Vascular Adhesion Protein-1 Research Articles

Inhibition of vascular adhesion protein 1 protects dopamine neurons from the effects of acute inflammation and restores habit learning in the striatum

BackgroundChanges 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.MethodWe 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.ResultsLPS 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.ConclusionsWe 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.

Study of operative results of fracture distal end radius AO type 2R3C1 and C2 treated by external-fixator and k-wires in adults

The wrist joint is one of the most important joints in human body, essential to carry out day to day activities. Fractures of the distal end of the radius are amongst the most common fractures encountered in clinical orthopaedic practice. Learning how to anatomically fix these fractures, so that good functional outcome is obtained is very important. The principle of ligamentotaxis can help in reduction of certain fractures. However, some specific fractures require additional stability. This can be done with certain closed procedures like K-wires and External fixator in adults. In this prospective study, we studied 26 patients from July 2020 to October 2021 having AO type 2R3C1 and C2 treated with K-wires + External fixator. Patients were followed up for an average of 9 months and functional outcome was calculated using Green O’Brien and Gartland and Werley scoring system.

Circulating Vascular Adhesion Protein-1 Level Predicts Risk of Cardiovascular Events and Mortality in Hemodialysis Patients

Circulating Vascular Adhesion Protein-1 Level Predicts Risk of Cardiovascular Events and Mortality in Hemodialysis Patients

Circulating Vascular Adhesion Protein-1 Level Predicts the Risk of Cardiovascular Events and Mortality in Hemodialysis Patients.

Background: Vascular adhesion protein-1 (VAP-1) is an oxidative enzyme of primary amines that facilitates the transmigration of inflammatory cells. Its oxidative and inflammatory effects are prominently increased in pathological conditions, such as metabolic, atherosclerotic, and cardiac diseases. However, the clinical significance of circulating VAP-1 levels in hemodialysis (HD) patients is unclear.Methods: A total of 434 HD patients were enrolled in a prospective multicenter cohort study between June 2016 and April 2019. Plasma VAP-1 levels were measured at the time of data entry, and the primary endpoint was defined as a composite of cardiovascular (CV) and cardiac events.Results: Circulating VAP-1 levels were positively correlated with plasma levels of cardiac remodeling markers, including brain natriuretic peptide, galectin-3, and matrix metalloproteinase-2. Multivariable logistic regression analysis revealed that patients with higher circulating VAP-1 levels were more likely to have left ventricular diastolic dysfunction [odds ratio, 1.40; 95% confidence interval [CI], 1.04–1.88]. The cumulative event rate of the composite of CV events was significantly greater in VAP-1 tertile 3 than in VAP-1 tertiles 1 and 2 (P = 0.009). Patients in tertile 3 were also associated with an increased cumulative event rate of cardiac events (P = 0.015), with a 2.06-fold higher risk each for CV (95% CI, 1.10–3.85) and cardiac (95% CI, 1.03–4.12) events after adjusting for multiple variables.Conclusions: Plasma VAP-1 levels were positively associated with left ventricular diastolic dysfunction and the risk of incident CV and cardiac events in HD patients. Our results indicate that VAP-1 may aid clinicians in identifying HD patients at a high risk of CV events.

Enhanced expression of the proinflammatory, profibrotic molecule, vascular adhesion protein-1 in carcinoid heart disease valves

Enhanced expression of the proinflammatory, profibrotic molecule, vascular adhesion protein-1 in carcinoid heart disease valves

Vascular Adhesion Protein-1 (VAP-1)/Semicarbazide-Sensitive Amine Oxidase (SSAO): A Potential Therapeutic Target for Atherosclerotic Cardiovascular Diseases.

Vascular adhesion protein-1 (VAP-1) is a semicarbazide-sensitive amine oxidase (SSAO), whose enzymatic activity regulates the adhesion/exudation of leukocytes in/from blood vessels. Due to its abundant expressions in vascular systems and prominent roles in inflammations, increasing attentions have been paid to the roles of VAP-1/SSAO in atherosclerosis, a chronic vascular inflammation that eventually drives clinical cardiovascular events. Clinical studies have demonstrated a potential value of soluble VAP-1 (sVAP-1) for the diagnosis and prognosis of cardiovascular diseases. Recent findings revealed that VAP-1 is expressed in atherosclerotic plaques and treatment with VAP-1 inhibitors alleviates the progression of atherosclerosis. This review will focus on the roles of VAP-1/SSAO in the progression of atherosclerotic lesions and therapeutic potentials of VAP-1 inhibitors for cardiovascular diseases.

Venestatin from parasitic helminths interferes with receptor for advanced glycation end products (RAGE)-mediated immune responses to promote larval migration.

Parasitic helminths can reside in humans owing to their ability to disrupt host protective immunity. Receptor for advanced glycation end products (RAGE), which is highly expressed in host skin, mediates inflammatory responses by regulating the expression of pro-inflammatory cytokines and endothelial adhesion molecules. In this study, we evaluated the effects of venestatin, an EF-hand Ca2+-binding protein secreted by the parasitic helminth Strongyloides venezuelensis, on RAGE activity and immune responses. Our results demonstrated that venestatin bound to RAGE and downregulated the host immune response. Recombinant venestatin predominantly bound to the RAGE C1 domain in a Ca2+-dependent manner. Recombinant venestatin effectively alleviated RAGE-mediated inflammation, including footpad edema in mice, and pneumonia induced by an exogenous RAGE ligand. Infection experiments using S. venezuelensis larvae and venestatin silencing via RNA interference revealed that endogenous venestatin promoted larval migration from the skin to the lungs in a RAGE-dependent manner. Moreover, endogenous venestatin suppressed macrophage and neutrophil accumulation around larvae. Although the invasion of larvae upregulated the abundance of RAGE ligands in host skin tissues, mRNA expression levels of tumor necrosis factor-α, cyclooxygenase-2, endothelial adhesion molecules vascular cell adhesion protein-1, intracellular adhesion molecule-1, and E-selectin were suppressed by endogenous venestatin. Taken together, our results indicate that venestatin suppressed RAGE-mediated immune responses in host skin induced by helminthic infection, thereby promoting larval migration. The anti-inflammatory mechanism of venestatin may be targeted for the development of anthelminthics and immunosuppressive agents for the treatment of RAGE-mediated inflammatory diseases.

Impairment of Whole Kidney Blood Flow Autoregulation in the Transition from Acute to Chronic Kidney Disease in Ischemia‐Reperfusion Rats

Efficient autoregulation of renal blood flow (RBF) is an essential mechanism of renal microcirculation to protect against glomerular injury. Patients surviving an episode of acute kidney injury (AKI) develops chronic kidney disease (CKD). Renal ischemia-reperfusion (IR) is a major cause of AKI and triggers inflammation and reactive oxygen species (ROS) accumulation. We hypothesized that IR‑induced inflammation and ROS accumulation leads to a persistent reduction of RBF and impairment of RBF autoregulation contributing to CKD progression. Whole kidney RBF autoregulation was assessed in vivo in Sprague-Dawley male IR induced by bilateral arterial ischemia for 60 minutes followed by 24 hours, 1-week and 4‑weeks of reperfusion. Plasma creatinine increased in IR at 24 hours (3.9±0.2 vs. 1.0±0.1 mg/dl in sham, P<0.05, n=6-7/group) and week 1 (1.4±0.1 vs. 1.1±0.0 mg/dl in sham, P<0.05, n=7-8/group). Systolic blood pressure was similar between sham and IR over the 4 weeks post-IR (113-135 mmHg). IR reduced baseline RBF (5.8±0.5 vs. 9.1±0.5 ml/min.gkw in sham, P<0.05, n=6/group) at 24 hours and further decreased RBF at week 1 (3.7±0.7 vs. 9.1±1.1 ml/min.gkw in sham, n=5-6/group). At week 4, RBF was still significantly low in IR (6.9±0.4 vs. 10.4±0.3 ml/min.gkw in sham, P<0.05, n=6/group). RBF remained stable during step reduction of renal perfusion pressure (RPP) from 120 to 100 mmHg in all shams with autoregulatory index (AI) less than 0.2, indicating intact autoregulation. RBF autoregulation, however, was completely impaired in IR at 24 hours, week 1 and week 4 as RBF passively decreased during reduction of RPP, yielding AI of 0.8±0.2, 1.1±0.2 and 0.9±0.3, respectively. Preglomerular microvessels (PGMV) were collected for mRNA measurement (n=6-8/group). IR elevated mRNA expression of p67phox 7‑fold at 24 hours and 2‑fold at week 1 (P<0.05 vs. respective shams). IR also elevated gp91phox mRNA expression 5-fold at 24 hours and 2-fold at week 1 (P<0.05 vs. shams). IR tended to elevate p47phox mRNA expression at 24 hours and reached a significance at week 1 (2-fold, P<0.05 vs. sham). Inflammatory mediators, monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion protein-1 (VCAM-1), were also assessed in PGMV. MCP-1 mRNA expression was increased in IR with a peak of 10-fold at 24 hours and then decreased at week 1 but still elevated compared to shams (2-fold, P<0.05). VCAM-1 mRNA expression remained unchanged at 24 hours but increased 2-fold at week 1 (P<0.05). We also assessed profibrotic markers (TGF-β, collagen IV and fibronectin). TGF-β mRNA expression started to increase in IR at 24 hours (2-fold) and reached a significance at week 1 (3-fold, P<0.05 vs. sham) and further increased at week 4 (4-fold). IR also increased mRNA expression of collagen IV 5-fold at week 1 and 4-fold at week 4 (P<0.05). Fibronectin mRNA expression was also increased in IR 4-fold at week 1 and remained at the same level at week 4 (P<0.05). In conclusion, these results demonstrate that IR leads to a persistent reduction of RBF and impairment of RBF autoregulation in male rats and suggest that renal hemodynamic dysfunction might be associated with activation of NADPH oxidase, MCP-1 and TGF-β in PGMV of IR.

Role of endothelial biomarkers in predicting acute kidney injury in Bothrops envenoming

Acute kidney injury (AKI) is a frequent and potentially fatal complication of snakebites. In the setting of snakebites, endothelial biomarkers may be used to predict disease severity and can play a major role in AKI pathophysiology. The aim of this study was to investigate the potential role of endothelial biomarkers in predicting AKI in Bothrops envenoming. Therefore, blood and urine samples were collected from 26 patients admitted to the emergency department after Bothrops envenoming at 3 different post-bite points in time: on admission (up to 8 h post-bite), 12–16 h, and 24–28 h post-bite, to investigate the time course of endothelial biomarkers in AKI following Bothrops snakebites. The diagnostic performance of injury biomarkers in Bothrops envenomation was evaluated. AKI was diagnosed using the Kidney Disease Improving Global Outcomes (KDIGO) criteria. There was an association between endothelial injury and increased risk for AKI in bothropic envenoming. Angiopoietin- 1 (Ang-1) and Vascular cell adhesion protein-1 (VCAM-1) were useful biomarkers to predict mild AKI [AUC-ROC: Ang-1 0.82, VCAM-1 0.76] within the interval of 8–16 h post Bothrops snakebites. The use of endothelial biomarkers VCAM-1 e Ang-1 within 12−16 h post-bite may be useful in the early stage of mild AKI related to Bothrops envenoming and might have an effect on the early intervention for renal protection in less severe Bothrops-related AKI.

SSAO/VAP-1 in Cerebrovascular Disorders: A Potential Therapeutic Target for Stroke and Alzheimer's Disease.

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.

Inhibition of vascular adhesion protein-1 enhances the anti-tumor effects of immune checkpoint inhibitors.

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. H2O2, 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 H2O2‐associated Th2/M2 conditions and may be an attractive target for the development of combination cancer immunotherapy with ICIs.

NG2/CSPG4, CD146/MCAM and VAP1/AOC3 are regulated by myocardin-related transcription factors in smooth muscle cells

The present work addressed the hypothesis that NG2/CSPG4, CD146/MCAM, and VAP1/AOC3 are target genes of myocardin-related transcription factors (MRTFs: myocardin/MYOCD, MRTF-A/MKL1, MRTF-B/MKL2) and serum response factor (SRF). Using a bioinformatics approach, we found that CSPG4, MCAM, and AOC3 correlate with MYOCD, MRTF-A/MKL1, and SRF across human tissues. No other transcription factor correlated as strongly with these transcripts as SRF. Overexpression of MRTFs increased both mRNA and protein levels of CSPG4, MCAM, and AOC3 in cultured human smooth muscle cells (SMCs). Imaging confirmed increased staining for CSPG4, MCAM, and AOC3 in MRTF-A/MKL1-transduced cells. MRTFs exert their effects through SRF, and the MCAM and AOC3 gene loci contained binding sites for SRF. SRF silencing reduced the transcript levels of these genes, and time-courses of induction paralleled the direct target ACTA2. MRTF-A/MKL1 increased the activity of promoter reporters for MCAM and AOC3, and transcriptional activation further depended on the chromatin remodeling enzyme KDM3A. CSPG4, MCAM, and AOC3 responded to the MRTF-SRF inhibitor CCG-1423, to actin dynamics, and to ternary complex factors. Coincidental detection of these proteins should reflect MRTF-SRF activity, and beyond SMCs, we observed co-expression of CD146/MCAM, NG2/CSPG4, and VAP1/AOC3 in pericytes and endothelial cells in the human brain. This work identifies highly responsive vascular target genes of MRTF-SRF signaling that are regulated via a mechanism involving KDM3A.

Markers of endothelial and epithelial pulmonary injury in mechanically ventilated COVID-19 ICU patients

BackgroundBiomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS.MethodsThis prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS.ResultsIn COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001).ConclusionsCOVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways.Trial registrationNCT04343053, Date of registration: April 13, 2020

Vascular Adhesion Protein 1 Mediates Gut Microbial Flagellin-Induced Inflammation, Leukocyte Infiltration, and Hepatic Steatosis

Toll-like receptor 5 ligand, flagellin, and vascular adhesion protein 1 (VAP-1) are involved in non-alcoholic fatty liver disease. This study aimed to determine whether VAP-1 mediates flagellin-induced hepatic fat accumulation. The effects of flagellin on adipocyte VAP-1 expression were first studied in vitro. Then, flagellin (100 ng/mouse) or saline was intraperitoneally injected into C57BL/6J (WT) and C57BL/6-Aoc3-/- (VAP-1 KO) mice on a high-fat diet twice a week every 2 weeks for 10 weeks. After that, the effects on inflammation, insulin signaling, and metabolism were studied in liver and adipose tissues. Hepatic fat was quantified histologically and biochemically. Because flagellin challenge increased VAP-1 expression in human adipocytes, we used VAP-1 KO mice to determine whether VAP-1 regulates the inflammatory and metabolic effects of flagellin in vivo. In mice, VAP-1 mediated flagellin-induced inflammation, leukocyte infiltration, and lipolysis in visceral adipose tissue. Consequently, an increased release of glycerol led to hepatic steatosis in WT, but not in KO mice. Flagellin-induced hepatic fibrosis was not mediated by VAP-1. VAP-1 KO mice harbored more inflammation-related microbes than WT mice, while flagellin did not affect the gut microbiota. Our results suggest that by acting on visceral adipose tissue, flagellin increased leukocyte infiltration that induced lipolysis. Further, the released glycerol participated in hepatic fat accumulation. In conclusion, the results describe that gut microbial flagellin through VAP-1 induced hepatic steatosis.

Vascular Adhesion Protein-1 Determines the Cellular Properties of Endometrial Pericytes.

Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible adhesion molecule and a primary amine oxidase involved in immune cell trafficking. Leukocyte extravasation into tissues is mediated by adhesion molecules expressed on endothelial cells and pericytes. Pericytes play a major role in the angiogenesis and vascularization of cycling endometrium. However, the functional properties of pericytes in the human endometrium are not known. Here we show that pericytes surrounding the spiral arterioles in midluteal human endometrium constitutively express VAP-1. We first characterize these pericytes and demonstrate that knockdown of VAP-1 perturbed their biophysical properties and compromised their contractile, migratory, adhesive and clonogenic capacities. Furthermore, we show that loss of VAP-1 disrupts pericyte-uterine natural killer cell interactions in vitro. Taken together, the data not only reveal that endometrial pericytes represent a cell population with distinct biophysical and functional properties but also suggest a pivotal role for VAP-1 in regulating the recruitment of innate immune cells in human endometrium. We posit that VAP-1 could serve as a potential biomarker for pregnancy pathologies caused by a compromised perivascular environment prior to conception.

Ethanol extract of Gynura bicolour reduces atherosclerosis risk by enhancing antioxidant capacity and reducing adhesion molecule levels

Context Gynura bicolour (Roxb. and Willd.) DC (Asteraceae) leaf is a common vegetable. Ethanol extracts of fresh G. bicolour leaves (GBEE) have several physiological effects, but studies on atherosclerosis are limited. Objective We investigated the oxidant scavenging ability and vascular adhesion molecule expression of these extracts. Materials and methods The antioxidant effects of 0.05–0.4 mg/mL GBEE were analyzed in vitro. Intracellular antioxidant capacity and adhesion molecule levels were detected in EA.hy926 cells pre-treated with 10–100 μg/mL GBEE for 8 h, then TNF-α for 3 h. The antioxidant capacity of red blood cells and the adhesion molecule levels in the thoracic aorta were detected in high-fat diet (HFD)-fed Sprague–Dawley rats treated with GBEE for 12 weeks. Results The in vitro EC50 values of GBEE based on its DPPH radical-scavenging ability, reducing power, and ferrous ion-chelating ability were 0.20, 3.21 and 0.49 mg/mL, respectively. In TNF-α-treated EA.hy926 cells, the thiobarbituric acid-reactive substance levels were decreased after 10, 50, or 100 μg/mL GBEE treatments (IC50: 19.1 mg/mL). When HFD-fed rats were co-treated with GBEE, the GBEE-H group exhibited 25% higher glutathione levels than the HFD group (p < 0.05). E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion protein-1 levels were decreased in TNF-α-treated EA.hy926 cells after GBEE treatment (by approximately 11–73%; p < 0.05), and the above three adhesion molecules levels were decreased in HFD-fed rats with combined GBEE treatment (by approximately 30–77%; p < 0.05). Conclusions GBEE can protect the vascular endothelium by reducing adhesion molecule expression and regulating antioxidants. It may have the potential to prevent atherosclerosis.

Hypercholesterolemia of obese mice with deletion of vascular adhesion protein-1 occurs without other atherosclerosis risk factor

Hypercholesterolemia of obese mice with deletion of vascular adhesion protein-1 occurs without other atherosclerosis risk factor

Carotid imaging changes and serum IL-1\u03b2, sICAM-1, and sVAP-1 levels in benign paroxysmal positional vertigo

Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo. This study was performed to evaluate serum levels of inflammatory factors and changes in B-mode carotid ultrasound findings in patients with BPPV. The study population consisted of 90 BPPV patients and 90 age- and sex-matched controls. ELISA was used to compare the levels of inflammatory factors, such as interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), soluble intercellular adhesion molecule-1 (sICAM-1), prostaglandin-E2 (PG-E2), and soluble vascular adhesion protein-1 (sVAP-1), between BPPV patients and controls. In addition, the results of ultrasonographic imaging to determine carotid intima-media thickness (C-IMT), carotid atheromatous plaque, and vertebral artery stenosis were also compared between the BPPV and control groups. Serum levels of IL-1β, sICAM-1, and sVAP-1 were significantly higher in BPPV patients than controls (P < 0.001, P < 0.05, and P < 0.001, respectively). C-IMT and vertebral artery stenosis were significantly different in BPPV patients compared to controls (both P < 0.05). There were no significant relations between other parameters and BPPV. IL-1β, sICAM-1, and sVAP-1 are potentially associated with the pathogenesis of BPPV, and C-ITM and carotid vertebral stenosis may be useful reference imaging findings for the diagnosis of BPPV.

Inhibition of vascular adhesion protein-1 modifies hepatic steatosis in vitro and in vivo.

BACKGROUNDNon-alcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance and dyslipidaemia and currently is estimated to affect up to a third of all individuals in developed countries. Current standard of care for patients varies according to disease stage, but includes lifestyle interventions common insulin sensitizers, antioxidants and lipid modifiers. However, to date specific therapies have shown little histological or fibrosis stage improvement in large clinical trials, and there is still no licensed therapy for NAFLD. Given the high prevalence, limited treatment options and significant screening costs for the general population, new treatments are urgently required.AIMTo assess the potential for inhibition of the amine oxidase enzyme vascular adhesion protein-1 (VAP-1) to modify hepatic lipid accumulation in NAFLD.METHODSWe have used immunochemical and qPCR analysis to document expression of VAP-1 and key functional proteins and transporters across the NAFLD spectrum. We then utilised hepatocytes in culture and human precision cut liver slices in concert with selective enzyme activity inhibitors to test the effects of activating the semicarbazide-sensitive amine oxidase activity of VAP-1 on hepatic lipid uptake and triglyceride export. A murine model of NAFLD was also used to determine the consequences of VAP-1 knockout and gene expression arrays were used to quantify the effects of VAP-1 activity on key lipid modifying and proinflammatory gene expression.RESULTSWe confirmed that increasing severity of NAFLD and progression to cirrhosis was associated with a significant increase in hepatocellular VAP-1 expression. Hepatocytes in vitro exposed to recombinant VAP-1 and its substrate methylamine showed increased lipid accumulation as determined by quantification of Oil Red O uptake. This was recapitulated using hydrogen peroxide, and lipid accumulation was accompanied by changes in expression of the lipid transporter molecules FABP3, FATP6, insulin receptor subunits and PPARα. Human liver tissue exposed to recombinant VAP-1 or substrates for endo/exogenous VAP-1 produced less triglyceride than untreated tissue and demonstrated an increase in steatosis. This response could be inhibited by using bromoethylamine to inhibit the SSAO activity of VAP-1, and mice deficient in VAP-1/AOC3 also demonstrated reduced steatosis on high fat diet. Exposure of human liver tissue to methylamine to activate VAP-1 resulted in increased expression of FABP2 and 4, FATP3-5, caveolin-1, VLDLR, PPARGC1 and genes associated with the inflammatory response.CONCLUSIONOur data confirm that the elevations in hepatic VAP-1 expression reported in nonalcoholic steatohepatitis can contribute to steatosis, metabolic disturbance and inflammation. This suggests that targeting the semicarbazide sensitive amine oxidase capacity of VAP-1 may represent a useful adjunct to other therapeutic strategies in NAFLD.

Identifying Potential Drug Targets for Sickle Cell Disease through Gene Expression and Pathway Analysis of GEO Data

Background: The pathogenesis of sickle cell disease (SCD) and its complications have been well characterized down to the molecular level. However, there remains a relative dearth of disease modifying therapies that reduce the frequency and number of vas-occlusive crises, hospitalizations, and deaths. Recent advancements in utilizing hydroxyurea and L-glutamine, which both impact unique disease pathways, should pave way for the identification of other molecular pathways as ideal drug targets. In this regard, our meta-analysis serves to identify key genes and associated pathways that are differentially expressed in SC patients. Methods: We employed our STARGEO platform to tag samples from the NCBI Gene Expression Omnibus and performed meta-analysis to compare SC and healthy control transcriptomes. For the meta-analysis, we tagged 285 peripheral blood samples from SC patients and 86 samples from healthy subjects as a control. We then analyzed the signature in Ingenuity Pathway Analysis to elucidate top disease functions from our analysis. Results: From our meta-analysis, we identified iron homeostasis signaling, NRF2-mediated oxidative stress response, cell senescence, and pyrimidine interconversion/biosynthesis as top canonical pathways that were upregulated in the peripheral blood samples from SC patients. Top upstream regulators included membrane associated protein and transporter ABCB6, non-coding RNY3, and erythroid maturation transcription factors GATA1, KLF1, and HIPK2 (with predicted activation). The most upregulated genes included inflammatory modulators RNF182 and IFI27, the latter of which has been shown to inhibit vascular endothelial growth and repair. Several membrane-associated protein coding genes such as GYPA, RAP1GAP, and PAQR9 were also upregulated in the SC samples. RAP1GAP is known to modulate neutrophil cell adhesion and homing while PAQR9 has roles in regulating protein quality control: a role also seen in similarly upregulated YOD1, a deubiquitinating enzyme involved in trafficking of misfolded proteins. Expectedly, also upregulated were HBBP1 and SOX6, which regulate globin genes and have been shown to silence γ-globin expression. Lastly, SLC6A19, the neutral amino acid transporter mutated in Hartnup disease, was also upregulated. Of the downregulated genes, WASF3, a member of the Wiskott-Aldrich syndrome protein family, has been linked to poor survival in many malignancies, including AML and CMML, but has not previously been linked to SCD pathogenesis. ENKUR was also downregulated and has been annotated as a tethering protein to cation channels as well as linked to pathways involving vascular leakage. SIGLEC10, which binds to vascular adhesion proteins, is a key suppressor of inflammatory responses to damage; it's downregulation along with ELAPOR1, a transmembrane protein involved in cellular response to stress, was also observed. Finally, based off the focus genes in our analysis we identified several networks with most being involved in amino acid metabolism, cellular assembly, function, and maintenance, hematological disease, and organismal injury. The top pathway is illustrated in Figure 1. Conclusions: Our study illustrates differentially expressed gene activity in SCD consistent with known pathophysiology such as immune response, endothelial damage and adherence, heme metabolism, and globin regulation. We also showed evidence of genes not previously studied in SCD, which may have novel roles such as those part of the ubiquitin-proteasome system like YOD1 and RNF182. Additionally, while some genes in our analysis like EKLF and GAT1 have been shown to enhance δ-globin expression, paving way for possible drug therapies for B-hemoglobinopathies, others like IFI27, PAQR9, RAP1GAP, ENKUR, SIGLEC10, WASF3, and SOX9 have yet to be studied as mediators of disease pathogenesis in SCD. A target to SOX9, a known suppressor of γ-globin, or ABCB6, a known modulator of erythroid cell shape and hydration, have particularly promising potential as disease modifying therapies. Finally, HIPK2, HBBP1, and SLC6A19 have previously been shown to have intriguing effects on hydroxyurea dosing and responsivity in SC patients and may also be candidate target molecules to enhance existing therapies. These data identify potential candidate pathways for mechanistic studies seeking to confirm a causative role in the pathogenesis of sickle cell disease. Disclosures No relevant conflicts of interest to declare.