2-Methylpyridine-1-ium-1-sulfonate from Allium hirtifolium: An anti-angiogenic compound which inhibits growth of MCF-7 and MDA-MB-231 cells through cell cycle arrest and apoptosis induction.

Natural products have well been recognized as sources of drugs in cancer treatment. Some medicinal plants contain the constituents with potent anti-angiogenic and anti-cancer effects, which have offered great hopes of being used as drugs for treating various cancers. The present study aims at identifying the anti-angiogenic effects of 2-Methylpyridine-1-ium-1-sulfonate (MPS) isolated from the ethyl acetate extract (EA) of Persian shallot (Allium hirtifolium). In a concentration-dependent manner, the MPS was able to inhibit endothelial cell migration and angiogenesis in both in vivo and in vitro assays, and also significantly suppressed proliferation of MCF-7 and MDA-MB-231 human breast cancer cell lines. Additionally, treatment with MPS showed a significant reduction in the vascular endothelial growth factor (VEGF) secretion level and production/activity of matrix metalloproteinases (MMP-2 and MMP-9) in the studied cells. The flow cytometry analysis indicated that MPS suppressed growth of MCF-7 and MDA-MB-231 cells at G0/G1 and S phases, respectively. Our results indicated that the induction of cell cycle arrest was correlated with the obvious changes in expression of p21, p27 and p53. According to the DNA fragmentation assay, MPS caused apoptosis in both cell lines, which confirms the results obtained with the growth assay. Moreover, the compound-mediated apoptosis accompanied with the increase in the Bax/Bcl-2 ratio and caspase-3 and -9 activities. Molecular docking results indicated that the MPS compound can surprisingly bind to VEGF and VEGF receptors and interacts with their critical amino acids. Finally, compounds with anticancer inhibitory activity (e.g. MPS) are abundant in nature and can be obtained from several sources. So, our data can be clinically developed for treating angiogenesis and cancer significantly.

[THE STUDY OF THE EFFECTS OF ANXYOLYTIC, ANTIOXIDANT, IMMUNOCORRECTOR AND HYPERBARIC OXYGENATION ON THE DYNAMICS OF MAIN BLOOD GAS AND ELECTROLYTE INDICES AND BEHAVIORAL RESPONSE IN EXPERIMENTAL STRESS MODEL].

Experiments on the model of immobilization stress in albino mice showed that a combination of mexidol, thymogen, and hyperbaric oxygenation reduced adverse effects of diazepam on behavioral response of animals in the black-and-white chamber and elevated cross maze tests and led to optimization of the blood gas composition as manifested by increased oxygen tension, normalization of the partial pressure of carbon dioxide, and restoration of the acid-base balance and blood bicarbonate level. The proposed combined treatment can be recommended for the treatment of patients with stress-induced pathology.

Antithrombogenic activity of antioxidant compounds.

Antithrombotic activities of enoxifol, a new antioxidant with antiaggregant activity demonstrated in vitro and in vivo, and antioxidant mexidol were compared on the rat model of arterial thrombosis induced by application of 50% ferric chloride. Acetylsalicylic acid (antiaggregant) served as the reference drug. All drugs exhibited dose-dependent antithrombotic activity. Enoxifol was more effective than mexidol, both drugs being more active than the reference drug (acetylsalicylic acid). Taking into account the pathogenesis of the thrombosis in this experimental model, we can hypothesize that the pronounced antithrombotic effect of enoxifol was due to its antiaggregant and antioxidant activities.

[Dynamics of the behavioral response and cortisole level caused by the combined action of mexidole, diazepam, thymogen, and hyperbaric oxygenation in mice under immobilization stress conditions].

Experiments on white mice under the model immobilization stress condition showed that a combined action of mexidole, diazepam, thymogen, and hyperbaric oxygenation (pathogenetic therapy) leads to optimization of the behavioral reactions, which is manifested by a decrease in the level of anxiety, increase in the locomotor and research activity, and normalization of the cortisole level. This effect is explained by a complex pharmacological action of all factors on the immune and endocrine mechanisms of the stress pathogenesis.

[Pharmacological correction of neuronal damage in sensomotor zone of frontal cortex under conditions of experimental cerebral blood flow pathology].

The administration of thiotriazoline, emoxypine and magnelong (a combined glycine-magnesium preparation) to animals with acute cerebral circulatory insufficiency showed significant neuroprotective effect in both acute and late ischemic periods, as indicated by the indices of cell density and number and the characteristics of apoptic and destructed neurons approaching those in the group of intact rats. Pyracetam showed cerebroprotective effect only in late ischemic period. Magnelong exhibited the most significant neuroprotective effect, maintaining cell density on the intact control level and reducing the number of apoptotic and destructed neurons.

Interaction between Shaoyao-Gancao-Tang and a laxative with respect to alteration of paeoniflorin metabolism by intestinal bacteria in rats.

Shaoyao-Gancao-Tang (SGT), a traditional Chinese herbal medicine (Kampo formulation) containing Shaoyao (Paeoniae Radix) and Gancao (Glycyrrhizae Radix), is co-administered with laxative sodium picosulfate as a premedication for relieving the pain accompanying colonoscopy. Paeoniflorin (PF), an active glycoside of SGT, is metabolized into the antispasmodic agent paeonimetabolin-I (PM-I) by intestinal bacteria after oral administration. The objective of the present study was to investigate whether the co-administered laxative (sodium picosulfate) influences the metabolism of PF to PM-I by intestinal bacteria. We found that the PF-metabolizing activity of intestinal bacteria in rat feces was significantly reduced to approximately 34% of initial levels by a single sodium picosulfate pretreatment and took approximately 6 days to recover. Repeated administration of SGT after the sodium picosulfate pretreatment significantly shortened the recovery period to around 2 days. Similar results were also observed for plasma PM-I concentration. Since PM-I has muscle relaxant activity, the present results suggest that repetitive administration of SGT after sodium picosulfate pretreatment might be useful to relieve the pain associated with colonoscopy.

The effects of Mexidol on the acquisition of food-related conditioned reflexes and synaptic ultrastructure in field CA1 of the rat hippocampus after single acoustic stimuli with ultrasonic components.

The effects of a complex acoustic signal with ultrasonic components on the ultrastructure of synapses field CA1 of the rat hippocampus were studied in conditions of two-week courses of the wide-spectrum antioxidant Mexidol (compared with an untreated group); the effects of complex acoustic signals on the dynamics of acquisition of a food-related conditioned reflex using a standard stimulus (a tone) and on the acquisition of a trace conditioned reflex to estimating time intervals were also studied, in the same groups of rats. Controls consisted of unstressed rats treated and not treated with Mexidol. Ultrastructural analysis of the redistribution of vesicles in the synaptic terminals of hippocampal field CA1 showed that synaptic transmission was impaired when assessed one day after exposure to the complex acoustic signal. Mexidol prevented impairment of synaptic transmission. The complex acoustic signal had negative effects on conditioned reflex activity in rats and Mexidol had normalizing actions on the acquisition of conditioned reflexes in stressed rats. These results lead to the conclusion that the antioxidant Mexidol can be applied to the prophylaxis of the impairments in CNS cognitive functions frequently seen in stress.

Differential activity of NO synthase inhibitors as chemopreventive agents in a primary rat tracheal epithelial cell transformation system.

A model to study the effectiveness of potential chemopreventive agents that inhibit neoplastic process by different mechanisms has been used to test the efficacy of seven nitric oxide synthase (NOS) inhibitors. Five selective inducible NOS (iNOS) inhibitors: S-methyl isothiourea (S-MITU), S-2-aminoethyl isothiourea (S-2-AEITU), S-ethyl isothiourea (S-EITU), aminoguanidine (AG), 2-amino-4-methyl pyridine (2-AMP), and two non selective general NOS inhibitors: l-N(6)-(1-iminoethyl) lysine (IEL) and N(omega)-nitro-l-arginine (NNLA), were tested for efficacy against a carcinogen, benzo[a]pyrene (B[a]P)-induced primary rat tracheal epithelial (RTE) cell transformation assay. RTE cells were treated with B[a]P alone or with five nontoxic concentrations of an NOS inhibitor and the resulting foci at the end of 30 days were scored for inhibition of transformation. The results indicate that all three isothiourea compounds inhibited B[a]P-induced RTE foci in a dose-dependent manner. S-AEITU was the most effective inhibitor with an IC(50) (the molar concentration that inhibits transformation by 50%) of 9.1 microM and 100% inhibition at the highest dose tested (30 microM). However, both S-EITU and S-MITU showed a maximum percent inhibition of 81% and 100% at 1 mM with an IC(50) of 84 and 110 microM, respectively. 2-AMP did not show any dose-dependent response, but was highly effective (57% inhibition) at an intermediate dose of 30 microM and an IC(50) of 25 microM. Similar to thiourea compounds, AG exhibited good dose-dependent inhibition with a maximum inhibition of 86% at 1 mM. NNLA and IEL were negative in this assay. Based on the IC(50) values, NOS inhibitors were rated for efficacy from high to low as follows: S-2-AEITU<2-AMP

["Fast" and "slow" components of psychotropic activity of the drugs with nootropic effects]. / "Bystrye" i "medlennye" komponenty psikhotropnogo deistviia preparatov s nootropnymi svoistvami.

A clinical-pharmacological study was carried out to evaluate correlation of "fast" (nonspecific) and "slow" (specific) components of the action of the drugs with nootropic properties (piracetam, mexidol, tanacan) and to estimate their contribution to achieving therapeutic efficacy. The study was performed during 28 days using standard quantitative assay techniques in 79 patients with "Organic emotional-liable (asthenic) disorders" (F06.6, ICD-10). It was found that "fast" component of the psychotropic action of the drugs tested was presented by stimulating and anxiolytic effects, while a "slow" one--by specific nootropic activity. All these effects were fully independent with no correlation found, and this could, probably, be attributed to different mechanisms of their realization. It is shown that nootropic activity of piracetam was most significant in its therapeutic effect; and anxiolytic effect was most important for mexidol action. Meanwhile, stimulating and anxiolytic activities as well as positive influence on long-term memory were main components of tanacan effect. The results obtained show an important role of both specific and nonspecific ("fast") effects in realization of therapeutic action of the drugs with nootropic effects in patients with cognitive-mnestic and neurosis-like disorders.

[The structure of the optic nerve in experimental glaucoma and in the means for its treatment]. / Stroenie zritel'nogo nerva pri éksperimental'noi glaukome i nekotorykh sposobakh ee lecheniia.

Using light and electron microscopy disorders of structure of the optic nerve were studied in rabbits with adrenaline induced glaucoma and after the action of antioxidants (Emoxipine, Erisode) used for preventive and medical purposes. Changes in glaucoma and after administration of drugs in axons and their myelinated sheath were similar but differently pronounced in right and left eye of the same animal. Positive effect of Erisode used for preventive and medical purposes was noted. Emoxipine enhanced the disturbances in optic nerve structure.

[The action of emoxipin, lithium oxybutyrate and pikamilon on the blood circulation of the ischemic brain]. / Izuchenie deistviia émoksipina, litiia oksibutirata i pikamilona na krovoobrashchenie ishemizirovannogo mozga.

Acute experiments were conducted on rats under nembutal anesthesia to compare the efficacy of emoxipin with that of lithium oxybutyrate and picamilon in the postischemic period after preventive and therapeutic injections in various doses. Emoxipin proved to be most effective in prevention of postischemic non-restoration of the flow of blood in the brain and in preservation of the autoregulation responses of the cerebral vessels. The possible mechanisms of the effect of the drug are discussed.

Potassium channel opener-augmented cardioplegia: protection of myocyte contractility with chronic left ventricular dysfunction.

BACKGROUND: An increased number of patients with preexisting left ventricular (LV) dysfunction and congestive heart failure (CHF) are undergoing cardiac surgery with a higher risk for decreased LV contractility after hyperkalemic cardioplegic arrest. Activation of adenosine triphosphate-sensitive potassium channels by potassium channel openers (PCO) within the myocyte appears to confer a protective effect in the setting of ischemia. Accordingly, the present study was designed to determine whether PCO supplementation during hyperkalemic cardioplegic arrest would provide protective effects on myocyte contractile function, particularly in the setting of CHF. METHODS AND RESULTS: LV myocytes were isolated from control pigs (n=7) and pigs with CHF (rapid pacing, 240 beats per minute; n=7) and then assigned to the following treatment groups: normothermia (cell culture media, 2 hours, 37 degrees C); cardioplegia (24 mEq/L K+, 2 hours, 4 degrees C; then 10 minutes of reperfusion); or PCO/cardioplegia (cardioplegia supplemented with 100 micromol/L of the PCO aprikalim). Myocyte velocity of shortening was reduced in both control (66+/-2 versus 33+/-1 microm/s) and CHFmyocytes (32+/-1 versus 22+/-1 microm/s) after hyperkalemic cardioplegic arrest (P<.05). Contractility after PCO cardioplegia was similar to normothermic values in control (57+/-2 microm/s) and CHF (33+/-1 microm/s) myocytes (P<.05). Intracellular free Ca2+ increased from normothermia during hyperkalemic cardioplegia in control (81+/-4 to 145+/-7 nmol/L) and CHF (262+/-30 to 823+/-55 nmol/L) myocytes (P<.05). PCO cardioplegia attenuated the intracellular increase in free Ca2+ during the cardioplegic interval in control (110+/-6 nmol/L) and CHF (383+22 nmol/L) myocytes (P<.05). CONCLUSIONS: PCO-augmented cardioplegic arrest preserved myocyte contractility and reduced the intracellular free Ca2+ release, which therefore may be of particular benefit in the setting of preexisting LV dysfunction.

Preservation of myocyte contractile function after hyperthermic cardioplegic arrest by activation of ATP-sensitive potassium channels.

BACKGROUND: Left ventricular (LV) dysfunction can occur after hyperkalemic cardioplegic arrest and subsequent reperfusion and rewarming. Activation of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels within the myocyte sarcolemma has been shown to be cardioprotective for myocardial reperfusion injury and ischemia and may play a contributory role in preconditioning for cardioplegic arrest. Accordingly, the present study tested the hypothesis that cardioplegic arrest and activation of KATP channels by a potassium channel opener (PCO) would attenuate alterations in ionic homeostasis and improve myocyte contractile function. METHODS AND RESULTS: Porcine LV myocytes were isolated and randomly assigned to the following treatment groups: normothermic control, incubation in cell culture media for 2 hours at 37 degrees C (n=60); hyperkalemic cardioplegia, incubation for 2 hours in hypothermic hyperkalemic cardioplegic solution (n=60); or PCO/cardioplegia, incubation in cardioplegic solution containing 100 micromol/L of the PCO aprikalim (n=60). Hyperkalemic cardioplegia and rewarming caused a significant reduction in myocyte velocity of shortening compared with normothermic control values (33+/-2 versus 66+/-2 microm/s, P<.05). Cardioplegic arrest with PCO supplementation significantly improved indices of myocyte contractile function when compared with hyperkalemic cardioplegia (58+/-4 microm/s, P<.05). Myocyte intracellular calcium increased during hyperkalemic cardioplegic arrest compared with baseline values (147+/-2 versus 85+/-2 nmol/L, P<.05). The increase in intracellular calcium was significantly reduced in myocytes exposed to the PCO-supplemented cardioplegic solution (109+/-4 nmol/L, P<.05). CONCLUSIONS: Cardioplegic arrest with simultaneous activation of KATP channels preserves myocyte contractile processes and attenuates the accumulation of intracellular calcium. These findings suggest that changes in intracellular calcium play a role in myocyte contractile dysfunction associated with cardioplegic arrest. Moreover, alternative strategies may exist for preservation of myocyte contractile function during cardioplegic arrest.

[The effect of 3-hydroxypyridine derivatives on postischemic disorders in the autoregulatory reactions of the cerebral vessels]. / Vliianie proizvodnykh 3-oksipiridina na postishemicheskie narusheniia autoreguliatornykh reaktsii mozgovykh sosudov.

Acute experiments on nembutal anesthetized rats showed improvement of cerebral blood flow autoregulation in the postischemic period under the effect of mexidol and the new 3-hydroxypyridine (3-HOP) derivatives LBK-10 and LBK-38 administered for prophylactic and therapeutic, purposes. The role of dopaminergic activity, solubility in lipids, and other factors in the mechanism of the activity of 3-HOP derivatives is analysed.

Contributory mechanisms for the beneficial effects of myocyte preconditioning during cardioplegic arrest.

BACKGROUND: Preconditioning protects the myocardium from ischemia and may be a potent means of endogenous cardioprotection during cardioplegic arrest and rewarming. However, fundamental mechanisms that potentially contribute to the beneficial effects of preconditioning during cardioplegic arrest and rewarming remain unclear. Accordingly, the overall goal of the present study was to examine the potential mechanisms by which preconditioning protects myocyte contractile function during simulated cardioplegic arrest and rewarming. METHODS AND RESULTS: Left ventricular isolated porcine myocyte contractile function was examined with the use of videomicroscopy under three conditions: (1) normothermia, maintained in cell medium (37 degrees C) for 2 hours; (2) simulated cardioplegic arrest and rewarming, incubated in crystalloid cardioplegic solution (24 mEq/L K+, 4 degrees C) for 2 hours followed by normothermic reperfusion; and (3) preconditioning/cardioplegic arrest and rewarming, hypoxia (20 minutes) and reoxygenation (20 minutes) followed by simulated cardioplegic arrest and rewarming. Cardioplegic arrest and rewarming caused a decline in steady-state myocyte shortening velocity compared with normothermic controls (22.0 +/- 1.6 versus 57.2 +/- 2.6 microns/s, respectively, P < .05), which was significantly improved with preconditioning (36.1 1.7 microns/s, P < .05). In the next series of experiments, the influence of nonmyocyte cell populations with respect to preconditioning and cardioplegic arrest was examined. Endothelial or smooth muscle cell cultures were subjected to a period of hypoxia (20 minutes) and reoxygenation (20 minutes) and the eluent incubated with naive myocytes, which were then subjected to simulated cardioplegic arrest and rewarming. Pretreatment with the eluent from endothelial cultures followed by cardioplegic arrest and rewarming improved myocyte function compared with cardioplegia-alone values (31.7 +/- 2.2 versus 24.7 +/- 1.6 microns/s, respectively, P < .05), whereas smooth muscle culture eluent pretreatment resulted in no change (23.7 +/- 4.0 microns/s, P = .81). Molecular mechanisms for the protective effects of preconditioning on myocyte contractile processes with cardioplegic arrest and rewarming were examined in a final series of experiments. Adenosine-mediated pathways or ATP-sensitive potassium channels were activated by augmenting cardioplegic solutions with adenosine (200 mumol/L) or the potassium channel opener aprikalim (100 mumol/L), respectively. Both adenosine and aprikalim augmentation significantly improved myocyte function compared with cardioplegia-alone values (53.5 +/- 1.7, 57.6 +/- 2.0 versus 25.7 +/- 1.4 microns/s, respectively, P < .05). CONCLUSIONS: The unique findings from the present study demonstrated that preconditioning provides protective effects on myocyte contractile processes independent of nonmyocyte cell populations and that these effects are mediated in part through the activation of adenosine pathways or ATP-sensitive potassium channels. Thus, preconditioning adjuvant to cardioplegia may provide a novel means of protecting myocardial function after cardioplegic arrest and rewarming.

[The effects of mexidol in pain syndromes]. / Effekty meksidola pri bolevykh sindromakh.

Models of neuropathic pain syndrome and adjuvant arthritis were used to study the effect of mexidole, an antioxidant from the 3-hydroxypyridine group. Mexidole was indicated to produce no preventive effect in pain syndromes, but to exhibit a therapeutic one. The use of mexidole in combination with the agents activating the monoaminergic systems in the central nervous system showed the presence of their reciprocal effect in neuropathic pain syndrome and its absence in adjuvant arthritis. Possible mechanisms of action of mexidole were also discussed.

Effects of long-term treatment with anthranoids and sodium picosulphate on the contents of vasoactive intestinal polypeptide, somatostatin and substance P in the rat colon.

OBJECTIVE: To examine the effects of chronic treatment and a single high-dose application of anthranoids and sodium picosulphate on the neuropeptide content of the rat colon. DESIGN AND METHODS: Over a 6-month period, eight groups of rats were each given one of the following: sennosides or sodium picosulphate in low daily doses (10 and 2.5 mg/kg/day, respectively), in high daily doses (40 and 10 mg/kg/day, respectively), and in high twice-weekly doses (30 and 7.5 mg/kg/day, respectively); high daily doses of danthron (500 mg/kg/day); and vehicle (tragacanth 0.5%) only. Four further groups of rats each received a single dose of vehicle or a high dose of one of the three laxatives. All rats were killed 48 h after the last dose. The ascending and descending colon were removed and separated into mucosa, submucosa, and muscularis externa. Vasoactive intestinal polypeptide (VIP), somatostatin, and substance P were extracted by boiling and homogenizing the tissue in acetic acid, and their levels were determined using validated radioimmunoassays. RESULTS: After long-term treatment with high doses of sennosides and danthron, but not after a single high-dose administration, there was a significant reduction in mucosal levels of VIP and somatostatin and in submucosal levels of somatostatin of both colonic segments, as well as in the level of VIP in the muscularis externa of the descending colon. Substance P levels remained unaffected. Sodium picosulphate had no effect. CONCLUSIONS: Chronic treatment with anthranoids in high doses, but not with sodium picosulphate, reduces VIP and somatostatin levels in the rat colon. This may represent damage to the enteric nervous tissue or a pharmacological effect of the anthranoids, causing decreased synthesis or increased breakdown of these peptides.

[The effect of mexidol on the rat periodontium during hypokinesia]. / Vliianie meksidola na parodont krys pri gipokinezii.

During 30-days-long hypokinesia changes in calcium-phosphoric metabolism, glycoprotein state, acid and alkaline phosphatase activity in bone tissue of the low jaw of rats proceed in some stages, that determines the nature of mexidol (3-oxipyridine derivative) effects. The remedy demonstrated the most expressed protective effect on parodontal tissues on the 15th day of animals' mobility limitation. The data obtained show that mexidol effecting hypokinesia develop in some stages and depend on the initial state of the organism. They also reflect indirectly the significance of the antioxidant status of the organism in mineralization of the parodontal bone tissue.

Effects of sennosides and nonanthranoid laxatives on cytochemistry of epithelial cells in rat colon.

The cytochemical effects of laxatives on rat colonic epithelial cells were studied. A total of 32 rats was divided into four groups. Three groups were treated with bisacodyl, picosulfate and sennosides for 12 weeks, and a fourth group served as control. The rectum, midcolon and cecum were studied for acidic mucins, lectin soybean agglutinin (SBA) and cytokeratin AE1. Most striking and consistent changes were found in the rectum including total acidic mucin content which significantly increased, with sulfomucin decreased and sialomucin increased in the three treatment groups. Cytokeratin AE1 expression increased on picosulfate and sennosides. SBA total binding increased on bisacodyl and picosulfate. The present findings were thought to be of functional origin and do not represent early precancerous lesions.