Kinetic radical-scavenging activity of colchicine and tropolone

The kinetics of radical-scavenging activities for colchicine and tropolone remain unknown. Their antioxidant activities were determined by the induction period (IP) method in the polymerization of methyl methacrylate initiated by thermal decomposition of 2,2'-azobisisobutyronitrile (AIBN, R*) or benzoyl peroxide (BPO, PhCOO*) using differential scanning calorimetry (DSC) under nearly anaerobic conditions. The IPs for colchicine and tropolone were very short despite the addition of a high concentration of these compounds relative to initiators; the stoichiometric factor (n, the number of moles of PhCOO* trapped by the antioxidant) was approximately 0.03 and 0.04 for colchicine and tropolone, respectively. The n value of these compounds for R* was less than that for PhCOO*. The rate constant of inhibition to that of propagation (kinh/kp) for both compounds was 23-27, and the difference between them was considerably small. Both compounds had weak antioxidant properties at very high concentrations.     

Kinetic study of the radical-scavenging activity of vitamin E and ubiquinone

Quantitative in vitro studies of antioxidant activities have been performed under aerobic conditions. However, since the biological system has lower oxygen tension, the effectiveness of antioxidants may be considerably different in vivo. alpha-Tocopherol, in vivo the most active tocopherol, is a very poor antioxidant in vitro. To clarify these points, the radical-scavenging activities of vitamin E (Toc) (alpha-, beta-, gamma- and delta-tocopherols) and ubiquinone were evaluated by the induction period method from the kinetics of polymerization of methyl methacrylate (MMA) initiated by thermal decomposition of 2,2'azobisisobutyronitrile (AIBN) (alkyl radical, R*), or benzoyl peroxide (BPO) (peroxyl radical, PhCOO*) under nearly anaerobic conditions. The ratio of the rate constant of inhibition to that of propagation (k(inh)/k(p)) for Toc was about 10 in a system with a molar ratio of AIBN to Toc of 100:1, whereas in the corresponding BPO system k(inh)/k(p) declined in the order alpha (47) > beta (15) > gamma (10) > delta (7). In contrast, with AIBN the number of free radicals trapped by the phenolic moiety (n) declined in the order delta (3.0) > gamma (2.5) > alpha (2.2) > beta (1.6), whereas with BPO n declined in the order delta (1.9) > gamma (1.4) > beta (1.0) > alpha (0.3). A similar tendency was found in systems with a molar ratio of 10:1. Also, ubiquinone-10 showed radical-scavenging activity, although the n (0.02) was much less than that for Toc. The low n value for alpha-Toc (n = 0.3) may be attributed to the formation of stable alpha-Toc during the induction period. With a n = about 1 for beta- and gamma-Toc, a dimerization coupling of Tocs is suggested. Thus, the radical-scavenging activity is affected by the number and position of the methyl groups in the benzene nucleus of the various tocopherol compounds.     

Bismuth increases hydroxyl radical-scavenging activity of histamine H2-receptor antagonists

The effects of histamine H2-receptor antagonists, alone or in a combination with bismuth, on *OH-provoked degradation of deoxyribose were studied. The histamine H2-receptor antagonists (cimetidine, ranitidine and roxatidine), themselves decreased the deoxyribose damage in Fenton-type systems. In combinations with bismuth, their inhibitory effect in Fenton system (Fe(III)/ascorbic acid + H2O2 was stronger. Moreover, unlike F(III) and Cu(II), which in the presence of ascorbic acid + H2O2 led to an increase in the *OH formation (deoxyribose damage), Bi(III) showed an opposite effect. The present results are interpreted in view of a better ( )OH scavenging activity of bismuth complexes of histamine H2-receptor antagonists as compared to that of the corresponding drugs. These findings might be one more explanation why bismuth salts, in combination with acid-reducing agents, are more effective anti-ulcer agents.     

Antioxidant and free radical-scavenging activity of Choto-san and its related constituents

The antioxidant properties of Choto-san and its related constituents such as Chotoko and Choto-san without Chotoko, and phenolic compounds contained in Chotoko such as epicatechin, caffeic, acid and quercetin were evaluated. In the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging assay, the scavenging activity of Chotoko (IC(50) 14.3 microg/ml) was found to be higher than that of Choto-san (IC(50) 206.2 microg/ml) and Choto-san without Chotoko (IC(50) 244.3 microg/ml). Epicatechin (IC(50) 10.4 microM), caffeic acid (IC(50) 13.8 microM), and quercetin (IC(50) 7.1 microM) also revealed scavenging activity against DPPH radicals. Choto-san (IC(50) 67.7 microg/ml) exhibited stronger inhibitory activity against superoxide anion formation than Choto-san without Chotoko (IC(50) 92.4 microg/ml) but weaker activity than Chotoko (IC(50) 18.3 microg/ml). The generation of superoxide anion was also inhibited by epicatechin (IC(50) 175.2 microM), caffeic acid (IC(50) 141.7 microM), and quercetin (IC(50) 18.7 microM). In a hydroxyl radical-scavenging experiment, Choto-san (IC(50) 2.4 mg/ml), Chotoko (IC(50) 2.2 mg/ml), Choto-san without Chotoko (IC(50) 2.8 mg/ml), epicatechin (IC(50) 3.9 mM), caffeic acid (IC(50) 3.6 mM), and quercetin (IC(50) 1.9 mM) exhibited activity. In NG108-15 cells, when added simultaneously with H(2)O(2) (500 microM), Choto-san (250 microg/ml), Chotoko (250 microg/ml), Choto-san without Chotoko (500 microg/ml), epicatechin (200 microM), caffeic acid (200 microM), and quercetin (200 microM) effectively protected cells from oxidative damage. In conclusion, the present results provide evidence that Choto-san acts as an antioxidant and cytoprotective agent against oxidative damage, which is due at least partly to the phenolic compounds contained in Chotoko.     

Radical generation, radical-scavenging activity, and cytotoxicity of eugenol-related compounds

To clarify the possible link between radicals and cytotoxicity of eugenol-related compounds, dimeric compounds were synthesized from eugenol (4-allyl-2-methoxy-phenol), butylated hydroxyanisole (BHA) (2-t-butyl-4-methoxyphenol) or MMP (2 methoxy-4-methylphenol); bis-EUG (3,3'-dimethoxy-5,5'-di-2-propenyl-1,1'-biphenyl-2,2'-diol), bis-BHA (3,3'-di-t-butyl-5,5'-dimethoxy-1,1'-biphenyl-2,2'-diol), and bis-MMP (3,3'-di-methoxy-5,5'-dimethyl-1,1'-biphenyl-2,2'-diol). The cytotoxic activity of these compounds was determined using a salivary gland tumor cell line (HSG), oral squamous cell carcinoma cell line (HSC-2) and human promyelocytic leukemia cell line (HL-60). A parabolic relationship between the cytotoxicity and log P (the octanol-water partition coefficient) was observed, showing that both BHA and bis-MMP, with a log P of 3-4, were the most cytotoxic. The cytotoxic activity of the 2-methoxy derivatives, eugenol, MMP and bis-MMP, against HSG cells was significantly enhanced by visible-light irradiation, possibly due to their high redox potential. Electron spin resonance (ESR) spectroscopy indicated that eugenol and BHA alone produced radicals under alkaline conditions (pH > 9.5), and eugenol most efficiently scavenges reactive oxygen species (O2-). Antioxidative reactivity of eugenol-related compounds was determined by measuring the inhibiting periods of the AIBN (2,2'-azobisisobutyronitrile)/MMA (methyl methacrylate) polymerization system, and the number of moles of peroxy radical trapped by moles of the relevant phenols (stoichiometric factor, n). It was found that the n values of eugenol and MMP were approximately 1, whereas those of BHA >2, suggesting that eugenol and MMP undergo dimerization through radical-radical couplings through quinone methides, whereas BHA undergoes the competitive interaction with poly-MMA radicals after oxidation by AIBN-peroxy radicals. BHA was an efficient peroxy radical-scavenger, but possibly reacted with polymer radicals of the lipid, thus mediating the cytotoxicity. The n value of bis-BHA was two, whereas those of bis-EUG and bis-MMP were 1.6-1.7, suggesting that the latter were further oxidized. The enthalpies of phenoxyl radical formation were determined using the semi-empirical PM3 quantum-mechanical method and the possible link to redox potential was discussed.     

褪黑激素的抗肿瘤活性研究

目的　研究褪黑激素对 S180 荷瘤小鼠肿瘤的抑制作用。方法　通过给小鼠接种 S180 瘤后 ,观察不同剂量褪黑激素对小鼠肿瘤瘤重及其体质量、肝、脾指数、白细胞数的影响。结果　褪黑激素大、中、小剂量组对 S180 荷瘤小鼠肿瘤均具有显著的抑制作用 (P <0 .0 1 ) ,且无降低小鼠体质量、肝、脾指数及白细胞数的作用。结论　褪黑激素对 S180 肿瘤具有抑制作用 ,有望成为新的抗肿瘤药物     

Time-dependent anticonvulsant activity of melatonin in hamsters

The objective of the present study was to assess whether the anticonvulsant activity of melatonin displays diurnal variability in hamsters. Convulsions were induced by administering 3-mercaptopropionic acid (3-MP). There was a significant diurnal variation in 3-MP-induced convulsions, hamsters being more prone to exhibit seizures during the night than during the day. Melatonin (50 mg/kg i.p.) had a maximal anticonvulsive effect in the early evening (20:00 h). The administration at 20:00 h of the central-type benzodiazepine antagonist, Ro 15-1788, although unable by itself to modify seizure threshold, blunted the anticonvulsant response to melatonin. The results indicate that the time-dependent anticonvulsant activity of melatonin is sensitive to central-type benzodiazepine antagonism.     

Antiviral, antibacterial and vitamin C-synergized radical-scavenging activity of Sasa senanensis Rehder extract

Sasa senanensis Rehder extract (SE) showed slightly higher cytotoxicity against human squamous cell carcinoma cell lines and human glioblastoma cell lines, as compared with human oral normal cells (gingival fibroblast, pulp cell, periodontal ligament fibroblast), and was more cytotoxic to human myelogenous and T-cell leukemia cell lines. SE showed a bacteriostatic effect on Fusobacterium nucleatum and Prevotella intermedia, but almost completely eliminated hydrogen sulfide (H2S) and methyl mercaptan (CH3SH) produced by these bacteria. SE protected human T-cell leukemia MT-4 cells from the cytopathic effect of human immunodeficiency virus (HIV) infection, and its anti-HIV activity was much higher than that of tannins and flavonoids, comparable with that of natural and synthetic lignins. SE also protected the MDCK cells from the cytopathic effect of influenza virus infection. SE synergistically enhanced the superoxide anion and hydroxyl radical-scavenging activity of vitamin C. The present study suggests the functionality of SE as a complementary alternative medicine.     

Structural basis of the anti-inflammatory activity of melatonin

The anti-inflammatory activity of melatonin (CAS 73-31-4) was examined, using the rat paw edema model, and compared with the non-steroidal anti-inflammatory drug (NSAID) indometacin (CAS 53-86-1) which exerts its effects by inhibition of prostaglandin production on acute inflammation. The experiments showed that melatonin has an important effect on acute inflammatory processes acting as an inhibitor in a similar manner to indometacin. The structural interactions of melatonin with cyclooxygenase (COX), the pharmacological target of NSAIDs, were investigated using computer graphics applications. The results indicated that melatonin has an excellent steric and electronic complementarity with COX. It was found, similarly to previously studied crystal structures of protein-inhibitor complexes, that almost all interactions were of the hydrophobic type but for the typical carboxylate or electronegative group interaction, at the mouth of the active site channel, with Arg 120 and Tyr 355. Therefore, it seems possible that melatonin might bind to the active site of COX-1 and COX-2 suggesting that it may act as a natural inhibitor of the functions of cyclooxygenase modulating in a natural manner the activity of this enzyme.     

Antiinflammatory activity of melatonin in central nervous system

Melatonin is mainly produced in the mammalian pineal gland during the dark phase. Its secretion from the pineal gland has been classically associated with circadian and circanual rhythm regulation. However, melatonin production is not confined exclusively to the pineal gland, but other tissues including retina, Harderian glands, gut, ovary, testes, bone marrow and lens also produce it. Several studies have shown that melatonin reduces chronic and acute inflammation. The immunomodulatory properties of melatonin are well known; it acts on the immune system by regulating cytokine production of immunocompetent cells. Experimental and clinical data showing that melatonin reduces adhesion molecules and pro-inflammatory cytokines and modifies serum inflammatory parameters. As a consequence, melatonin improves the clinical course of illnesses which have an inflammatory etiology. Moreover, experimental evidence supports its actions as a direct and indirect antioxidant, scavenging free radicals, stimulating antioxidant enzymes, enhancing the activities of other antioxidants or protecting other antioxidant enzymes from oxidative damage. Several encouraging clinical studies suggest that melatonin is a neuroprotective molecule in neurodegenerative disorders where brain oxidative damage has been implicated as a common link. In this review, the authors examine the effect of melatonin on several neurological diseases with inflammatory components, including dementia, Alzheimer disease, Parkinson disease, multiple sclerosis, stroke, and brain ischemia/reperfusion but also in traumatic CNS injuries (traumatic brain and spinal cord injury).     

L-苹果酸对褪黑素催眠作用的影响

目的考察γ 氨基丁酸合成酶抑制剂L 苹果酸对褪黑素催眠作用的影响。方法采用褪黑素协同戊巴比妥钠睡眠及脑电图描记方法。结果L 苹果酸 ( 6 0 0mg/kg)连续灌胃 5d具有明显抑制褪黑素延长小鼠戊巴比妥钠睡眠时间的作用。脑电图分析表明 ,L 苹果酸 ( 4 2 0mg/kg)还能明显抑制褪黑素引起的大鼠总睡眠时间和慢波睡眠时间的增加 ,及抑制褪黑素引起的觉醒时间的减少 ,但对睡眠潜伏期和快波睡眠时间无明显影响。结论首次发现褪黑素的催眠作用能被γ 氨基丁酸合成酶抑制剂L 苹果酸拮抗。褪黑素催眠作用的机制可能由GABA能神经系统介导     

Comparative radical-scavenging activity of curcumin and tetrahydrocurcumin with thiols as measured by the induction period method

BACKGROUND: The in vivo radical-scavenging activity of curcumin (CUR) and THC (tetrahydrocurcumin, a metabolite of CUR) does not occur in isolation, but through an intricate antioxidant network together with co-antioxidants such as glutathiones (GSH). In the present investigation, the radical-scavenging activity of CUR and THC with 2-mercapto-1-methylimidazole (MMI, a thiol) was studied using the induction period method. MATERIALS AND METHODS: The induction period (IP) and propagation rate (Rp) for mixtures of MMI with THC or CUR were determined by differential scanning calorimetry (DSC) monitoring of the polymerization of methyl methacrylate (MMA) initiated by thermal decomposition of benzoyl peroxide (BPO, a source of peroxy radical, PhCOO*) or 2,2'-azobisisobutyronitrile (AIBN, a source of alkyl radical, R*) under nearly anaerobic conditions. RESULTS: The stoichiometric number of PhCOO* radicals that could be trapped per molecule (n) was 3.4 and 3.3 for CUR and THC, and that of the R* radical was 3.1 and 2.5, respectively. At a molar ratio of antioxidant:co-antioxidant (MMI) = 1:5, a THC/MMI mixture with PhCOO* enhanced the total radical-scavenging activity, possibly due to partial regeneration of THC, whereas a CUR/MMI mixture with PhCOO* reduced it. Similarly, CUR/MMI and THC/MMI mixtures with R*, particularly the former, reduced the total radical-scavenging activity, possibly due, in part, to destructive interference between the antioxidant and the co-antioxidant. CONCLUSION: THC oxidized by peroxy radicals may be more antioxidative than the corresponding CUR in the interplay with GSH.     

Gastroprotective activity of modified glutamyl-tryptophan dipeptide analogs and melatonin

The gastroprotective action of synthetic dipeptides glutamyl-tryptophane (EW), iso-valeroyl-glutamyl-tryptophane (ivEW) and nicotinoyl-glutamyl-tryptophane (nEW) in comparison to melatonin was studied in experiments on male with the model indometacine and starvation stress-induced stomach ulcers. It was shown, that EW and melatonin exhibit antiulcer activity upon preventive intragastric administration on the model of starvation stress stomach ulcers. At the same time, ivEW, nEW, EW and melatonin exhibit antiulcer activity during the treatment of model indometacine-induced stomach ulcers. The maximum gastroprotective action was observed for ivEW on the model of indomethacin-induced stomach ulcer. The therapeutic efficiency of substances studied is based on their cytoprotective, antioxidant and immunomodulating action.     

Free radical scavenging and antioxidative activity of melatonin derivatives

This article describes the synthesis and antioxidative properties of melatonin derivatives. Tryptamines and cysteinyl or mercaptopropionyl derivatives were deliberately condensed with coupling reagents to give melatonin derivatives 4a-d and 5a, b. The preliminary evaluation indicated that compound 4c showed improved scavenging activity compared with vitamin C (IC50 43 microM vs 65 microM, where IC50 is the concentration of the test compound that induced a change of 50% in absorbance during the 30 min observation) on diphenyl-p-picrylhydrazyl (DPPH) tests. Derivative 5b, which possesses the thiolactyl moiety, showed moderate potency compared with melatonin (IC50 235 microM vs 690 microM) in the H(2)O(2) scavenging test. Intriguingly, 4c displayed 2-fold more potency than melatonin (IC50 51 microM vs 125 microM) in scavenging NO in the macrophage model. These results suggested that the cysteinyl-conjugated derivative 4c may be a suitable lead to further optimize potent antioxidants for certain oxidative stress conditions.     

Free radical-scavenging delta-lactones from Boletus calopus

The methanol extracts from the fruiting body of the mushroom Boletus calopus showed free radical-scavenging activity. Bioactivity-guided fractionation of the methanol extracts led to a new hydroxylated calopin named calopin B, along with the known delta-lactones calopin and cyclocalopin A. The structure of the new calopin analogue was elucidated by spectroscopic methods. All compounds showed potent free radical-scavenging activity against superoxide, DPPH, and ABTS radicals with IC (50) values of 1.2 - 5.4 microg/mL.     

松果体素对老龄大鼠血浆中抗氧化酶活性和过氧化氢反应的影响

为研究松果体素对老龄大鼠血浆中抗氧化酶活性和过氧化氢反应的影响，本文检测了老龄大鼠实验组和对照组血浆中超氧化物歧化酶（SOD），谷胱甘肽还原酶（GSH）、过氧化脂质（MAO）含量变化，结果表明；实验组血浆中超氧化物歧化酶（SOD）、谷胱甘肽还原酶（GSH）含量升高，而过氧化脂质（MAO）含量降低，由此可见，松果体素可驱除自由基，延缓衰老。     

ESR study on the structure and hydroxyl radical-scavenging activity relationships of ginsenosides isolated from Panax ginseng C A Meyer

Ginsenosides have been regarded as the main active components of Panax ginseng C. A. Meyer, and the antioxidant activity of ginsenosides in vivo is well described. However, there has been virtually no report describing the direct free radical-scavenging activities of ginsenosides through the long history of ginseng research. The hydroxyl radical (*OH)-scavenging activity test using an electron spin resonance spectrometer (ESR) is suggested to be the most appropriate to measure the antioxidant activities of ginsenosides. Therefore, we investigated the *OH-scavenging and ferrous metal ion-chelating activities of several ginsenosides of Panax ginseng using ESR for the identification of active ginsenosides and its structure and activity relationships. As a result, 20(S)-Rg(3) showed the strongest activity, and the next were in the decreasing order of Rb(1), Rg(1), Rc, Rb(2), and Rd when dissolved with water. The *OH-scavenging activities of ginsenosides were related to the ferrous metal ion-chelating activities of their aglycone, 20(S)-protopanaxadiol. In addition, the ferrous metal ion-chelating activities of ginsenosides were thought to be influenced by their types of hydrophilic sugar moieties.     

Anxiolytic-like activity of agomelatine and melatonin in three animal models of anxiety

The activity of the novel antidepressant agomelatine was evaluated in three models of anxiety and compared with that of melatonin and two anxiolytics, diazepam and buspirone. All drugs were tested 2 h before and 2 h after the dark phase of the diurnal cycle. Morning and evening agomelatine (10-75 mg/kg) administration increased animals' responses in the elevated plus maze and Vogel tests. Melatonin (10-75 mg/kg) enhanced open arms exploration in the evening experiment and was inactive in the Vogel test. In the conditioned ultrasonic vocalization test, agomelatine, but not melatonin, was active in the morning and evening experiment. Melatonin antagonist, S22153 (20 mg/kg), enhanced the action of morning and evening agomelatine administration in the Vogel and conditioned ultrasonic vocalization tests, while in the elevated plus maze test, S22153 inhibited effects of evening but not morning melatonin and agomelatine administration. These results indicate the involvement of both the melatonin and the 5-HT2C receptors in the mechanism of anxiolytic-like action of agomelatine.     

Methylphenidate-induced motor activity in rats: modulation by melatonin and vasopressin

Methylphenidate (MPH), a dopamine (DA) reuptake inhibitor, is well known to enhance motor activity, in part depending on the time of its application during the light-dark cycle. Moreover, after MPH administration, the hypothalamo-neurohypophysial axis including the neuropeptide vasopressin (AVP) was found influenced. Both the latter and behavioural effects of central AVP can also be modulated by the pineal gland with its light-dark-dependent activity. The present study was performed to investigate whether the pineal gland, its hormone melatonin (Mel), and AVP are involved in the MPH-evoked stimulation of activity. After application of 10 mg/kg MPH, the motor activity in pinealectomised (PE) rats was significantly higher than in sham-operated (SO) animals. After application of 250 microg Mel before MPH treatment, the stimulation of motor activity was diminished in PE rats and augmented in SO animals; however, when SO and PE rats were compared after Mel pretreatment, the reaction to MPH was nearly identical. Blocking the endogenous AVP by 25 or 1 microg of the V1a receptor antagonist d(CH(2))(5)[Tyr(Me)(2)]AVP (AAVP) before MPH treatment significantly augmented the motor activity in SO rats only and abolished the differences seen between SO and PE animals after MPH application. The present results indicate that the behavioural stimulation of MPH was modulated by both the pineal gland with its hormone Mel as well as the neuropeptide AVP.