring. METHODS: Pregnant mice at the 14th embryonic day (E14) were intratracheally instilled with saline 0.9% solution (control group) or Klebsiella spp. (3 × 108 CFU) (sepsis group) and started on meropenem after 5 h. The offspring was sacrificed at postnatal day (P) 2, P8, P30, and P60 and samples of liver, lung, and brain were collected for TNF-α, IL-1ß, and IL-6 measurements by ELISA. Synaptophysin, PSD95, and ß-tubulin levels were analyzed by Western blot. Motor tests were performed at all analyzed ages and behavioral assessments were performed in offspring at P30 and P60. RESULTS: Gestational sepsis induces a systemic pro-inflammatory response in neonates at P2 and P8 characterized by an increase in cytokine levels. Maternal sepsis induced systemic downregulation of pro-inflammatory cytokines, while in the hippocampus, neocortex, frontal cortex, and cerebellum an inflammatory response was detected. These changes in the brain immunity were accompanied by a reduction of synaptophysin and PSD95 levels in the hippocampus, neocortex, frontal cortex, and cerebellum, in all ages. Behavioral tests demonstrated motor impairment in neonates, and depressive-like behavior, fear-conditioned memory, and learning impairments in animals at P30 and P60, while spatial memory abilities were affected only at P60, indicating that gestational sepsis not only induces an inflammatory response in neonatal mouse brains, but also affects neurodevelopment, and leads to a plethora of behavioral alterations and cognitive impairments in the offspring. CONCLUSION: These data suggest that maternal sepsis may be causatively related to the development of depression, learning, and memory impairments in the litter.


Assuntos
Encéfalo/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Sepse/imunologia , Animais , Comportamento Animal , Encéfalo/metabolismo , Disfunção Cognitiva/etiologia , Feminino , Inflamação , Camundongos , Atividade Motora/fisiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Sepse/complicações , Sinapses/metabolismo
11.
Mediators Inflamm ; 2020: 1839762, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33110395

RESUMO

Sepsis is characterized by a life-threatening organ dysfunction caused by an unbalanced host response to microbe infection that can lead to death. Besides being currently the leading cause of death in intensive care units worldwide, sepsis can also induce long-term consequences among survivors, such as cognitive impairment. Statins (lipid-lowering drugs widely used to treat dyslipidemia) have been shown to possess pleiotropic anti-inflammatory and antimicrobial effects. These drugs act inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, the limiting step in cholesterol biosynthesis. In this work, we evaluated the therapeutic effects of simvastatin in an animal model of sepsis. In previous study from our group, statin pretreatment avoided cognitive damage and neuroinflammation in sepsis survivors. Herein, we focused on acute inflammation where sepsis was induced by cecal ligation and puncture (CLP), and the animals were treated with simvastatin (2 mg/kg) 6 h after surgery. We measured plasma biochemical markers of organ dysfunction, cell migration, cell activation, bacterial elimination, production of nitric oxide 24 h after CLP, survival rate for 7 days, and cognitive impairment 15 days after CLP. One single administration of simvastatin 6 h after CLP was able to prevent both liver and kidney dysfunction. In addition, this drug decreased cell accumulation in the peritoneum as well as the levels of TNF-α, MIF, IL-6, and IL-1ß. Simvastatin diminished the number of bacterial colony forming units (CFU) and increased the production of nitric oxide production in the peritoneum. Simvastatin treatment increased survival for the first 24 h, but it did not alter survival rate at the end of 7 days. Our results showed that posttreatment with simvastatin hampered organ dysfunction, increased local production of nitric oxide, improved bacterial clearance, and modulated inflammation in a relevant model of sepsis.


Assuntos
Citocinas/metabolismo , Sepse/tratamento farmacológico , Sepse/metabolismo , Sinvastatina/uso terapêutico , Animais , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Óxido Nítrico/metabolismo , Lavagem Peritoneal , Células-Tronco
12.
MethodsX ; 6: 1871-1875, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31508324

RESUMO

Circulating non-esterified fatty acids (NEFA) are toxic to mammalian cells. They increase in diseases such as diabetes and sepsis. Herein we propose a serum albumin-fatty acid saturation test. •We based our test on three methodologies: isoelectric focusing (IF) of human plasma albumin, staining proteins after isoelectric focusing in gels with Coomassie Brilliant Blue, and serum albumin measurement with bromocresol green.•The test consists in the determination of albumin IF and staining with bromocresol green. If albumin is saturated with NEFA, it focuses on lower pH, meaning it is the threshold to bind to them. Excessive NEFA is free and toxic. Many other tests are available for NEFA quantification as NEFA kit assay. All colorimetric assays are used for quantification of NEFA and other tests need expensive equipment to read out the results, and they do not measure albumin levels.•Our method focused on albumin-NEFA saturation instead of just NEFA quantification. Critically ill patients have an alteration in both albumin and NEFA. Therefore, our test undergoes less daytime variation compared to assays that measure absolute NEFA values, allowing a more reliable use as an indicator of albumin-fatty acid saturation and NEFA toxicity.

13.
Biochem Biophys Res Commun ; 519(1): 53-60, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31474338

RESUMO

Trophic factors are involved in different cellular responses. Previously we demonstrated that IL-4 treatment induces an increase in retinal ganglion cell survival (RGCS) and regulates cholinergic differentiation of retinal cells in vitro. Data from literature show that IGF-1 also promotes RGCS, an effect mediated by PI-3K/AKT pathway. The aim of this study was to investigate the role of IGF-1 and IGF-1R on RGCS mediated by IL-4 treatment and the role of M1 acetylcholine receptors in this effect. Here we show that the effect of IL-4 on RGCS depends on IGF-1 and IGF-1R activation, the PI-3K/AKT and NFkB intracellular pathways and depends on M1 mAChRs activation. IGF-1 increases the levels of M1 mAChRs in 15min, 45min, 24 h and 48 h in mixed retinal cells culture, modulates the levels of IL-4, pIGF-1R, IGF-1R. IL-4 modulates IGF-1, pIGF-1R and IGF-1R levels in different time intervals. These results put in evidence a crosstalk between IL-4 and IGF-1 and a role of M1 mAChRs, IGF-1 and IGF-1R in RGCS mediated by IL-4.


Assuntos
Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-4/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptor Muscarínico M1/metabolismo , Células Ganglionares da Retina/metabolismo , Animais , Sobrevivência Celular , Células Cultivadas , Ratos , Células Ganglionares da Retina/citologia
14.
J Med Food ; 22(11): 1175-1182, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31290703

RESUMO

This study evaluated the effects of tomato sauce and lycopene on hepatic and cardiac cell biomarkers in rats fed a high-fat diet. Animals were split into five groups: control group, high-fat group (HG), high-fat tomato sauce group, high-fat lycopene 2 mg, and high-fat lycopene 4 mg. Food and water were offered ad libitum, whereas tomato sauce and lycopene (2 and 4 mg/day) were offered daily for 60 days. Body, heart, and liver weights, cardiosomatic and hepatosomatic indices, and serum parameters were also analyzed in rats. The animals' hearts and liver were processed, and cells were examined by flow cytometry. Results showed that the groups receiving tomato sauce and lycopene had lower glycemia. The serum concentration of high-density lipoprotein cholesterol, hepatic enzymes, and tumor necrosis factor-α did not change upon treatment. Tomato sauce and lycopene supplementation did not increase interleukin-1ß in response to a high-fat diet. Cell cycle analysis of cardiac and liver cells showed a lower percentage of cells in the G0/G1 phase and an increase in the G2/M phase in HG. Both lycopene and tomato sauce reversed this effect. Both lycopene and tomato sauce reversed this effect and prevented high-fat diet-stimulated cardiac and liver cell death. Supplementation of tomato sauce and lycopene showed beneficial effects on cardiac and liver cell metabolism; therefore, it is suggested as a nutritional approach for the prevention and treatment of cardiovascular diseases and nonalcoholic hepatic steatosis.


Assuntos
Fígado/metabolismo , Licopeno/farmacologia , Miocárdio/metabolismo , Solanum lycopersicum/química , Animais , Apoptose , Biomarcadores , Doenças Cardiovasculares , Ciclo Celular , HDL-Colesterol/sangue , Dieta Hiperlipídica , Feminino , Hepatopatia Gordurosa não Alcoólica , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
15.
Clin Chim Acta ; 495: 422-428, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31082361

RESUMO

Fatty acids are fundamental as energy and structural source to the human cells. They are not usually found free in human circulation. Alteration in fatty acids metabolism is linked to diseases such as diabetes, preeclampsia, heart disease, and some infectious diseases. Increased levels of non-esterified fatty acids (NEFA) may cause cell dysfunction and lipotoxicity. Since physiologically fatty acids are transported bound to albumin, we propose here a simple and cheap test that consists of albumin isoelectric focusing determination to measure the potential systemic NEFA cytotoxicity. For validation of this method, albumin isoelectric focusing in 51 serum samples from 40 critically ill patients and 11 controls was compared with NEFA/albumin ratios measured by HPLC. We called this approach an albumin saturation test. This test may indicate to physicians the potential NEFA lipotoxicity guiding them throughout better patient management. The albumin saturation test can point out serum albumin-NEFA saturation through a cheap assay that could be performed by any care facility.


Assuntos
Ácidos Graxos/análise , Focalização Isoelétrica/métodos , Albumina Sérica/análise , Transporte Biológico , Estudos de Casos e Controles , Ácidos Graxos/toxicidade , Humanos , Focalização Isoelétrica/economia , Métodos
16.
Eur J Pharmacol ; 854: 272-281, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30974105

RESUMO

Diverse disturbances in immune-endocrine circuitries are involved in the development and aggravation of several chronic metabolic diseases (CMDs), including obesity, diabetes, and metabolic syndrome. The chronic inflammatory syndrome observed in CMDs culminates in dysregulated immune responses with low microbial killing efficiency, by means low host innate immune response, and loss of ability to eliminate the pathogens, which results in a high prevalence of infectious diseases, including pneumonia, tuberculosis, and sepsis. Herein, we review evidence pointing out PPARγ as a putative player in immune-endocrine disturbances related to increased risk of infections in CMDs. Cumulated evidence indicates that PPARγ activation modulates host cells to control inflammation during CMDs because of PPARγ agonists have anti-inflammatory and pro-resolutive properties, increasing host ability to eliminate pathogen, modulating hormone production, and restoring glucose and lipid homeostasis. As such, we propose PPARγ as a putative therapeutic adjuvant for patients with CMDs to favor a better infection control.


Assuntos
Sistema Endócrino/fisiopatologia , Infecções/complicações , Doenças Metabólicas/imunologia , Doenças Metabólicas/fisiopatologia , PPAR gama/metabolismo , Animais , Doença Crônica , Humanos , Doenças Metabólicas/complicações , Doenças Metabólicas/metabolismo , Risco
17.
Oxid Med Cell Longev ; 2018: 6053492, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30538802

RESUMO

The Mediterranean diet, rich in olive oil, is beneficial, reducing the risk of cardiovascular diseases and cancer. Olive oil is mostly composed of the monounsaturated fatty acid omega-9. We showed omega-9 protects septic mice modulating lipid metabolism. Sepsis is initiated by the host response to infection with organ damage, increased plasma free fatty acids, high levels of cortisol, massive cytokine production, leukocyte activation, and endothelial dysfunction. We aimed to analyze the effect of omega-9 supplementation on corticosteroid unbalance, inflammation, bacterial elimination, and peroxisome proliferator-activated receptor (PPAR) gamma expression, an omega-9 receptor and inflammatory modulator. We treated mice for 14 days with omega-9 and induced sepsis by cecal ligation and puncture (CLP). We measured systemic corticosterone levels, cytokine production, leukocyte and bacterial counts in the peritoneum, and the expression of PPAR gamma in both liver and adipose tissues during experimental sepsis. We further studied omega-9 effects on leukocyte rolling in mouse cremaster muscle-inflamed postcapillary venules and in the cerebral microcirculation of septic mice. Here, we demonstrate that omega-9 treatment is associated with increased levels of the anti-inflammatory cytokine IL-10 and decreased levels of the proinflammatory cytokines TNF-α and IL-1ß in peritoneal lavage fluid of mice with sepsis. Omega-9 treatment also decreased systemic corticosterone levels. Neutrophil migration from circulation to the peritoneal cavity and leukocyte rolling on the endothelium were decreased by omega-9 treatment. Omega-9 also decreased bacterial load in the peritoneal lavage and restored liver and adipose tissue PPAR gamma expression in septic animals. Our data suggest a beneficial anti-inflammatory role of omega-9 in sepsis, mitigating leukocyte rolling and leukocyte influx, balancing cytokine production, and controlling bacterial growth possibly through a PPAR gamma expression-dependent mechanism. The significant reduction of inflammation detected after omega-9 enteral injection can further contribute to the already known beneficial properties facilitated by unsaturated fatty acid-enriched diets.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/fisiopatologia , Ácido Oleico/farmacologia , Sepse/fisiopatologia , Animais , Quimiotaxia de Leucócito/efeitos dos fármacos , Modelos Animais de Doenças , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Camundongos , Azeite de Oliva/química
18.
Front Immunol ; 9: 901, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29760707

RESUMO

Neutrophils are the first cells of our immune system to arrive at the site of inflammation. They release cytokines, e.g., chemokines, to attract further immune cells, but also actively start to phagocytose and kill pathogens. In the case of sepsis, this tightly regulated host defense mechanism can become uncontrolled and hyperactive resulting in severe organ damage. Currently, no effective therapy is available to fight sepsis; therefore, novel treatment targets that could prevent excessive inflammatory responses are warranted. Src Family tyrosine Kinases (SFK), a group of tyrosine kinases, have been shown to play a major role in regulating immune cell recruitment and host defense. Leukocytes with SFK depletion display severe spreading and migration defects along with reduced cytokine production. Thus, we investigated the effects of dasatinib, a tyrosine kinase inhibitor, with a strong inhibitory capacity on SFKs during sterile inflammation and polymicrobial sepsis in mice. We found that dasatinib-treated mice displayed diminished leukocyte adhesion and extravasation in tumor necrosis factor-α-stimulated cremaster muscle venules in vivo. In polymicrobial sepsis, sepsis severity, organ damage, and clinical outcome improved in a dose-dependent fashion pointing toward an optimal therapeutic window for dasatinib dosage during polymicrobial sepsis. Dasatinib treatment may, therefore, provide a balanced immune response by preventing an overshooting inflammatory reaction on the one side and bacterial overgrowth on the other side.


Assuntos
Dasatinibe/farmacologia , Infiltração de Neutrófilos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Sepse/imunologia , Animais , Adesão Celular/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos , Quinases da Família src/antagonistas & inibidores
19.
PLoS One ; 11(4): e0153607, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27078880

RESUMO

Sepsis is characterized by inflammatory and metabolic alterations, which lead to massive cytokine production, oxidative stress and organ dysfunction. In severe systemic inflammatory response syndrome, plasma non-esterified fatty acids (NEFA) are increased. Several NEFA are deleterious to cells, activate Toll-like receptors and inhibit Na+/K+-ATPase, causing lung injury. A Mediterranean diet rich in olive oil is beneficial. The main component of olive oil is omega-9 oleic acid (OA), a monounsaturated fatty acid (MUFA). We analyzed the effect of OA supplementation on sepsis. OA ameliorated clinical symptoms, increased the survival rate, prevented liver and kidney injury and decreased NEFA plasma levels in mice subjected to cecal ligation and puncture (CLP). OA did not alter food intake and weight gain but diminished reactive oxygen species (ROS) production and NEFA plasma levels. Carnitine palmitoyltransferase IA (CPT1A) mRNA levels were increased, while uncoupling protein 2 (UCP2) liver expression was enhanced in mice treated with OA. OA also inhibited the decrease in 5' AMP-activated protein kinase (AMPK) expression and increased the enzyme expression in the liver of OA-treated mice compared to septic animals. We showed that OA pretreatment decreased NEFA concentration and increased CPT1A and UCP2 and AMPK levels, decreasing ROS production. We suggest that OA has a beneficial role in sepsis by decreasing metabolic dysfunction, supporting the benefits of diets high in monounsaturated fatty acids (MUFA).


Assuntos
Ácidos Graxos/metabolismo , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Ácido Oleico/farmacologia , Sepse/fisiopatologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Western Blotting , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Ácidos Graxos Monoinsaturados/farmacologia , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Expressão Gênica/efeitos dos fármacos , Canais Iônicos/genética , Canais Iônicos/metabolismo , Rim/metabolismo , Rim/fisiopatologia , Fígado/metabolismo , Fígado/fisiopatologia , Masculino , Malondialdeído/metabolismo , Camundongos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sepse/metabolismo , Sepse/mortalidade , Análise de Sobrevida , Taxa de Sobrevida , Proteína Desacopladora 2
20.
Int J Med Microbiol ; 306(1): 20-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26652129

RESUMO

Pseudomonas aeruginosa is an opportunistic bacterium causing lung injury in immunocompromised patients correlated with high morbidity and mortality. Many bacteria, including P. aeruginosa, use extracellular signals to synchronize group behaviors, a process known as quorum sensing (QS). In the P. aeruginosa complex QS system controls expression of over 300 genes, including many involved in host colonization and disease. P. aeruginosa infection elicits a complex immune response due to a large number of immunogenic factors present in the bacteria or released during infection. Here, we focused on the mechanisms by which P. aeruginosa triggers lung injury and inflammation, debating the possible ways that P. aeruginosa evades the host immune system, which leads to immune suppression and resistance.


Assuntos
Interações Hospedeiro-Patógeno , Lesão Pulmonar/patologia , Pneumonia Bacteriana/patologia , Pseudomonas aeruginosa/patogenicidade , Regulação Bacteriana da Expressão Gênica , Humanos , Evasão da Resposta Imune , Inflamação/patologia , Pseudomonas aeruginosa/imunologia , Pseudomonas aeruginosa/fisiologia , Percepção de Quorum
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