RESUMO
Genes of host plants and parasitic nematodes govern the plant-nematode interaction. The biological receptors and parasitism effectors are variable among plant species and nematode populations, respectively. In the present study, hatch testing and bioassays on cabbage, oilseed radish, and mustard were conducted to compare the biological characteristics among six populations of the beet cyst nematode Heterodera schachtii. Genetic patterns of the vap1 gene for the studied populations were distinct as shown by denaturing the gradient gel electrophoresis of PCR-amplified gene fragments. Concurrently, significant differences in the hatching rates, number of penetrated J2 in roots, and eggs/cyst ratios among the six nematode populations for the three cruciferous species were observed. In conclusion, analyzing the population genetic structure of H. schachtii plays a pivotal role in illustrating the variability in the plant-nematode interaction among its populations and plant species, which in its role leads to developing nematode management depending on plant resistance.
Assuntos
Tylenchoidea , Animais , Tylenchoidea/genética , Mostardeira , Variação Genética , Doenças das Plantas/genética , Doenças das Plantas/parasitologiaRESUMO
The discovery of a dual MAO-B/SSAO inhibitor PXS-5131 is reported. The compound offers a compact and rigid three-dimensional structure with superior selectivity over MAO-A. Potency and selectivity are linked to both the double bond geometry and stereochemistry of the allylamine moiety, highlighting the importance of optimal set up of these features in the class of amine oxidase inhibitors. PXS-5131 possesses an attractive preclinical pharmacokinetic profile and has anti-inflammatory properties in models of acute inflammation and neuroinflammation.
Assuntos
Amina Oxidase (contendo Cobre) , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Monoaminoxidase , Inibidores da Monoaminoxidase/farmacologiaRESUMO
BACKGROUND: Vascular adhesion protein-1 (VAP-1) is believed to play a role in inflammation. Studies have suggested that VAP-1-mediated activation of inflammation is dependent on NF-κB, leading to secretion of the interleukin (IL)-8; however, no reports have addressed the association between VAP-1 and NF-κB/IL-8 signaling in oral squamous cell carcinoma (OSCC). This study aimed to investigate the role of VAP-1 in OSCC and further explore whether VAP-1 is involved in the regulation of neutrophil infiltration in the tumor microenvironment (TME). METHODS: Immunochemistry staining was used to observe VAP-1 expression. CCK-8 and Transwell assays were used to measure cell proliferation, migration, and invasion. OSCC xenograft mouse models were used for in vivo verification of the VAP-1 function. The expression of NF-κB and IL-8 were determined by qRT-PCR and western blot. ELISA for IL-8 was also conducted. The relationship between VAP-1 expression and neutrophil infiltration was analyzed by immunofluorescence. RESULTS: VAP-1 was overexpressed in human OSCC tissues. Downregulation of VAP-1 suppressed OSCC cells proliferation, migration, and invasion in vitro and inhibited tumor proliferation and metastasis in vivo. Additionally, downregulation of VAP-1 inhibited NF-κB/IL-8 signaling in vitro and in vivo. VAP-1 expression was positively correlated with neutrophil infiltration in human OSCC tissues. Moreover, blocking VAP-1 decreased neutrophil infiltration by reducing IL-8 production. CONCLUSIONS: VAP-1 downregulation in OSCC suppresses tumor growth and metastasis by inhibiting NF-κB/IL-8 signaling and reducing neutrophil infiltration in the TME, suggesting that VAP-1 may be a potential therapeutic target for OSCC.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Animais , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Regulação para Baixo , Neoplasias de Cabeça e Pescoço/genética , Humanos , Inflamação , Interleucina-8/metabolismo , Camundongos , Neoplasias Bucais/patologia , NF-kappa B/metabolismo , Infiltração de Neutrófilos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Microambiente TumoralRESUMO
Modulation of the immunosuppressive tumor microenvironment (TME) is essential for enhancing the anti-tumor effects of immune checkpoint inhibitors (ICIs). Adhesion molecules and enzymes such as vascular adhesion protein-1 (VAP-1), which are expressed in some cancers and tumor vascular endothelial cells, may be involved in the generation of an immunosuppressive TME. In this study, the role of VAP-1 in TME was investigated in 2 murine colon cancer models and human cancer cells. Intraperitoneal administration of the VAP-1-specific inhibitor U-V296 inhibited murine tumor growth by enhancing IFN-γ-producing tumor antigen-specific CD8+ T cells. U-V296 exhibited significant synergistic anti-tumor effects with ICIs. In the TME of mice treated with U-V296, the expression of genes associated with M2-like macrophages, Th2 cells (Il4, Retnla, and Irf4), angiogenesis (Pecam1), and fibrosis (Acta2, Loxl2) were significantly decreased, and the Th1/Th2 balance was increased. H2 O2 , an enzymatic product of VAP-1, which promoted the production of IL-4 by mouse Th2 and inhibited IFN-γ by mouse Th1 and human tumor-infiltrating lymphocytes, was decreased in tumors and CD31+ tumor vascular endothelial cells in the TMEs of mice treated with VAP-1 inhibitor. TCGA database analysis showed that VAP-1 expression was a negative prognostic factor in human cancers, exhibiting a significant positive correlation with IL-4, IL4R, and IL-13 expression and a negative correlation with IFN-γ expression. These results indicated that VAP-1 is involved in the immunosuppressive TMEs through H2 O2 -associated Th2/M2 conditions and may be an attractive target for the development of combination cancer immunotherapy with ICIs.
Assuntos
Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Moléculas de Adesão Celular/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias/imunologia , Neoplasias/terapia , Amina Oxidase (contendo Cobre)/imunologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Moléculas de Adesão Celular/imunologia , Linhagem Celular Tumoral , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Feminino , Imunoterapia/mortalidade , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Changes in dopaminergic neural function can be induced by an acute inflammatory state that, by altering the integrity of the neurovasculature, induces neuronal stress, cell death and causes functional deficits. Effectively blocking these effects of inflammation could, therefore, reduce both neuronal and functional decline. To test this hypothesis, we inhibited vascular adhesion protein 1 (VAP-1), a membrane-bound protein expressed on the endothelial cell surface, that mediates leukocyte extravasation and induces oxidative stress. METHOD: We induced dopaminergic neuronal loss by infusing lipopolysaccharide (LPS) directly into the substantia nigra (SN) in rats and administered the VAP-1 inhibitor, PXS-4681A, daily. RESULTS: LPS produced: an acute inflammatory response, the loss of dopaminergic neurons in the SN, reduced the dopaminergic projection to SN target regions, particularly the dorsolateral striatum (DLS), and a deficit in habit learning, a key function of the DLS. In an attempt to protect SN neurons from this inflammatory response we found that VAP-1 inhibition not only reduced neutrophil infiltration in the SN and striatum, but also reduced the associated striatal microglia and astrocyte response. We found VAP-1 inhibition protected dopamine neurons in the SN, their projections to the striatum and promoted the functional recovery of habit learning. Thus, we reversed the loss of habitual actions, a function usually dependent on dopamine release in DLS and sensitive to striatal dysfunction. CONCLUSIONS: We establish, therefore, that VAP-1 inhibition has an anti-inflammatory profile that may be beneficial in the treatment of dopamine neuron dysfunction caused by an acute inflammatory state in the brain.
Assuntos
Amina Oxidase (contendo Cobre)/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Moléculas de Adesão Celular/metabolismo , Corpo Estriado/metabolismo , Neurônios Dopaminérgicos/metabolismo , Hábitos , Aprendizagem/fisiologia , Compostos Alílicos/farmacologia , Compostos Alílicos/uso terapêutico , Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Moléculas de Adesão Celular/antagonistas & inibidores , Corpo Estriado/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Aprendizagem/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêuticoRESUMO
The vascular adhesion protein-1 (VAP-1) inhibitor ASP8232 reduces albuminuria in patients with type 2 diabetes and chronic kidney disease. A mechanism-based model was developed to quantify the effects of ASP8232 on renal markers from a placebo-controlled Phase 2 study in diabetic kidney disease with 12 weeks of ASP8232 treatment. The model incorporated the available pharmacokinetic, pharmacodynamic (plasma VAP-1 concentration and activity), serum and urine creatinine, serum cystatin C, albumin excretion rate, urinary albumin-to-creatinine ratio, and urine volume information in an integrated manner. Drug-independent time-varying changes and different drug effects could be quantified for these markers using the model. Through simulations, this model provided the opportunity to dissect the relationship and longitudinal association between the estimated glomerular filtration rate and albuminuria and to quantify the pharmacological effects of ASP8232. The developed drug-independent model may be useful as a starting point for other compounds affecting the same biomarkers in a similar time scale.
Assuntos
Albuminúria/tratamento farmacológico , Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Moléculas de Adesão Celular/antagonistas & inibidores , Nefropatias Diabéticas/tratamento farmacológico , Modelos Biológicos , Compostos Orgânicos/farmacologia , Administração Oral , Idoso , Albuminúria/sangue , Albuminúria/etiologia , Amina Oxidase (contendo Cobre)/metabolismo , Biomarcadores/sangue , Biomarcadores/urina , Moléculas de Adesão Celular/metabolismo , Ensaios Clínicos Fase II como Assunto , Simulação por Computador , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/urina , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Compostos Orgânicos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
ASP8232 is a novel inhibitor of vascular adhesion protein-1 that was under evaluation for reducing residual albuminuria in patients with diabetic kidney disease. To characterize the pharmacokinetics (PK) of ASP8232 and its effect on vascular adhesion protein 1 (VAP-1) plasma activity and VAP-1 concentrations (pharmacodynamics, PD) in an integrated and quantitative manner, a target mediated drug disposition model was developed based on pooled data from four completed clinical trials with ASP8232 in healthy volunteers, and in patients with diabetic kidney disease and diabetic macular edema, respectively. In this model, the binding of ASP8232 to its soluble and membrane-bound target in the central and peripheral compartments were included. The model was able to adequately describe the non-linear PK and PD of ASP8232. The observed difference in PK between healthy volunteers and renally impaired patients could be explained by an effect of baseline estimated glomerular filtration rate on ASP8232 clearance and relative bioavailability. The relationship between ASP8232 concentration and VAP-1 inhibition was successfully established and can be applied to simulate drug exposure and degree of VAP-1 inhibition for any given dose of ASP8232 across the spectrum of renal function.
Assuntos
Albuminúria/tratamento farmacológico , Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Moléculas de Adesão Celular/antagonistas & inibidores , Nefropatias Diabéticas/tratamento farmacológico , Modelos Biológicos , Compostos Orgânicos/farmacocinética , Administração Oral , Albuminúria/sangue , Albuminúria/etiologia , Amina Oxidase (contendo Cobre)/sangue , Amina Oxidase (contendo Cobre)/metabolismo , Disponibilidade Biológica , Variação Biológica da População , Moléculas de Adesão Celular/sangue , Moléculas de Adesão Celular/metabolismo , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Simulação por Computador , Nefropatias Diabéticas/sangue , Relação Dose-Resposta a Droga , Feminino , Absorção Gastrointestinal , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Voluntários Saudáveis , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Compostos Orgânicos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Eliminação Renal , Distribuição TecidualRESUMO
Inflammation is a natural response to tissue injury. Uncontrolled inflammatory response leads to inflammatory disease. Acute pancreatitis is one of the main reasons for hospitalization amongst gastrointestinal disorders worldwide. It has been demonstrated that endogenous hydrogen sulfide (H2S), a gasotransmitter and substance P, a neuropeptide, are involved in the inflammatory process in acute pancreatitis. Cell adhesion molecules (CAM) are key players in inflammatory disease. Immunoglobulin (Ig) gene superfamily, selectins, and integrins are involved at different steps of leukocyte migration from blood to the site of injury. When the endothelial cells get activated, the CAMs are upregulated which leads to them interacting with leukocytes. This review summarizes our current understanding of the roles H2S, substance P and adhesion molecules play in acute pancreatitis.
Assuntos
Moléculas de Adesão Celular/genética , Sulfeto de Hidrogênio/metabolismo , Pancreatite/metabolismo , Substância P/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Inflamação/genética , Inflamação/patologia , Integrinas/genética , Leucócitos/metabolismo , Leucócitos/patologia , Pancreatite/genética , Pancreatite/patologia , Selectinas/genética , Substância P/metabolismoRESUMO
The semicarbazide-sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1) or primary amine oxidase (PrAO), is a deaminating enzyme highly expressed in vessels that generates harmful products as a result of its enzymatic activity. As a multifunctional enzyme, it is also involved in inflammation through its ability to bind and promote the transmigration of circulating leukocytes into inflamed tissues. Inflammation is present in different systemic and cerebral diseases, including stroke and Alzheimer's disease (AD). These pathologies show important affectations on cerebral vessels, together with increased SSAO levels. This review summarizes the main roles of SSAO/VAP-1 in human physiology and pathophysiology and discusses the mechanisms by which it can affect the onset and progression of both stroke and AD. As there is an evident interrelationship between stroke and AD, basically through the vascular system dysfunction, the possibility that SSAO/VAP-1 could be involved in the transition between these two pathologies is suggested. Hence, its inhibition is proposed to be an interesting therapeutical approach to the brain damage induced in these both cerebral pathologies.
Assuntos
Doença de Alzheimer/terapia , Amina Oxidase (contendo Cobre)/metabolismo , Moléculas de Adesão Celular/metabolismo , Transtornos Cerebrovasculares/terapia , Acidente Vascular Cerebral/terapia , Doença de Alzheimer/metabolismo , Aminas/metabolismo , Animais , Adesão Celular , Angiopatia Amiloide Cerebral/metabolismo , Transtornos Cerebrovasculares/metabolismo , Progressão da Doença , Células Endoteliais/metabolismo , Glucose/metabolismo , Humanos , Inflamação/terapia , Leucócitos/citologia , Camundongos , Ratos , Acidente Vascular Cerebral/metabolismoRESUMO
Psoriasis is a chronic inflammatory skin condition and angiotensin-converting enzyme (ACE) is a key circulating enzyme converting angiotensin (Ang) I to the vasoactive peptide Ang II. The exact role of ACE insertion (I)/deletion (D) polymorphism (rs106180) in psoriasis is not clear. We aimed to examine whether the ACE I/D and Ang II type 1 receptor (AT1R) A1166 C-polymorphisms (rs106165), lipid profile, and stress oxidative are associated with susceptibility to psoriasis. One hundred patients with psoriasis and 100 sex- and age-matched unrelated healthy controls were recruited for this case-control study. ACE I/D and AT1R A1166 C polymorphisms were identified by the polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism, respectively, malondialdehyde (MDA) was detected by the high-performance liquid chromatography, serum arylesterase (ARE) activity of paraoxonase and catalase activities were detected by the spectrophotometry, superoxide dismutase (SOD) activity and vascular adhesion protein (VAP)-1 were measured by ELISA. The presence of C allele of AT1R A1166 C and I allele of ACE considerably increased the risk of psoriasis by 6.42-fold (P < 0.001). The distribution of II-genotype of ACE was significantly higher in psoriasis patients than in control group and increased the risk of disease by 3.11-times (P = 0.023). The higher levels of MDA in patients and the higher activity of SOD, ARE, and CAT was observed in healthy controls with I/D+I/I-genotype of ACE I/D. This study for the first time demonstrated that the ACE I/D and AT1R A 1166 C genes polymorphisms robustly increases the risk of developing psoriasis in population from west of Iran. In addition, these individuals had significantly higher VAP-1 and MDA concentration and lower enzymatic and nonenzymatic antioxidant-status, suggesting that psoriatic patients carrying C allele of AT1R1166 polymorphism may be more susceptible to cardiovascular disease and myocardial infarction compared with A allele.
RESUMO
BACKGROUND: [68Ga]Ga-DOTA-Siglec-9 is a positron emission tomography (PET) radioligand for vascular adhesion protein 1 (VAP-1), a protein involved in leukocyte trafficking. The tracer facilitates the imaging of inflammation and infection. Here, we studied the pharmacokinetic modelling of [68Ga]Ga-DOTA-Siglec-9 in osteomyelitis and soft tissue infections in pigs. METHODS: Eight pigs with osteomyelitis and soft tissue infections in the right hind limb were dynamically PET scanned for 60 min along with arterial blood sampling. The fraction of radioactivity in the blood accounted for by the parent tracer was evaluated with radio-high-performance liquid chromatography. One- and two-tissue compartment models were used for pharmacokinetic evaluation. Post-mortem soft tissue samples from one pig were analysed with anti-VAP-1 immunofluorescence. In each analysis, the animal's non-infected left hind limb was used as a control. RESULTS: Tracer uptake was elevated in soft tissue infections but remained low in osteomyelitis. The kinetics of [68Ga]Ga-DOTA-Siglec-9 followed a reversible 2-tissue compartment model. The tracer metabolized quickly; however, taking this into account, produced more ambiguous results. Infected soft tissue samples showed endothelial cell surface expression of the Siglec-9 receptor VAP-1. CONCLUSION: The kinetics of [68Ga]Ga-DOTA-Siglec-9 uptake in porcine soft tissue infections are best described by the 2-tissue compartment model.
Assuntos
Radioisótopos de Gálio , Osteomielite/veterinária , Tomografia por Emissão de Pósitrons , Traçadores Radioativos , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico , Infecções dos Tecidos Moles/veterinária , Doenças dos Suínos/diagnóstico , Animais , Biomarcadores , Cinética , Imagem Molecular , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Suínos , Doenças dos Suínos/etiologia , Doenças dos Suínos/metabolismoRESUMO
Beyond cholesterol reduction, statins mediate their beneficial effects on stroke patients through pleiotropic actions. They have shown anti-inflammatory properties by a number of different mechanisms, including the inhibition of NF-κB transcriptional activity and the consequent increase and release of adhesion molecules. We have studied simvastatin's effects on the vascular enzyme semicarbazide-sensitive amine oxidase/vascular adhesion protein 1 (SSAO/VAP-1), which is involved in stroke-mediated brain injury. SSAO/VAP-1 has leukocyte-binding capacity and mediates the expression of other adhesion proteins through signaling molecules generated by its catalytic activity. Our results indicate that soluble SSAO/VAP-1 is released into the bloodstream after an ischemic stimulus, in parallel with an increase in E-selectin and VCAM-1 and correlating with infarct volume. Simvastatin blocks soluble SSAO/VAP-1 release and prevents E-selectin and VCAM-1 overexpression as well. Simvastatin also effectively blocks SSAO/VAP-1-mediated leukocyte adhesion, although it is not an enzymatic inhibitor of SSAO in vitro. In addition, simvastatin-induced changes in adhesion molecules are greater in human brain endothelial cell cultures expressing SSAO/VAP-1, compared to those not expressing it, indicating some synergic effect with SSAO/VAP-1. We think that part of the beneficial effect of simvastatin in stroke is mediated by the attenuation of the SSAO/VAP-1-dependent inflammatory response.
Assuntos
Amina Oxidase (contendo Cobre)/metabolismo , Isquemia Encefálica/metabolismo , Moléculas de Adesão Celular/metabolismo , Inflamação/metabolismo , Sinvastatina/farmacologia , Acidente Vascular Cerebral/metabolismo , Animais , Encéfalo/metabolismo , Isquemia Encefálica/tratamento farmacológico , Adesão Celular , Linhagem Celular , Modelos Animais de Doenças , Selectina E/metabolismo , Células Endoteliais , Células Endoteliais da Veia Umbilical Humana , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamação/tratamento farmacológico , Masculino , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Acidente Vascular Cerebral/patologia , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Amino acid residues 283-297 from sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) form a cyclic peptide ligand targeting vascular adhesion protein-1 (VAP-1). VAP-1 is associated with the transfer of leukocytes from blood to tissues upon inflammation. Therefore, analogs of Siglec-9 peptide are good candidates for visualizing inflammation non-invasively using positron emission tomography (PET). Gallium-68-labeled 1,4,7,10-tetraazacyclododecane-N,N',Nâ³,Nâ´-tetraacetic acid (DOTA)-conjugated Siglec-9 has been evaluated extensively for this purpose. Here, we explored two alternative strategies for radiolabeling Siglec-9 peptide using a 1,4,7-triazacyclononane-triacetic acid (NOTA)-chelator to bind [68Ga]Ga or [18F]AlF. The radioligands were evaluated by in vivo PET imaging and ex vivo γ-counting of turpentine-induced sterile skin/muscle inflammation in Sprague-Dawley rats. Both tracers showed clear accumulation in the inflamed tissues. The whole-body biodistribution patterns of the tracers were similar.
Assuntos
Antígenos CD , Radioisótopos de Flúor , Isótopos de Gálio , Compostos Heterocíclicos , Marcação por Isótopo/métodos , Tomografia por Emissão de Pósitrons/métodos , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico , Animais , Antígenos CD/química , Antígenos CD/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos com 1 Anel , Ratos , Ratos Sprague-Dawley , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/química , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/farmacologiaRESUMO
Vascular adhesion protein-1 (VAP-1) is a member of the copper-containing amine oxidase/semicarbazide-sensitive amine oxidase (AOC/SSAO) enzyme family. SSAO enzymes catalyze oxidative deamination of primary amines, which results in the production of the corresponding aldehyde, hydrogen peroxide and ammonium. VAP-1 is continuously expressed as a transmembrane glycoprotein in the vascular wall during development and facilitates the accumulation of inflammatory cells into the inflamed environment in concert with other leukocyte adhesion molecules. The soluble form of VAP-1 is released into the circulation mainly from vascular endothelial cells. Over- and under-expression of sVAP-1 result in alterations of the reported reaction product levels, which are involved in the pathogenesis of multiple human diseases. The combination of enzymatic and adhesion capacities as well as its strong association with inflammatory pathologies makes VAP-1 an interesting therapeutic target for drug discovery. In this article, we will review the general characteristics and biological functions of VAP-1, focusing on its important role as a prognostic biomarker in human pathologies. In addition, the potential therapeutic application of VAP-1 inhibitors will be discussed.
Assuntos
Amina Oxidase (contendo Cobre)/sangue , Aterosclerose/sangue , Moléculas de Adesão Celular/sangue , Diabetes Mellitus/sangue , Inflamação/sangue , Obesidade/sangue , Acidente Vascular Cerebral/sangue , Aterosclerose/epidemiologia , Biomarcadores/sangue , Diabetes Mellitus/epidemiologia , Medicina Baseada em Evidências , Oftalmopatias/sangue , Oftalmopatias/epidemiologia , Humanos , Inflamação/epidemiologia , Obesidade/epidemiologia , Prevalência , Acidente Vascular Cerebral/epidemiologiaRESUMO
Primary sclerosing cholangitis (PSC), first described in the mid-1850s, is a complex liver disease that is heterogeneous in its presentation. PSC is characterized by chronic cholestasis associated with chronic inflammation of the biliary epithelium, resulting in multifocal bile duct strictures that can affect the entire biliary tree. Chronic inflammation leads to fibrosis involving the hepatic parenchyma and biliary tree, which can lead to cirrhosis and malignancy. The etiology of PSC is not fully understood, which in part explains the lack of effective medical therapy for this condition. However, we have begun to better understand the molecular pathogenesis of PSC. The recognition of specific clinical subtypes and their pattern of progression could improve phenotypic and genotypic classification of the disease. We review our current understanding of this enigmatic disorder and discuss important topics for future studies.
Assuntos
Colangite Esclerosante , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/etiologia , Neoplasias dos Ductos Biliares/terapia , Ductos Biliares Intra-Hepáticos , Colagogos e Coleréticos/uso terapêutico , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/etiologia , Colangiocarcinoma/terapia , Colangiopancreatografia Retrógrada Endoscópica , Colangite Esclerosante/diagnóstico , Colangite Esclerosante/etiologia , Colangite Esclerosante/terapia , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/etiologia , Neoplasias do Colo/terapia , Terapia Combinada , Diagnóstico Diferencial , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/etiologia , Neoplasias da Vesícula Biliar/terapia , Predisposição Genética para Doença , Humanos , Imunidade Inata , Imunossupressores , Intestinos/microbiologia , Transplante de Fígado , Metagenoma , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
Purpose: Non-alcoholic fatty liver disease (NAFLD) represents a heterogeneous spectrum of liver diseases that encompass simple steatosis, non-alcoholic steatohepatitis (NASH), and advanced fibrosis or cirrhosis. Periodontitis is a chronic infectious disease with multiple causal factors that presents a complex interaction between the microbial biofilm and the host's immune response. The aim of this study was to investigate the concentrations of Vascular Adhesion Protein-1 (VAP-1) and Thrombospondin-1 (TSP-1) in patients with coexisting periodontitis and NAFLD. Patients and Methods: This study included 48 patients, who were dental and periodontal assessed. Of these patients, 25 were diagnosed with NAFLD. After performing the periodontal clinical examination, gingival crevicular fluid (GCF) samples were collected. Enzyme-linked immunosorbent assay (ELISA) dedicated kits tests were used for the detection and quantitative determination of VAP-1 and TSP-1 in GCF samples. Statistical methods were applied for the comparison and correlation of data. Results: VAP-1 and TSP-1 levels showed significant differences between all test and control groups (p<0.0001). Statistically significant correlations (p<0.05) between VAP-1 and periodontal and liver parameters were found in patients with NAFLD and periodontitis. Conclusion: Periodontal inflammation is more marked in patients with periodontitis-NAFLD association. Vascular adhesion and angiogenesis could be affected in patients with periodontitis and NAFLD. These findings could suggest that addressing periodontal inflammation in individuals with the periodontitis-NAFLD association may have a broader impact on vascular adhesion and angiogenesis, highlighting the interplay between oral health and liver conditions for comprehensive patient care.
RESUMO
Vascular adhesion protein-1 (VAP-1) is both an endothelial adhesion molecule involved in leukocytes emigration, and an oxidase belonging to the family of semicarbazide-sensitive amine oxidases (SSAOs). The enzyme activity of VAP-1 plays an important role in the migration of myeloid-derived suppressor cells (MDSCs) into tumor site, and SSAO inhibitors can block the function of VAP-1. The effects of SSAO inhibitors on leukocyte infiltration and tumor progression were evaluated in H22 hepatocellular carcinoma-bearing C57BL/6 mice. Tumor weight and volume were measured after SSAO inhibitor treatment. Then, MDSCs recruitment and neo-angiogenesis were determined using immunostaining. SSAO inhibitors significantly blocked the catalytic activity of VAP-1 in tumor, attenuated tumor progression, and reduced neo-angiogenesis. CD11b(+) and Gr-1(+) MDSCs, which normally infiltrate into tumors, were significantly diminished in tumor-bearing mice treated with SSAO inhibitors. The present study demonstrated that SSAO inhibitors might have an anti-tumor effect on hepatocellular carcinoma by inhibiting recruitment of CD11b(+) and Gr-1(+) cells and hindering angiogenesis, which could be attributed to impairing the catalytic activity of VAP-1.
Assuntos
Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Animais , Western Blotting , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The biodistribution of radiotracer peptide KETO[18F]FDG-VAP-P1 was evaluated by ex vivo radiation count in organs and in vivo PET imaging of healthy mice. The peptide was quickly eliminated by the kidneys. The local inflammation caused by a sterile polyurethane sponge was evaluated by PET images. In addition, dosimetry estimates of KETO[18F]FDG-VAP-P1 tracer are determined for mice using Monte Carlo simulations. Thus, the results of this study indicate that KETO[18F]FDG-VAP-P1 is a potential radiotracer for inflammation imaging.
Assuntos
Fluordesoxiglucose F18 , Inflamação , Camundongos , Animais , Distribuição Tecidual , Inflamação/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , PeptídeosRESUMO
Vascular adhesion protein-1 (VAP-1) is a bifunctional protein that has the ability to catalyze the deamination of primary amines and is involved in the production of hydrogen peroxide, aldehydes, and advanced glycation end products (AGEs). VAP-1 is usually stored in intracellular vesicles of endothelial cells, smooth muscles, and adipocytes. It is responsible for leukocyte transmigration and adhesion. Overexpression of VAP-1 exacerbates oxidative stress and modulates a variety of inflammatory mediators linked with diabetic complications. Numerous studies have suggested the association of increased insulin levels with serum VAP-1 (sVAP-1). Preclinical research evidence suggests the increased activity of sVAP-1 in type 1 and 2 diabetes. Scientific reports on VAP-1 inhibitors have shown a reduction in severity in diabetic animal models. VAP-1 is a potential target of a therapeutically effective line of treatment for diabetes and diabetic complications such as nephropathy and retinopathy. The primary focus of this review is the role of VAP-1 in diabetes and its associated microvascular complications.
Assuntos
Amina Oxidase (contendo Cobre)/metabolismo , Moléculas de Adesão Celular/metabolismo , Diabetes Mellitus , Angiopatias Diabéticas , Hipoglicemiantes/farmacologia , Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Animais , Moléculas de Adesão Celular/antagonistas & inibidores , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/metabolismo , HumanosRESUMO
Vascular smooth muscle cells (VSMCs) are the main stromal cells in the medial layer of the vascular wall. These cells produce the extracellular matrix (ECM) and are involved in many pathological changes in the vascular wall. Semicarbazide-sensitive amine oxidase (SSAO) and lysyl oxidase (LOX) are vascular enzymes associated with the development of atherosclerosis. In the vascular smooth muscle cells, increased SSAO activity elevates reactive oxygen species (ROS) and induces VSMCs death; increased LOX induces chemotaxis through hydrogen peroxide dependent mechanisms; and decreased LOX contributes to endothelial dysfunction. This study investigates the relationship between SSAO and LOX in VSMCs by studying their activity, protein, and mRNA levels during VSMCs passaging and after silencing the LOX gene, while using their respective substrates and inhibitors. At the basal level, LOX activity decreased with passage and its protein expression was maintained between passages. ßAPN abolished LOX activity (** p < 0.01 for 8 vs. 3 and * p < 0.05 for 5 vs. 8) and had no effect on LOX protein and mRNA levels. MDL72527 reduced LOX activity at passage 3 and 5 (## p < 0.01) and had no effect on LOX protein, and mRNA expression. At the basal level, SSAO activity also decreased with passage, and its protein expression was maintained between passages. MDL72527 abolished SSAO activity (**** p < 0.0001 for 8 vs. 3 and * p < 0.05 for 5 vs. 8), VAP-1 expression at passage 5 (** p < 0.01) and 8 (**** p < 0.0001), and Aoc3 mRNA levels at passage 8 (* p < 0.05). ßAPN inhibited SSAO activity (**** p < 0.0001 for 5 vs. 3 and 8 vs. 3 and * p < 0.05 for 5 vs. 8), VAP-1 expression at passage 3 (* p < 0.05), and Aoc3 mRNA levels at passage 3 (* p < 0.05). Knockdown of the LOX gene (**** p < 0.0001 for Si6 vs. Sictrl and *** p < 0.001 for Si8 vs. Sictrl) and LOX protein (** p < 0.01 for Si6 and Si8 vs. Sictrl) in VSMCs at passage 3 resulted in a reduction in Aoc3 mRNA (#### p < 0.0001 for Si6 vs. Sictrl and ### p < 0.001 for Si8 vs. Sictrl) and VAP-1 protein (# p < 0.05 for Si8 vs. Sictrl). These novel findings demonstrate a passage dependent decrease in LOX activity and increase in SSAO activity in rat aortic VSMCs and show an association between both enzymes in early passage rat aortic VSMCs, where LOX was identified as a regulator of SSAO activity, protein, and mRNA expression.