Vasorelaxant and hypotensive effects of an ethanolic extract of Nymphaea pubescens and its main compound quercetin 3-methyl ether 3'-O-ß-xylopyranoside.

Aim: Nymphaea plants were traditionally used to treat diseases associated with endothelial dysfunction. The present study investigated the effects of an ethanolic extract of Nymphaea pubescens Willd. (commonly named water lily, WL) and its main compound 1 (quercetin 3-methyl ether 3'-O-ß-xylopyranoside) on vascular function in rats. Materials and methods: The vasorelaxant effects of the WL extract and its main compound 1 and their underlying mechanisms of action were evaluated on isolated mesenteric arteries from Wistar rats. Blood pressure and heart rate were measured in anesthetized rats after infusion (i.v) of vehicle, WL extract, and compound 1 (at 0.01, 0.025, 0.05, 0.1, 0.5, and 1 mg/kg). Nifedipine was used as a positive control. Results: Both WL extract and compound 1 induced vasorelaxant effects (with EC50 of 0.08 ± 0.01 mg/mL and 42.8 ± 6.3 µM, respectively) that were reduced by endothelium removal. A significant decrease in these relaxations was observed with L-NAME but not with apamin-charybdotoxin or indomethacin. In the endothelium-denuded condition, WL extract-induced relaxation was enhanced by 4-aminopyridine and glibenclamide, while iberiotoxin and ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one) had no effect. In contrast, compound 1-induced relaxation was not changed by any of these inhibitors. Both WL extract and compound 1 enhanced sodium nitroprusside-induced relaxation and inhibited receptor-operated Ca2+ channels. Only the WL extract was able to reduce PE-induced contraction (p < 0.001). As compared to the vehicle, the infusion of WL extract and compound 1 lowered systolic and diastolic blood pressure. Interestingly, the hypotensive effect of the compound was similar to that of nifedipine. The rebound tachycardia found at the highest dose of nifedipine was not observed with the WL extract or compound 1 (p < 0.05). Conclusion and discussion: Our study demonstrated a vasorelaxant effect of the WL extract and its main compound quercetin 3-methyl ether 3'-O-ß-xylopyranoside, relying on the potentiation of the NO-cGMP pathway and calcium inhibitory effects. These vasorelaxant effects were associated with a potent hypotensive effect, providing pharmacological evidence for the traditional use of this plant.

Increased gut permeability and intestinal inflammation precede arthritis onset in the adjuvant-induced model of arthritis.

BACKGROUND: Intestinal inflammation, dysbiosis, intestinal permeability (IP), and bacterial translocation (BT) have been identified in patients with spondyloarthritis but the time at which they appear and their contribution to the pathogenesis of the disease is still a matter of debate. OBJECTIVES: To study the time-course of intestinal inflammation (I-Inf), IP, microbiota modification BT in a rat model of reactive arthritis, the adjuvant-induced arthritis model (AIA). METHODS: Analysis was performed at 3 phases of arthritis in control and AIA rats: preclinical phase (day 4), onset phase (day 11), and acute phase (day 28). IP was assessed by measuring levels of zonulin and ileal mRNA expression of zonulin. I-inf was assessed by lymphocyte count from rat ileum and by measuring ileal mRNA expression of proinflammatory cytokines. The integrity of the intestinal barrier was evaluated by levels of iFABP. BT and gut microbiota were assessed by LPS, soluble CD14 levels, and 16S RNA sequencing in mesenteric lymph node and by 16S rRNA sequencing in stool, respectively. RESULTS: Plasma zonulin levels increased at the preclinical and onset phase in the AIA group. Plasma levels of iFABP were increased in AIA rats at all stages of the arthritis course. The preclinical phase was characterized by a transient dysbiosis and increased mRNA ileal expression of IL-8, IL-33, and IL-17. At the onset phase, TNF-α, IL-23p19, and IL-8 mRNA expression were increased. No changes in cytokines mRNA expression were observed at the acute phase. Increased CD4+ and CD8+ T cell number was measured in the AIA ileum at day 4 and day 11. No increase in BT was observed. CONCLUSION: These data show that intestinal changes precede the development of arthritis but argue against a strict "correlative" model in which arthritis and gut changes are inseparable.

The new quinazoline derivative (N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine) vasodilates isolated mesenteric arteries through endothelium-independent mechanisms and has acute hypotensive effects in Wistar rats.

During the screening of new N2,N4-disubstituted quinazoline 2,4-diamines as phosphodiesterase-5 inhibitors and pulmonary artery vasodilators, one N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine (compound 8) presented a greater selectivity for systemic than pulmonary vasculature. The present study aimed to characterize its vasorelaxant and hypotensive effects in Wistar rats. Vasorelaxant effects of compound 8 and underlying mechanisms were evaluated on isolated mesenteric arteries. Acute hypotensive effect was evaluated in anesthetized rats. Additionally, cell viability and cytochrome P450 (CYP) activities were studied in rat isolated hepatocytes. Nifedipine was used as a comparator. Compound 8 induced a strong vasorelaxant effect, similar to nifedipine. This was unaffected by endothelium removal but was decreased by inhibitors of guanylate cyclase (ODQ) and KCa channel (iberiotoxin). Compound 8 enhanced sodium nitroprusside-induced relaxation, but inhibited vasoconstriction evoked by α1-adrenergic receptor activation and extracellular Ca2+ influx via receptor-operated Ca2+ channels. Acute intravenous infusion of compound 8 (0.05 and 0.1 mg/kg) produced hypotension. It showed similar potency to nifedipine for lowering diastolic and mean arterial blood pressure, but less so for the effect on systolic blood pressure. Compound 8 had no effect on hepatocyte viability and CYP activities except at high concentration (10 µM) at which a weak inhibitory effect on CYP1A and 3A was observed. In conclusion, this study identified a N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine with a potent vasodilator effect on resistance vessels, leading to an acute hypotensive effect and a low risk of liver toxicity or drug-drug interactions. These vascular effects were mediated mainly through sGC/cGMP pathway, opening of KCa channels, and inhibition of calcium entry.

Cytokines and intestinal epithelial permeability: A systematic review.

BACKGROUND: The intestinal mucosa is composed of a well-organized epithelium, acting as a physical barrier to harmful luminal contents, while simultaneously ensuring absorption of physiological nutrients and solutes. Increased intestinal permeability has been described in various chronic diseases, leading to abnormal activation of subepithelial immune cells and overproduction of inflammatory mediators. This review aimed to summarize and evaluate the effects of cytokines on intestinal permeability. METHODS: A systematic review of the literature was performed in the Medline, Cochrane and Embase databases, up to 01/04/2022, to identify published studies assessing the direct effect of cytokines on intestinal permeability. We collected data on the study design, the method of assessment of intestinal permeability, the type of intervention and the subsequent effect on gut permeability. RESULTS: A total of 120 publications were included, describing a total of 89 in vitro and 44 in vivo studies. TNFα, IFNγ or IL-1ß were the most frequently studied cytokines, inducing an increase in intestinal permeability through a myosin light-chain-mediated mechanism. In situations associated with intestinal barrier disruption, such as inflammatory bowel diseases, in vivo studies showed that anti-TNFα treatment decreased intestinal permeability while achieving clinical recovery. In contrast to TNFα, IL-10 decreased permeability in conditions associated with intestinal hyperpermeability. For some cytokines (e.g. IL-17, IL-23), results are conflicting, with both an increase and a decrease in gut permeability reported, depending on the study model, methodology, or the studied conditions (e.g. burn injury, colitis, ischemia, sepsis). CONCLUSION: This systematic review provides evidence that intestinal permeability can be directly influenced by cytokines in numerous conditions. The immune environment probably plays an important role, given the variability of their effect, according to different conditions. A better understanding of these mechanisms could open new therapeutic perspectives for disorders associated with gut barrier dysfunction.

Relevance of circulating markers of endothelial activation for cardiovascular risk assessment in rheumatoid arthritis: a narrative review.

Rheumatoid arthritis (RA) is associated with excessive cardiovascular mortality secondary to premature atherosclerosis, in which endothelial activation (EA) plays a central role. EA is characterized by loss of vascular integrity, expression of leucocyte adhesion molecules, transition from antithrombotic to prothrombotic phenotype, cytokines production, shedding of membrane microparticles and recruitment of endothelial progenitor cells. As EA is an early event in atherogenesis, circulating markers of EA are putative markers of vascular pathology and cardiovascular (CV) risk. After a presentation of biology of EA, the present review analyzed the available data regarding changes in EA markers in RA in link with the vascular pathology and CV events, discussed their relevance as biomarkers of CV risk and proposed future directions.

Quinazoline-based human phosphodiesterase 5 inhibitors exhibited a selective vasorelaxant effect on rat isolated pulmonary arteries involving NO-sGC-cGMP pathway and calcium inhibitory effects.

Phosphodiesterase 5 (PDE5) inhibitors are an attractive option among the currently available therapies in the management of pulmonary arterial hypertension (PAH). Good selectivity for PDE5 is associated with reduced side effects and greater vasorelaxant effect on pulmonary arteries (PA). This study investigated the vasorelaxant effects of a series of quinazoline-based PDE5 inhibitors and their precise mechanisms action using rat isolated PA and aorta, as compared to sildenafil. Their effects on rat hepatocytes (viability and CYP activities) were also evaluated. Compounds 5 and 11 displayed lower human PDE5 IC50 of the analogs studied here and induced a greater relaxant effect on PA (EC50 0.94 ± 0.30 and 1.03 ± 0.23 µM, respectively). As compared to sildenafil (EC50 = 0.05 ± 0.02 µM on PA), the relaxant effect of 5 and 11 on PA was lower but their selectivity for PA compared to aorta was higher. The effects of 5 and 11 were reduced by NG-nitro-L-arginine methyl ester, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one, but not by indomethacin or potassium channels blockers. They also enhanced the relaxant effect of sodium nitroprusside, and inhibited extracellular Ca2+ influx and intracellular Ca2+release. Compounds 5 and 11 did not reduce hepatocyte viability except at concentration > 10 µM, inhibited CYP3A at 10 µM, like sildenafil, but did not induce CYP1A. In conclusion, this study identified 2 quinazoline analogues with good PDE5 inhibitory activity and good selectivity for the pulmonary vasculature. Their relaxant effect involves both the potentiation of nitric oxide-sGC-cGMP pathway and calcium inhibition. These compounds are potential leads for developing new drugs for PAH.

Tofacitinib improved peripheral endothelial dysfunction and brain-derived neurotrophic factor levels in the rat adjuvant-induced arthritis model.

This study aimed to explore the effect of Tofacitinib on endothelial dysfunction and cerebral levels of brain-derived neurotrophic factor (BDNF) in the adjuvant-induced arthritis (AIA) rat model. Tofacitinib (10 mg/kg twice a day) or vehicle was administered from the first signs of inflammation. Arthritis scores were daily monitored while other parameters including endothelial function assessed from aortic rings, radiographic scores, blood pressure, heart rate, circulating levels of triglycerides, cholesterol, and interleukin (IL)-1ß, tumor necrosis factor-α (TNF-α), IL-17A, and cerebral BDNF levels were determined after 3 weeks of treatment. A group of non-AIA rats served as controls. In AIA rats, as compared with vehicle, Tofacitinib significantly reduced arthritis and radiographic scores, decreased total cholesterol and low-density lipoprotein cholesterol (LDL-C), but changed neither blood pressure nor heart rate and proinflammatory cytokines levels. It also fully restored acetylcholine (Ach)-induced relaxation (p < 0.05) through increased nitric oxide (NO) synthase activity, reduced BH4 deficiency and O2 -° production, decreased cyclo-oxygenase-2 (COX-2)/arginase activities, and enhanced endothelium-derived hyperpolarizing factor (EDHF) production. These effects translated into a decrease in atherogenic index and an elevation of BDNF levels in the prefrontal cortex (p < 0.05) and hippocampus (p < 0.001). The present study identified Tofacitinib as an efficient therapeutic option to reduce cardiovascular risk and improve BDNF-dependent cognition in arthritis.

Animal models to study pathogenesis and treatments of cardiac disorders in rheumatoid arthritis: Advances and challenges for clinical translation.

Although cardiac diseases such as acute myocardial infarction, heart failure and arrhythmias are the leading cause of cardiovascular complications in rheumatoid arthritis (RA), their pathogenesis is far from being understood and optimal therapeutic options to treat specifically these disorders in RA are lacking. Preclinical studies on animal models of arthritis can help to decipher the complex link between arthritis and the heart, and to identify critical pathways and novel therapeutic targets. This review presented the available data on cardiac disorders in animal models of RA, as well as the current knowledge on pathophysiology and pharmacology of these disorders. Future directions for translational studies in a cardiorheumatic perspective are proposed.

Intestinal permeability in spondyloarthritis and rheumatoid arthritis: A systematic review of the literature.

OBJECTIVES: To describe the current methods usable to assess intestinal permeability in spondyloarthritis (SpA) and rheumatoid arthritis (RA), to analyze the available data on intestinal permeability in SpA and RA patients and the effects of drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) on intestinal permeability. METHODS: A systematic review was conducted. Medline, Embase, and Cochrane Library databases were searched. Studies published in the last 40 years (January 1980-September 2020) with patients with SpA and/or RA assessing the intestinal permeability were selected. RESULTS: A total of 2916 articles were collected, after discarding 1125 duplicate articles, we analyzed the titles and abstracts of 1791 studies. There were 459 articles that met the inclusion criteria and whose text was read. A total of 23 studies were included in the final analysis. Sample sizes ranged from 6 to 206 participants. In patients with spondyloarthritis, a large majority of studies reported an increase in intestinal permeability regardless of the method used. No increase in intestinal permeability was found in RA patients compared to healthy subject in half of the studies. NSAID treatment does not appear to influence intestinal permeability in SpA and seems to increase the intestinal permeability in RA patients as much as in healthy subjects. CONCLUSION: The results of our review suggest the existence of increased intestinal permeability in SpA patients even in the absence of NSAIDs use and regardless of the method assessing the intestinal permeability. Studies in RA patients are more controversial.

Methotrexate and cardiovascular risk in rheumatic diseases:A comprehensive review.

Introduction: Management of inflammatory rheumatic diseases has evolved based on improved treatment strategies and better management of comorbidities, specifically cardiovascular risk. Methotrexate is one of the first-line treatments in the management of inflammatory rheumatic diseases, but its cardiovascular effects are poorly understood. The purpose of this review is to assess the cardiovascular impact of methotrexate in inflammatory rheumatic disease.Areas covered: Current knowledge about the mechanism of action of methotrexate on cardiovascular tissue is presented. A review of the literature in the Medline, Cochrane and Embase databases was performed. Current data about the cardiovascular effects of methotrexate in rheumatoid arthritis, psoriatic arthritis, and psoriasis are presented.Expert opinion: Mechanism of action of methotrexate is based on the antagonism of purines. It reduces systemic inflammation and oxidative stress and improves the major cardiovascular risk factors. Methotrexate improves cardiovascular risk in rheumatoid arthritis, psoriasis and psoriatic arthritis, but the mechanisms involved are partially identified. Data are controversial regarding its effects on endothelial function and atherosclerosis. Conversely, in the general population and in patients with HIV infection, methotrexate does not modify cardiovascular outcomes. Thus, methotrexate only improves cardiovascular risk by reducing systemic inflammation, and should not be used to prevent cardiovascular events.

Mammalian Arginase Inhibitory Activity of Methanolic Extracts and Isolated Compounds from Cyperus Species.

Polyphenolic enriched extracts from two species of Cyperus, Cyperus glomeratus and Cyperus thunbergii, possess mammalian arginase inhibitory capacities, with the percentage inhibition ranging from 80% to 95% at 100 µg/mL and 40% to 64% at 10 µg/mL. Phytochemical investigation of these species led to the isolation and identification of two new natural stilbene oligomers named thunbergin A-B (1-2), together with three other stilbenes, trans-resveratrol (3), trans-scirpusin A (4), trans-cyperusphenol A (6), and two flavonoids, aureusidin (5) and luteolin (7), which were isolated for the first time from C.thunbergii and C. glomeratus. Structures were established on the basis of the spectroscopic data from MS and NMR experiments. The arginase inhibitory activity of compounds 1-7 was evaluated through an in vitro arginase inhibitory assay using purified liver bovine arginase. As a result, five compounds (1, 4-7) showed significant inhibition of arginase, with IC50 values between 17.6 and 60.6 µM, in the range of those of the natural arginase inhibitor piceatannol (12.6 µM). In addition, methanolic extract from Cyperus thunbergii exhibited an endothelium and NO-dependent vasorelaxant effect on thoracic aortic rings from rats and improved endothelial dysfunction in an adjuvant-induced arthritis rat model.

Impact of glucocorticoids on systemic sirtuin 1 expression and activity in rats with adjuvant-induced arthritis.

The class III histone deacetylase sirtuin 1 (SIRT1) plays a pivotal role in numerous biological and physiological functions, including inflammation. An association between SIRT1 and proinflammatory cytokines might exist. In addition to their important role in inflammation associated with rheumatoid arthritis (RA), proinflammatory cytokines mediate the development of systemic effects. Here, we evaluated systemic SIRT1 expression and enzymatic activity, in peripheral blood mononuclear cells (PBMCs) and in liver isolated from rats with adjuvant-induced arthritis (AIA), treated or not with low or high doses of glucocorticoids (GCs). We also measured the production of tumour necrosis factor alpha (TNF) and interleukin-1 beta (IL-1 beta) in PBMCs and liver. We found that SIRT1 expression and activity increased in PBMCs of AIA rats compared to healthy controls and decreased under GC treatment. Similarly, we observed an increased SIRT1 activity in the liver of AIA rats compared to healthy controls which decreased under high doses of GCs. We also found an increase in IL-1 beta and TNF levels in the liver of AIA rats compared to healthy controls, which decreased under high doses of GC. We did not observe a significant correlation between SIRT1 activity and proinflammatory cytokine production in PBMC or liver. In contrast, a strong positive correlation was found between the liver levels of TNF and IL-1 beta (rho=0.9503, p=7.5x10-21). Our results indicate that increased inflammation in AIA rats compared to healthy control is accompanied by an increased SIRT1 activity in both PBMCs and liver, which could be decreased under GC treatment.

Adjuvant-induced arthritis is a relevant model to mimic coronary and myocardial impairments in rheumatoid arthritis.

OBJECTIVES: To determine if the adjuvant-induced arthritis model reproduced coronary and cardiac impairments observed in rheumatoid arthritis patients. The link between disease activity and circulating levels of angiotensin II and endothelin-1 have been studied, as well as the myocardial susceptibility to ischemia. METHODS: At the acute inflammatory phase, coronary reactivity was assessed in isolated arteries, and cardiac function was studied in isolated perfused hearts, before and after global ischemia/reperfusion. Ischemic insult was evaluated by the infarct size, lactate dehydrogenase and creatine phosphokinase levels in coronary effluents. Cardiac myeloperoxidase activity was measured, as well as angiotensin II and endothelin-1 levels. RESULTS: Compared to controls, adjuvant-induced arthritis had reduced coronary Acetylcholine-induced relaxation associated with cardiac hypertrophy, both being correlated with plasma levels of endothelin-1 and angiotensin II, and arthritis score. Although cardiac function at baseline was similar from controls, adjuvant-induced arthritis rats exhibited lower cardiac functional recovery, increased myeloperoxidase activity, higher infarct size and creatine phosphokinase levels after ischemia/reperfusion. CONCLUSIONS: The adjuvant-induced arthritis model displays coronary endothelial dysfunction associated with myocardial hypertrophy and a reduced tolerance to ischemia. This model might be useful for deciphering the pathophysiology of cardiac dysfunction in rheumatoid arthritis and paves the way for studying the role of endothelin-1 and angiotensin II.

A reconciling hypothesis centred on brain-derived neurotrophic factor to explain neuropsychiatric manifestations in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease characterized by synovitis leading to joint destruction, pain and disability. Despite efficient antirheumatic drugs, neuropsychiatric troubles including depression and cognitive dysfunction are common in RA but the underlying mechanisms are unclear. However, converging evidence strongly suggests that deficit in brain-derived neurotrophic factor (BDNF) signalling contributes to impaired cognition and depression. Therefore, this review summarizes the current knowledge on BDNF in RA, proposes possible mechanisms linking RA and brain BDNF deficiency including neuroinflammation, cerebral endothelial dysfunction and sedentary behaviour, and discusses neuromuscular electrical stimulation as an attractive therapeutic option.

Polyphenolic compounds of Euphorbia umbellata (Pax) Bruyns (Euphorbiaceae) improved endothelial dysfunction through arginase inhibition.

Euphorbia umbellata is used for its anti-inflammatory properties; however, there are limited data available regarding its effects on vascular function. Its bark is rich in polyphenolic compounds, which potentially improve endothelial dysfunction (ED). This study proposes to investigate the effects of E. umbellata bark extracts and its polyphenolic compounds on arginase (ARG) activity and nitric oxide (NO)-related targets. Chromatographic procedures were used for the chemical characterisation of the extracts. Furthermore, in silico (molecular docking), in vitro (ARG inhibition), in vivo (streptozotocin-induced hyperglycemia model), and ex vivo (l-arginine metabolism, vascular reactivity, western blot, and biochemical) techniques were carried out. Quercetin, gallic acid, and ellagic acid were identified in the extracts. In silico screening predicted that gallic acid and quercetin would have the most promising interactions with ARG -identified cavities. This was confirmed in vitro as both compounds had a direct inhibitory effect on ARG, as was the case regarding the extracts. Oral treatment preserved endothelium-dependent vasodilation through ARG inhibition together with an increase in l-arginine bioavailability and endothelial NO synthase expression. Biochemical parameters determined the lack of toxicity for sub-chronic treatment. E. umbellata bark extracts and its compounds can contribute to ED treatment, at least partly, through the inhibition of vascular ARG.

Arginase inhibitory properties of flavonoid compounds from the leaves of Mulberry (Morus alba, Moraceae).

OBJECTIVES: We aimed to isolate and identify bioactive molecules from Morus alba (Moraceae) leaves having arginase inhibitory activity towards the combat of clinical outcomes related to endothelial dysfunction. METHOD: Extraction and isolation were carried out by successive macerations, prepurification by using a Solid Phase Extraction (SPE) and separation using preparative PLC. The structures of the isolated components were established and confirmed by spectroscopic analyses, including the ESI-HRMS and NMR spectroscopic investigations. Biological evaluation was performed by using an in vitro assay with liver bovine purified arginase and by an ex vivo aortic ring study. KEY FINDINGS: We demonstrated that a phenolic extract from the leaves of M. alba possesses mammalian arginase inhibitory capacities. Investigation of the chemical constituents of its leaves results in the isolation and identification of ten compounds investigated in vitro for their arginase inhibitory capacities. Four compounds showed significant inhibition of arginase, with percentage inhibition ranging from 54% to 83% at 100 µm. In isolated rat aortic rings incubated with NO synthase inhibitor, Luteolin-7-diglucoside compound (2) was able to increase acetylcholine-induced relaxation. CONCLUSIONS: These results demonstrated the attractive ability of M. alba to be a potential source for the discovery of new active products on vascular system.

Cardiovascular risk in psoriatic arthritis, a narrative review.

INTRODUCTION: Psoriatic arthritis (PsA) is a chronic inflammatory rheumatism characterized for a long time by a high degree of cardiovascular risk. Chronic inflammation is one of the mechanisms that explain this cardiovascular excess of risk through direct and indirect pathways. In recent years, epidemiological data have changed somewhat since the increasing use of bio-drugs that are effective in reducing this inflammation. The purpose of this review is to assess the current state of cardiovascular morbidity and mortality in PsA and thus to assess the cardiovascular risk in case of PsA. METHOD: We conducted a literature review using Pubmed and Medline databases with the following keywords "Psoriatic Arthritis" AND "cardiovascular" including articles from the last three years. RESULTS: It appears that in case of PsA, there is an increased prevalence of high blood pressure, diabetes, obesity and dyslipidemia, and therefore of metabolic syndrome. Insulin resistance is closely linked to PsA. On the other hand, the data are more contrasted for active smoking. There is also arterial inflammation specific to PsA. Finally, at the therapeutic level, the impact of NSAIDs remains controversial, while methotrexate and bio-drugs are beneficial at the cardiovascular level. CONCLUSION: PsA is characterized by an increase in cardiovascular morbidity in relation with insulin resistance. Current treatments seem to improve this risk with a decrease in cardiovascular mortality in comparison with patients with plaque psoriasis but this requires confirmation in larger prospective studies.

Vasorelaxant effects of Crataegus pentagyna: Links with arginase inhibition and phenolic profile.

ETHNOPHARMACOLOGICAL RELEVANCE: Crataegus leaves, flowers and fruits have been traditionally used to improve blood circulation, numerous preclinical and clinical studies supporting the cardiovascular benefits of Crataegus preparations. In this respect, there is very limited data on Crataegus pentagyna; in addition, the chemical profile of this species is still incompletely elucidated. AIM OF THE STUDY: The objective of this study was to examine the cardiovascular benefits of Crataegus pentagyna Waldst. et Kit. ex Willd. (small-flowered black hawthorn, Rosaceae) extracts (leaf, flower and fruit ethyl acetate extracts) and the underlying mechanisms. We hypothesized that C. pentagyna extracts might exert vasodilatory effects and inhibit arginase activity due, in large part, to their polyphenolic constituents. MATERIALS AND METHODS: C. pentagyna extracts induced-relaxation and the mechanisms involved were studied ex vivo in isolated aortic rings from Sprague-Dawley rats. The inhibitory effects on bovine liver arginase I were assessed by an in vitro assay. Metabolite profiling of C. pentagyna extracts was performed and the most endothelium- and nitric oxide synthase-dependent; flower extract additionally reduced Ca2+ entry and, to a lesser extent, Ca2+ release from the sarcoplasmic reticulum. C. pentagyna proved to be an important source of arginase inhibitors with potential benefits in endothelial dysfunction that remains to be explored.