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1.
Int J Mol Sci ; 22(21)2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34768787

RESUMO

The intestinal barrier plays an extremely important role in maintaining the immune homeostasis of the gut and the entire body. It is made up of an intricate system of cells, mucus and intestinal microbiota. A complex system of proteins allows the selective permeability of elements that are safe and necessary for the proper nutrition of the body. Disturbances in the tightness of this barrier result in the penetration of toxins and other harmful antigens into the system. Such events lead to various digestive tract dysfunctions, systemic infections, food intolerances and autoimmune diseases. Pathogenic and probiotic bacteria, and the compounds they secrete, undoubtedly affect the properties of the intestinal barrier. The discovery of zonulin, a protein with tight junction regulatory activity in the epithelia, sheds new light on the understanding of the role of the gut barrier in promoting health, as well as the formation of diseases. Coincidentally, there is an increasing number of reports on treatment methods that target gut microbiota, which suggests that the prevention of gut-barrier defects may be a viable approach for improving the condition of COVID-19 patients. Various bacteria-intestinal barrier interactions are the subject of this review, aiming to show the current state of knowledge on this topic and its potential therapeutic applications.


Assuntos
Infecções Bacterianas/terapia , Haptoglobinas/metabolismo , Mucosa Intestinal/metabolismo , Probióticos/uso terapêutico , Precursores de Proteínas/metabolismo , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/patologia , Fenômenos Fisiológicos Bacterianos , Microbioma Gastrointestinal , Humanos , Mucosa Intestinal/microbiologia , Muco/metabolismo , Junções Íntimas/metabolismo
2.
Nutrients ; 13(10)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34684316

RESUMO

(1) Background: The use of antibiotics affects the composition of gut microbiota. Studies have suggested that the colonization of gut microbiota in early life is related to later food allergies. Still, the relationship between altered intestinal microbiota in adulthood and food allergies is unclear. (2) Methods: We established three mouse models to analyze gut microbiota dysbiosis' impact on the intestinal barrier and determine whether this effect can increase the susceptibility to and severity of food allergy in later life. (3) Results: The antibiotic-induced gut microbiota dysbiosis significantly reduced Lachnospiraceae, Muribaculaceae, and Ruminococcaceae, and increased Enterococcaceae and Clostridiales. At the same time, the metabolic abundance was changed, including decreased short-chain fatty acids and tryptophan, as well as enhanced purine. This change is related to food allergies. After gut microbiota dysbiosis, we sensitized the mice. The content of specific IgE and IgG1 in mice serum was significantly increased, and the inflammatory response was enhanced. The dysbiosis of gut microbiota caused the sensitized mice to have more severe allergic symptoms, ruptured intestinal villi, and a decrease in tight junction proteins (TJs) when re-exposed to the allergen. (4) Conclusions: Antibiotic-induced gut microbiota dysbiosis increases the susceptibility and severity of food allergies. This event may be due to the increased intestinal permeability caused by decreased intestinal tight junction proteins and the increased inflammatory response.


Assuntos
Antibacterianos/efeitos adversos , Disbiose/induzido quimicamente , Disbiose/microbiologia , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/microbiologia , Microbioma Gastrointestinal , Intestinos/microbiologia , Intestinos/patologia , Animais , Biodiversidade , Modelos Animais de Doenças , Suscetibilidade a Doenças , Disbiose/complicações , Feminino , Haptoglobinas/metabolismo , Inflamação/patologia , Injeções Intraperitoneais , Metaboloma , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Ovalbumina/administração & dosagem , Filogenia , Precursores de Proteínas/metabolismo , Receptor PAR-2/metabolismo , Índice de Gravidade de Doença , Proteínas de Junções Íntimas/metabolismo
3.
Sci Rep ; 11(1): 17815, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497333

RESUMO

Toll-like receptors (TLRs) in the liver compartment have repeatedly been attributed to the development of non-alcoholic fatty liver disease (NAFLD). Knowledge on TLR expression in blood cells and their relation to intestinal microbiota and NAFLD development is limited. Here, we determined TLR expression patterns in peripheral blood mononuclear cells (PBMCs) of NAFLD patients and controls, their relation to intestinal microbiota and the impact of TLRs found altered in NAFLD development. Markers of intestinal permeability in blood and TLR mRNA expression in PBMCs were determined in 37 NAFLD patients and 15 age-matched healthy controls. Fecal microbiota composition was evaluated in 21 NAFLD patients and 9 controls using 16S rRNA gene amplicon sequencing. Furthermore, TLR1-/- and C57BL/6 mice (n = 5-6/group) were pair-fed a liquid control or a fat-, fructose- and cholesterol-rich diet. Intestinal microbiota composition and markers of intestinal permeability like zonulin and bacterial endotoxin differed significantly between groups with the latter markers being significantly higher in NAFLD patients. Expression of TLR1-8 and 10 mRNA was detectable in PBMCs; however, only TLR1 expression, being higher in NAFLD patients, were significantly positively correlated with the prevalence of Holdemanella genus while negative correlations were found with Gemmiger and Ruminococcus genera. TLR1-/- mice were significantly protected from the development of diet-induced NAFLD when compared to wild-type mice. While intestinal microbiota composition and permeability differed significantly between NAFLD patients and healthy subjects, in PBMCs, only TLR1 expression differed between groups. Still, targeting these alterations might be a beneficial approach in the treatment of NAFLD in some patients.


Assuntos
Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptor 1 Toll-Like/metabolismo , Adiponectina/sangue , Adulto , Animais , Biomarcadores/metabolismo , Glicemia/metabolismo , Modelos Animais de Doenças , Feminino , Microbioma Gastrointestinal/fisiologia , Haptoglobinas/metabolismo , Humanos , Resistência à Insulina/fisiologia , Mucosa Intestinal/metabolismo , Leptina/sangue , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Permeabilidade , Precursores de Proteínas/metabolismo
4.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207114

RESUMO

Haptoglobin (Hp) is a blood plasma glycoprotein that plays a critical role in tissue protection and the prevention of oxidative damage. Haptoglobin is an acute-phase protein, its concentration in plasma changes in pathology, and the test for its concentration is part of normal clinical practice. Haptoglobin is a conservative protein and is the subject of research as a potential biomarker of many diseases, including malignant neoplasms. The Human Hp gene is polymorphic and controls the synthesis of three major phenotypes-homozygous Hp1-1 and Hp2-2, and heterozygous Hp2-1, determined by a combination of allelic variants that are inherited. Numerous studies indicate that the phenotype of haptoglobin can be used to judge the individual's predisposition to various diseases. In addition, Hp undergoes various post-translational modifications (PTMs). Glioblastoma multiform (GBM) is the most malignant primary brain tumor. In our study, we have analyzed the state of Hp proteoforms in plasma and cells using 1D (SDS-PAGE) and 2D electrophoresis (2DE) with the following mass spectrometry (LC ES-MS/MS) or Western blotting. We found that the levels of α2- and ß-chain proteoforms are up-regulated in the plasma of GBM patients. An unprocessed form of Hp2-2 (PreHp2-2, zonulin) with unusual biophysical parameters (pI/Mw) was also detected in the plasma of GBM patients and glioblastoma cells. Altogether, this data shows the possibility to use proteoforms of haptoglobin as a potential GBM-specific plasma biomarker.


Assuntos
Biomarcadores Tumorais , Glioblastoma/etiologia , Glioblastoma/metabolismo , Haptoglobinas/metabolismo , Linhagem Celular Tumoral , Cromatografia Líquida , Biologia Computacional/métodos , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica , Glioblastoma/diagnóstico , Humanos , Prognóstico , Proteólise , Proteômica/métodos , Espectrometria de Massas em Tandem
5.
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
6.
Sci Rep ; 11(1): 12041, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103548

RESUMO

Recent evidence supports involvement of the acute phase protein haptoglobin in numerous events during mammalian reproduction. The present study represents an in-depth investigation of haptoglobin expression and secretion in the porcine oviduct and uterus, and assesses its effect on porcine in vitro embryo production. A systematic study was made of sows in different oestrous stages: late follicular, early luteal and late luteal stages. Relative haptoglobin mRNA abundance was quantified by RT-qPCR. In addition, expression of the protein was analysed by immunohistochemistry and the results were complemented by Western-blot and proteomic analyses of the oviductal and uterine fluids. In vitro porcine fertilization and embryo culture were carried out in the presence of haptoglobin. The results indicate that haptoglobin mRNA expression in the porcine oviduct and uterus is most abundant during the late luteal stage of the oestrous cycle. By means of Western blot and proteomic analyses haptoglobin presence was demonstrated in the oviduct epithelium and in the oviductal and uterine fluids in different stages of the oestrous cycle. The addition of haptoglobin during gamete co-incubation had no effect on sperm penetration, monospermy or efficiency rates; however, compared with the control group, blastocyst development was significantly improved when haptoglobin was present (haptoglobin: 64.50% vs. control: 37.83%; p < 0.05). In conclusion, the presence of haptoglobin in the oviduct and uterus of sows at different stages of the oestrous cycle suggests that it plays an important role in the reproduction process. The addition of haptoglobin during in vitro embryo production improved the blastocyst rates.


Assuntos
Estro , Haptoglobinas/química , Suínos/fisiologia , Animais , Blastocisto/química , Desenvolvimento Embrionário , Endométrio/metabolismo , Ciclo Estral/genética , Tubas Uterinas/metabolismo , Feminino , Fertilização In Vitro , Haptoglobinas/metabolismo , Técnicas In Vitro , Fase Luteal , Oviductos/metabolismo , Proteômica/métodos , RNA Mensageiro/metabolismo , Útero/metabolismo
7.
Front Immunol ; 12: 686240, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177935

RESUMO

A disruption of the crosstalk between the gut and the lung has been implicated as a driver of severity during respiratory-related diseases. Lung injury causes systemic inflammation, which disrupts gut barrier integrity, increasing the permeability to gut microbes and their products. This exacerbates inflammation, resulting in positive feedback. We aimed to test whether severe Coronavirus disease 2019 (COVID-19) is associated with markers of disrupted gut permeability. We applied a multi-omic systems biology approach to analyze plasma samples from COVID-19 patients with varying disease severity and SARS-CoV-2 negative controls. We investigated the potential links between plasma markers of gut barrier integrity, microbial translocation, systemic inflammation, metabolome, lipidome, and glycome, and COVID-19 severity. We found that severe COVID-19 is associated with high levels of markers of tight junction permeability and translocation of bacterial and fungal products into the blood. These markers of disrupted intestinal barrier integrity and microbial translocation correlate strongly with higher levels of markers of systemic inflammation and immune activation, lower levels of markers of intestinal function, disrupted plasma metabolome and glycome, and higher mortality rate. Our study highlights an underappreciated factor with significant clinical implications, disruption in gut functions, as a potential force that may contribute to COVID-19 severity.


Assuntos
COVID-19/imunologia , Microbioma Gastrointestinal/imunologia , Inflamação/imunologia , Intestinos/fisiologia , SARS-CoV-2/fisiologia , Feminino , Glicômica , Haptoglobinas/metabolismo , Humanos , Lipidômica , Masculino , Metabolômica , Pessoa de Meia-Idade , Permeabilidade , Precursores de Proteínas/metabolismo , Junções Íntimas/metabolismo
8.
Am J Physiol Gastrointest Liver Physiol ; 321(1): G11-G17, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34009040

RESUMO

Intestinal permeability is an important diagnostic marker, yet its determination by established tests, which measure the urinary excretion of orally administered tracer molecules, is time consuming and can only be performed prospectively. Here, we aim to validate proposed surrogate biomarkers, which allow measuring intestinal permeability more easily. In this cross-sectional study, we included two independent cohorts comprising nonobese (Healthy cohort, n = 51) and individuals with obesity (Obesity cohort, n = 27). The lactulose/mannitol (lac/man) ratio was determined in all individuals as an established marker of intestinal permeability. Furthermore, we measured six potential surrogate biomarkers, being albumin, calprotectin, and zonulin, measured in feces, as well as intestinal fatty acid binding protein (I-FABP), lipopolysaccharide binding protein (LBP) and zonulin, measured in plasma. Correlation analyses and multiple linear regression models were conducted to assess possible associations between the established lac/man ratio and the proposed biomarkers by also evaluating a potential effect of age, body mass index (BMI), and sex. The lac/man ratio correlated with plasma LBP levels in all cohorts consistently and with the amount of fecal zonulin in overweight and obese individuals. Multiple linear regression models showed that the association between the lac/man ratio and plasma LBP was independent of age, BMI, and sex. Fecal zonulin levels were associated with the lac/man ratio as well as BMI, but not age and sex. Our data suggest plasma LBP as a promising biomarker for intestinal permeability in adults and fecal zonulin as a potential biomarker in overweight and obese individuals.NEW & NOTEWORTHY This study shows that biomarkers from blood and fecal samples are associated with the cumbersome established tests of intestinal permeability throughout different cohorts. Therefore, such biomarkers could be used to assess gut barrier function in prospective cohort studies and large-scale clinical trials for which tracer-based tests may not be feasible.


Assuntos
Biomarcadores/análise , Haptoglobinas/metabolismo , Mucosa Intestinal/metabolismo , Permeabilidade , Precursores de Proteínas/metabolismo , Adulto , Biomarcadores/metabolismo , Estudos Transversais , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Microbioma Gastrointestinal/fisiologia , Humanos , Masculino , Obesidade/metabolismo , Estudos Prospectivos
9.
Front Immunol ; 12: 665300, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981312

RESUMO

The irruption of SARS-CoV-2 during 2020 has been of pandemic proportions due to its rapid spread and virulence. COVID-19 patients experience respiratory, digestive and neurological symptoms. Distinctive symptom as anosmia, suggests a potential neurotropism of this virus. Amongst the several pathways of entry to the nervous system, we propose an alternative pathway from the infection of the gut, involving Toll-like receptor 4 (TLR4), zonulin, protease-activated receptor 2 (PAR2) and zonulin brain receptor. Possible use of zonulin antagonists could be investigated to attenuate neurological manifestations caused by SARS-CoV-19 infection.


Assuntos
COVID-19/complicações , Haptoglobinas/metabolismo , Doenças do Sistema Nervoso/complicações , Precursores de Proteínas/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/virologia , Encéfalo/metabolismo , Encéfalo/virologia , COVID-19/metabolismo , COVID-19/virologia , Proteínas do Sistema Complemento/metabolismo , Gastroenteropatias/complicações , Gastroenteropatias/metabolismo , Gastroenteropatias/virologia , Humanos , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/virologia , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Receptor 4 Toll-Like/metabolismo
10.
Anim Reprod Sci ; 229: 106766, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34015726

RESUMO

Serum amyloid A (SAA) and Haptoglobin (Hp) are acute phase proteins, produced during inflammation, such as placentitis. In horses, SAA and SAA1 are protein coding genes. Objectives were to analyze SAA and Hp concentrations and relative abundance of SAA, SAA1 and Hp mRNA transcript in maternal and fetal tissues after experimental induction of placentitis or mares of a control group. Serum Amyloid A family proteins were in marked abundance in the stroma of the endometrium and chorioallantois associated with inflammatory cells. Maternal plasma SAA concentrations were greater (P = 0.01) in mares with experimentally induced placentitis compared to those of the control group. Maternal Hp from the groups were not different, but fetal Hp concentrations of mares with experimentally induced placentitis were greater (P = 0.02). Maternal plasma SAA and Hp concentrations were greater than fetal plasma concentrations in mares with experimentally induced placentitis (P < 0.05). Relative abundance of SAA mRNA transcript was greater in the maternal, fetal liver and chorioallantois of mares with experimentally induced placentitis (P < 0.05) compared to those in the control group. Interestingly, relative abundance of SAA1 mRNA transcript was greater in the chorioallantois of mares with experimentally induced placentitis (P < 0.05). The SAA and Hp concentrations, therefore, were greater in mares with induced placentitis. Furthermore, relative abundance of SAA1 mRNA transcript is specifically greater in the chorioallantois of mares with placentitis, which warrants further studies to elucidate the immunological response of SAA1 in the chorioallantois of mares with placentitis.


Assuntos
Haptoglobinas/metabolismo , Doenças dos Cavalos/sangue , Doenças Placentárias/veterinária , Proteína Amiloide A Sérica/metabolismo , Infecções Estreptocócicas/veterinária , Animais , Feminino , Feto , Doenças dos Cavalos/induzido quimicamente , Doenças dos Cavalos/microbiologia , Cavalos , Doenças Placentárias/sangue , Doenças Placentárias/microbiologia , Gravidez , Infecções Estreptocócicas/sangue , Infecções Estreptocócicas/metabolismo , Streptococcus equi
11.
J Neuroimmunol ; 357: 577607, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34044209

RESUMO

Systemic inflammation is known to alter behaviour, and since it has been reported that individuals with autism spectrum disorder (ASD) have higher levels of circulating cytokines, it has been hypothesized that systemic inflammation may exacerbate behaviours characteristic of ASD. The acute phase proteins α-2-macroglobulin, C-reactive protein, haptoglobin, serum amyloid P, serum amyloid A, ferritin and tissue plasminogen activator, as well as markers of intestinal permeability (intestinal fatty acid binding protein and lipopolysaccharide) were quantitated in the plasma of very young children with ASD. Behaviour severity was measured using the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observation Schedule (ADOS) and the Vineland Adaptive Behaviour Scale (VABS). An increase in circulating I-FABP correlated with more severe deficits in communication, communication + social interaction as well as maladaptive behaviour. The acute phase protein haptoglobin was associated with more severe social interaction and communication + social interaction. In summary, I-FABP, a marker of intestinal epithelial damage, was associated with more severe behavioural phenotypes in very young children with ASD. In addition, the acute phase protein, haptoglobin, was associated with behaviour.


Assuntos
Transtorno do Espectro Autista/imunologia , Proteínas de Ligação a Ácido Graxo/sangue , Haptoglobinas/metabolismo , Intestinos/patologia , Transtorno do Espectro Autista/sangue , Pré-Escolar , Proteínas de Ligação a Ácido Graxo/imunologia , Feminino , Haptoglobinas/imunologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Permeabilidade
12.
Nutrients ; 13(4)2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921866

RESUMO

Persistence of damage induced by unhealthy diets during youth has been little addressed. Therefore, we investigated the impact of a short-term fructose-rich diet on liver metabolic activity in adolescent rats and the putative persistence of alterations after removing fructose from the diet. Adolescent rats were fed a fructose-rich diet for three weeks and then switched to a control diet for further three weeks. Body composition and energy balance were not affected by fructose-rich diet, while increased body lipids and lipid gain were found after the rescue period. Switching to a control diet reversed the upregulation of plasma fructose, uric acid, lipocalin, and haptoglobin, while plasma triglycerides, alanine aminotransferase, lipopolysaccharide, and tumor necrosis factor alpha remained higher. Hepatic steatosis and ceramide were increased by fructose-rich diet, but reversed by returning to a control diet, while altered hepatic response to insulin persisted. Liver fatty acid synthase and stearoyl-CoA desaturase (SCD) activities were upregulated by fructose-rich diet, and SCD activity remained higher after returning to the control diet. Fructose-induced upregulation of complex II-driven mitochondrial respiration, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, and peroxisome proliferator activated receptor α also persisted after switching to control diet. In conclusion, our results show prolonged fructose-induced dysregulation of liver metabolic activity.


Assuntos
Dieta da Carga de Carboidratos/efeitos adversos , Ingestão de Alimentos/fisiologia , Frutose/administração & dosagem , Resistência à Insulina/fisiologia , Mitocôndrias/metabolismo , Alanina Transaminase/sangue , Animais , Composição Corporal , Ceramidas/metabolismo , Modelos Animais de Doenças , Metabolismo Energético , Fígado Gorduroso/etiologia , Frutose/sangue , Haptoglobinas/metabolismo , Lipídeos/sangue , Lipocalinas/sangue , Lipopolissacarídeos/sangue , Fígado/metabolismo , Ratos , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/sangue , Regulação para Cima/fisiologia , Ácido Úrico/sangue
13.
Biomolecules ; 11(5)2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919169

RESUMO

Here, we report on the role of haptoglobin (Hp), whose expression depends on the synthesis of interleukin 6 (IL-6), related to the pathogenesis of multiple sclerosis (MS), as a possible marker of muscle improvement achieved after treatment with the polyphenol epigallocatechin gallate (EGCG) and an increase in the ketone body beta-hydroxybutyrate (BHB) in the blood. After 4 months of intervention with 27 MS patients, we observed that Hp does not significantly increase, alongside a significant decrease in IL-6 and a significant increase in muscle percentage. At the same time, Hp synthesis is considerably and positively correlated with IL-6 both before and after treatment; while this correlation occurs significantly reversed with muscle percentage before treatment, no correlation is evident after the intervention. These results seem to indicate that Hp could be a marker of muscle status and could be a diagnosis tool after therapeutic intervention in MS patients.


Assuntos
Haptoglobinas/análise , Esclerose Múltipla/metabolismo , Músculo Esquelético/metabolismo , Ácido 3-Hidroxibutírico/análise , Ácido 3-Hidroxibutírico/sangue , Adulto , Biomarcadores/sangue , Catequina/análogos & derivados , Catequina/farmacologia , Feminino , Haptoglobinas/metabolismo , Humanos , Interleucina-6/análise , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiologia , Projetos Piloto
14.
Biochem Biophys Res Commun ; 556: 199-206, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33848934

RESUMO

Circulating cell-free hemoglobin (CFH) contributes to endothelial injury in several inflammatory and hemolytic conditions. We and others have shown that CFH causes increased endothelial permeability, but the precise mechanisms of CFH-mediated endothelial barrier dysfunction are not fully understood. Based on our previous study in a mouse model of sepsis demonstrating that CFH increased apoptosis in the lung, we hypothesized that CFH causes endothelial barrier dysfunction through this cell death mechanism. We first confirmed that CFH causes human lung microvascular barrier dysfunction in vitro that can be prevented by the hemoglobin scavenger, haptoglobin. While CFH caused a small but significant decrease in cell viability measured by the membrane impermeable DNA dye Draq7 in human lung microvascular endothelial cells, CFH did not increase apoptosis as measured by TUNEL staining or Western blot for cleaved caspase-3. Moreover, inhibitors of apoptosis (Z-VAD-FMK), necrosis (IM-54), necroptosis (necrostatin-1), ferroptosis (ferrostatin-1), or autophagy (3-methyladenine) did not prevent CFH-mediated endothelial barrier dysfunction. We conclude that although CFH may cause a modest decrease in cell viability over time, cell death does not contribute to CFH-mediated lung microvascular endothelial barrier dysfunction.


Assuntos
Apoptose , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Hemoglobinas/metabolismo , Pulmão/irrigação sanguínea , Microcirculação , Células Cultivadas , Haptoglobinas/metabolismo , Humanos , Fatores de Tempo
15.
Front Immunol ; 12: 579140, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746942

RESUMO

Hashimoto thyroiditis (HT) is the most common autoimmune disease worldwide, characterized by chronic inflammation and circulating autoantibodies against thyroid peroxidase and thyroglobulin. Patients require hormone replacement with oral levothyroxine, and if untreated, they can develop serious adverse health effects and ultimately death. There is a lot of evidence that the intestinal dysbiosis, bacterial overgrowth, and increased intestinal permeability favor the HT development, and a thyroid-gut axis has been proposed, which seems to impact our entire metabolism. Here, we evaluated alterations in the gut microbiota in Brazilian patients with HT and correlated this data with dietary habits, clinical data, and systemic cytokines and zonulin concentrations. Stool samples from 40 patients with HT and 53 controls were analyzed using real-time PCR, the serum cytokine levels were evaluated by flow cytometry, zonulin concentrations by ELISA, and the dietary habits were recorded by a food frequency questionnaire. We observed a significant increase (p < 0.05) in the Bacteroides species and a decrease in Bifidobacterium in samples of patients with HT. In addition, Lactobacillus species were higher in patients without thyroid hormone replacement, compared with those who use oral levothyroxine. Regarding dietary habits, we demonstrated that there are significant differences in the consumption of vegetables, fruits, animal-derived proteins, dairy products, saturated fats, and carbohydrates between patients and control group, and an inverse correlation between animal-derived protein and Bacteroides genus was detected. The microbiota modulation by diet directly influences the inflammatory profile due to the generated microbiota metabolites and their direct or indirect action on immune cells in the gut mucosa. Although there are no differences in systemic cytokines in our patients with HT, we detected increased zonulin concentrations, suggesting a leaky gut in patients with HT. These findings could help understand the development and progression of HT, while further investigations to clarify the underlying mechanisms of the diet-microbiota-immune system axis are still needed.


Assuntos
Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Doença de Hashimoto/imunologia , Intestinos/imunologia , Adulto , Bactérias/classificação , Bactérias/genética , Citocinas/sangue , Citocinas/imunologia , Citocinas/metabolismo , Disbiose/microbiologia , Fezes/microbiologia , Comportamento Alimentar , Feminino , Haptoglobinas/imunologia , Haptoglobinas/metabolismo , Doença de Hashimoto/sangue , Doença de Hashimoto/microbiologia , Humanos , Intestinos/microbiologia , Intestinos/fisiologia , Masculino , Pessoa de Meia-Idade , Permeabilidade , Precursores de Proteínas/sangue , Precursores de Proteínas/imunologia , Precursores de Proteínas/metabolismo , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
16.
J Ethnopharmacol ; 272: 113949, 2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-33610707

RESUMO

ETHNO-PHARMACOLOGICAL RELEVANCE: The genus Aloe has a long history of usage in medicine. Aloe barbadensis Miller, commonly known as Aloe vera, is said to possess anti-diabetic, anti-inflammatory, anti-cancer, anti-microbial, immunomodulation, wound healing properties. AIM OF THE STUDY: In diabetes mellitus, loss in intestinal permeability is observed with high levels of zonulin and low levels of glucagon-like peptide-1 (GLP-1) leading to hyperglycemia. The aim of the study was to understand the role of peptide/polypeptide fraction (PPF) of Aloe vera in the alleviation of diabetes through maintaining the intestinal permeability by regulating the zonulin and GLP-1 levels. MATERIALS AND METHODS: The PPF of Aloe vera was obtained through trichloroacetic acid precipitation. The anti-diabetic potential of the PPF was tested through DPP-IV inhibition, glucose diffusion assay, and by using Rin-m5F cells. The anti-diabetic potential of the PPF was tested at a dose of 0.450 mg/kg bw in vivo using streptozotocin-induced diabetic Wistar rats. The effect of PPF on fasting plasma glucose, insulin, glucagon, Zonulin, GLP-1, DPP-IV, levels were studied in diabetic rats. The histopathological studies of the pancreas, small intestine, and liver were carried out for organ-specific effects. RESULTS: PPF has the ability to reduce fasting plasma glucose levels with concomitant increase in insulin levels in streptozotocin-induced diabetic rats. It was also observed that increase in GLP-1 levels with a decrease in DPP-IV and zonulin levels thereby mitigating the loss of intestinal permeability. These findings correlate with the small intestine's histopathological observation where the excessive proliferation of epithelium in the small intestine of diabetic rats was reduced after PPF treatment. CONCLUSION: These results suggest that the PPF of Aloe vera alleviates diabetes through islet cell rejuvenation via GLP-1/DPP-IV pathway and thereby suggesting the usage of PPF as an alternate medicine for diabetes mellitus with the possibility to reduce the intestinal permeability and zonulin levels.


Assuntos
Aloe/química , Diabetes Mellitus Experimental/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Haptoglobinas/metabolismo , Hipoglicemiantes/farmacologia , Extratos Vegetais/farmacologia , Precursores de Proteínas/metabolismo , Animais , Glicemia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Glucagon/sangue , Glucose-6-Fosfato/metabolismo , Glicogênio/metabolismo , Hexoquinase/metabolismo , Hipoglicemiantes/uso terapêutico , Inflamação/metabolismo , Insulina/sangue , Intestino Delgado/patologia , Fígado/patologia , Óxido Nítrico/metabolismo , Pâncreas/patologia , Extratos Vegetais/uso terapêutico , Ratos Wistar , Estreptozocina
17.
Mol Neurodegener ; 16(1): 6, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33557896

RESUMO

BACKGROUND: Previous studies have reported that gut microbiota, permeability, short-chain fatty acids (SCFAs), and inflammation are altered in Parkinson's disease (PD), but how these factors are linked and how they contribute to disease processes and symptoms remains uncertain. This study sought to compare and identify associations among these factors in PD patients and controls to elucidate their interrelations and links to clinical manifestations of PD. METHODS: Stool and plasma samples and clinical data were collected from 55 PD patients and 56 controls. Levels of stool SCFAs and stool and plasma inflammatory and permeability markers were compared between patients and controls and related to one another and to the gut microbiota. RESULTS: Calprotectin was increased and SCFAs decreased in stool in PD in a sex-dependent manner. Inflammatory markers in plasma and stool were neither intercorrelated nor strongly associated with SCFA levels. Age at PD onset was positively correlated with SCFAs and negatively correlated with CXCL8 and IL-1ß in stool. Fecal zonulin correlated positively with fecal NGAL and negatively with PD motor and non-motor symptoms. Microbiota diversity and composition were linked to levels of SCFAs, inflammatory factors, and zonulin in stool. Certain relationships differed between patients and controls and by sex. CONCLUSIONS: Intestinal inflammatory responses and reductions in fecal SCFAs occur in PD, are related to the microbiota and to disease onset, and are not reflected in plasma inflammatory profiles. Some of these relationships are distinct in PD and are sex-dependent. This study revealed potential alterations in microbiota-host interactions and links between earlier PD onset and intestinal inflammatory responses and reduced SCFA levels, highlighting candidate molecules and pathways which may contribute to PD pathogenesis and clinical presentation and which warrant further investigation.


Assuntos
Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/fisiologia , Haptoglobinas/metabolismo , Inflamação/metabolismo , Doença de Parkinson/metabolismo , Precursores de Proteínas/metabolismo , Idoso , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
PLoS One ; 16(2): e0246959, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33592073

RESUMO

The aim of this study was to investigate effects of pre-transport diets, transport durations and transport conditions on immune cell subsets, haptoglobin, cortisol and bilirubin of young calves upon arrival at the veal farm. An experiment was conducted with a 2 × 2 × 2 factorial arrangement with 3 factors: 1) provision of rearing milk or electrolytes at the collection center (CC); 2) transport duration (6 or 18 hours) and 3) transport condition (open truck or conditioned truck). Holstein-Friesian and cross-bred calves were used (N = 368; 18 ± 4 days; 45.3 ± 3.3 kg). Blood samples were collected from calves (N = 128) at the collection center, immediately post-transport (T0) and 4, 24, 48 hours, week 1, 3 and 5 post-transport. Blood was analyzed for cortisol, bilirubin, haptoglobin, IgG and IgM. Moreover, cell counts of neutrophils, lymphocytes, monocytes, basophils and eosinophils were measured in blood samples taken at the collection center and T0. In these same blood samples, different lymphocyte populations were characterized by flow cytometry, including CD14+ cells, NK cells, δγ+ T cells, CD8+ cells, CD4+ cells and CD21+ cells. Calves transported in the conditioned truck had higher amounts of white blood cell count (WBC) (Δ = 1.39 × 109/l; P = 0.01), monocytes (Δ = 0.21 × 109/l; P = 0.04), neutrophils (Δ = 0.93 × 109/l; P = 0.003), than calves transported in the open truck regardless, of pre-transport diet or transport duration. The study showed that transport condition and duration influenced parts of the innate immune system of young veal calves. Cortisol, bilirubin and WBC seemed to be connected by similar underlying mechanisms in relation to transport conditions. However, it is unclear which specific pathways in the immune system of young calves are affected by different transport conditions (e.g. temperature, humidity, draught).


Assuntos
Criação de Animais Domésticos , Bilirrubina/sangue , Dieta , Haptoglobinas/metabolismo , Carne Vermelha , Animais , Bovinos , Hidrocortisona/sangue
19.
Gene ; 776: 145429, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33444685

RESUMO

Gallbladder cancer (GBC) with poor prognosis has been a major cause of cancer-related deaths worldwide. In this study, we aimed to screen and identify crucial genes in GBC through integrative analysis of multiple datasets and further experimental validation. A candidate crucial gene, up-regulated haptoglobin (HP), was firstly screened, and then further analysis and validation mainly focused on whether higher enrichment level of HP was responsible for pathophysiological process of GBC. HP was found with diverse expression patterns in various cancer types, and the dynamic expression patterns indicated its spatiotemporal characteristics in different tissues and disease stages, implicating its role in multiple biological processes. Further experimental validation showed that HP could promote the GBC-SD cell proliferation, migration and invasion, implying its role in pathophysiological process of GBC. HP may have a crucial role in occurrence and development of GBC, and it provides possibility as a potential biomarker or target in cancer prognosis and treatment.


Assuntos
Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/fisiopatologia , Haptoglobinas/genética , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Biologia Computacional/métodos , Bases de Dados Genéticas , Transição Epitelial-Mesenquimal/genética , Neoplasias da Vesícula Biliar/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Haptoglobinas/metabolismo , Haptoglobinas/fisiologia , Humanos , Invasividade Neoplásica/genética , Prognóstico , Transdução de Sinais/genética
20.
Epilepsia ; 62(2): 529-541, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33428780

RESUMO

OBJECTIVE: A large number of studies have highlighted the important role of the gut microbiota in the pathophysiology of neurological disorders, suggesting that its manipulation might serve as a treatment strategy. We hypothesized that the gut microbiota participates in absence seizure development and maintenance in the WAG/Rij rat model and tested this hypothesis by evaluating potential gut microbiota and intestinal alterations in the model, as well as measuring the impact of microbiota manipulation using fecal microbiota transplantation (FMT). METHODS: Initially, gut microbiota composition and intestinal histology of WAG/Rij rats (a well-recognized genetic model of absence epilepsy) were studied at 1, 4, and 8 months of age in comparison to nonepileptic Wistar rats. Subsequently, in a second set of experiments, at 6 months of age, untreated Wistar or WAG/Rij rats treated with ethosuximide (ETH) were used as gut microbiota donors for FMT in WAG/Rij rats, and electroencephalographic (EEG) recordings were obtained over 4 weeks. At the end of FMT, stool and gut samples were collected, absence seizures were measured on EEG recordings, and microbiota analysis and histopathological examinations were performed. RESULTS: Gut microbiota analysis showed differences in beta diversity and specific phylotypes at all ages considered and significant variances in the Bacteroidetes/Firmicutes ratio between Wistar and WAG/Rij rats. FMT, from both Wistar and ETH-treated WAG/Rij donors to WAG/Rij rats, significantly decreased the number and duration of seizures. Histological results indicated that WAG/Rij rats were characterized by intestinal villi disruption and inflammatory infiltrates already at 1 month of age, before seizure occurrence; FMT partially restored intestinal morphology while also significantly modifying gut microbiota and concomitantly reducing absence seizures. SIGNIFICANCE: Our results demonstrate for the first time that the gut microbiota is modified and contributes to seizure occurrence in a genetic animal model of absence epilepsy and that its manipulation may be a suitable therapeutic target for absence seizure management.


Assuntos
Antibacterianos/farmacologia , Anticonvulsivantes/farmacologia , Epilepsia Tipo Ausência/microbiologia , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Animais , Bacteroidetes , Butiratos/metabolismo , Colo/patologia , DNA Bacteriano/análise , DNA Ribossômico/genética , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia Tipo Ausência/genética , Epilepsia Tipo Ausência/fisiopatologia , Epilepsia Tipo Ausência/terapia , Etossuximida/farmacologia , Ácidos Graxos Voláteis/metabolismo , Firmicutes , Motilidade Gastrointestinal , Haptoglobinas/metabolismo , Íleo/patologia , Propionatos/metabolismo , Precursores de Proteínas/metabolismo , Proteobactérias , Ratos , Ratos Wistar , Convulsões/genética , Convulsões/microbiologia , Convulsões/fisiopatologia
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