Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.588
Filtrar
1.
Medicine (Baltimore) ; 98(28): e16429, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305465

RESUMO

Significant liver histological changes (SLHC) were defined as moderate to severe liver inflammation (A2 or higher) and/or fibrosis (F2 or higher) using the METAVIR scoring system. This study aimed to develop an algorithm for the non-invasive detection of SLHC in patients with chronic hepatitis B (CHB) and normal or mildly elevated alanine transaminase (ALT) levels.Using liver histology as gold standard, we developed a simple algorithm for the diagnosis of SLHC in a training set (504 patients), and then validated the diagnostic accuracy in a validation set (166 patients).A new algorithm (AAG) attributed to age, ALT, and gamma-glutamyl transpeptidase (GGT) was developed. In the training set, the area under ROC curve (AUROC) of AAG was significantly higher than that of ALT, aspartate transaminase (AST), GPR, and APRI for the diagnosis of SLHC (0.74, 0.68, 0.65, 0.56, and 0.53, respectively; all P < .05). In the validation set, the AUROC of AAG was also higher than that of ALT, AST, GPR, and APRI (0.73, 0.65, 0.62, 0.62, and 0.61, respectively; all P < .05). Using AAG ≥ 2, the sensitivity and negative predictive value was 84% to 98% and 75% to 94%, respectively, for the diagnosis of SLHC. Using AAG ≥ 6, the specificity and positive predictive value was 93% to 97% and 67% to 79%, respectively, for the diagnosis of SLHC.The AAG algorithm represents a novel noninvasive method for the diagnosis of SLHC in CHB patients with normal or mildly elevated ALT levels.


Assuntos
Alanina Transaminase/sangue , Algoritmos , Hepatite B Crônica/diagnóstico , Inflamação/diagnóstico , Cirrose Hepática/diagnóstico , Adulto , Biomarcadores/sangue , Biópsia , Feminino , Hepatite B Crônica/enzimologia , Humanos , Inflamação/enzimologia , Fígado/patologia , Cirrose Hepática/enzimologia , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade
2.
Sheng Li Xue Bao ; 71(2): 319-326, 2019 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-31008492

RESUMO

AMP-activated protein kinase (AMPK) is a key enzyme in the regulation of cellular energy homeostasis. Recent studies demonstrated that AMPK also plays an important role in the modulation of inflammation, an energy-intensive molecular response. The commonly used AMPK activators include 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and A-769662. In addition, the biological activities of metformin and adiponectin are closely related to activation of AMPK. Numerous studies have shown that these AMPK activators play an effectively protective role in animal models of acute lung injury, asthma, colitis, hepatitis, atherosclerosis and other inflammatory diseases. Therefore, AMPK activators may have promising potential for the prevention and treatment of inflammation related diseases.


Assuntos
Proteínas Quinases Ativadas por AMP/fisiologia , Adiponectina/farmacologia , Aminoimidazol Carboxamida/farmacologia , Ativação Enzimática , Inflamação/enzimologia , Metformina/farmacologia , Animais , Pironas/farmacologia , Tiofenos/farmacologia
3.
Medicine (Baltimore) ; 98(17): e15414, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31027143

RESUMO

Alpha-fetoprotein (AFP), as the most widely used biomarker of hepatocellular carcinoma (HCC), was correlated with ongoing liver damage. The aim of this study was to evaluate the ability of inflammatory correction-based AFP to identify HCC from other liver diseases.From March 2012 to March 2017, among 926 participants, a total of 501 patients whose transaminases were higher than the upper limit of normal range, including 166 treatment-naïve HCC patients were enrolled in our retrospective study. The liver function, white blood cell (WBC) count and serum AFP level of all patients were collected at the initial stage of admission. The area under the receiver-operating curve (AUROC) of AFP, AFP/(Aspartate aminotransferase*Alanine aminotransferase) [AFP/(AST*ALT)] and AFP/WBC were compared between the HCC group and the control groups for the quantifying diagnostic efficacy.AUROCs of our novel index AFP/(AST*ALT) were up to 0.853 (95% confidence interval, CI 0.818-0.887, P < .001) and 0.825 (95% CI 0.782-0.868, P < .001), respectively, when differentiating HCC from non-HCC patients and from cirrhosis patients, which was superior to AFP and AFP/WBC. Diagnostic performance of AFP/(AST*ALT) could be verified in hepatitis B virus (HBV)- or hepatitis C virus (HCV)-associated HCC patients as well. What's more, AFP/(AST*ALT) had a significant positive and moderate correlation with tumor diameter and presence of cancerous emboli or not (Spearman correlation coefficients were 0.323 and 0.305, respectively; both P < .001). For predicting HCC, the optimal cut-off value of AFP/(AST*ALT) is 1.603, and the sensitivity and specificity were 82.8% and 72.7%, respectively, which were significantly higher than the AFP and AFP/WBC.The serum AFP levels based on correction of liver inflammation can effectively improve the diagnostic performance of HCC, providing a new indicator that is simple, economical and pervasive for clinic.


Assuntos
Carcinoma Hepatocelular/sangue , Neoplasias Hepáticas/sangue , Transaminases/sangue , alfa-Fetoproteínas/metabolismo , Adulto , Área Sob a Curva , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/imunologia , Feminino , Humanos , Inflamação/sangue , Inflamação/enzimologia , Inflamação/imunologia , Contagem de Leucócitos , Fígado/enzimologia , Fígado/imunologia , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/imunologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos
4.
Pharmazie ; 74(3): 168-174, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30961684

RESUMO

Inflammation and vascular smooth muscle cells (VSMCs) play key roles in the development of many cardiovascular diseases (CVDs). Although vitamin D decreases the risks of inflammation related diseases including CVDs, the links between vitamin D, VSMCs and vascular inflammation remained unclear. In this study, we investigated the anti-inflammatory effect and signaling pathways of vitamin D in lipopolysaccharide (LPS)-induced VSMCs. 1,25(OH)2D3 treatment inhibited the significant upregulation of COX-2, PGE2, TNF-α and IL-6 and p38 phosphorylation induced by LPS in A10 cells. Blocking p38 signaling attenuated the inhibitory effect of 1,25(OH)2D3 on the upregulation of COX-2 and phosphorylation of p38. These results indicate 1,25(OH)2D3 suppresses inflammatory response in LPS-induced VSMCs through p38 MAPK signaling pathway.


Assuntos
Calcitriol/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Células Cultivadas , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/antagonistas & inibidores , Dinoprostona/biossíntese , Dinoprostona/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/patologia , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , NF-kappa B/metabolismo , Fosforilação , Ratos , Fator de Necrose Tumoral alfa/metabolismo
5.
Cell Physiol Biochem ; 52(2): 280-301, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30816675

RESUMO

Acid sphingomyelinase hydrolyzes sphingomyelin to ceramide and phosphorylcholine. Ceramide molecules spontaneously interact with each other and generate ceramide-enriched membrane domains. These ceramide-enriched domains further fuse, forming large ceramideenriched platforms that participate in the organization of receptors and in the amplification of signaling molecules. Recent studies have suggested several bacteria and bacterial toxins that stimulate the activation and the translocation of acid sphingomyelinase, which leads to the release of ceramide. The acid sphingomyelinase/ceramide system also regulates the internalization of bacteria into the host cell, the subsequent cytokine release, inflammatory response, and initiation of host cell apoptosis. In addition, ceramide has been implicated in the fusion of phagosomes and lysosomes upon bacterial infection. Thus, this system modulates the reorganization of cell membrane receptors and intracellular signaling molecules during bacteria-host interactions. The acid sphingomyelinase and ceramide system may thus serve as a novel therapeutic target for treating infections.


Assuntos
Infecções Bacterianas/imunologia , Toxinas Bacterianas/imunologia , Ceramidas/imunologia , Transdução de Sinais/imunologia , Esfingomielina Fosfodiesterase/imunologia , Animais , Infecções Bacterianas/patologia , Ativação Enzimática/imunologia , Humanos , Inflamação/enzimologia , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/patologia , Lisossomos/imunologia , Lisossomos/microbiologia , Fagossomos/imunologia , Fagossomos/microbiologia
6.
Med Sci Monit ; 25: 2112-2121, 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30898992

RESUMO

BACKGROUND Our research was designed to investigate the relationship of spleen tyrosine kinase (Syk) and inflammatory factors with coronary heart disease (CHD) and the risk factors of CHD. MATERIAL AND METHODS In our study, 226 patients were enrolled, from October 2017 to March 2018. Clinical and biochemical data were collected. We collected samples of peripheral blood monocytes (PBMs) from the enrolled patients. The patients were divided in 4 groups: patients without coronary artery disease (control group), patients with stable angina pectoris (SAP group), patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS group), and patients with ST-segment elevation acute myocardial infarction group (STEMI group). We detect the protein levels of Syk and inflammatory factors expression by western blot. RESULTS Our results found the protein levels of Syk and inflammatory factors expression in the NSTE-ACS and STEMI groups were higher than those in the SAP and control groups. The protein levels of Syk and inflammatory factors expression in the SAP group were higher than those in the control group. Moreover, there were many risk factors significantly associated with Syk. Besides that, these risk factors were also independent risk factors of CHD. CONCLUSIONS Our results found that the level of Syk was associated with the severity of CHD. From our study, we found that higher levels of Syk and inflammatory factors protein were associated with worse results of the CHD. For the first time, Syk was reported to be a promising therapeutic factor for CHD patients.


Assuntos
Quinase Syk/biossíntese , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Inflamação/sangue , Inflamação/enzimologia , Masculino , Pessoa de Meia-Idade , Monócitos/enzimologia , Intervenção Coronária Percutânea/métodos , Fatores de Risco , Quinase Syk/sangue , Transcriptoma
7.
Int J Mol Med ; 43(5): 2241-2251, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896805

RESUMO

Osteoarthritis (OA) is the most common type of degenerative joint disease and secreted inflammatory molecules serve a pivotal role in it. Peimine has been reported to have anti­inflammatory activity. In order to investigate the potential therapeutic role of Peimine in OA, mouse articular chondrocytes were treated with IL­1ß and different doses of Peimine in vitro. The data revealed that Peimine not only suppressed IL­1ß­induced production of nitric oxide (NO) and prostaglandin E2, but also reduced the protein levels of inducible NO synthase (iNOS) and cyclooxygenase­2 (COX­2). In addition, Peimine inhibited the IL­1ß­induced mRNA expression of matrix metalloproteinase (MMP)­1, MMP­3, MMP­9, MMP­13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)­4 and ADAMTS­5. Furthermore, Peimine inhibited IL­1ß­induced activation of the mitogen­activated protein kinase (MAPK) pathway. The protective effect of Peimine on IL­1ß­treated chondrocytes was attenuated following activation of the MAPK pathway, as demonstrated by the increased expression levels of MMP­3, MMP­13, ADAMTS­5, iNOS and COX­2 compared with the Peimine group. The in vivo data suggested that Peimine limited the development of OA in the mouse model. In general, the data indicate that Peimine suppresses IL­1ß­induced inflammation in mouse chondrocytes by inhibiting the MAPK pathway, suggesting a promising therapeutic role for Peimine in the treatment of OA.


Assuntos
Cevanas/uso terapêutico , Condrócitos/enzimologia , Condrócitos/patologia , Regulação para Baixo , Inflamação/enzimologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas ADAMTS/metabolismo , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Sobrevivência Celular/efeitos dos fármacos , Cevanas/farmacologia , Condrócitos/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/biossíntese , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Inflamação/patologia , Interleucina-1beta , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Osteoartrite/patologia
8.
Biochimie ; 160: 28-33, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30763639

RESUMO

Osteoarthritis (OA) is one of the main locomotor disorders in horses. Although nonsteroidal anti-inflammatory drugs are the first-line treatment for OA, opioids could also be used. In previous studies, opioids showed promising anti-inflammatory and analgesic effects. In this study, we aimed to investigate the effects of two opioids (morphine and methadone) against inflammation in lipopolysaccharide (LPS)-stimulated synoviocytes by analyzing microsomal prostaglandin E synthase-1 (mPGES-1) and prostaglandin-endoperoxide synthase 2 (PTGS2) expression. Synoviocytes were obtained from the joints at the distal limbs of dead animals. The cytotoxic effects of LPS, morphine, and methadone were investigated by using a cell viability assay with crystal violet dye. Synoviocytes were treated with LPS, LPS plus morphine, or LPS plus methadone for 3, 6, and 12 h, and mPGES-1 and PTGS2 expression was measured using real-time polymerase chain reaction. LPS, and morphine did not affect the viability of synoviocytes, even at high concentrations. LPS treatment increased mPGES-1 and PTGS2 expression, whereas morphine inhibited the increase in mPGES-1 and PTGS2 expression in LPS-stimulated synoviocytes. Methadone did not inhibit mPGES-1 or PTGS2 expression. These results suggest that morphine may exhibit anti-inflammatory effect; therefore, it might be beneficial for the treatment of OA.


Assuntos
Ciclo-Oxigenase 2/química , Inflamação/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Metadona/farmacologia , Microssomos/enzimologia , Morfina/farmacologia , Prostaglandina-E Sintases/antagonistas & inibidores , Sinoviócitos/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Animais , Células Cultivadas , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Cavalos , Inflamação/induzido quimicamente , Inflamação/enzimologia , Masculino , Sinoviócitos/imunologia , Sinoviócitos/metabolismo , Sinoviócitos/patologia
9.
J Biol Chem ; 294(5): 1697-1705, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30710016

RESUMO

Prostaglandin endoperoxide H synthases-1 and -2, commonly called cyclooxygenases-1 and -2 (COX-1 and -2), catalyze the committed step in prostaglandin biosynthesis-the conversion of arachidonic acid to prostaglandin endoperoxide H2 Both COX isoforms are sequence homodimers that function as conformational heterodimers having allosteric (Eallo) and catalytic (Ecat) subunits. At least in the case of COX-2, the enzyme becomes folded into a stable Eallo/Ecat pair. Some COX inhibitors (i.e. nonsteroidal anti-inflammatory drugs and coxibs) and common fatty acids (FAs) modulate Ecat activity by binding Eallo. However, the interactions and outcomes often differ between isoforms. For example, naproxen directly and completely inhibits COX-1 by binding Ecat but indirectly and incompletely inhibits COX-2 by binding Eallo. Additionally, COX-1 is allosterically inhibited up to 50% by common FAs like palmitic acid, whereas COX-2 is allosterically activated 2-fold by palmitic acid. FA binding to Eallo also affects responses to COX inhibitors. Thus, COXs are physiologically and pharmacologically regulated by the FA tone of the milieu in which each operates-COX-1 in the endoplasmic reticulum and COX-2 in the Golgi apparatus. Cross-talk between Eallo and Ecat involves a loop in Eallo immediately downstream of Arg-120. Mutational studies suggest that allosteric modulation requires a direct interaction between the carboxyl group of allosteric effectors and Arg-120 of Eallo; however, structural studies show some allosterically active FAs positioned in COX-2 in a conformation lacking an interaction with Arg-120. Thus, many details about the biological consequences of COX allosterism and how ligand binding to Eallo modulates Ecat remain to be resolved.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Ácidos Graxos/metabolismo , Inflamação/tratamento farmacológico , Domínio Catalítico , Humanos , Inflamação/enzimologia , Inflamação/patologia
10.
Chemosphere ; 222: 355-363, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30710761

RESUMO

Hexavalent chromium [Cr(VI)] is the main harmful component in the atmosphere released by chemical industry. The study was conducted to assess Cr(VI) inducing cardiovascular diseases (CVDs) in vitro by investigating the effects of Cr(VI) on bovine hemoglobin (BHb) and human umbilical vein endothelial cells (HUVECs). Multi-spectroscopic techniques and molecular docking method were used to determine the interaction of Cr(VI) and BHb. Fluorescence spectra results showed that the quenching constant (Ksv) decreased with temperature raise, indicating that Cr(VI) quenches BHb fluorescence through static quenching mechanism. The number of binding sites was 1.14 (310 K), enthalpy and entropy changes revealed the interaction of Cr(VI) and BHb was driven by hydrogen bonds. The results of synchronous fluorescence and circular dichroism (CD) spectra suggested that Cr(VI) could change BHb conformation and influence the microenvironment of Trp and Tyr residues. Moreover, in order to study Cr(VI) induced HUVECs damage, inflammatory factors were detected at the mRNA level, JNK and p38 MAPK pathways were analyzed. The results shown that Cr(VI) could induce mRNA expression of NLRP3, ICAM-1, VCAM-1, TNF-α and IL-1ß, and increased intracellular ROS. Furthermore, Cr(VI) could induce oxidative stress in HUVECs, and then activate JNK and p38 MAPK pathways, ultimately lead to apoptosis of HUVECs by activating mitochondrial apoptosis pathways. These results suggested that Cr(VI) might bring about CVDs by both changing the BHb conformation and inducing HUVECs damage.


Assuntos
Cromo/toxicidade , Células Endoteliais/efeitos dos fármacos , Hemoglobinas/efeitos dos fármacos , Simulação de Acoplamento Molecular , Termodinâmica , Animais , Sítios de Ligação , Bovinos , Hemoglobinas/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/enzimologia , Inflamação/metabolismo , Conformação Molecular/efeitos dos fármacos , Análise Espectral
11.
BMC Neurosci ; 20(1): 6, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30786875

RESUMO

BACKGROUND: Epidemiologic studies strongly suggest that the pathophysiology of late-onset Alzheimer disease (AD) versus early-onset AD has environmental rather than genetic causes, thus revealing potentially novel therapeutic targets to limit disease progression. Several studies supporting the "pathogen hypothesis" of AD demonstrate a strong association between pathogens and the production of ß-amyloid, the pathologic hallmark of AD. Although the mechanism of pathogen-induced neurodegeneration of AD remains unclear, astrocytes, a key player of the CNS innate immune response and producer/metabolizer of ß-amyloid, have been implicated. We hypothesized that Chlamydia pneumoniae infection of human astrocytes alters the expression of the amyloid precursor protein (APP)-processing secretases, ADAM10, BACE1, and PSEN1, to promote ß-amyloid formation. Utilizing immunofluorescent microscopy, molecular, and biochemical approaches, these studies explore the role of an intracellular respiratory pathogen, Chlamydia pneumoniae, as an environmental trigger for AD pathology. Human astrocytoma cells in vitro were infected with Chlamydia pneumoniae over the course of 6-72 h. The gene and protein expression, as well as the enzymatic activity of non-amyloidogenic (ADAM10), and pro-amyloidogenic (BACE1 and PSEN1) secretases were qualitatively and quantitatively assessed. In addition, the formation of toxic amyloid products as an outcome of pro-amyloidogenic APP processing was evaluated through various modalities. RESULTS: Chlamydia pneumoniae infection of human astrocytoma cells promoted the transcriptional upregulation of numerous genes implicated in host neuroinflammation, lipid homeostasis, microtubule function, and APP processing. Relative to that of uninfected astrocytes, BACE1 and PSEN1 protein levels were enhanced by nearly twofold at 48-72 h post-Chlamydia pneumoniae infection. The processing of APP in Chlamydia pneumoniae-infected astrocytes favors the pro-amyloidogenic pathway, as demonstrated by an increase in enzymatic activity of BACE1, while that of ADAM10 was decreased. Fluorescence intensity of ß-amyloid and ELISA-quantified levels of soluble-APP by products revealed temporally similar increases, confirming a BACE1/PSEN1-mediated processing of APP. CONCLUSIONS: Our findings suggest that Chlamydia pneumoniae infection of human astrocytes promotes the pro-amyloidogenic pathway of APP processing through the upregulation of expression and activity of ß-secretase, upregulated expression of γ-secretase, and decreased activity of α-secretase. These effects of astrocyte infection provide evidence for a direct link between Chlamydia pneumoniae and AD pathology.


Assuntos
Doença de Alzheimer/enzimologia , Peptídeos beta-Amiloides/metabolismo , Astrócitos/enzimologia , Infecções por Chlamydophila/enzimologia , Chlamydophila pneumoniae , Proteína ADAM10/metabolismo , Doença de Alzheimer/imunologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Astrócitos/imunologia , Astrócitos/patologia , Linhagem Celular Tumoral , Infecções por Chlamydophila/imunologia , Infecções por Chlamydophila/patologia , Expressão Gênica , Humanos , Inflamação/enzimologia , Inflamação/patologia , Proteínas de Membrana/metabolismo , Presenilina-1/metabolismo
12.
Expert Opin Ther Pat ; 29(3): 199-213, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30760060

RESUMO

INTRODUCTION: Aldose reductase (ALR2) is both the key enzyme of the polyol pathway, whose activation under hyperglycemic conditions leads to the development of chronic diabetic complications, and the crucial promoter of inflammatory and cytotoxic conditions, even under a normoglycemic status. Accordingly, it represents an excellent drug target and a huge effort is being done to disclose novel compounds able to inhibit it. AREAS COVERED: This literature survey summarizes patents and patent applications published over the last 5 years and filed for natural, semi-synthetic and synthetic ALR2 inhibitors. Compounds described have been discussed and analyzed from both chemical and functional angles. EXPERT OPINION: Several ALR2 inhibitors with a promising pre-clinical ability to address diabetic complications and inflammatory diseases are being developed during the observed timeframe. Natural compounds and plant extracts are the prevalent ones, thus confirming the use of phytopharmaceuticals as an increasingly pursued therapeutic trend also in the ALR2 inhibitors field. Intriguing hints may be taken from synthetic derivatives, the most significant ones being represented by the differential inhibitors ARDIs. Differently from classical ARIs, these compounds should fire up the therapeutic efficacy of the class while minimizing its side effects, thus overcoming the existing limits of this kind of inhibitors.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Aldeído Redutase/metabolismo , Animais , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/enzimologia , Inibidores Enzimáticos/efeitos adversos , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Patentes como Assunto
13.
Nature ; 566(7745): 548-552, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30760924

RESUMO

Singlet molecular oxygen (1O2) has well-established roles in photosynthetic plants, bacteria and fungi1-3, but not in mammals. Chemically generated 1O2 oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine4, whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 15. Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure6. However, whether indoleamine 2,3-dioxygenase 1 forms 1O2 and whether this contributes to blood pressure control have remained unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of 1O2. We observed that in the presence of hydrogen peroxide, the enzyme generates 1O2 and that this is associated with the stereoselective oxidation of L-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophan-derived hydroperoxide acts in vivo as a signalling molecule, inducing arterial relaxation and decreasing blood pressure; this activity is dependent on Cys42 of protein kinase G1α. Our findings demonstrate a pathophysiological role for 1O2 in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions.


Assuntos
Pressão Sanguínea/fisiologia , Inflamação/sangue , Inflamação/fisiopatologia , Oxigênio Singlete/metabolismo , Vasodilatadores/metabolismo , Animais , Linhagem Celular , Proteína Quinase Dependente de GMP Cíclico Tipo I/antagonistas & inibidores , Proteína Quinase Dependente de GMP Cíclico Tipo I/química , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Cisteína/metabolismo , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/química , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação/enzimologia , Masculino , Oxirredução/efeitos dos fármacos , Ratos , Transdução de Sinais , Oxigênio Singlete/química , Triptofano/química , Triptofano/metabolismo
14.
Int J Mol Sci ; 20(2)2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30654600

RESUMO

Histamine is a well-known mediator of inflammation that is released from mast cells and basophils. To date, many studies using histamine receptor antagonists have shown that histamine acts through four types of receptors: H1, H2, H3, and H4. Thus, histamine plays more roles in various diseases than had been predicted. However, our knowledge about histamine-producing cells and the molecular mechanisms underlying histamine production at inflammatory sites is still incomplete. The histamine producing enzyme, histidine decarboxylase (HDC), is commonly induced at inflammatory sites during the late and chronic phases of both allergic and non-allergic inflammation. Thus, histamine levels in tissues are maintained at effective concentrations for hours, enabling the regulation of various functions through the production of cytokines/chemokines/growth factors. Understanding the regulation of histamine production will allow the development of a new strategy of using histamine antagonists to treat inflammatory diseases.


Assuntos
Histidina Descarboxilase/metabolismo , Inflamação/enzimologia , Inflamação/patologia , Animais , Histamina/farmacologia , Humanos , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo
15.
Thromb Haemost ; 119(3): 421-430, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30616245

RESUMO

BACKGROUND: Inflammation plays an important role in thrombus formation, and Sirtuin 1 (SIRT1) negatively regulates inflammation via deacetylating nuclear factor-kappa B. However, the relationship between SIRT1-regulated inflammation and deep vein thrombosis (DVT) is still unknown. OBJECTIVE: The aim of this study was to investigate whether SIRT1 plays a critical role in inferior vena cava (IVC) stenosis-induced DVT. MATERIALS AND METHODS: Thrombus weight and histopathologic analysis of IVC were evaluated at different time points after IVC stenosis in rats. Serum levels of inflammatory cytokines and protein expressions of SIRT1, acetylated p65 (Ace-p65), phosphorylated p65 (p-p65) and tissue factor (TF) in thrombosed IVC were assessed. Besides, the effects of resveratrol (RES, a SIRT1 agonist) and EX527 (a selective SIRT1 inhibitor) on DVT were evaluated. RESULTS: Thrombus weight was increased from 1 to 3 days after IVC stenosis, and then was decreased afterwards. Leukocytes infiltration appeared and serum levels of cytokines were significantly increased in rats of IVC stenosis. SIRT1 protein expression was significantly down-regulated at 1 hour and 1 day after stenosis, while p-p65, Ace-p65 and TF protein expressions appeared a contrary trend. RES reduced thrombus weight, leukocytes infiltration, levels of tumour necrosis factor-α and interleukin-1ß and protein expressions of Ace-p65 and TF as well. Moreover, RES significantly increased the protein and messenger ribonucleic acid expressions of SIRT1, while EX527 abolished the protective effects of RES. CONCLUSION: SIRT1 activation attenuated IVC stenosis-induced DVT via anti-inflammation in rats. Therefore, SIRT1 may be a potential therapeutic target that could ameliorate DVT.


Assuntos
Mediadores da Inflamação/metabolismo , Inflamação/enzimologia , Transdução de Sinais , Sirtuína 1/metabolismo , Fator de Transcrição RelA/metabolismo , Veia Cava Inferior/enzimologia , Trombose Venosa/enzimologia , Acetilação , Animais , Anti-Inflamatórios/farmacologia , Carbazóis/farmacologia , Modelos Animais de Doenças , Feminino , Fibrinolíticos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Inflamação/imunologia , Inflamação/patologia , Inflamação/prevenção & controle , Mediadores da Inflamação/imunologia , Masculino , Fosforilação , Ratos Sprague-Dawley , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Fatores de Tempo , Veia Cava Inferior/efeitos dos fármacos , Veia Cava Inferior/imunologia , Veia Cava Inferior/patologia , Trombose Venosa/imunologia , Trombose Venosa/patologia , Trombose Venosa/prevenção & controle
16.
Mol Cell ; 73(3): 413-428.e7, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30598363

RESUMO

Receptor-interacting protein kinase (RIPK) 1 functions as a key mediator of tissue homeostasis via formation of Caspase-8 activating ripoptosome complexes, positively and negatively regulating apoptosis, necroptosis, and inflammation. Here, we report an unanticipated cell-death- and inflammation-independent function of RIPK1 and Caspase-8, promoting faithful chromosome alignment in mitosis and thereby ensuring genome stability. We find that ripoptosome complexes progressively form as cells enter mitosis, peaking at metaphase and disassembling as cells exit mitosis. Genetic deletion and mitosis-specific inhibition of Ripk1 or Caspase-8 results in chromosome alignment defects independently of MLKL. We found that Polo-like kinase 1 (PLK1) is recruited into mitotic ripoptosomes, where PLK1's activity is controlled via RIPK1-dependent recruitment and Caspase-8-mediated cleavage. A fine balance of ripoptosome assembly is required as deregulated ripoptosome activity modulates PLK1-dependent phosphorylation of downstream effectors, such as BUBR1. Our data suggest that ripoptosome-mediated regulation of PLK1 contributes to faithful chromosome segregation during mitosis.


Assuntos
Caspase 8/metabolismo , Instabilidade Cromossômica , Neoplasias do Colo/enzimologia , Fibroblastos/enzimologia , Mitose , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Aneuploidia , Animais , Apoptose , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Caspase 8/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Segregação de Cromossomos , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Proteína de Domínio de Morte Associada a Fas/genética , Proteína de Domínio de Morte Associada a Fas/metabolismo , Fibroblastos/patologia , Células HT29 , Humanos , Inflamação/enzimologia , Inflamação/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais
17.
Biomed Pharmacother ; 111: 347-358, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30593001

RESUMO

Psoriasis is a debilitating autoimmune disease of the skin characterized by acanthosis and hyperkeratosis resulting from excessive growth of keratinocytes in the epidermis and inflammatory infiltrates in the dermis. Innate immune cells such as dendritic cells (DCs), perform a critical role in the pathophysiology of psoriasis by presenting inflammatory/costimulatory signals for differentiation of Th17 cells. Recent studies point to the involvement of spleen tyrosine kinase (SYK) in inflammatory signaling cascade of DCs. However, it is yet to be determined whether SYK inhibition in DCs would lead to diminishment of psoriatic inflammation. Therefore, our study evaluated the effects of SYK inhibitor, R406 on imiquimod (IMQ)-induced psoriasis-like inflammation, expression of costimulatory/inflammatory molecules in DCs and their relationship with Th17/Treg cells. Our data show that R406 causes attenuation of IMQ-induced dermal inflammation as shown by reduction in ear/back skin thickness, acanthosis and myeloperoxidase activity. This was concurrent with reduction in inflammatory cytokines and co-stimulatory molecules in CD11c + DCs such as IL-6, IL-23, MHCII, and CD40. This favoured the suppression of Th17 cells and upregulation of Treg cells in R406-treated mice with psoriasis-like inflammation. Direct activation of TLR7 by IMQ in splenocytic cultures led to increased SYK expression in CD11c + DCs and release of IL-23/IL-6. IMQ-induced IL-6/IL-23 levels were significantly diminished by SYK inhibitor, R406 in splenocytic cultures. In essence, our study shows that SYK inhibition supresses psoriasis-like inflammation by modifying DC function in mice. Further, it implies that SYK inhibition could be a prospective therapeutic approach for the treatment of psoriasis-like inflammation.


Assuntos
Mediadores da Inflamação/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Psoríase/tratamento farmacológico , Baço/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/enzimologia , Células Dendríticas/patologia , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Proteínas Quinases/farmacologia , Psoríase/enzimologia , Psoríase/patologia , Distribuição Aleatória , Baço/enzimologia , Baço/patologia , Células Th17/enzimologia , Células Th17/patologia
18.
Microbiol Mol Biol Rev ; 83(1)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30567936

RESUMO

The literature review presented here details recent research involving members of the poly(ADP-ribose) polymerase (PARP) family of proteins. Among the 17 recognized members of the family, the human enzyme PARP1 is the most extensively studied, resulting in a number of known biological and metabolic roles. This review is focused on the roles played by PARP enzymes in host-pathogen interactions and in diseases with an associated inflammatory response. In mammalian cells, several PARPs have specific roles in the antiviral response; this is perhaps best illustrated by PARP13, also termed the zinc finger antiviral protein (ZAP). Plant stress responses and immunity are also regulated by poly(ADP-ribosyl)ation. PARPs promote inflammatory responses by stimulating proinflammatory signal transduction pathways that lead to the expression of cytokines and cell adhesion molecules. Hence, PARP inhibitors show promise in the treatment of inflammatory disorders and conditions with an inflammatory component, such as diabetes, arthritis, and stroke. These functions are correlated with the biophysical characteristics of PARP family enzymes. This work is important in providing a comprehensive understanding of the molecular basis of pathogenesis and host responses, as well as in the identification of inhibitors. This is important because the identification of inhibitors has been shown to be effective in arresting the progression of disease.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Imunidade/imunologia , Inflamação/enzimologia , Poli(ADP-Ribose) Polimerases/imunologia , Animais , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Plantas/enzimologia , Poli(ADP-Ribose) Polimerases/química , Conformação Proteica , Estresse Fisiológico/imunologia
19.
PLoS One ; 13(12): e0208279, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30571701

RESUMO

Multiple organ dysfunction caused by hyperinflammation remains the major cause of mortality during sepsis. Excessive M1-macrophage activation leads to systemic inflammatory responses. Gene related to anergy in lymphocytes (Grail) is regarded as an important regulator of T cells that functions by diminishing cytokine production. However, its role in regulating macrophage activation and organ injury during sepsis remains unclear. Our aim was to examine the effects of Grail on macrophage reactivity and organ injury in endotoxemic animals. Wild-type and Grail knockout mice were injected with vehicle or Escherichia coli lipopolysaccharide and observed for 24 h. Changes in blood pressure, heart rate, blood glucose, and biochemical variables were then examined. Moreover, levels of neutrophil infiltration, MMP-9, and caspase 3 were analyzed in the lungs of animals. The expression of pro-inflammatory cytokines in J774A, RAW264.7, and primary peritoneal macrophages stimulated with LPS were also assessed in the presence or absence of Grail. Results indicated that loss of Grail expression enhances the induction of pro-inflammatory cytokines in J774A, RAW264.7, and primary peritoneal macrophages treated with LPS. Furthermore, LPS-induced macrophage hyperactivation was alleviated by ectopic Grail overexpression. In vivo studies showed that Grail deficiency exacerbates organ damage in endotoxemic animals. Levels of neutrophil infiltration, MMP-9, and caspase 3 were significantly increased in the lungs of Grail-deficient endotoxemic mice. Thus, these results suggest that Grail contributes to the attenuation of hyperinflammation caused by activated macrophages and prevents organ damage in endotoxemic mice. We suggest that Grail signaling could be a therapeutic target for endotoxemia.


Assuntos
Inflamação/enzimologia , Inflamação/prevenção & controle , Macrófagos Peritoneais/enzimologia , Especificidade de Órgãos , Ubiquitina-Proteína Ligases/metabolismo , Animais , Peso Corporal , Caspase 3/metabolismo , Creatinina/sangue , Citocinas/metabolismo , Endotoxemia/sangue , Endotoxemia/metabolismo , Endotoxemia/patologia , Deleção de Genes , Hemodinâmica , Inflamação/patologia , Mediadores da Inflamação/metabolismo , L-Lactato Desidrogenase/sangue , Lipopolissacarídeos , Pulmão/enzimologia , Pulmão/patologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Células RAW 264.7
20.
Neuroimmunomodulation ; 25(4): 225-237, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30566959

RESUMO

OBJECTIVES: The appearance of endogenous tyrosine hydroxylase-positive cells (TH+ cells) in collagen-induced arthritis was associated with an anti-inflammatory effect. Here we investigated putative anti-inflammatory and antinociceptive effects of the transfer of induced, bone marrow stem cell-derived TH+ cells (iTH+ cells) on murine antigen-induced arthritis (AIA). METHODS: Bone marrow-derived stem cells were differentiated into iTH+ cells. These cells were transferred to mice immunized against methylated bovine serum albumin (mBSA) 2 days before AIA was induced by injection of mBSA into one knee joint. In AIA control mice and iTH+-treated mice the severity of AIA, pain-related behavior, humoral and cellular responses, and the invasion of macrophages into the dorsal root ganglia were assessed. RESULTS: The intravenous transfer of iTH+ cells before AIA induction did not cause a sustained suppression of AIA severity but significantly reduced inflammation-evoked pain-related behavior. The iTH+ cells used for transfer exhibited enormous production of interleukin-4. A major difference between AIA control mice and iTH+-treated AIA mice was a massive invasion of the dorsal root ganglia by iNOS-negative, arginine 1-positive macrophages corresponding to an M2 phenotype. The differences in other cellular and humoral immune parameters such as release of cytokines from stimulated lymphocytes between AIA control mice and iTH+-treated mice were small. CONCLUSIONS: The transfer of iTH+ cells may cause a long-lasting reduction of arthritis-induced pain even if it does not ameliorate inflammation. The invasion of M2 macrophages into the dorsal root ganglia is likely to be an important mechanism of antinociception.


Assuntos
Manejo da Dor/métodos , Dor/enzimologia , Transplante de Células-Tronco/métodos , Tirosina 3-Mono-Oxigenase/administração & dosagem , Animais , Células Cultivadas , Feminino , Inflamação/enzimologia , Inflamação/patologia , Inflamação/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dor/patologia , Manejo da Dor/tendências , Transplante de Células-Tronco/tendências , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA