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1.
Iran J Med Sci ; 46(5): 373-382, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34539012

RESUMO

Background: Acute liver failure (ALF) is a fatal clinical situation that rapidly leads to the loss of normal liver function. Esculetin is a natural herbal compound used for the management of various diseases such as cardiovascular and renal disorders. In this study, we evaluated the protective effects of esculetin in a mouse model of ALF. Methods: This article is a report on an experimental study that was conducted at Iran University of Medical Sciences in 2019. Forty-eight male C57BL/6 mice were randomly divided into control, LPS/D-Gal, and LPS/D-Gal+Esculetin (40 mg/kg) groups (n=16 per group). ALF was induced with an intraperitoneal injection of lipopolysaccharide (LPS)/D-galactosamine (D-Gal).The LPS/D-Gal group received a mixture of LPS (50 µg/kg) and D-Gal (400 mg/kg). The LPS/D-Gal+Esculetin group received esculetin by gavage 24 hours and one hour before receiving LPS/D-Gal. Six hours after LPS/D-Gal injection, the mice were sacrificed. Liver injury markers, including alanine aminotransferase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP), were measured in the serum. Oxidative stress indices and inflammatory markers such as interleukin-1 beta (IL-1ß), IL-6, and tumor necrosis factor-alpha (TNF-α) were measured in hepatic tissue. The histopathology of liver tissue was also assessed. The data were analyzed using one-way ANOVA, followed by the post hoc Tukey test. Results: Esculetin lowered oxidative stress and myeloperoxidase activity (P<0.001); reduced the serum levels of ALT (P=0.037), AST (P=0.032), and ALP (P=0.004); and decreased the hepatic levels of IL-1ß (P=0.002), IL-6 (P=0.004), toll-like receptor 4 (P<0.001), TNF-α (P=0.003), and nuclear factor-kappa B (P<0.001) as compared with LPS/D-Gal. Additionally, esculetin ameliorated hepatic tissue injury following LPS/D-Gal challenge. Conclusion: Esculetin can reduce liver injury through the mitigation of oxidative burden, inflammation, and neutrophil infiltration and also exerts hepatoprotective effects against ALF.


Assuntos
Galactosamina/farmacologia , Lipopolissacarídeos/farmacologia , Falência Hepática Aguda/tratamento farmacológico , Umbeliferonas/farmacologia , Animais , Modelos Animais de Doenças , Galactosamina/uso terapêutico , Interleucina-1beta/análise , Interleucina-1beta/sangue , Interleucina-6/análise , Interleucina-6/sangue , Irã (Geográfico) , Lipopolissacarídeos/uso terapêutico , Falência Hepática Aguda/patologia , Falência Hepática Aguda/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/análise , Fragmentos de Peptídeos/sangue , Fatores de Proteção , Receptor 4 Toll-Like/análise , Receptor 4 Toll-Like/sangue , Umbeliferonas/uso terapêutico
2.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33658371

RESUMO

Synucleinopathies are neurodegenerative diseases with both central and peripheral immune responses. However, whether the peripheral immune changes occur early in disease and their relation to brain events is yet unclear. Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) can precede synucleinopathy-related parkinsonism and provides a prodromal phenotype to study early Parkinson's disease events. In this prospective case-control study, we describe monocytic markers in a cohort of iRBD patients that were associated with the brain-imaging markers of inflammation and neuronal dysfunction. Using 11C-PK11195 positron emission tomography (PET), we previously showed increased immune activation in the substantia nigra of iRBD patients, while 18F-DOPA PET detected reduced putaminal dopaminergic function. Here we describe that patients' blood monocytic cells showed increased expression of CD11b, while HLA-DR expression was decreased compared to healthy controls. The iRBD patients had increased classical monocytes and mature natural killer cells. Remarkably, the levels of expression of Toll-like receptor 4 (TLR4) on blood monocytes in iRBD patients were positively correlated with nigral immune activation measured by 11C-PK11195 PET and negatively correlated with putaminal 18F-DOPA uptake; the opposite was seen for the percentage of CD163+ myeloid cells. This suggesting a deleterious role for TLR4 and, conversely, a protective one for the CD163 expression. We show an association between peripheral blood monocytes and brain immune and dopaminergic changes in a synucleinopathy-related disorder, thus suggesting a cross-talk among periphery and brain during the disease.


Assuntos
Neurônios , Tomografia por Emissão de Pósitrons , Transtorno do Comportamento do Sono REM , Substância Negra , Idoso , Biomarcadores/sangue , Antígeno CD11b/sangue , Antígeno CD11b/imunologia , Feminino , Antígenos HLA-DR/sangue , Antígenos HLA-DR/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Neurônios/imunologia , Neurônios/metabolismo , Transtorno do Comportamento do Sono REM/sangue , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/imunologia , Substância Negra/diagnóstico por imagem , Substância Negra/imunologia , Substância Negra/metabolismo , Receptor 4 Toll-Like/sangue , Receptor 4 Toll-Like/imunologia
3.
J Orthop Surg Res ; 16(1): 130, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33573686

RESUMO

BACKGROUND: Although integrated traditional Chinese medicine (TCM) has long been indicated to be effective in the treatment of sciatica and is widely used in the management of this condition, the mechanism by which integrated TCM alleviates sciatica has not yet been fully defined, and the effect of integrated TCM on gene expression in the peripheral blood of patients with sciatica is still unknown. We performed this study to investigate the effect of integrated TCM on peripheral blood gene expression in patients with sciatica and to explore new clues for studying the mechanism of integrated TCM in alleviating sciatica. METHODS: We used a microarray to identify differentially expressed genes (DEGs) in the peripheral blood of patients with sciatica and healthy controls (DEGs-baseline), bioinformatic analysis to reveal the characteristics of DEGs-baseline, and the key genes that contribute to the gene dysregulation. A microarray was also used to identify DEGs in the peripheral blood of patients with sciatica after integrated TCM treatment compared with those at baseline, and the expression levels of DEGs were validated by qRT-PCR. RESULTS: We identified 153 DEGs-baseline, which included 131 upregulated genes and 22 downregulated genes. Bioinformatic analysis revealed that most of the DEGs-baseline were related to immunity and the inflammatory response and that TLR4, MMP9, MPO, CAMP, RETN, TLR5, and IL1RN were key genes involved in the dysregulation of genes in the peripheral blood of patients with sciatica. The expression levels of TLR5, IL1RN, SLC8A1, RBM20, GPER1, IL27, SOCS1, and GRTP1-AS1 were decreased in the peripheral blood of patients after integrated TCM treatment compared with that at baseline, which was accompanied by relief of pain. CONCLUSION: Integrated TCM treatment relieved pain while regulating the gene expression of TLR5, IL1RN, SLC8A1, RBM20, GPER1, IL27, SOCS1, and GRTP1-AS1 in the peripheral blood of patients with sciatica. Our study provides new clues for studying the mechanism of TCM in treating sciatica.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Medicina Tradicional Chinesa , Ciática/tratamento farmacológico , Ciática/genética , Adulto , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/genética , Masculino , Metaloproteinase 9 da Matriz/sangue , Metaloproteinase 9 da Matriz/genética , Pessoa de Meia-Idade , Manejo da Dor/métodos , Peroxidase/sangue , Peroxidase/genética , Ciática/sangue , Receptor 4 Toll-Like/sangue , Receptor 4 Toll-Like/genética , Receptor 5 Toll-Like/sangue , Receptor 5 Toll-Like/genética , Resultado do Tratamento , Adulto Jovem
4.
Exp Mol Pathol ; 119: 104609, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33516663

RESUMO

Toll-like receptor 4 (TLR4) is a crucial regulator of inflammatory reactions and vascular remodeling. Elevated TLR4 expression has been proved to be correlated with an increased risk of aortic aneurysm (AA). This study aimed to explore the influence of TLR4 gene polymorphisms on TLR4 expression levels and its probable functional significance in AA disease. A total of 294 AA patients and 285 controls were enrolled in the study and serum TLR4 levels were detected by ELISA. All the participants were genotyped for two tag-SNPs in TLR4 (rs1927914 in the promoter region and rs11536889 in the 3'-untranslated region) using the KASP method. Relative luciferase activity was measured by the dual-luciferase reporter assay system. The rs1927914 TC, TC/CC genotypes and C allele showed associations with increased serum TLR4 levels in the total population and AA patients (all P<0.05). Further stratified analysis demonstrated that AA subjects with TC or TC/CC genotype of rs1927914 had significantly higher serum levels of TLR4 than those with TT genotype in male, age>60y, hypertension, diabetes, TAA type and size>5.0 cm subgroups (all P<0.05). In binary logistic analysis, rs1927914 TC genotype and dominant model presented significant associations with high TLR4 levels (OR = 1.579 and 1.431, P = 0.020 and 0.049, respectively) after adjusting age, hypertension and diabetes. However, rs11536889 polymorphism had no significant influence on serum TLR4 levels. Regarding rs1927914, luciferase activity of the C allele construct was significantly increased in comparison with the T allele construct (0.589 ± 0.004 vs. 0.340 ± 0.014, P<0.001). Our results provided evidence that rs1927914 polymorphism contributed to serum TLR4 levels, possibly by influencing promoter activity of TLR4, and could be a novel genetic factor in the formation of AA.


Assuntos
Aneurisma Aórtico/sangue , Aneurisma Aórtico/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Receptor 4 Toll-Like/sangue , Receptor 4 Toll-Like/genética , Alelos , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas
5.
Artigo em Inglês | MEDLINE | ID: mdl-33010450

RESUMO

Toll-like receptors (TLR) are crucial for recognizing bacterial, viral or fungal pathogens and to orchestrate the appropriate immune response. The widely expressed TLR2 and TLR4 differentially recognize various pathogens to initiate partly overlapping immune cascades. To better understand the physiological consequences of both immune responses, we performed comparative lipidomic analyses of local paw inflammation in mice induced by the TLR2 and TLR4 agonists, zymosan and lipopolysaccharide (LPS), respectively, which are commonly used in models for inflammation and inflammatory pain. Doses for both agonists were chosen to cause mechanical hypersensitivity with identical strength and duration. Lipidomic analysis showed 5 h after LPS or zymosan injection in both models an increase of ether-phosphatidylcholines (PC O) and their corresponding lyso species with additional lipids being increased only in response to LPS. However, zymosan induced stronger immune cell recruitment and edema formation as compared to LPS. Importantly, only in LPS-induced inflammation the lipid profile in the contralateral paw was altered. Fittingly, the plasma level of various cytokines and chemokines, including IL-1ß and IL-6, were significantly increased only in LPS-treated mice. Accordingly LPS induced distinct changes in the lipid profiles of ipsilateral and contralateral paws. Here, oxydized fatty acids, phosphatidylcholines and phosphatidylethanolamines were uniquely upregulated on the contralateral side. Thus, both models cause increased levels of PC O and lyso-PC O lipids at the site of inflammation pointing at a common role in inflammation. Also, LPS initiates systemic changes, which can be detected by changes in the lipid profiles.


Assuntos
Reação de Fase Aguda/sangue , Edema/sangue , Lipopolissacarídeos/administração & dosagem , Fosfatidilcolinas/sangue , Fosfatidiletanolaminas/sangue , Zimosan/administração & dosagem , Reação de Fase Aguda/induzido quimicamente , Reação de Fase Aguda/genética , Reação de Fase Aguda/patologia , Animais , Edema/induzido quimicamente , Edema/genética , Edema/patologia , Ácidos Graxos/sangue , Ácidos Graxos/classificação , Regulação da Expressão Gênica , Membro Posterior/irrigação sanguínea , Membro Posterior/efeitos dos fármacos , Membro Posterior/metabolismo , Interleucina-1beta/sangue , Interleucina-1beta/genética , Interleucina-6/sangue , Interleucina-6/genética , Lipidômica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilcolinas/classificação , Fosfatidiletanolaminas/classificação , Transdução de Sinais , Receptor 2 Toll-Like/sangue , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/sangue , Receptor 4 Toll-Like/genética
6.
Int J Immunopathol Pharmacol ; 34: 2058738420974888, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33233960

RESUMO

This study aimed to investigate the clinical significance of serum microRNA-219-5p (miR-219-5p) in patients with multiple organ dysfunction syndrome (MODS) caused by acute paraquat (PQ) poisoning, and its correlation with Toll-like Receptor 4 (TLR4). Luciferase reporter assay was used to investigate in vitro the correlation of miR-219-5p with TLR4. Serum miR-219-5p levels were evaluated by quantitative real-time polymerase chain reaction. Serum levels of TLR4, IL-1ß, and TNF-α were measured by Enzyme-linked immune sorbent assay (ELISA). ROC analysis was performed to assess the diagnostic significance, Kaplan-Meier survival curves and Cox regression analysis were used to evaluate the prognostic value of miR-219-5p in MODS patients. TLR4 was a target gene of miR-219-5p and was increased in MODS patients. Serum miR-219-5p level was decreased and negatively correlated with TLR4 level in MODS patients (r = -0.660, P < 0.001), which had important diagnostic value and negatively correlated with APACHE II score in MODS patients. The miR-219-5p expression was markedly associated with the WBC, ALT, AST, PaCO2, Lac, and APACHE II score. Non-survivals had more patients with low miR-219-5p expression. Patients with low miR-219-5p expression had shorter survival time. MiR-219-5p and APACHE II score were two independently prognostic factors for 28-day survival. MiR-219-5p was negatively correlated with, while TLR4 was positively correlated with the levels of IL-1ß and TNF-α. The serum miR-219-5p level may be a potential biomarker for acute PQ-induced MODS diagnosis and prognosis. Furthermore, miR-219-5p may be associated with the progression of MODS by regulating TLR4-related inflammatory response.


Assuntos
Herbicidas/envenenamento , MicroRNAs/sangue , Insuficiência de Múltiplos Órgãos/induzido quimicamente , Insuficiência de Múltiplos Órgãos/diagnóstico , Paraquat/envenenamento , Receptor 4 Toll-Like/sangue , Adulto , Biomarcadores/sangue , Citocinas/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Células HEK293 , Humanos , Mediadores da Inflamação/sangue , Masculino , MicroRNAs/genética , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/mortalidade , Valor Preditivo dos Testes , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Receptor 4 Toll-Like/genética , Regulação para Cima , Adulto Jovem
7.
Bull Exp Biol Med ; 169(6): 795-797, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33098506

RESUMO

The effects of TLR4 blocker on blood cell morphology, concentrations proinflammatory cytokines, and functional state of the liver and kidneys were studied in outbred male rats (n=60) after intravenous injection of 20 mg/kg LPS isolated from opportunistic Proteus mirabilis strain ATCC 51393. TLR4 blocker TLR4-IN-C34 was injected intravenously in a dose of 1 mg/kg/day over 3 days. Systemic inflammatory reaction induced by LPS was characterized by elevation of serum TNFα, IL-1ß, IL-6, erythrocyte sedimentation rate, leukocytosis, and thrombocytosis. Increased activity of hepatocyte enzymes (ALT, alkaline phosphatase, and lactate dehydrogenase), retention of nitrogen metabolites (urea and creatinine), elevated content of protein oxidation products, and enhanced protein catabolism were also observed. Administration of TLR4 blocker reduced parameters of inflammatory reaction and prevented the development of hypercatabolic syndrome; endotoxicosis and kidney function indicators approached the normal levels.


Assuntos
Anti-Inflamatórios/farmacologia , Leucocitose/tratamento farmacológico , Lipopolissacarídeos/antagonistas & inibidores , Piranos/farmacologia , Sepse/tratamento farmacológico , Trombocitose/tratamento farmacológico , Receptor 4 Toll-Like/antagonistas & inibidores , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Animais não Endogâmicos , Creatinina/sangue , Modelos Animais de Doenças , Regulação da Expressão Gênica , Injeções Intravenosas , Interleucina-1beta/sangue , Interleucina-1beta/genética , Interleucina-6/sangue , Interleucina-6/genética , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , L-Lactato Desidrogenase/sangue , Leucocitose/sangue , Leucocitose/patologia , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Proteus mirabilis/química , Ratos , Sepse/sangue , Sepse/patologia , Transdução de Sinais , Trombocitose/sangue , Trombocitose/patologia , Receptor 4 Toll-Like/sangue , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Ureia/sangue
8.
Mediators Inflamm ; 2020: 2960517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013197

RESUMO

Insulin resistance has been shown to be the common pathogenesis of many metabolic diseases. Metainflammation is one of the important characteristics of insulin resistance. Macrophage polarization mediates the production and development of metainflammation. Toll-like receptor 4 (TLR4) mediates macrophage activity and is probably the intersection of immunity and metabolism, but the detailed mechanism is probably not fully understood. Activated protein 1 (AP1) signaling pathway is very important in macrophage activation-mediated inflammation. However, it is unclear whether AP1 signaling pathway mediates metabolic inflammation in the liver. We aimed to investigate the effects of macrophage TLR4-AP1 signaling pathway on hepatocyte metabolic inflammation, insulin sensitivity, and lipid deposition, as well as to explore the potential of TLR4-AP1 as new intervention targets of insulin resistance and liver steatosis. TLR4 and AP1 were silenced in the RAW264.7 cells by lentiviral siRNA transfection. In vivo transduction of lentivirus was administered in mice fed with high-fat diet. Insulin sensitivity and inflammation were evaluated in the treated cells or animals. Our results indicated that TLR4/AP-1 siRNA transfection alleviated high-fat diet-induced systemic and hepatic inflammation, obesity, and insulin resistance in mice. Additionally, TLR4/AP-1 siRNA transfection mitigated palmitic acid- (PA-) induced inflammation in RAW264.7 cells and metabolic abnormalities in cocultured AML hepatocytes. Herein, we propose that TLR4-AP1 signaling pathway activation plays a crucial role in high fat- or PA-induced metabolic inflammation and insulin resistance in hepatocytes. Intervention of the TLR4 expression regulates macrophage polarization and metabolic inflammation and further alleviates insulin resistance and lipid deposition in hepatocytes.


Assuntos
Fígado Gorduroso/sangue , Insulina/sangue , Receptor 4 Toll-Like/sangue , Fator de Necrose Tumoral alfa/sangue , Animais , Western Blotting , Colesterol/sangue , Ensaio de Imunoadsorção Enzimática , Ácidos Graxos não Esterificados/sangue , Teste de Tolerância a Glucose , Inflamação/sangue , Interleucina-10/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Triglicerídeos/sangue
9.
Medicine (Baltimore) ; 99(40): e22152, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019392

RESUMO

BACKGROUND: Gestational diabetes mellitus (GDM) produces numerous problems for maternal and fetal outcomes. However, the precise molecular mechanisms of GDM are not clear. METHODS: In our study, we randomly assigned 22 pregnant women with fasting glucose concentrations, 1 hour oral glucose tolerance test (1H-OGTT) and 2 hour oral glucose tolerance test (2H-OGTT), different than 28 normal pregnant women from a sample of 107 pregnant women at the First Affiliated Hospital of Jinan University in China. Lipopolysaccharide (LPS), interleukin 1 alpha (IL-1α), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α) were measured from blood plasma of pregnant women and umbilical arteries using ultraviolet spectrophotometry. Hematoxylin & Eosin (H&E), Periodic acid-Schiff (PAS) or Masson staining were performed to examine whether diabetes mellitus altered the morphology of placenta. Quantitative PCR (Q-PCR), western blotting and immunofluorescent staining were performed to examine whether diabetes mellitus and autophagy altered the gene expressions of the placental tissue. RESULTS: We found that women with GDM exhibited increased placental weight and risk of neonatal infection. The concentrations of IL-6 protein and IL-8 protein in GDM were increased in both maternal and umbilical arterial blood. H&E, Masson and PAS staining results showed an increased number of placental villi and glycogen deposition in patients with GDM, but no placental sclerosis was found. Q-PCR results suggested that the expression levels of HIF-1α and the toll like receptor 4 (TLR4)/ myeloid differential protein-88 (MyD88)/ nuclear factor kappa-B (NF-κB) pathway were increased in the GDM placenta. Through Western Blotting, we found that the expression of NF-kappa-B inhibitor alpha (IKBα) and Nuclear factor-κB p65 (NF-κB p65) in GDM placenta was significantly enhanced. We also showed that the key autophagy-related genes, autophagy-related 7 (ATG7) and microtubule-associated protein 1A/1B-light chain 3 (LC3), were increased in GDM compared with normal pregnant women. CONCLUSIONS: Our results suggest that women with GDM exhibit an increased risk of neonatal infection via inflammation and autophagy in the placenta.


Assuntos
Diabetes Gestacional/sangue , Placenta/patologia , Adulto , Diabetes Gestacional/genética , Feminino , Sangue Fetal , Teste de Tolerância a Glucose , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Recém-Nascido , Inflamação/sangue , Inflamação/genética , Placenta/microbiologia , Gravidez , Resultado da Gravidez , Receptor 4 Toll-Like/sangue
10.
Curr Med Sci ; 40(5): 910-916, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33123905

RESUMO

We aimed to explore the anti-inflammatory activity of mollugin extracted from Rubia cordifolia L, a traditional Chinese medicine, on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. Thirty C57BL/6 mice were divided into a control group (n=6), a model group (n=6), and three experimental groups (40, 20, 10 mg/kg of mollugin, n=6 each). DSS solution (3%) was given to mice in the model group and experimental groups from day 4 to day 10 to induce the mouse UC model. Mice in the experimental groups were intragastrically administrated mollugin from day 1 to day 10. Animals were orally given distilled water in the control group for the whole experiment time and in the model group from day 1 to day 3. The changes in colon pathology were detected by hematoxylin and eosin (HE) staining. Interleukin-1ß (IL-1ß) in the serum, and tumor necrosis factor-α (TNF-α) and interferon-γ (IFN) in the tissues were measured by enzyme linked immunosorbent assay. Expression levels of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 in the colon tissues were detected by immunohistochemistry. Results showed that mollugin could significantly reduce weight loss and the disease activity index in the DSS-induced UC mouse model. HE examinations demonstrated that mollugin treatment effectively improved the histological damage (P<0.05). The overproduction of IL-1ß and TNF-α was remarkably inhibited by mollugin treatment at doses of 20 and 40 mg/kg (P<0.05). Additionally, the levels of TLR4 in colon tissues were significantly reduced in mollugin-treated groups compared with the DSS group. Our findings demonstrated that mollugin ameliorates DSS-induced UC by inhibiting the production of pro-inflammatory chemocytokines.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Interleucina-1beta/sangue , Piranos/farmacologia , Receptor 4 Toll-Like/sangue , Fator de Necrose Tumoral alfa/sangue , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Colite Ulcerativa/sangue , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Camundongos , Piranos/química , Rubia/química
11.
Ann Hematol ; 99(10): 2265-2277, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32803313

RESUMO

ß-Thalassemia is an inherited single gene disorder related to reduced synthesis of the ß-globin chain of hemoglobin. Patients with ß-thalassemia present variable clinical severity ranging from asymptomatic trait to severe transfusion-dependent anemia and multiple organs complications. Moreover, multiple immune abnormalities are a major concern in ß-thalassemia patients. Aberrant neutrophil effector function plays a pivotal role in infection susceptibility in these patients. In severe and persistent inflammation, immature neutrophils are released from the bone marrow and are functionally different compared with mature ones. Despite some abnormalities reported for thalassemia patient's immune system, few data exist on the characterization of human neutrophils in ß-thalassemia. The aim of this study was to investigate the phenotype and function of circulating neutrophil subsets in patients with ß-thalassemia major and with ß-thalassemia intermedia divided in transfusion-dependent and non-transfusion-dependent. By the use of immunochemical and cytofluorimetric analyses, we observed that patients' CD16+ neutrophils exhibit abnormalities in their phenotype and functions and the abnormalities vary according to the clinical form of the disease and to the neutrophil subset (CD16bright and CD16dim). Abnormalities include altered surface expression of the innate immune receptor CD45, Toll-like receptor 4, and CD32, reduced ability to produce an oxidative burst, and elevated levels of membrane lipid peroxidation, especially in patients with a more severe form of the disease. Overall, our results indicating the occurrence of an immuno-senescent phenotype on circulating neutrophils from thalassemia patients suggest the usefulness of neutrophil feature assessment as a tool for better clinical management of ß-thalassemia.


Assuntos
Neutrófilos/imunologia , Talassemia beta/sangue , Adulto , Antígenos CD/sangue , Transfusão de Componentes Sanguíneos , Senescência Celular , Terapia por Quelação , Feminino , Ferritinas/sangue , Humanos , Imunofenotipagem , Quelantes de Ferro/uso terapêutico , Contagem de Leucócitos , Peroxidação de Lipídeos , Masculino , Pessoa de Meia-Idade , Ativação de Neutrófilo , Neutrófilos/química , Neutrófilos/classificação , Explosão Respiratória , Esplenectomia , Receptor 4 Toll-Like/sangue , Adulto Jovem , Talassemia beta/imunologia , Talassemia beta/terapia
12.
Int J Mol Med ; 46(1): 131-140, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32626914

RESUMO

Acute lung injury (ALI) is a common lung disease with a high mortality rate, which is characterized by an excessive uncontrolled inflammatory response. MicroRNA (miR)­17 has previously emerged as a novel regulatory molecule of inflammatory response in various complex diseases; however, the anti­inflammatory action and associated molecular mechanisms of miR­17 in ALI have not been fully elucidated. The aim of the present study was to investigate the role of miR­17 in the inflammatory response in ALI and to elucidate the potential underlying mechanism. Using a lipopolysaccharide (LPS)­induced ALI mouse model, it was observed that miR­17 was significantly downregulated in lung tissues compared with the control group. In this model, ectopic expression of miR­17 attenuated lung pathological damage, reduced lung wet/dry ratio and lung permeability, and increased survival rate in ALI mice. In addition, agomiR­17 injection significantly suppressed LPS­induced inflammation, as evidenced by a reduction in the activity of myeloperoxidase and the production of interleukin (IL)­6, IL­1ß and tumor necrosis factor­α in lung tissues. Of note, toll­like receptor (TLR) 4, an upstream regulator of the nuclear factor (NF)­κB inflammatory signaling pathway, was directly targeted by miR­17, and its translation was suppressed by miR­17 in vitro and in vivo. Using an LPS­induced RAW264.1 macrophage injury model, it was observed that miR­17 overexpression suppressed the pro­inflammatory effect of LPS, while these inhibitory effects were markedly abrogated by TLR4 overexpression. In addition, TLR4 knockdown by si­TLR4 mimicked the effects of miR­17 overexpression on LPS­induced cytokine secretion in the in vitro model. Further experiments revealed that miR­17 significantly reduced the expression of key proteins in the NF­κB pathway, including IKKß, p­IκBα and nuclear p­p65, and suppressed the NF­κB activity in ALI mice. Collectively, these results indicated that miR­17 protected mice against LPS­induced lung injury via inhibiting inflammation by targeting the TLR4/NF­κB pathway; therefore, miR­17 may serve as a potential therapeutic target for ALI.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lipopolissacarídeos/toxicidade , MicroRNAs/metabolismo , Lesão Pulmonar Aguda/sangue , Animais , Western Blotting , Proliferação de Células/efeitos dos fármacos , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , NF-kappa B/sangue , Células RAW 264.7 , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/sangue , Fator de Necrose Tumoral alfa/sangue
13.
Heart Vessels ; 35(12): 1717-1726, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32524234

RESUMO

Inflammation has been suggested to play a key role in the pathogenesis of atrial fibrillation (AF). Our hypothesis was that this inflammation, mediated by intermediate monocytes and toll-like receptor 4 (TLR4), causes the formation and expansion of low-voltage zones (LVZs). Prior to ablation, the monocyte subsets of 78 AF patients and TLR4 expression of 66 AF patients were analyzed via a flow cytometric analysis. Based on the CD14/CD16 expression, the monocytes were divided into three subsets: classical, intermediate, and non-classical. At the beginning of the ablation session, voltage mapping was performed. LVZs were defined as all bipolar electrogram amplitudes of < 0.5 mV. Correlations between the flow cytometric analysis results and presence of LVZs, as well as the total area of the LVZ, were examined. Patients with LVZs clearly had a higher proportion of intermediate monocytes (10.0 ± 3.6% vs. 7.2 ± 2.7%, p < 0.001) than those without LVZs. TLR4 was much more frequently expressed in the intermediate monocytes than other two monocyte subsets (p < 0.001). Moreover, the TLR4 expression level in intermediate monocytes correlated positively with the total area of the LVZs (r = 0.267, p = 0.030), especially in patients with paroxysmal AF (r = 0.365, p = 0.015). The intermediate monocytes and TLR4 expression positively correlated with LVZs in AF patients.


Assuntos
Potenciais de Ação , Fibrilação Atrial/sangue , Frequência Cardíaca , Mediadores da Inflamação/sangue , Inflamação/sangue , Monócitos/metabolismo , Receptor 4 Toll-Like/sangue , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Biomarcadores/sangue , Feminino , Proteínas Ligadas por GPI/sangue , Humanos , Inflamação/diagnóstico , Receptores de Lipopolissacarídeos/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores de IgG/sangue
14.
Int J Mol Sci ; 21(11)2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32545403

RESUMO

The progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) is linked to systemic inflammation. Currently, two of the aspects that need further investigation are diagnosis and treatment of NASH. In this sense, the aim of this study was to assess the relationship between circulating levels of cytokines, hepatic expression of toll-like receptors (TLRs), and degrees of NAFLD, and to investigate whether these levels could serve as noninvasive biomarkers of NASH. The present study assessed plasma levels of cytokines in 29 normal-weight women and 82 women with morbid obesity (MO) (subclassified: normal liver (n = 29), simple steatosis (n = 32), and NASH (n = 21)). We used enzyme-linked immunosorbent assays (ELISAs) to quantify cytokine and TLR4 levels and RTqPCR to assess TLRs hepatic expression. IL-1ß, IL-8, IL-10, TNF-α, tPAI-1, and MCP-1 levels were increased, and adiponectin levels were decreased in women with MO. IL-8 was significantly higher in MO with NASH than in NL. To sum up, high levels of IL-8 were associated with the diagnosis of NASH in a cohort of women with morbid obesity. Moreover, a positive correlation between TLR2 hepatic expression and IL-8 circulating levels was found.


Assuntos
Interleucina-8/sangue , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/sangue , Obesidade Mórbida/sangue , Receptor 2 Toll-Like/metabolismo , Adipocinas/sangue , Adulto , Cirurgia Bariátrica , Estudos de Casos e Controles , Feminino , Humanos , Fígado/metabolismo , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade Mórbida/cirurgia , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/sangue , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
15.
Transplant Proc ; 52(8): 2394-2402, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32444127

RESUMO

Data binding the expression of Toll-like 4 receptor (TLR4), transplanted kidney (KT) function, and symptomatic CMV infection (CMV+) are scarcely available. OBJECTIVE: To investigate the relationship between TLR4 expression (TLR4ex) in patients who had a relapse of CMV and transplant function. MATERIALS AND METHODS: TLR4ex was measured in peripheral blood mononuclear cells of KT recipients. We compared TLR4ex among 30 CMV+ patients and 87 patients without CMV infection (CMVneg). At the beginning (day 0) TLR4ex, as well as concentrations of cyclosporin A and tacrolimus were determined. All patients, CMV+ and CMVneg patients were divided according to the respective median of TLR4ex into groups of low-TLR4 expression (L-TLR4ex) and high-TLR4 expression (H-TLR4ex). Estimated glomerular filtration rate (EGFR) was assessed on day 0 and after the follow-up (F-up). The magnitudes of EGFR change (ΔEGFR) were evaluated. Stable treatment along the F-up period (median 11.9 months) was applied. RESULTS: TLR4ex of CMV+ in 67% was below median for all patients. For day 0, in CMV+: no link of TLR4ex with EGFR was found; TLR4ex was lower but day 0 EGFR did not differ from H-TLR4ex. In CMVneg, a GFR-TLR4ex link was present. Post F-up. In CMV+ with L-TLR4ex, EGFR declined, with no change in H-TLR4ex. In CMVneg with H-TLR4ex, EGFR increased, with no change in L-TLR4ex. Both regression and receiver operating characteristic curve analyses points out the impact of CMV+ and TLR4ex on eGFR and ΔEGFR. CONCLUSION: In CMV+, low TLR4ex increases the risk of EGFR deterioration. In CMVneg, high TLR4ex raises the chance of EGFR improvement.


Assuntos
Infecções por Citomegalovirus/genética , Rejeição de Enxerto/genética , Transplante de Rim/efeitos adversos , Leucócitos Mononucleares/metabolismo , Receptor 4 Toll-Like/sangue , Adulto , Ciclosporina/sangue , Infecções por Citomegalovirus/virologia , Feminino , Taxa de Filtração Glomerular , Rejeição de Enxerto/virologia , Humanos , Rim/virologia , Masculino , Pessoa de Meia-Idade , Tacrolimo/sangue
16.
Epileptic Disord ; 22(2): 183-193, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32301731

RESUMO

The purpose of this study was to compare HMGB-1, TLR4, IL-1ß, IL-1R1, and TNF-α levels in patients with mild and severe epilepsy with those in a healthy control group. Children aged 4-17 years, diagnosed with epilepsy for at least three years and with no progressive neurological disease, metabolic disease or infection, were selected for the study. The severe epilepsy group consisted of 28 children with at least one episode a week despite receiving three or more antiepileptic drugs. The mild epilepsy group consisted of 29 children with no seizures in the previous year, receiving only one antiepileptic drug, while 27 healthy children were selected as the control group. HMGB-1, TLR4, IL-1R1, TNF-α and IL-1ß levels were investigated in these three groups. The MRI findings and clinical characteristics of the patients in the epilepsy group were also compared with these markers. HMGB-1, TLR4, TNF-α, and IL-1ß levels in the severe epilepsy group were higher than in the control group and the mild epilepsy group (p<0.05), and were higher in the mild epilepsy group than in the control group (p<0.05). IL-1R1 was also higher in the severe epilepsy group than in the control group (p<0.05). In this first report to identity a possible correlation between HMGB-1, TLR4, IL-1ß, IL-1R1, and TNF-α levels and severity of epilepsy, our data demonstrates that the serum level of these cytokines is higher in cases of drug-refractory epilepsy.


Assuntos
Epilepsia/sangue , Epilepsia/diagnóstico , Epilepsia/fisiopatologia , Proteína HMGB1/sangue , Inflamação/sangue , Interleucina-1beta/sangue , Receptor 4 Toll-Like/sangue , Fator de Necrose Tumoral alfa/sangue , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/sangue , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/fisiopatologia , Feminino , Humanos , Masculino , Índice de Gravidade de Doença
17.
J Coll Physicians Surg Pak ; 30(3): 245-249, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32169129

RESUMO

OBJECTIVE: To investigate the relationship between small intestinal bacterial overgrowth (SIBO) and Endotoxin (ET) concentration in peripheral blood, and levels of toll-like receptors (TLR) 2 and TLR4 expression on surface of peripheral blood mononuclear cells (PBMCs) in patients with ulcerative colitis. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: The First Hospital of Hebei Medical University, from July 2018 to October 2019. METHODOLOGY: The 130 patients with ulcerative colitis were included in case group. Another 72 healthy cases were selected as control group. SIBO, ET, TLR2, and TLR4, were determined, and compared. RESULTS: Positive rate of SIBO in case group was higher than that in control group (p <0.001). Lactulose hydrogen breath test (LHBT) intestine set value, peripheral blood ET concentration, and TLR2 and TLR4 expression levels on surface of PBMCs in case group were higher than those in control group (all p <0.001); the above indexes in SIBO-positive patients in case group were higher than those in SIBO-negative patients in case group (all p <0.001). Pearson's correlation analysis showed that LHBT intestine set value of SIBO-positive patients in case group was positively correlated with ET concentration, and TLR2 and TLR4 expression levels on surface of PBMCs (r= 0.910, p <0.001; r = 0.970, p <0.001; and r = 0.965, p <0.001 respectively). ET concentration of SIBO-positive patients in case group was positively correlated with expression levels of TLR2 and TLR4 on surface of PBMCs (r=0.962, p <0.001; and r = 0.829 p <0.001 respectively). CONCLUSION: Patients with ulcerative colitis are easy to occur SIBO, and SIBO increases blood endotoxin, TLR2 and TLR4 levels. Synergistic effects of endotoxin and endotoxin receptors TLR2 and TLR4 overexpression mediate body inflammation and may be involved in progression of ulcerative colitis. Patients with ulcerative colitis with excessive growth of small intestinal bacteria are more likely to have hypertoxemia.


Assuntos
Síndrome da Alça Cega/complicações , Colite Ulcerativa/sangue , Colite Ulcerativa/complicações , Endotoxinas/sangue , Receptor 2 Toll-Like/sangue , Receptor 4 Toll-Like/sangue , Adulto , Síndrome da Alça Cega/sangue , Estudos de Casos e Controles , Feminino , Humanos , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Biomed Res Int ; 2020: 8306903, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33426065

RESUMO

Background: Inflammation may be involved in the pathogenesis of acute aortic dissection (AAD). Toll-like receptor 4 (TLR4) is known to play a critical role in regulating the immune and inflammatory processes. To date, the relationship between genetic variation of TLR4 and AAD is far from clear. The purpose of our study was to illustrate the relevance of TLR4 polymorphisms with the susceptibility to AAD. Methods: A total of 222 AAD patients and 222 controls were enrolled in this study. Frequency distributions of TLR4 polymorphisms (rs10759932 in the promoter and rs11536889 in the 3'-untranslated region) were determined by the KASP method. Clinical parameters were acquired from subjects' medical records, and serum TLR4 levels were collected from our previously published data. Results: We found that rs10759932 polymorphism was associated with a reduced risk of AAD in the overall population (CC vs. TT: OR = 0.393, 95%CI = 0.164-0.939, P = 0.036; recessive model: OR = 0.439, 95%CI = 0.196-0.984, P = 0.045) and subgroup analyses stratified by sex. The GC genotype and dominant model of rs11536889 conferred a significantly higher risk of AAD compared with GG genotype in female subjects (GC vs. GG: OR = 3.382, 95%CI = 1.051-10.885, P = 0.041; dominant model: OR = 3.043, 95%CI = 1.041-8.900, P = 0.042). In addition, a significant interaction between the rs11536889 recessive model and dyslipidemia was observed for an increased risk of AAD (P interaction = 0.038, OR = 15.229) after the adjustment for potential clinical covariates. We also used the false-positive report probability (FPRP) analysis to validate the significant results. Furthermore, rs11536889 polymorphism could affect the maximal aortic diameters of AAD (P = 0.037), while AAD patients carrying CC genotype of rs10759932 showed lower serum TLR4 levels than TT genotype carriers (P = 0.043). Conclusions: Our findings provide evidence for the association between TLR4 polymorphisms and AAD susceptibility in a Chinese Han population, which may have some implications for understanding the role of TLR4 in the pathophysiology of AAD.


Assuntos
Aneurisma Dissecante , Aneurisma Aórtico , Polimorfismo de Nucleotídeo Único/genética , Receptor 4 Toll-Like/genética , Adulto , Idoso , Aneurisma Dissecante/sangue , Aneurisma Dissecante/epidemiologia , Aneurisma Dissecante/genética , Aneurisma Dissecante/patologia , Aorta/patologia , Aneurisma Aórtico/sangue , Aneurisma Aórtico/epidemiologia , Aneurisma Aórtico/genética , Aneurisma Aórtico/patologia , Estudos de Casos e Controles , China , Feminino , Interação Gene-Ambiente , Humanos , Masculino , Pessoa de Meia-Idade , Receptor 4 Toll-Like/sangue
19.
Ann Surg ; 271(5): 922-931, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-30480558

RESUMO

OBJECTIVE AND BACKGROUND: Pattern recognition receptors (PRRs) on immune and parenchymal cells can detect danger-associated molecular patterns (DAMPs) released from cells damaged during ischemia-reperfusion injury (IRI), in heart attack or stroke settings, but also as an unavoidable consequence of solid organ transplantation. Despite IRI being a significant clinical problem across all solid organ transplants, there are limited therapeutics and patient-specific diagnostics currently available. METHODS: We screened portal blood samples obtained from 67 human liver transplant recipients both pre- [portal vein (PV) sample] and post-(liver flush; LF) reperfusion for their ability to activate a panel of PRRs, and analyzed this reactivity in relation to biopsy-proven IRI. RESULTS: PV samples from IRI+ orthotopic liver transplantation (OLT) patients (n = 35) decreased activation of hTLR4- and hTLR9-transfected cells, whereas PV from IRI- patients (n = 32) primarily increased hTLR7 and hNOD2 activation. LF samples from OLT-IRI patients significantly increased activation of hTLR4 and hTLR9 over IRI- LF. In addition, the change from baseline reactivity to hTLR4/9/NOD2 was significantly higher in IRI+ than IRI- OLT patients. CONCLUSIONS: These results demonstrate that TLR4/7/9 and NOD2 are involved in either promoting or attenuating hepatic IRI, and suggest a diagnostic screening of portal blood for reactivity to these PRRs might prove useful for prediction and/or therapeutic intervention in OLT patients before transplantation.


Assuntos
Biomarcadores/sangue , Transplante de Fígado , Proteína Adaptadora de Sinalização NOD2/sangue , Reconhecimento Automatizado de Padrão , Medicina de Precisão , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/prevenção & controle , Receptor 4 Toll-Like/sangue , Feminino , Humanos , Imunidade Inata , Masculino , Pessoa de Meia-Idade , Proteína Adaptadora de Sinalização NOD2/imunologia , Transdução de Sinais , Receptor 4 Toll-Like/imunologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-30924423

RESUMO

OBJECTIVE: Hashimoto's thyroiditis (HT) is an autoimmune disorder caused by the interaction between genes and environmental triggers. HT is the most common endocrine disorder, as well as the most common cause of hypothyroidism. Autoimmunity plays a crucial role in the pathogenesis of HT and recent studies suggest that Toll-like receptor (TLR) signals lead to increased inflammatory response. The aim of our study is to investigate whether TLR-2 and TLR-4 levels and gene polymorphisms contribute to the damaged immune response leading to HT. METHODS: Using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, single-nucleotide polymorphisms (SNPs) of TLR2 gene Arg677Trp, Arg753Gln, 196-174 del and TLR4 gene Asp299Gly, Thr399Ile were studied in 100 patients with HT and 100 healthy controls. Also, we investigated serum levels of TLR-2 and TLR-4 in the immunopathogenesis of HT. TLR-2 and TLR-4 serum levels were found to be significantly higher in HT patients than the control group. However, no statistical significance was found between patient and control groups in terms of genotype frequencies and allele frequency distribution of TLR2 gene Arg677Trp, Arg753Gln, 196-174 del and TLR4 gene Asp299Gly, Thr399Ile polymorphisms. RESULT: TLR2 gene Arg677Trp, Arg753Gln, 196-174 del and TLR4 gene Asp299Gly, Thr399Ile polymorphism do not appear to have a role in the development of HT disease. However, in our study, serum levels of TLR-2 and TLR-4 were found to be higher in HT patients than control groups. CONCLUSION: These findings suggest that TLR-2 and TLR-4 play an important role in the immunopathologic mechanism of disease by causing an increase in proinflammatory response.


Assuntos
Doença de Hashimoto/sangue , Receptor 2 Toll-Like/sangue , Receptor 4 Toll-Like/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Doença de Hashimoto/diagnóstico , Doença de Hashimoto/genética , Doença de Hashimoto/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Regulação para Cima , Adulto Jovem
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