Vascular adhesion protein-1 (VAP-1) in vascular inflammatory 					diseases

Danielli, Marianna; Thomas, Roisin; Quinn, Lauren; Tan, Bee K.

doi:10.1024/0301-1526/a001031

Cited by 9 publications

(4 citation statements)

References 72 publications

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“…Sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) is a transmembrane protein that binds sialic acid and favors cell-cell adhesion in immunological processes [42]. Our results of higher levels of Siglec-9 in the l-GCF group are in line with the results found in two cohorts of mainly healthy older individuals showing an inverse relationship between Siglec-9 and fluid cognitive ability [18].…”

Section: Discussionsupporting

confidence: 88%

Plasma levels of neurology-related proteins are associated with cognitive performance in an older population with overweight/obesity and metabolic syndrome

et al. 2023

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Cognitive impairment is present in a broad spectrum of medical conditions and in aging. Here, we aimed to identify plasma proteins related to cognitive function in a sample of older adults with overweight/obesity and metabolic syndrome. A total of 129 subjects (mean age 64.7 years; 36% females) were grouped according to low (l-GCF, N=65) or high (h-GCF, N=64) global cognitive function and matched according to education, sex, age, and body mass index. Cognitive performance was assessed using neuropsychological tests. Plasma levels of 92 neurology-related proteins were assessed using a proximity extension assay. An elastic net regression analysis was used to identify proteins more associated with cognitive performance. Additionally, the protein expression levels were compared between the two groups by means of a t-test with false discovery rate correction. Pearson correlations were used to assess associations between the protein levels and scores from the neurocognitive tests. Six proteins (alpha-2-MRAP, HAGH, Siglec-9, MDGA1, IL12, and EDA2R) were identified as potential contributors to cognitive performance, remaining significantly increased in l-GCF compared to h-GCF participants after correction for multiple testing. Negative correlations (r= −0.23 to −0.18, i.e., lower protein levels, higher cognitive function) were found between global cognitive function and Siglec-9, NMNAT1, HAGH, LXN, gal-8, alpha-2-MRAP, IL12, PDGF-R-alpha, NAAA, EDA2R, CLEC1B, and LAT. Mini-mental state examination z scores showed the strongest correlations with protein levels, specifically negative correlations with CLEC1b, LXN, LAT, PLXNB3, NMNAT1, gal-8, HAGH, NAAA, CTSS, EZR, KYNU, MANF (r=−0.38 to −0.26) and a positive correlation with ADAM23 (r= 0.26). In summary, we identified several plasma proteins that were significantly associated with cognitive performance in older adults with obesity and metabolic syndrome, although further research is needed to replicate the results in larger samples and to include a predictive perspective.

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Section: Discussionsupporting

confidence: 88%

Plasma levels of neurology-related proteins are associated with cognitive performance in an older population with overweight/obesity and metabolic syndrome

et al. 2023

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“…Vascular adhesion protein-1 (VAP-1) is a proinflammatory protein in the cell membrane that facilitates leukocyte migration after TNF-α, IFN-γ or IL-1β stimulation [87]. VAP-1 showed higher values in SLE and could be a potential marker of atherosclerosis [88].…”

Section: Immune Cellsmentioning

confidence: 99%

Update of Potential Biomarkers in Risk Prediction and Monitoring of Atherosclerosis in Systemic Lupus Erythematosus to Prevent Cardiovascular Disease

Blachut,

Przywara-Chowaniec,

Tomasik

et al. 2023

Biomedicines

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Systemic lupus erythematosus is a chronic connective tissue disease associated with an increased risk of premature atherosclerosis. It is estimated that approximately 10% of SLE patients develop significant atherosclerosis each year, which is responsible for premature cardiovascular disease that is largely asymptomatic. This review summarizes the most recent reports from the past few years on biomarkers of atherosclerosis in SLE, mainly focusing on immune markers. Persistent chronic inflammation of the vascular wall is an important cause of cardiovascular disease (CVD) events related to endothelial dysfunction, cell proliferation, impaired production and function of nitric oxide and microangiopathic changes. Studies on pathogenic immune mediators involved in atherosclerosis will be crucial research avenues for preventing CVD.

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“…The circulating sVAP-1 level is associated with disease severity and could be used to predict the presence of significant fibrosis in NASH, suggesting that sVAP-1 alone or in combination with other potential fibrosis markers could be used as biomarkers for NASH disease progression ( Kurkijärvi et al, 1998 ; Weston and Adams, 2011 ). Given the role of VAP-1 in inflammatory diseases, inhibition of its activity offers a promising target for drug development ( Danielli et al, 2022 ). In various preclinical NASH models, gene knockout or pharmacological inhibition of VAP-1 can reduce oxidative stress and recruitment of inflammatory cells to the liver and attenuate liver fibrosis ( Foot et al, 2013 ; Weston et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

The first selective VAP-1 inhibitor in China, TT-01025-CL: safety, tolerability, pharmacokinetics, and pharmacodynamics of single- and multiple-ascending doses

Yang,

Yu,

Sheng

et al. 2024

Front. Pharmacol.

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Introduction: TT-01025-CL is an oral, irreversible small molecule that potently inhibits vascular adhesion protein-1 (VAP-1) for the treatment of inflammation associated with non-alcoholic steatohepatitis (NASH). The objectives of this study were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of TT-01025-CL, a VAP-1 inhibitor, in healthy Chinese volunteers.Methods: Double-blind, placebo-controlled, dose-escalation studies were conducted in subjects randomized to receive oral once-daily TT-01025-CL (ranges: 10–300 mg [single dose]; 20–100 mg for 7 days [multiple doses]) or placebo under fasting conditions. Safety and tolerability were monitored throughout the study. Pharmacokinetic (PK) parameters were determined using non-compartment analysis. The activity of semicarbazide-sensitive amine oxidase (SSAO)-specific amine oxidase and the accumulation of methylamine in plasma were evaluated as pharmacodynamic (PD) biomarkers.Results: A total of 36 (single-dose group) and 24 (multiple-dose group) subjects were enrolled in the study. No serious adverse events (AEs) were reported, and no subject discontinued due to an AE. All treatment-emergent adverse events (TEAEs) were mild and moderate in intensity. No dose-dependent increase in the intensity or frequency of events was observed. TT-01025-CL was rapidly absorbed after administration. In the single-ascending dose (SAD) study, median Tmax ranged from 0.5 to 2 h and mean t1/2z ranged from 2.09 to 4.39 h. PK was linear in the range of 100–300 mg. The mean Emax of methylamine ranged from 19.167 to 124.970 ng/mL, with mean TEmax ranging from 13.5 to 28.0 h. The complete inhibition (>90%) of SSAO activity was observed at 0.25–0.5 h post-dose and was maintained 48–168 h post-dose. In the multiple-ascending dose (MAD) study, a steady state was reached by day 5 in the 40 mg and 100 mg dose groups. Negligible accumulation was observed after repeated dosing. PK was linear in the range of 20–100 mg. Plasma methylamine appeared to plateau at doses of 20 mg and above, with mean Emax ranging from 124.142 to 156.070 ng/mL and mean TEmax ranging from 14.2 to 22.0 h on day 7. SSAO activity in plasma was persistently inhibited throughout the treatment period. No evident change in methylamine and SSAO activity was observed in the placebo groups.Conclusion: TT-01025-CL was safe and well-tolerated at a single dose of up to 300 mg and multiple doses of up to 100 mg once daily for 7 consecutive days. Absorption and elimination occurred rapidly in healthy volunteers. Linearity in plasma exposure was observed. TT-01025-CL inhibited SSAO activity rapidly and persistently in humans. The profile of TT-01025-CL demonstrates its suitability for further clinical development.

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Vascular adhesion protein-1 (VAP-1) in vascular inflammatory diseases

Cited by 9 publications

References 72 publications

Plasma levels of neurology-related proteins are associated with cognitive performance in an older population with overweight/obesity and metabolic syndrome

Plasma levels of neurology-related proteins are associated with cognitive performance in an older population with overweight/obesity and metabolic syndrome

Update of Potential Biomarkers in Risk Prediction and Monitoring of Atherosclerosis in Systemic Lupus Erythematosus to Prevent Cardiovascular Disease

The first selective VAP-1 inhibitor in China, TT-01025-CL: safety, tolerability, pharmacokinetics, and pharmacodynamics of single- and multiple-ascending doses

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