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As a common air pollutant, formaldehyde is widely present in nature, industrial production and consumer products. Endogenous formaldehyde is mainly produced through the oxidative deamination of methylamine catalysed by semicarbazide‐sensitive amine oxidase (SSAO) and is ubiquitous in human body fluids, tissues and cells. Vascular endothelial cells and smooth muscle cells are rich in this formaldehyde‐producing enzyme and are easily damaged owing to consequent cytotoxicity. Consistent with this, increasing evidence suggests that the cardiovascular system and stages of heart development are also susceptible to the harmful effects of formaldehyde. Exposure to formaldehyde from different sources can induce heart disease such as arrhythmia, myocardial infarction (MI), heart failure (HF) and atherosclerosis (AS). In particular, long‐term exposure to high concentrations of formaldehyde in pregnant women is more likely to affect embryonic development and cause heart malformations than long‐term exposure to low concentrations of formaldehyde. Specifically, the ability of mouse embryos to effect formaldehyde clearance is far lower than that of the rat embryos, more readily allowing its accumulation. Formaldehyde may also exert toxic effects on heart development by inducing oxidative stress and cardiomyocyte apoptosis. This review focuses on the current progress in understanding the influence and underlying mechanisms of formaldehyde on cardiovascular disease and heart development.

Purpose To investigate the mechanism of soluble vascular adhesion protein-1 (sVAP-1) accumulation induced by vascular endothelial growth factor (VEGF) in the vitreous of patients with diabetic retinopathy (DR). Study design Experimental. Methods Protein levels of sVAP-1 and N epsilon-(hexanoyl)lysine (HEL), an oxidative stress marker, in the vitreous samples from patients with proliferative diabetic retinopathy (PDR) with or without intravitreal bevacizumab (IVB) injection were determined by ELISA. The effect of VEGF on both mRNA expression of Vap-1 and secretion of sVAP-1 in rat retinal capillary endothelial cells (TR-iBRB2) was analyzed by real-time PCR and western blotting, respectively. In addition, the impact of VEGF on production and activation ratios of matrix metalloproteinase (MMP)-2 and MMP-9 was examined by gelatin zymography. Hydrogen peroxide production and reactive oxygen species (ROS) levels were assessed in the supernatants of TR-iBRB2 cells treated with VEGF. Results IVB injection decreased vitreous levels of sVAP-1 and HEL in patients with PDR. VEGF stimulation released sVAP-1 protein from TR-iBRB2 cells as a consequence of membrane-anchored VAP-1 shedding by MMP-2 and MMP-9. In addition, VEGF increased hydrogen peroxide generation and ROS augmentation through spermine oxidation by sVAP-1 as semicarbazide-sensitive amine oxidase (SSAO) in the supernatant of cultured endothelial cells. Conclusions The current data demonstrate that proangiogenic factor VEGF induces sVAP-1 release from retinal capillary endothelial cells and facilitates hydrogen peroxide generation via enzymatic property of sVAP-1, followed by the increase of oxidative stress, one of the crucial factors in the pathogenesis of DR.

Vascular adhesion protein‐1 (VAP‐1) plays a dual role with its adhesive and enzymatic properties, facilitating leukocyte migration to sites of inflammation and catalyzing the breakdown of primary amines into harmful by‐products, which are linked to diabetic complications. Present in various tissues, VAP‐1 also circulates in a soluble form in the bloodstream. Diabetes is associated with several complications such as cardiovascular disease, retinopathy, nephropathy, and neuropathy, significantly contributing to disability and mortality. These complications arise from hyperglycemia‐induced oxidative stress, inflammation, and the formation of advanced glycation end‐products (AGEs). Earlier research, including our own from the 1990s and early 2000s, has underscored the critical role of VAP‐1 in these pathological processes, prompting extensive investigation into its contribution to diabetic complications. In this review, we examine the involvement of VAP‐1 in diabetes and its complications, alongside its link to other conditions related to diabetes, such as cancer and metabolic dysfunction‐associated fatty liver disease. We also explore the utility of soluble VAP‐1 as a biomarker for diabetes, its complications, and other related conditions. Since the inhibition of VAP‐1 to treat diabetic complications is a novel and promising treatment option, further studies are needed to translate the beneficial effect of VAP‐1 inhibitors observed in animal studies to clinical trials recruiting human subjects. Besides, future studies should focus on using serum sVAP‐1 levels for risk assessment in diabetic patients, identifying those who need intensive glycemic control, and determining the patient population that would benefit most from VAP‐1 inhibitor therapies. Vascular adhesion protein‐1 (VAP‐1) has adhesive and enzymatic functions, aiding leukocyte migration to inflammation sites and producing by‐products linked to diabetic complications. This review focuses on the impact of VAP‐1 on diabetes and its complications, its association with related diseases, and the potential of soluble VAP‐1 as a biomarker.

Sepsis-induced myocardial dysfunction (SIMD) is a fatal complication with limited therapeutic options. Semicarbazide-sensitive amine oxidase (SSAO) contributes to oxidative stress and leukocyte recruitment, yet its role in SIMD remains unexplored. This study investigates whether hydralazine, a potent SSAO inhibitor, protects against SIMD by evaluating the involvement of SSAO inhibition. Using a murine model of LPS-induced sepsis, hydralazine was administered 30 min post-injection. Over a 7-day observation period, survival rates, cardiac function (assessed by echocardiography), and myocardial injury (evaluated via plasma biomarkers including CK, CK-MB, LDH, and AST, alongside histopathology) were monitored. Additional analyses included measurements of oxidative stress markers (T-AOC, GSH-PX, SOD, MDA, GSH), inflammatory chemokine levels using a Luminex panel, and myocardial SSAO activity via HPLC. The results demonstrated that hydralazine at doses of 5 and 10 mg/kg significantly improved 7-day survival rates from 20% to 90% and enhanced cardiac function in septic mice. It also reduced myocardial injury and histological damage while attenuating systemic inflammation through suppression of chemokine elevation. Furthermore, hydralazine boosted systemic and myocardial antioxidant capacity and normalized the sepsis-induced increase in myocardial SSAO activity, suggesting a potential mechanism for its protective effects. In conclusion, hydralazine shows robust cardioprotection in experimental sepsis by decreasing oxidative stress and inflammatory cell infiltration. The inhibition of SSAO activity may be a pivotal underlying molecular mechanism.

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. βAPN 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). βAPN 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.

Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical antipsychotic drug olanzapine increases body weight include central dysregulations leading to hyperphagia and direct peripheral impairment of fat cell lipolysis. Several investigations have reproduced in vitro direct actions of antipsychotics on rodent adipocytes, cultured preadipocytes, or human adipose tissue-derived stem cells. However, to our knowledge, no such direct action has been described in human mature adipocytes. The aim of the present study was to compare in human adipocytes the putative direct alterations of lipolysis by antipsychotics (haloperidol, olanzapine, ziprazidone, risperidone), antidepressants (pargyline, phenelzine), or anxiolytics (opipramol). Lipolytic responses to the tested drugs, and to recognized lipolytic (e.g., isoprenaline) or antilipolytic agents (e.g., insulin) were determined, together with glucose transport and amine oxidase activities in abdominal subcutaneous adipocytes from individuals undergoing plastic surgery. None of the tested drugs were lipolytic. Surprisingly, only opipramol exhibited substantial antilipolytic properties in the micromolar to millimolar range. An opipramol antilipolytic effect was evident against isoprenaline-, forskolin-, or atrial natriuretic peptide-stimulated lipolysis. Opipramol did not impair insulin activation of glucose transport but inhibited monoamine oxidase (MAO) activity to the same extent as antidepressants recognized as MAO inhibitors (pargyline, harmine, or phenelzine), whereas antipsychotics were inefficient. Considering its unique properties, opipramol, which is not associated with weight gain in treated patients, is a good candidate for drug repurposing because it limits exaggerated lipolysis, prevents hydrogen peroxide release by amine oxidases in adipocytes, and is thereby of potential use to limit lipotoxicity and oxidative stress, two deleterious complications of diabetes and obesity.

Regulatory myeloid immune cells, such as myeloid-derived suppressor cells (MDSCs), populate inflamed or cancerous tissue and block immune cell effector functions. The lack of mechanistic insight into MDSC suppressive activity and a marker for their identification has hampered attempts to overcome T cell inhibition and unleash anti-cancer immunity. Here, we report that human MDSCs were characterized by strongly reduced metabolism and conferred this compromised metabolic state to CD8 + T cells, thereby paralyzing their effector functions. We identified accumulation of the dicarbonyl radical methylglyoxal, generated by semicarbazide-sensitive amine oxidase, to cause the metabolic phenotype of MDSCs and MDSC-mediated paralysis of CD8 + T cells. In a murine cancer model, neutralization of dicarbonyl activity overcame MDSC-mediated T cell suppression and, together with checkpoint inhibition, improved the efficacy of cancer immune therapy. Our results identify the dicarbonyl methylglyoxal as a marker metabolite for MDSCs that mediates T cell paralysis and can serve as a target to improve cancer immune therapy. Myeloid-derived suppressor cells (MDSCs) residing within tumors can impede immune responses. Knolle and colleagues show that MDSCs poison immune cells by producing methylglyoxal, which functionally alters their cellular metabolism and hence their effector responses.

In theabstract, there were mistakes in the first sentence of the Results section which was incorrectly written as “MIA induced remarkably decreased thresholds of weight bearing and paw withdrawal, alterations in the tibial and femoral structures (reactive sclerosis, increased trabeculation, and cortical erosions), histopathological damage (disorganized cartilage structure, hypocellularity, decreased matrix staining and tidemark integrity, and increased synovial hyperplasia and osteophyte formation), and changes in the astrocyte and microglia density in the lumbar spinal cord.” The incorrect sentence read “All measurement timepoints for these complex protocols were chosen on the basis of our experience and data available in literature on the different pathophysiological parameters of the model (Blom et al., 2007; Baragi et al., 2009; Walsh et al., 2007a; Xie et al., 2012).” The incorrect sentence read “The most prominent MIA-induced alterations of the subchondral trabecular bone microarchitecture were bone resorption (indicated by decreased volume density and trabecular number), increased trabecular separation and pattern factor, and cortical erosions (indicated by increased open pore space volume and open porosity compared to the contralateral side) (Figures 6A–F.

Introduction: Soluble vascular adhesion protein-1 (sVAP-1), which is identical to semicarbazide-sensitive amine oxidase (SSAO), contributes to oxidative stress and vascular dysfunction. The AOC3 gene that encodes VAP-1 is mainly expressed in vascular endothelial and smooth muscle cells, but AOC3 expression in adipose tissue and vascular implications remain unclear. The aim of this study was to investigate the association of adipose AOC3 expression and circulating sVAP-1/SSAO with arterial stiffness in patients with severe obesity. Methods: We studied 49 Japanese patients who underwent laparoscopic sleeve gastrectomy. AOC3 expression was measured in visceral and subcutaneous adipose tissues obtained during surgery. Circulating sVAP-1 concentration, SSAO activity, oxidative stress markers, and cardio-ankle vascular index (CAVI) were assessed. Correlation and multiple regression analyses were performed. Results: Serum sVAP-1 concentration correlated strongly with SSAO activity (rs = 0.683, p < 0.001) and was directly associated with CAVI. Visceral AOC3 Gene Index (AOC3 expression × visceral fat area) was independently associated with serum sVAP-1 concentration, whereas subcutaneous AOC3 expression was not. Subcutaneous fat area showed an inverse association with SSAO activity. In stratified analysis, patients with visceral-dominant obesity had higher CAVI, serum sVAP-1 concentration, and SSAO activity than those with subcutaneous-dominant obesity. Conclusions: Visceral fat-derived AOC3 expression correlates with serum sVAP-1 concentration that appears to contribute to arterial stiffness in obesity. In contrast, subcutaneous fat may be associated with reduced SSAO activity. These findings highlight the fat depot-specific role of adipose tissue in vascular health and implicate VAP-1 as a potential mediator of obesity-related atherosclerosis.

Background and purpose: Methylamine is an endogenous aliphatic amine exhibiting anorexigenic properties in mice. The aim of this work was to show whether methylamine also modifies feeding behaviour in rats and, if so, to identify the mediator(s) responsible for such effects. Experimental approach: Microdialysis experiments with the probe inserted in the periventricular hypothalamic nucleus were carried out in 12 h starved, freely moving rats. Collected perfusate samples following methylamine injection (i.c.v.) were analysed for nitric oxide by chemiluminescence and for dopamine and 5‐hydroxytryptamine content by HPLC. Kv1.6 potassium channel expression was reduced by antisense strategy and this decrease quantified by semi‐quantitative RT‐PCR analysis. Key results: Methylamine showed biphasic dose‐related effects on rat feeding. At doses of 15–30 μg per rat, it was hyperphagic whereas higher doses (60–80 μg) were hypophagic. Methylamine stimulated central nitric oxide (+115% vs. basal) following hyperphagic and dopamine release (60% over basal values) at hypophagic doses, respectively. Treatment with L‐NG‐nitro‐L‐arginine‐methyl ester (i.c.v. 2 μg 10 μl−1) or with α‐methyl‐p‐tyrosine (i.p. 100 mg kg−1) before methylamine injection, reduced nitric oxide output and hyperphagia, or dopamine release and hypophagia respectively. Moreover, hypophagia and hyperphagia, as well as nitric oxide and dopamine release were significantly reduced by down‐regulating brain Kv1.6 potassium channel expression. Conclusions and implications: The effects of methylamine on feeding depend on the hypothalamic release of nitric oxide and dopamine as a result of interaction at the Kv1.6 channels. The study of methylamine levels in the CNS may provide new perspectives on the physio‐pathogy of alimentary behaviour. British Journal of Pharmacology (2007) 150, 1003–1010. doi:10.1038/sj.bjp.0707170