Metabolic disposition of [14C] metanil yellow in rats

The absorption, metabolism and excretion of [14C] metanil yellow was studied in rats. Following administration of a single oral dose of 5 mg dye (7.6 microCi)/kg body weight, 80.5% of the dose was excreted in the urine and faeces within 96 hr, with the majority being accounted for in the faeces. Liver, kidney, spleen and testis retained no count whereas 13.6% of the radioactivity was retained by gastrointestinal tract. Analysis of urine and faeces detected two azo-reduction metabolites of metanil yellow which were characterized by TLC and IR, NMR and mass spectroscopic studies as metanilic acid and p-aminodiphenylamine.     

Long-term low-dose mutation studies in human cells: metanil yellow and orange II

We tested the mutagenic effects of two commonly used fold colors, metanil yellow and orange II, in AHH-1 human lymphoblast cells. The cell line, which is competent for oxidative metabolism of various chemicals, was exposed to both compounds in high-dose x short-term (3 day) or high-dose x long-term (10-day) and low-dose x long-term (20-day) treatments. Concentrations of metanil yellow and orange II as low as 22 nM and 12 nM, respectively, were sufficient to induce mutation rates which were equal to twice the spontaneous mutation rate at the HPRT locus in AHH-1 cells.     

Effect of metanil yellow and malachite green on DNA synthesis in N-nitrosodiethylamine induced preneoplastic rat livers

Metanil yellow (MY) and malachite green (MG) are textile dyes, which, despite the ban occurs unsrupulously as food colouring agents. Accordingly they constitute a serious public health hazard and are of sufficient environmental concern. We have earlier reported that both MY and MG have tumor enhancing effects on the development of hepatic preneoplastic lesions induced by N-nitrosodiethylamine in rats. In order to understand the possible mechanisms by which MY and MG enhance tumor development, in this study we have tested the effects of MY and MG on DNA synthesis and PCNA expression in preneoplastic hepatic lesions during N-nitrosodiethylamine (DEN) induced hepatocarcinogenesis in male Wistar (WR) rats. Rats were administered 200 ppm DEN through drinking water for a period of one month. Administration of DEN for a period of one month showed an upregulation of cell cycle regulatory proteins namely cyclin D1, CDK4, cyclin E and CDK2. Accordingly, in other experiments, the animals were further administered MY and MG for a period of one month following one month DEN treatment. The effects of MY and MG were monitored on the basis of cell proliferation markers--DNA synthesis and PCNA expression both by immunohistochemical and immunoblotting. Following DEN administration, MY, MG and PB showed stimulation of DNA synthesis and increased PCNA expression when compared with either the corresponding controls or only DEN treated animals. In the present study, enhancing effect of MY, MG and PB on the cell proliferation markers during DEN-induced hepatic preneoplasia in rats was observed.     

Modulatory effects of PLG and its peptidomimetics on haloperidol-induced catalepsy in rats.

A behavioral model of dopaminergic function in the rat was used to examine the anticataleptic effects of L-prolyl-L-leucyl-glycinamide (PLG) and peptidomimetic analogs of PLG. Administration of 1 mg/kg PLG intraperitoneally significantly attenuated haloperidol (1 mg/kg)-induced catalepsy (as measured by the standard horizontal bar test), whereas doses of 0.1 and 10 mg/kg PLG did not. Eight synthetic PLG peptidomimetics (Calpha, alpha-dialkylated glycyl residues with lactam bridge constraint [1-4] and without [5-8]) were tested in the same manner (at a dose of 1 microg/kg) and categorized according to their activity, i.e. very active (5), moderately active (2, 3, 4, and 6), and inactive (1, 7, and 8). The catalepsy-reversal action of the diethylglycine-substituted peptidomimetic 5 was examined further and found to exhibit a U-shaped dose-response effect with an optimal dose of 1 microg/kg. The similarity between the effects of PLG and the synthetic peptidomimetics suggests a common mechanism of action. Finally, the synthetic peptidomimetics examined here, particularly peptidomimetic 5, were more effective than PLG in attenuating haloperidol-induced catalepsy.     

内皮素对麻醉大鼠动脉压力感受器反射的调制作用

在27只隔离灌流颈动脉窦区的麻醉大鼠,观察了内皮素（ET-1）对动脉压力感受器反射的调制作用。结果如下：（1）在颈动脉窦区灌流1nmol／L的ET-1时,压力感受器机能曲线向左下方移位,曲线的最大斜率（PS）由0.40±0.02增至0.51±0.02kPa／kPa（P＜0.01）,压力感受器反射性血压下降幅度（RD）由5.66±0.23增至6.76±0.22kPa（P＜0.01）。由此提示,这一剂量的FT-1对压力感受器反射有易化作用。（2）用10nmol／L的ET-1灌流时,压力感受器机能曲线则向右上方移位,PS降至0.28±0.01kPa／kPa（P＜0.01）,RD降至4．16±0.19kPa（P＜0.01）;100nmol／L的ET-1可使压力感受器机能曲线向右上方移位更为明显,PS降至0.19±0.03kPa（P＜0.001）,RD进一步降至3.33±0.38kPa（P＜0.001）。这些结果表明,上述两种剂量的ET-1对压力感受器反射有抑制作用。（3）ETA受体选择性阻断剂BQ123（0.15μmol／L）可以阻断ET-1（10nmol／L）对压力感受器反射的抑制效应。（4）预先灌流KATP通道阻断剂格列苯脲（10μmol／L）,也可阻断ET-1的效应。综上所述,ET-1对压力感受器反射有双重效应,低剂量时有易化作用,而较高剂量时则有抑制作用,后一作用由ET-1型受体介导并有KATP通道的参与。     

Modulatory effects of indomethacin on androgen metabolism in human gingival and oral periosteal fibroblasts.

The non-steroidal anti-inflammatory agent indomethacin (I) suppresses gingival inflammation and alveolar bone resorption. Androgens particularly 5 alpha-dihydrotestosterone (DHT) have anabolic effects on connective tissue and bone matrices. Human oral periosteal fibroblasts (HPF) and gingival fibroblasts (HGF) instigate healing in inflammatory periodontal lesions. The aim of this investigation was to compare the modulatory effects of I on the metabolism of two androgen substrates in human oral periosteal and gingival fibroblasts in culture. Monolayer cultures of both cell types (5(th)-9(th) passage) were established in Eagle's MEM and incubated with 14C-testosterone/14C-4-androstenedione and serial concentrations of I (0.5-50 microg/ml) for 24 h. The steroid metabolites were solvent extracted from the medium, separated by TLC and quantified using a radioisotope scanner. Both androgen substrates were metabolized mainly to DHT and 4-androstenedione/testosterone respectively, expressing 5 alpha-reductase and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity in both HPF and HGF. There were 51% and 73% increases in the levels of DHT over controls, with HGF and HPF respectively (n = 6; n = 4, P < 0.01) in response to I at 1-5 microg/ml, often reaching control values at 50 microg/ml. The expression of 17 beta-HSD activity showed less stimulation than the levels of DHT. Both androgen substrates were effective in this metabolic conversion, which is applicable to healing responses in both males and females in vivo. There were 57% increases (n = 4; P < 0.01) over controls, in the formation of androstanediol from 14C-4-androstenedione at 10 microg of I, in HPF. This transformation may regulate androgen action in androgen-dependent tissue. In addition to its anti-inflammatory properties, indomethacin can contribute to anabolic reparatory responses, by increasing the expression of steroid metabolizing enzymes in gingival and periosteal fibroblasts, in the inflammatory periodontal lesion.     

Modulatory effects of dietary lipids on immune system functions

Dietary lipid manipulation may affect a great number of immune parameters, such as lymphocyte proliferation, cytokine synthesis, natural killer (NK) cell activity, phagocytosis and so on. The immunomodulation induced by dietary fatty acids may be applied in the amelioration of inflammatory disorders, such as autoimmune diseases. However, the mechanisms that participate in these processes are still poorly understood. It is probable that modulation of immune system by fatty acids of the diet may occur by alteration of membrane fluidity, lipid peroxide formation, eicosanoid production or regulation of gene expression. However, recent studies have reported the effects of several free fatty acids on apoptosis induction of in vitro cultures. In fact, a possible explanation of the effects that fatty acids promote on the immune system cells could be associated with an apoptotic process performed in an irreversible way. In vivo studies have demonstrated the ability of fatty acids to alter the survival of animals fed diets containing oils and infected with a pathogenic bacterium. Experimental infection in animals fed dietary lipids produces a modification of resistance to micro-organisms. The present review analyses all of these parameters that dietary fatty acids are capable of altering in order to modify the immune response. Further studies will be needed to establish the mechanisms involved in immune system regulation, reduction of symptoms derived from autoimmune pathologies and so on.     

Modulatory effects of proctolin on a crab ventilatory muscle

Proctolin enhances nerve-evoked, phasic contractions of a selected respiratory muscle of the shore crab, Carcinus maenas, but has no effect on muscle tonus. Proctolin also increases the work and power output of this muscle. These effects are functionally appropriate in view of previous reports that proctolin stimulates the ventilatory rhythm. They also suggest that proctolin exerts coordinated modulatory control at the central and peripheral levels of the gill ventilatory system. In contrast, serotonin, dopamine and octopamine have no effect on this muscle.     

辣椒素敏感神经对心血管活动的调控作用

辣椒素敏感Ｃ类纤维广泛分布于心血管系统,对心脏有正性变时,变力作用,对血管有舒张作用,保护缺血心肌。ＣＳＰＮＳ的上述心血管效应通过激活其末梢的辣椒素受体,进而释放降下素基因相关肽和／或－一氧化氮而发挥作用     

Modulatory effects of bombyxin on ecdysteroidogenesis in Bombyx mori prothoracic glands

In the present study, we investigated the modulatory effects of ecdysteroidogenesis of prothoracic glands (PGs) by bombyxin, an endogenous insulin-like peptide in the silkworm, Bombyx mori. The results showed that bombyxin stimulated ecdysteroidogenesis during a long-term incubation period and in a dose-dependent manner. Moreover, the injection of bombyxin into day 4-last instar larvae increased ecdysteroidogenesis 24 h after the injection, indicating its possible in vivo function. Phosphorylation of the insulin receptor and Akt, and the target of rapamycin (TOR) signaling were stimulated by bombyxin, and stimulation of Akt phosphorylation and TOR signaling appeared to be dependent on phosphatidylinositol 3-kinase (PI3K). Bombyxin inhibited the phosphorylation of adenosine 5′-monophosphate-activated protein kinase (AMPK), and the inhibition appeared to be PI3K-independent. Bombyxin-stimulated ecdysteroidogenesis was blocked by either an inhibitor of PI3K (LY294002) or a chemical activator of AMPK (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside, AICAR), indicating involvement of the PI3K/Akt and AMPK signaling pathway. Bombyxin did not stimulate extracellular signal-regulated kinase (ERK) signaling of PGs. Bombyxin, but not prothoracicotropic hormone (PTTH) stimulated cell viability of PGs. In addition, bombyxin treatment also affected mRNA expression levels of insulin receptor, Akt, AMPKα, -β, and -γ in time-dependent manners. These results suggest that bombyxin modulates ecdysteroidogenesis in B. mori PGs during development.     

Modulatory effects of static magnetic fields on blood pressure in rabbits

Acute effects of locally applied static magnetic fields (SMF) on pharmacologically altered blood pressure (BP) in a central artery of the ear lobe of a conscious rabbit were evaluated. Hypotensive and vasodilator actions were induced by a Ca(2+) channel blocker, nicardipine (NIC). Hypertensive and vasoconstrictive actions were induced by a nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME). The hemodynamic changes in the artery exposed to SMF were measured continuously and analyzed by penetrating microphotoelectric plethysmography (MPPG). Concurrently, BP changes in a central artery contralateral to that of the exposed ear lobe were monitored. SMF intensity was 1 mT and the duration of exposure was 30 min. A total of 180 experimental trials were carried out in 34 healthy adult male rabbits weighing 2.6-3.8 kg. Six experimental procedures were chosen at random: (1) sham exposure without pharmacological treatment; (2) SMF exposure alone; (3) decreased BP induced by a single intravenous (iv) bolus injection of NIC (100 microM/kg) without SMF exposure; (4) decreased BP induced by injection of NIC with SMF exposure; (5) increased BP induced by a constant iv infusion of L-NAME (10 mM/kg/h) without SMF exposure; (6) increased BP induced by infusion of L-NAME with SMF exposure. The results demonstrated that SMF significantly reduced the vasodilatation with enhanced vasomotion and antagonized the reduction of BP via NIC-blocked Ca(2+) channels in vascular smooth muscle cells. In addition, SMF significantly attenuated the vasoconstriction and suppressed the elevation of BP via NOS inhibition in vascular endothelial cells and/or central nervous system neurons. These results suggest that these modulatory effects of SMF on BP might, in part, involve a feedback control system for alteration in NOS activity in conjunction with modulation of Ca(2+) dynamics.     

Modulatory effects of garlic extracts on proliferation of T-lymphocytes in vitro stimulated with concanavalin A.

Different active components from the garlic (Allium sativum) possess immunomodulatory activity both in vitro and in vivo. However, mechanisms of their actions are not sufficiently elucidated. In this study we examined the effects of garlic aqueous extract (GAE) and garlic ethanolic extract (GEE), prepared from two different garlic powder samples, on proliferation of rat thymocytes and splenocytes in culture, stimulated with concanavalin A (Con A). It has been shown that the extracts from both samples significantly modulate lymphocyte proliferation, triggered by this potent T-cell mitogen, depending on the type and dilutions of extracts and concentrations of Con A. The extracts, alone, were not mitogenic for lymphocytes. Generally, higher concentrations of the extracts showed inhibitory effects, whereas lower concentrations significantly augmented proliferation of lymphocytes. The stimulatory effect of GAE was stronger using splenocytes and suboptimal concentrations of Con A as a consequence of increased interleukin 2 (IL-2) production as well as the expression of IL-2 receptor alpha (IL-2Ralpha). The relationship between these two phenomena was demonstrated using neutralizing anti-IL-2Ralpha monoclonal antibody. The inhibitory effect of GAE correlated with a decrease in IL-2 production, but was not followed by down-regulation of IL-2Ralpha expression. The addition of IL-2 almost completely abolished inhibition of lymphocyte proliferation in the presence of higher concentrations of GAE.     

Protective effects of zinc on cadmium toxicity in rodents

A study of acute and subacute toxicity of cadmium ions [Cd(II)] was carried out on male Swiss mice and Sprague-Dawley rats with and without previous administration of zinc chloride. The LD₅₀ of Cd(II) as cadmium sulfate (ip) was lower in animals previously given 10 mg/kg of zinc(II) chloride (sc). Factors such as animal weight variations, biochemical parameters, and accumulation patterns of Cd(II) and Zn(II) were taken into consideration when the subacute toxicity was evaluated. Alteration of the activities of glutamic pyruvic transaminase (GPT) and of glutamic oxaloacetic transaminase (GOT) was observed in short-term-exposure (<6 h) cases. These alterations reverted to normal after 1 wk. The activity of alkaline phosphatase (ALP) and the concentrations of cholesterol and triglycerides in serum are also changed, especially so in the groups given CdSO₄ alone. In the experimental groups treated with ZnCl₂ prior to administration of cadmium, proteinuria was detected 5 wk after the treatment. Also at 5 wk, both Zn-treated and nontreated groups showed an abnormally low liver mass with respect to total body mass. Both Cd and Zn are retained preferentially in the liver but show also in the kidneys. If CdSO₄ and ZnCl₂ are given simultaneously, especially after 1 wk of treatment, Cd is accumulated in greater amounts in these organs when compared to the groups given only cadmium sulfate.