Erucin exhibits vasorelaxing effects and antihypertensive activity by H2 S-releasing properties.

BACKGROUND AND PURPOSE: Hydrogen sulfide (H2 S)-releasing agents are viewed as potential antihypertensive drugs. Recently, natural isothiocyanates emerged as original H2 S-donor agents. Among them, erucin, present in some edible cruciferous plants, shows suitable H2 S-releasing properties and features of "druggability." The aim of this work was to investigate the erucin-mediated release of H2 S inside vascular cells, its vasorelaxing effects, and activity on BP of normo and hypertensive animals. EXPERIMENTAL APPROACH: Intracellular H2 S-release and the hyperpolarizing effect of erucin were tested using fluorescent dye, in human aortic smooth muscle cells (HASMCs). Its direct vasorelaxing effect and ability to inhibit noradrenaline-induced vasoconstriction were evaluated on endothelium-intact or -denuded rat aortic rings. Its vasodilator properties were tested in coronary arteries using Langendorff-perfused rat hearts. Finally, erucin's antihypertensive activity was evaluated in vivo in normotensive and spontaneously hypertensive rats (SHRs) by recording systolic BP using the tail-cuff method. KEY RESULTS: Erucin induced the release of H2 S inside HASMCs. Moreover, erucin hyperpolarized the membrane of HASMCs membrane in a concentration-dependent manner. It induced vasodilatation of rat aortic rings, in endothelium-denuded vessels. This effect was further improved by the presence of endothelial NO. When pre-incubated with rat aortic rings, erucin induced concentration-dependent inhibition of noradrenaline-induced vasoconstriction. Erucin did not affect basal coronary flow but restored the flow to normal in pre-contracted coronary vessels. Finally, in vivo, erucin decreased systolic BP in SHRs by about 25%, and restored the BP to values observed in normotensive rats. CONCLUSIONS AND IMPLICATIONS: Erucin is an H2 S donor endowed with vasorelaxing and antihypertensive effects

Nutraceutical Value of Citrus Flavanones and Their Implications in Cardiovascular Disease

Background- Cardiovascular diseases, including myocardial infarction, dyslipidaemia and coronary artery pathology, are a major cause of illness and death in Western countries. Therefore, identifying effective therapeutic approaches and their cellular signalling pathways is a challenging goal for medicine. In this regard, several epidemiological studies demonstrate a relationship between the intake of flavonoid-rich foods and the reduction of cardiovascular risk factors and mortality. In particular, flavonoids present in citrus fruits, such as oranges, bergamots, lemons and grapefruit (95% from flavanones), are emerging for their considerable nutraceutical value. Methods- In this review an examination of literature was performed while considering both epidemiological, clinical and pre-clinical evidence supporting the beneficial role of the flavanone class. We evaluated studies in which citrus fruit juices or single flavanone administration and cardiovascular risk factors were analysed; to identify these studies, an electronic search was conducted in PUBMED for papers fulfilling these criteria and written in English. Results- In addition to epidemiological evidence and clinical studies demonstrating that fruits in the Citrus genus significantly reduce the incidence of cardiovascular disease risk, pre-clinical investigations highlight cellular and subcellular targets that are responsible for these beneficial effects. There has been special attention on evaluating intracellular pathways involved in direct cardiovascular and cardiometabolic effects mediated by naringenin, hesperetin and eriodictyol or their glycosylated derivatives. Conclusions- Although some mechanisms of action remain unclear and bioavailability problems remain to be solved, the current evidence supports the use of a nutraceutical approach with citrus fruits to prevent and cure several aspects of cardiovascular disease

Improving the solubility of a new class of antiinflammatory pharmacodynamic hybrids, that release nitric oxide and inhibit cycloxygenase-2 isoenzyme

The development of a novel class of pharmacodynamic hybrids that inhibits COX-2 isoform is reported. These molecules display enhanced nitric oxide releasing properties due to the presence of an ionisable moiety. The in vivo analgesic/anti-inflammatory activity was maintained in relation to the parent compounds

Novel analgesic/anti-inflammatory agents: 1,5-diarylpyrrole nitrooxyalkyl ethers and related compounds as cyclooxygenase-2 inhibiting nitric oxide donors

A series of 3-substituted 1,5-diarylpyrroles bearing a nitrooxyalkyl side chain linked to different spacers were designed. New classes of pyrrole-derived nitrooxyalkyl inverse esters, carbonates, and ethers (7-10) as COX-2 selective inhibitors and NO donors were synthesized and are herein reported. By taking into account the metabolic conversion of nitrooxyalkyl ethers (9, 10) into corresponding alcohols, derivatives 17 and 18 were also studied. Nitrooxy derivatives showed NO-dependent vasorelaxing properties, while most of the compounds proved to be very potent and selective COX-2 inhibitors in in vitro experimental models. Further in vivo studies on compounds 9a,c and 17a highlighted good anti-inflammatory and antinociceptive activities. Compound 9c was able to inhibit glycosaminoglycan (GAG) release induced by interleukin-1β (IL-1β), showing cartilage protective properties. Finally, molecular modeling and (1)H- and (13)C-NMR studies performed on compounds 6c,d, 9c, and 10b allowed the right conformation of nitrooxyalkyl ester and ether side chain of these molecules within the COX-2 active site to be assessed

Efficacy of isothiocyanate-based compounds on different forms of persistent pain.

Current pharmacotherapy for persistent pain related to neuropathy or articular diseases is unsatisfactory, due to the large number of unresponsive patients and side effects. Isothiocyanates (ITCs) are a class of natural or synthetic compounds characterized by the general formula R-NCS. ITCs show antihyperalgesic effects in models of central and peripheral nervous tissue injury and anti-inflammatory properties. The pharmacodynamics are strictly related to the release of the gasotransmitter hydrogen sulfide (H2S) from their moiety. In particular, phenyl ITC (PITC) and 3-carboxyphenyl ITC (3C-PITC) exhibit interesting slow H2S-release properties suitable for treating painful pathology. The aim of the present work was to evaluate the efficacy of PITC and 3C-PITC against mechanical hyperalgesia and spontaneous pain induced by nerve injury and osteoarthritis

Contribution of irisin pathway in protective effects of mandarin juice (Citrus reticulata Blanco) on metabolic syndrome in rats fed with high fat diet

The beneficial effects of Citrus fruits and their secondary metabolites on the cardio- vascular system are well established. Moreover, growing evidence suggests beneficial role for prevention of obesity and related dysfunctions. Citrus reticulata Blanco (Rutaceae) is one of the most consumed Citrus fruits, but it is poorly investigated. Mandarin juice obtained from C. reticulata fruits, collected in the Horti Simplicium of Pisa Charterhouse, presents a high amount of flavanone glycosides, including hesper- idin and a number of polymethoxyflavonoids, in particular nobiletin and tangeretin. On Wistar rats fed with a high fat diet for 21 days, mandarin juice significantly con- tained the percentage weight gain, reduced visceral adipose tissue and the inflamma- tory markers TNF and IL-6. Furthermore, mandarin juice influenced irisin pathway, increasing its plasma levels. Finally, supplementation with mandarin juice contributed to improve mitochondrial membrane potential, partially compromised with high fat diet, making mitochondria less susceptible to harmful events, such as ischemia. Taken together, these results suggest that C. reticulata, through its main metabolites, is able to produce beneficial effects in metabolic syndrome and to promote browning pro- cess, through involvement of the novel interesting irisin pathway

Antioxidant and antisenescence effects of bergamot juice

Aging is one of the main risk factor for the onset of cardiovascular diseases; one of the possible explanations could be linked to the age-associated overproduction of free radicals. This increase of oxidative stress can be overcome with a high intake of food antioxidants. In this context, a number of studies have been addressed to assess the antiaging potential of natural antioxidant compounds. Recently, it has been shown that the juice of bergamot (Citrus bergamia Risso et Poiteau), a fruit mostly produced in the Ionian coastal areas of Southern Italy (Calabria), is a valuable source of health-promoting constituents with, among other, antioxidant properties. In order to investigate the potential antiaging effects of this Mediterranean natural antioxidant source, bergamot juices of three different cultivars ("fantastico," "femminello," and "castagnaro") were herein characterized by the mean of high-performance liquid chromatography-photodiode array-electrospray ionization-tandem mass spectrometry. Then, juices were investigated for the evaluation of total polyphenolic and flavonoid contents, cell-free model antioxidant activities, and in vitro antiaging properties on two different cellular models of induced myocardial senescence. The best performing juice was also assessed in vivo. The phytochemical profiles confirmed that juices were rich in flavonoids, both flavone and flavanone glycosides. In addition, two limonoid glycosides were also identified in all cultivars. Each cultivar showed different phenolic and flavonoid contents. In tube results showed the juice robust antioxidant activities that correlate with their phenolic and flavonoid contents. Moreover, for the first time, the ability of juice to counteract the chemical-induced senescence was here demonstrated in both cellular models. Lastly, the in vivo data obtained from mouse hearts evidenced an increase in transcription of genes involved in antiaging and antioxidant responses. The overall results suggest that bergamot juice exerts antioxidant and antisenescence effects, making it useful for nutraceutical purposes