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Tanshinone IIA and cryptotanshinone are two pharmacologically active diterpenoids extracted from the roots of Salvia milthiorriza Bunge, a plant used in Chinese traditional medicine for the treatment of some cardiovascular and cerebrovascular disease. Until now, the molecular mechanisms of action of these two diterpenoids on platelets are partially known. To clarify this aspect, here we utilized an integrated study of pharmacology and computational analysis. Our results demonstrate that cryptotanshinone is able to inhibit in a concentration dependent manner the rat platelet aggregation and also is endowed of Gi-coupled P2Y12 receptor antagonist as demonstrated by docking studies. This computational method was also performed for tanshinone IIA demonstrating even for this diterpenoid an interaction with the same receptor. The findings from our study enable a better understanding of tanshinone IIA and cryptotanshinone biological properties, which could ultimately lead to the development of novel pharmaceutical strategies for the treatment and/or prevention of some cardiovascular disease.

The potential anxiolytic and anti-depressive activity of CMP1 was studied in the elevated plus-maze test and in the forced swimming test. Furthermore, CMP1 sedative activity was evaluated in pentobarbital treated animals; the effect of CMP1 on spontaneous motor activity (total locomotion) was also evaluated. Our data show that CMP1, at doses that did not affect locomotion, was able to induce anxiolytic and sedative, but not anti-depressive effects. In conclusion, our results represent first evidence for an anxiolytic activity of this diterpenoid from Salvia cinnabarina.

Interleukin (IL)17 is a novel cytokine that has been suggested to play a key role in sustaining chronic inflammation in autoimmune diseases. Since its discovery, much attention has been given to mediators and factors responsible for the development of IL-17-producing cells while very few studies have investigated the inflammatory properties of this cytokine. Here we aimed to characterize the inflammatory properties of IL-17 and to establish if this cytokine per se can initiate an inflammatory reaction or if its main role is to contribute to the exacerbation of ongoing inflammation. To this aim we used two different mouse models of inflammation: the paw oedema and the airpouch. Interestingly, injection of IL-17 in the hind paw did not cause oedema while administration in the pre-inflamed tissues of 6-day-old air pouches induced a long lasting inflammatory reaction that was sustained between 4 and 24h post-injection. Phenotypic analysis of cellular infiltrates demonstrated selective PMN recruitment in exudates and pouch lining tissues. This event was accompanied by induction of a distinct set of pro-inflammatory cytokines including IL-1beta, IL-6, TNF-alpha and chemokines KC and MCP-1. Co-administration of a neutralizing anti-KC antibody with IL-17 significantly reduced its inflammatory response suggesting a key role for this chemokine in mediating the inflammatory effects of IL-17. In conclusion these results demonstrate that IL-17 does not initiate an inflammatory reaction while, if injected in pre-inflamed tissues, is able to further amplify biochemical and cellular events characteristic of the early stages of the inflammatory reaction.

In questo lavoro viene confrontata la produzione degli amari e degli elisir realizzata parallelamente con la macerazione e con la tecnica estrattiva del Naviglio Estrattore. Le cinetiche ottenute dalle misure sperimentali evidenziano che il processo che si basa sulla estrazione rapida solido-liquido dinamica è più rapido. Inoltre il recupero di alcol impiegato in questo tipo di estrazione è pari al 90% (v/v), mentre nel caso della macerazione è pari al 70% (v/v). I test di assaggio degli amari hanno evidenziato una preferenza più marcata per il liquore ottenuto mediante impiego del Naviglio Estrattore.

We have studied the effect of propolis and its main active ingredient caffeic acid phenetyl ester (CAPE) on formation of aberrant crypt foci (ACF) and tumors in the rat colon in vivo. CAPE (50 mg/kg i.p.) reduced the formation of ACF and tumor induced by azoxymethane, while propolis ethanolic extract was without effect. These results suggest a potential anti-carcinogenesis of CAPE but not propolis.

Epub 2002 Oct 18.

impact factor 6.9

impact factor 10.4

1 The effect of cannabinoid drugs on peristalsis in the guinea-pig ileum was studied. Peristalsis was induced by delivering fluid into the oral end of an isolated intestinal segment. Longitudinal muscle reflex contraction, threshold pressure and threshold volume to trigger peristalsis, compliance of the intestinal wall during the preparatory phase (a reflection of the resistance of the wall to distension) and maximal ejection pressure during the emptying phase of peristalsis were measured. 2 The cannabinoid agonists WIN 55,212-2 (0.3-300 nM) and CP55,940 (0.3-300 nM) significantly decreased longitudinal muscle reflex contraction, compliance and maximal ejection pressure, while increased threshold pressure and volume to elicit peristalsis. These effects were net: modified by the opioid antagonist naloxone (1 mu M) and by the alpha-adrenoceptor antagonist phentolamine (1 mu M). 3 The inhibitory effect of both WIN 55,212-2 and CP55,940 on intestinal peristalsis was antagonized by the cannabinoid CB1 receptor antagonist SR141716A (0.1 mu M), but not by the cannabinoid CB2 receptor antagonist SR144528 (0.1 mu M). 4 In absence of other drugs, the CB1 receptor antagonists SR141716A (0.01-1 mu M) and AM281 (0.01-1 mu M) slightly (approximatively 20%) but significantly increased maximal ejection pressure during the empty phase of peristalsis without modifying longitudinal muscle reflex contraction, threshold pressure, threshold volume to trigger peristalsis and compliance. 5 It is concluded that activation of CB1 receptors reduces peristalsis efficiency in the isolated guinea-pig, and that the emptying phase of peristalsis could be tonically inhibited by the endogenous cannabinoid system.

impact factor 10.337

We have studied the effect of WIN 55,212-2 (a psychoactive cannabinoid agonist), cannabinol (a nonpsychoactive cannabinoid agonist), SR141716A, a cannabinoid CB1 antagonist, and SR144528, a cannabinoid CB2 antagonist, on gastric emptying in the rat. WIN 55,212-2 (0.1-5 mg/kg, i.p.) and cannabinol (0.1-25 mg/kg, i.p.) dose-dependently delayed gastric emptying while SR141716A (1 mg/kg and 5 mg/kg) and SR144528 (1 mg/kg) were without effect. SR141716A (1 mg/kg), but not SR144528 (1 mg/kg), counteracted the inhibitory effect of the two cannabinoid agonists. These results suggest that cannabinoid agonists delay gastric emptying through activation of cannabinoid CB1 receptors, while the endogenous cannabinoid system does not seem to modulate gastric motility.

impact factor: 10.4

1 This study examined the effects of sodium rhein (0.03-30 mu M) on the contractions of the isolated circular muscle of guinea-pig ileum induced by acetylcholine (100 nM), substance P (3 nM) and electrical stimulation (10 Hz for 0.3 s, 100 mA, 0.5 ms pulse duration). The effect of sodium rhein was also evaluated on the ascending excitatory reflex using a partitioned bath (oral and anal compartments). Ascending excitatory enteric nerve pathways were activated by electrical field stimulation (10 Hz for 2 s, 20 mA, 0.5 pulse duration) in the anal compartment and the resulting contraction of the guinea-pig intestinal circular muscle in the oral compartment was recorded. 2 Sodium rhein (0.3, 3 and 30 mu M) significantly potentiated (52 +/- 11% at 30 mu M) acetylcholine-induced contractions. In the presence of tetrodotoxin (0.6 mu M) or omega-conotoxin GVIA (10 nM) sodium rhein (3 and 30 mu M) did not enhance, but significantly reduced (49 +/- 10% and 44 +/- 8%, respectively, at 30 mu M) acetylcholine-induced contractions. 3 Sodium rhein (0.3, 3 and 30 mu M) significantly increased (65 +/- 11% at 30 mu M) substance P-induced contractions. In the presence of tetrodotoxin (0.6 mu M), omega-conotoxin GVIA (10 nM) or atropine (0.1 mu M), sodium rhein (3 and 30 mu M) significantly reduced (50 +/- 10%, 55 +/- 8% and 46 +/- 10%, respectively, at 30 (mu M) substance P-induced contractions. 4 N-G-nitro-L-arginine methyl ester (L-NAME, 100 mu M) abolished the potentiating effect of sodium rhein on acetylcholine and substance P-induced contractions. At the highest concentration (30 mu M), sodium rhein, in presence of L-NAME, reduced the acetylcholine (30 +/- 6%)- or substance P (36 +/- 6%)induced contractions. 5 Sodium rhein (30 mu M) significantly potentiated (29 +/- 9%) the electrically-evoked contractions. L-NAME (100 mu M), but not phentolamine, enhanced the effect of sodium rhein. Sodium rhein (30 mu M) significantly increased (32 +/- 9%) the ascending excitatory reflex when applied in the oral, but not in the anal compartment. 6 These results indicate that sodium rhein (i) activates excitatory cholinergic nerves on circular smooth muscle presumably through a facilitation of Ca2+ entry through the N-type Ca2+ channel, (ii) has a direct inhibitory effect on circular smooth muscle and (iii) does not affect enteric ascending neuroneural transmission. Nitric oxide could have a modulatory excitatory role on sodium rhein-induced changes of agonist-induced contractions and an inhibitory modulator role on sodium rhein-induced changes of electrically-induced contractions.

1 The effect of papaverine, a well known smooth muscle relaxant, was investigated on neural transmission within the enteric nervous system. Segments of guinea-pig ileum were placed in a partitioned bath to enable drugs, including papaverine, to be applied to enteric nerve pathways without interfering with the recording of the smooth muscle contraction. Ascending excitatory enteric nerve pathways were activated by electrical field stimulation in the anal compartment (10 Hz for 2 s, 45 mA, 0.5 ms pulse duration) and the resulting contraction of the intestinal circular muscle in the oral compartment was recorded isotonically. 2 Tetrodotoxin (0.6 mu M) and hexamethonium (100 mu M) both abolished, or greatly reduced, the contractions when applied to either compartment indicating that nicotinic synapses are involved in this pathway. 3 Papaverine (0.3-30 mu M) applied independently to each compartment depressed in a concentration-dependent manner, the nerve-mediated contractions. The IC50 of this inhibitory effect was 3.53 mu M for the oral and 4.76 mu M for the anal compartments, respectively. Two other phosphodiesterase (PDE) inhibitors, 3-isobutyl-1-methylxanthine (IBMX 10-300 mu M) and theophylline (30-1000 mu M) added to the anal compartment also inhibited the nerve mediated contractions. Papaverine applied to the anal bath, after IBMX 100 mu M (or theophylline 300 mu M) further inhibited the nerve-mediated contractions, but was less effective than when applied alone. 4 Phentolamine (1 mu M), an alpha-adrenoceptor antagonist, reduced the inhibitory effect of papaverine, but not that of IBMX (100 mu M) or theophylline (300 mu M). A combination of phentolamine and IBMX (or theophylline) prevented the inhibitory effect of papaverine. 5 Tetrodotoxin, but not papaverine or hexamethonium, inhibited the contraction elicited by electrical stimulation just anal to the partition indicating that papaverine did not affect the generation or conduction of nerve action potentials. 6 Verapamil (1 mu M) and nifedipine (1 mu M), two smooth muscle relaxants which act by blocking L-type calcium channels. only inhibited the contractions when applied directly to the recording (oral) compartment. This indicates that L-type Ca2+ channels are probably not involved in synaptic transmission in these ascending pathways and thus that the PDE inhibitors do not inhibit synaptic transmission by acting on these channels, co-Conotoxin GVIA (10 nM), a potent inhibitor of the N-type Ca2+ channels. blocked the nerve-mediated contractions applied to either compartment. Whether the PDE inhibitors exert their inhibitory actions via those channels remains to be established. 7 The results indicate that the PDE inhibitors, papaverine, IBMX and theophylline inhibit excitatory enteric neural pathways by depressing synaptic transmission. The inhibitory effect of papaverine (but not IMBX or theophylline) involves, at least in part, the release of noradrenaline from sympathetic nerves acting on alpha-adrenoceptors on enteric neurones.

The effect of NG-nitro-L-arginine methyl ester (L-NAME) on castor oil-induced diarrhea was studied in control rats and those treated with isosorbide dinitrate or isosorbide-5-mononitrate. Castor oil (2 ml) produced diarrhea that lasted at least 8 h. Pretreatment of the rats with L-NAME (1-25 mg/kg i.p.) 15 min before castor oil did not block the castor oil-induced diarrhea beyond 3 h after challenge but delayed its appearance (P < .05-.001). However, diarrhea was inhibited (P < .01-.001) during the entire 8 h if rats were treated twice with L-NAME (25 mg/kg) (15 min before and 3 h after castor oil). These findings suggest that L-NAME, once administered, loses its activity 3 h after its administration. The nitric oxide synthase substrate, L-arginine (150-600 mg/kg), reversed (P < .05-.01) the inhibitory effect of L-NAME on diarrhea induced by castor oil. This effect is enantiomer-specific because D-arginine (900 mg/kg) was without an effect. These results suggest that castor oil-induced diarrhea in rats involves the L-arginine nitric oxide pathway. This is further supported by the effect of isosorbide dinitrate (0.6-120 mg/kg) and isosorbide-5-mononitrate (0.6-120 mg/kg). When administered to castor oil-treated rats, these two nitric oxide-generating agents prevented in a dose-dependent fashion (P < .01-.001) the inhibitory effect of L-NAME (25 mg/kg).