DIALLIL TIOSULFINATO - appr

DIALLIL TIOSULFINATO

L’allicina, o diallil tiosulfinato, è il principio attivo più importante e rappresentativo dell’aglio (Allium sativus). Questa sostanza non si riscontra nel bulbo integro, ma si forma quando gli spicchi che lo costituiscono – detti bulbilli – vengono tagliati, masticati o altrimenti triturati. In seguito a queste azioni meccaniche, dai succhi vacuolari si libera un enzima, chiamato allinasi, che agisce su un amminoacido, l’alliina, trasformandolo in allicina. A sua volta, questa sostanza instabile è precorritrice del disolfuro di diallile, una molecola volatile che origina dalla perdita di un atomo di ossigeno dalla molecola di allicina. Grazie all’elevata volatilità, il disolfuro di diallile conferisce all’aglio tritato il tipico odore pungente.
Il Diallil Tiosulfinato è un composto solforganico precursore del disolfuro di diallile (DADS) in grado di aumentare la concentrazione di glutatione intracellulare. Il glutatione è un tripeptide naturale, vale a dire una sostanza costituita da tre amminoacidi (cisteina, acido glutammico e glicina).
Attraverso una serie di reazioni la Cisteina viene trasformata grazie all’azione di 2 importanti enzimi: cistationina-beta-sintasi (CBS) e cistationina-gamma-liasi (CSE) in idrogeno solforato prodotto al livello arterioso con particolare riferimento alla circolazione periferica.
L’idrogeno solforato (H2S) è infatti un vero e proprio mediatore gassoso pro-erettogeno che, attraverso l’apertura dei canali potassio ATP (K ATP), con conseguente aumento del transfer di ioni CA++, produce attraverso un preciso meccanismo di iperpolarizzazione sulle cellule muscolari lisce, un effetto di rilassamento sulle stesse. Il rilassamento della muscolatura liscia periferica determina a sua volta il richiamo di sangue con conseguente fenomeno dell’erezione. 

STUDI CLINICI

Therapeutic applications of organosulfur compounds as novel hydrogen sulfide donors and/or mediators (Xianfeng Gu and Yi Zhun Zhu)

Hydrogen sulfide, once considered as toxic gas, is now recognized as an important biological mediator. The deficiency of hydrogen sulfide could lead to various pathological changes, such as arterial and pulmonary hypertension, Alzheimer’s disease, gastric mucosal injury and liver cirrhosis. However, excessive production of hydrogen sulfide, by using inorganic hydrogen sulfide donors such as NaHS, may contribute to the pathogenesis of inflammatory diseases, septic shock, cerebral stroke and mental retardation in patients with Down syndrome. Therefore, an increasing interest in organic molecules that are capable of regulating the formation of hydrogen sulfide has extended in recent years. Allium vegetables are one natural source of organic sulfur-containing compounds and have been widely investigated regarding their therapeutic applications, and it has been proven that the ingredients of garlic, such as diallyl disulfide, diallyl trisulfide and S-ally cysteine act as hydrogen sulfide donors or mediators in pharmaceutical studies. In addition, S-propargyl cysteine (ZYZ-802) and S-propyl cysteine, two synthetic cysteine analogs, have been examined and could be used to treat ischemic heart disease via modulation of the hydrogen sulfide pathway. In addition, drugs containing hydrogen sulfide-releasing moieties have been synthesized and widely reported in recent years, such as S-nonsteroidal anti-inflammatory drugs and the derivative of Lawesson’s reagents, which exhibit varied biological effects in experiments. As cystathionine β-synthase and cystathionine γ-lyase are the enzymes that are able to catalyze the production of endogenous hydrogen sulfide from cysteine, their inhibitors, such as dl-propylargylglycine and β-cyanoalanine, have been frequently used in studies on the biological mechanism of hydrogen sulfide. All these hydrogen sulfide donors, mediators and inhibitors have provided useful tools in the research of a variety of biological effects and are promising drug candidates of hydrogen sulfide.

Traduzione: Il solfuro di idrogeno, un tempo considerato come gas tossico, è ormai riconosciuto come un importante mediatore biologico. La carenza di acido solfidrico può infatti portare a varie patologie, come l’ipertensione arteriosa e polmonare, la malattia di Alzheimer, la lesione della mucosa gastrica e la cirrosi epatica. Tuttavia, la produzione eccessiva di acido solfidrico, utilizzando inorganici donatori di idrogeno solforato, come NAHS, può contribuire alla patogenesi delle malattie infiammatorie, shock settico, ictus cerebrale e ritardo mentale nei pazienti con sindrome di Down. Pertanto nel corso degli anni si è assistito ad un crescente interesse delle varie molecole organiche che sono in grado di regolare la formazione di idrogeno solforato. L’aglio è una fonte naturale di composti contenenti zolfo organici che sono stati ampiamente studiati per quanto riguarda le loro applicazioni terapeutiche, ed è stato dimostrato che i princìpi attivi in esso contenuti, quali il Diallile diosulfinato, diallil trisolfuro e S-alleato possono agire come donatori di idrogeno solforato o suoi mediatori. Inoltre, S-propargil cisteina (ZYZ-802) e S-propile cisteina, due analoghi sintetici della cisteina, sono stati esaminati e potrebbero essere utilizzati per il trattamento di cardiopatia ischemica mediante la modulazione della via di idrogeno solforato. Inoltre, i farmaci contenenti idrogeno disolfuro sono stati sintetizzati e ampiamente riportato negli ultimi anni, come farmaci anti-infiammatori non steroidei. Come cistationina β-sintasi e cistationina γ-liasi sono gli enzimi che sono in grado di catalizzare la produzione endogena di solfuro di idrogeno da cisteina, loro inibitori, quali dl-propylargylglycine e β-cyanoalanine, sono stati frequentemente utilizzati negli studi sul meccanismo biologico di idrogeno solforato. Tutti questi “donatori”, mediatori e inibitori di idrogeno solforato hanno fornito strumenti utili nella ricerca di una varietà di effetti biologici e sono promettenti droghe candidate di idrogeno solforato.

Hydrogen sulfide mediates the vasoactivity of garlic (Gloria A. Benavides, Giuseppe L. Squadrito, Robert W. Mills, Hetal D. Patel, T. Scott Isbell, Rakesh P. Patel, Victor M. Darley-Usmar, Jeannette E. Doeller and David W. Kraus)
Abstract: The consumption of garlic is inversely correlated with the progression of cardiovascular disease, although the responsible mechanisms remain unclear. Here we show that human RBCs convert garlic-derived organic polysulfides into hydrogen sulfide (H2S), an endogenous cardioprotective vascular cell signaling molecule. This H2S production, measured in real time by a novel polarographic H2S sensor, is supported by glucose-maintained cytosolic glutathione levels and is to a large extent reliant on reduced thiols in or on the RBC membrane. H2S production from organic polysulfides is facilitated by allyl substituents and by increasing numbers of tethering sulfur atoms. Allyl-substituted polysulfides undergo nucleophilic substitution at the α carbon of the allyl substituent, thereby forming a hydropolysulfide (RSnH), a key intermediate during the formation of H2S. Organic polysulfides (R-Sn-R′; n > 2) also undergo nucleophilic substitution at a sulfur atom, yielding RSnH and H2S. Intact aorta rings, under physiologically relevant oxygen levels, also metabolize garlic-derived organic polysulfides to liberate H2S. The vasoactivity of garlic compounds is synchronous with H2S production, and their potency to mediate relaxation increases with H2S yield, strongly supporting our hypothesis that H2S mediates the vasoactivity of garlic. Our results also suggest that the capacity to produce H2S can be used to standardize garlic dietary supplements.
Results: Garlic-induced H2S production and GSH and GSSG levels. Representative polarographic traces of garlic-induced H2S production in 20% (vol/vol) RBCs in anoxic 10 mM PBS with 50 μM DTPA, with (black line) and without (blue line) 10 mM glucose (Glc), with sequential 1 mg/ml garlic additions at arrows, compared with the same garlic additions to 10 mM PBS and 50 μM DTPA alone in the absence of RBCs (red line) (pH 7.35) at 37°C. (B) HPLC analysis of GSH (black bars) and GSSG (expressed in GSH equivalents; white bars) in 40% (vol/vol) RBCs subject to no treatment, 10 mM glucose (Glc), 10 mM glucose and 1 mg/ml garlic, 1 mg/ml garlic alone, 10 mM IAA, and 10 mM IAM; each bar represents the mean ± SD of three to five experiments.*, GSH and GSSG levels are statistically different compared with levels in untreated RBCs by Student’s t test (P ≤ 0.01). (C and D) Representative polarographic traces of H2S production in anoxic 10 mM PBS with 50 μM DTPA in the absence of RBCs, with 2 mM each GSH, cysteine (Cys), homocysteine (Hcys), or N-acetylcysteine (NAC) (pH 7.35) at 37°C upon addition of 1 mg/ml garlic at arrow (C) and garlic-induced H2S production in 20% (vol/vol) RBCs with 10 mM glucose previously treated with 10 mM IAA (blue line) or 10 mM IAM (red line) compared with untreated RBCs (black line) with 1 mg/ml garlic additions at arrows (D). 

Potent activation of nitric oxide synthase by garlic: a basis for its therapeutic applications (Das I, Khan NS, Sooranna SR)
Abstract: Garlic (Allium sativum L.) is thought to have a variety of therapeutic applications including inhibition of platelet aggregation. Many of the therapeutic actions of garlic parallel the physiological effects of nitric oxide and may be explained by its ability to increase nitric oxide synthase activity intracellularly. Our studies showed that both water and alcoholic extracts of garlic are very potent inhibitors of platelet aggregation induced by epinephrine and ADP. Similar dilutions of garlic extract also activated nitric oxide synthase activity in isolated platelets in vitro. The same extract was also very effective in activating nitric oxide synthase activity in placental villous tissue. The addition of garlic extracts increased nitric oxide synthase activity in a dose-dependent manner. Nitrite levels in the supernatants of incubated placental villous tissue were similarly increased. Activation of calcium-dependent nitric oxide synthase and the subsequent production of nitric oxide is probably the most novel mechanism yet claimed by which garlic can exert its therapeutic properties. PMID: 7555034 [PubMed – indexed for MEDLINE]

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Quanto proposto è ad esclusivo scopo informativo e non sostituisce il medico a cui bisogna rivolgersi per i problemi relativi alla salute.