Marrubium vulgare L. (Horehound, Lamiaceae) is a widespread Mediterranean plant used in folk medicine to cure a variety of diseases. Chemically, this genus is best known for its furanic labdane diterpene marrubiin, which has potent antinociceptive [1] and expectorant [2] effects. Other furanic labdane diterpenes including premarrubenol, marrubenol and premarrubiin have been repeatedly reported to occur in this plant [3], [4] but pharmacological information about these components is lacking. In a previous report, we have demonstrated that treatment with an aqueous extract of the aerial parts of M. vulgare significantly lowered the systolic blood pressure in spontaneously hypertensive rats (SHR), related to a vasodilatory effect exhibited by the extract ex vivo as well as in vitro [5]. The present study deals mainly with the isolation and structural elucidation of the compounds responsible for the vasorelaxant activity ascribed to this plant.Preincubation of rat aorta with the cyclohexane fraction of M. vulgare water extract evoked a dose-dependent inhibition of KCl-induced contraction while the aqueous fraction showed no effect ( Table 1). Bio-guided fractionation of this cyclohexane extract by column chromatography gave several fractions, two of which showed a high activity. The first one was further purified using preparative TLC on silica gel (Si 60 F 254 Merck) with hexane-diethyl ether (4 : 6) as mobile phase, yielding 10. C, COSY, HMQC, HMBC) allowed us to identify it as marrubenol, previously isolated from M. vulgare [7]. Table 2 gives, for the first time, the complete NMR assignments of marrubenol. Its structure was further confirmed by comparison with marrubenol obtained by reduction of marrubiin (Fig. 1).The effects of marrubiin and marrubenol on the contractions evoked by high-KCl depolarizing solution in aortic segments were compared to the effect of the calcium channel blocker verapamil, a well known antihypertensive drug which inhibits the contraction evoked by high-KCl solution in arteries [8]. Marrubenol and marrubiin inhibited the aortic contraction in a concentration-dependent manner (Fig. 2) AbstractCrude extracts of the aerial parts of Marrubium vulgare show a potent in vitro inhibition of KCl-induced contraction of rat aorta. Bio-guided fractionations, spectroscopic analysis and chemical derivatization revealed the furanic labdane diterpenes marrubenol and marrubiin as the most active compounds.
The hypotensive effects of the water extract of Marrubium vulgare L. and Foeniculum vulgare L. were investigated in spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto rats (WKY). Oral administration of Marrubium or Foeniculum extract lowered the systolic blood pressure of SHR but not of WKY. In SHR, Foeniculum but not Marrubium treatment increased water, sodium and potassium excretion. Ex vivo as well as in vitro, Marrubium extract inhibited the contractile responses of rat aorta to noradrenaline and to KCl (100 mM). Inhibition was greater in aorta from SHR compared to WKY and was not affected by the NO synthase inhibitor N-nitro-L-arginine. Vascular effects of Foeniculum extract were less pronounced than those of Marrubium and were blocked by N-nitro-L-arginine. These results indicate that hypotensive activity of Marrubium and Foeniculum extracts seems to be mediated through different pathways: Foeniculum appeared to act mainly as a diuretic and a natriuretic while Marrubium displayed vascular relaxant activity.
1 The objective of the present study was to investigate the mechanism of the relaxant activity of marrubenol, a diterpenoid extracted from Marrubium vulgare. In rat aorta, marrubenol was a more potent inhibitor of the contraction evoked by 100 mM KCl (IC 50 : 11.870.3 mM, maximum relaxation: 9370.6%) than of the contraction evoked by noradrenaline (maximum relaxation: 3071.5%). 2 In fura-2-loaded aorta, marrubenol simultaneously inhibited the Ca 2 þ signal and the contraction evoked by 100 mM KCl, and decreased the quenching rate of fura-2 fluorescence by Mn 2 þ . 3 Patch-clamp data obtained in aortic smooth muscle cells (A7r5) indicated that marrubenol inhibited Ba 2 þ inward current in a voltage-dependent manner (K D : 872 and 4076 mM at holding potentials of À50 and À100 mV, respectively). 4 These results showed that marrubenol inhibits smooth muscle contraction by blocking L-type calcium channels.
Water extract of Marrubium vulgare is widely used as antihypertensive treatment in folk medicine. We have compared the effect of 10-week-long treatment with amlodipine or Marrubium water extract on systolic blood pressure (SBP), cardiovascular remodeling and vascular relaxation in spontaneously hypertensive rats (SHR). Both treatments produced similar decrease in SBP. Amlodipine treatment reduced left ventricle, aortic and mesenteric artery weight. Marrubium treatment had a significant antihypertrophic effect in aorta only. Relaxation to acetylcholine (ACh) of mesenteric artery was improved by Marrubium but not by amlodipine treatment. These results demonstrate that, in addition to its antihypertensive effect, Marrubium water extract improved the impaired endothelial function in SHR.
This study aimed to estimate the incidence of KRAS, NRAS, and BRAF mutations in the Moroccan population, and investigate the associations of KRAS and NRAS gene mutations with clinicopathological characteristics and their prognosis value. To achieve these objectives, we reviewed medical and pathology reports for 210 patients. RAS testing was investigated by Sanger sequencing and Pyrosequencing technology. BRAF (exon 15) status was analyzed by the Sanger method. The expression of MMR proteins was evaluated by Immunohistochemistry. KRAS and NRAS mutations were found in 36.7% and 2.9% of 210 patients, respectively. KRAS exon 2 mutations were identified in 76.5% of the cases. RAS-mutated colon cancers were significantly associated with female gender, presence of vascular invasion, classical adenocarcinoma, moderately differentiated tumors, advanced TNM stage III-IV, left colon site, higher incidence of distant metastases at the time of diagnostic, microsatellite stable phenotype, lower number of total lymph nodes, and higher means of positive lymph nodes and lymph node ratio. KRAS exon 2-mutated colon cancers, compared with KRAS wild-type colon cancers were associated with the same clinicopathological features of RAS-mutated colon cancers. NRAS-mutated patients were associated with lower total lymph node rate and the presence of positive lymph node. Rare RAS-mutated tumors, compared with wild-type tumors were more frequently moderately differentiated and associated with lower lymph node rate. We found that KRAS codon 13-mutated, tumors compared to codon 12-mutated tumors were significantly correlated with a higher death cases number, a lower rate of positive lymph, lower follow-up time, and poor overall survival. Our findings show that KRAS and NRAS mutations have distinct clinicopathological features. KRAS codon 13-mutated status was the worst predictor of prognosis at all stages in our population.
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