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1.
The kinetics of 1,2-propanediol (PD) metabolism in vivo have been determined by employing the Michaelis-Menten rate equation; it was found that maximum metabolizing capacity was 8.33 mmole PD/kg/hr in the rat, which is equivalent to 1.06 kg/day for an average 70-kg human. The rate equation could be suitably used for optimizing the dosage schedule of a drug from the linear elimination pattern; in the present case this gave a Km value of 17.86 mmole/kg on the basis of the elimination rate of PD. The competitive inhibition of PD elimination by preadministration of pyrazole (Ki = 44 mumole/kg) demonstrated that the first step of the biotransformation of PD catalyzed by the NAD-dependent dehydrogenase might be the rate-limiting step for its in vivo metabolism. The low threshold level of the compound and significant rate of metabolism suggested that the CNS toxicity reported in clinical studies might be due to some of its metabolites such as lactaldehyde and other oxo compounds. Thus, PD could not be considered as an inert and innocuous substance.  相似文献   

2.
Lactate utilization and influx in resting and working rat red muscle   总被引:1,自引:0,他引:1  
1. The behavior of lactate was studied during electrical stimulation and influx was measured under resting conditions of rat soleus muscle. 2. Lactate utilization was measured with (U-14C) lactate and results from electrical stimulation of the soleus muscle present evidence that this substance is mainly oxidized. 3. Under resting conditions, lactate influx showed a saturable transport system with an apparent Km of 11 mM. This low affinity for lactate suggests that lactate transport has a limiting factor for the muscle. 4. The increased lactate utilization under electrical stimulation (1,114 +/- 344 mumol/g/hr, at 20 mM lactate) corresponds to increased lactate permeability as compared to the influx rate (20.81 +/- 1.65 mumol/g/hr at 20 mM lactate) in resting conditions. 5. Alanine, epinephrine or S.I.T.S. 4-amino-4'isothiocyanostilbene-2-2'-disulphonate) do not affect lactate permeability in the soleus muscle.  相似文献   

3.
Yao Y  Li R  Ma Y  Wang X  Li C  Zhang X  Ma R  Ding Z  Liu L 《Biochimica et biophysica acta》2012,1823(4):920-929
α-Lipoic acid (LA) has been shown to improve the diabetic cardiac symptoms. However, the underlying mechanisms have not been elucidated precisely. We have reported recently that LA potentially protected neurons from substance-induced apoptosis. We hypothesized that LA could attenuate cardiac cells death induced by oxidative stress derived from high glucose. To test this possibility, we examined the effects of LA on d-glucose/glucose oxidase (DG/GO, 30mM/5mU)-induced injury in rat cardiomyoblast H9c2 cells. We observed that LA pretreatment significantly increased cell viability in DG/GO-challenged cells. LA pretreatment also attenuated DG/GO-induced apoptosis as evidenced by decreases in both nuclear condensation and loss of mitochondrial potential. In addition, LA activated ERK1/2 and moderately increased ROS production. Blockade of ERK1/2 activation by PD98059 completely abolished LA-induced protection against DG/GO challenge. Inhibition of ROS by N-acetylcysteine abrogated LA-induced ERK1/2 activation and cytoprotection. Furthermore, we observed that the ROS production induced by LA was significantly slower and milder than that by DG/GO. Our results suggest that pretreatment with LA moderately increased ROS production to induce a preconditioning-like effect by ERK1/2 activation thereby increased tolerance of H9c2 cells to DG/GO challenge.  相似文献   

4.
Concentrations of K, P and Na were determined in skeletal and cardiac muscle cells of rat embryos. High K and P levels--133 and 166 mmole/kg wet weight, resp.,--were found in skeletal muscles of 13 day old embryos, the concentration of Na in these cells being 81 mmole/kg w. w. On the 18th day of development, K and P in skeletal muscle cells decreased down to 79 and 118 mmole/kg w. w., resp., while the concentration of Na increased to 165 mmole/kg w. w. In 19 day old embryos, the concentrations of K and P increased, although they did not reach the level typical of skeletal muscles of adult rats. The concentrations of K and P in cardiac muscle cells of 13 day embryos were found equal to 100 and 108 mmole/kg w. w., resp., on the 19th day of development these concentrations reached the level typical of the cardiac muscle cells of adult rats.  相似文献   

5.
John P. Durham 《Life sciences》1980,26(17):1423-1430
Isoproterenol (0.3 mmole/kg body wt.), when injected into the mouse intraperitoneally, increases the weight by 35% and stimulates DNA synthesis 30-fold in the parotid gland. The induction of both hypertrophy and hyperplasia is completely inhibited by ethanol at a dose of 200 mmole/kg body wt. but is almost unaffected by 60 mmole/kg. The full inhibiton of both growth parameters is observed when ethanol is administered up to 5 hr after isoproterenol. Partial inhibition is observed when ethanol is given as long as 15 hr after isoproterenol. It contrast ethanol did not alter the secretion of α-amylase in response to isoproterenol. Ethanol had no effect upon the rise in cyclic GMP level caused by isoproterenol but augmented the rise in cyclic GMP In agreement with these invivo observations, low concentrations of ethanol activated adenylate cyclase invitro, however guanylate cyclase activity was quite strongly inhibited. Although high levels of ethanol (300 mmole/kg) inhibited the induction of both ornithine decarboxylase and S-adenosylmethionine decarboxylase little inhibition was seen at 200 mmole/kg suggesting that the interference with polyamine metabolism is not the mechanism of the ethanol effect upon isoproterenol-induced parotid growth.  相似文献   

6.
Rats inoculated with Trypanosoma brucei brucei EATRO 427 and having a high degree of parasitemia were treated with a series of intra-peritoneal injections of Salicylhydroxamic acid (SHAM) plus glycerol. Permanent cures were obtained with 380 mg/kg SHAM plus 3.8 g/kg glycerol, a dosage regime which was just sublethal. Using a regime with which permanent cure was obtained, the SHAM concentration in the blood plasma remained above 2 mmole/liter for about 20 min, while the glycerol concentration remained above 22 mmole/liter for about 1 hr. The brain concentration of SHAM was close to the plasma concentration. The concentration of glycerol in the brain remained far below the plasma concentration, reaching 6 to 8 mmole/liter between 1 and 2 hr after the beginning of treatment. Treatment with glycerol did not affect the mobility of the trypanosomes nor the survival of infected rats after treatment with suramin.  相似文献   

7.
Previous studies demonstrated the inhibitory participation of serotonergic (5-HT) and oxytocinergic (OT) neurons on sodium appetite induced by peritoneal dialysis (PD) in rats. The activity of 5-HT neurons increases after PD-induced 2% NaCl intake and decreases after sodium depletion; however, the activity of the OT neurons appears only after PD-induced 2% NaCl intake. To discriminate whether the differential activations of the 5-HT and OT neurons in this model are a consequence of the sodium satiation process or are the result of stimulation caused by the entry to the body of a hypertonic sodium solution during sodium access, we analyzed the number of Fos-5-HT- and Fos-OT-immunoreactive neurons in the dorsal raphe nucleus and the paraventricular nucleus of the hypothalamus-supraoptic nucleus, respectively, after isotonic vs. hypertonic NaCl intake induced by PD. We also studied the OT plasma levels after PD-induced isotonic or hypertonic NaCl intake. Sodium intake induced by PD significantly increased the number of Fos-5-HT cells, independently of the concentration of NaCl consumed. In contrast, the number of Fos-OT neurons increased after hypertonic NaCl intake, in both depleted and non-depleted animals. The OT plasma levels significantly increased only in the PD-induced 2% NaCl intake group in relation to others, showing a synergic effect of both factors. In summary, 5-HT neurons were activated after body sodium status was reestablished, suggesting that this system is activated under conditions of satiety. In terms of the OT system, both OT neural activity and OT plasma levels were increased by the entry of hypertonic NaCl solution during sodium consumption, suggesting that this system is involved in the processing of hyperosmotic signals.  相似文献   

8.
Hypercholesterolemia, an independent risk factor for increased oxidative renal injury, is associated with the formation of oxidized low-density lipoprotein. Production of reactive oxygen species and nitrogen species have been implicated in diet-induced hypercholesterolemia, principally as means of oxidising low-density lipoproteins. This in turn initiates the accumulation of cholesterol in macrophages, which sets key event in the initiation of atherosclerosis. The aim of the present work is to evaluate the effects of eicosapentaenoic acid (EPA), DL alpha-lipoic acid (LA) and eicosapentaenoate-lipoate derivative (EPA-LA) in controlling the atherogenic disturbances. Four groups of male Wistar rats were fed with a high cholesterol diet (rat chow supplemented with 4% cholesterol and 1% cholic acid; HCD) for 30 days. Among them, 3 groups of rats were treated with either EPA (35 mg/kg body weight/day, oral gavage), LA (20 mg/kg body weight/day, oral gavage) or EPA-LA derivative (50 mg/kg body weight/day, oral gavage) from 16th day to 30th day of the experimental period. Abnormal increase in the levels of reactive oxygen species, 3-nitrotyrosine, malondialdehyde and protein carbonyl as well as an elevation in the activities of xanthine oxidase, lactate dehydrogenase, alkaline phosphatase and acid phosphatase was observed in renal tissue of HCD fed rats. HCD fed rats also showed an increased susceptibility of the apo B-containing lipoproteins to in vitro oxidation. These changes were restored partially in the EPA and LA administered groups. However, the combined derivative EPA-LA almost ameliorated the hypercholesterolemic-oxidative changes in the HCD fed rats.  相似文献   

9.
Experimental hyperlipidemia has shown to decrease cytochrome P450 3A4 and 2C11 expression and to increase liver concentrations and the plasma protein binding of halofantrine (HF) enantiomers. The present study examined the effect of hyperlipidemic (HL) serum on the metabolism of HF enantiomers by primary rat hepatocytes. Hepatocytes from normolipidemic (NL) and HL (poloxamer 407 treated) rats were incubated with rac-HF in cell media with or without additional rat serum (5%). In those incubations with rat serum, the hepatocytes were preincubated or coincubated with serum from NL or HL rats. Rat serum-free hepatocyte incubations served as controls. Stereospecific assays were used to measure HF and desbutylhalofantrine (its major metabolite) enantiomer concentrations in whole well contents (cells + media). Concentrations of desbutylhalofantrine were not measurable. The disappearance (apparent metabolism) of (-)-HF exceeded that of antipode, but HF metabolism did not differ between hepatocytes from NL and HL rats. Coincubation of HL rat serum with NL hepatocytes caused a significant decrease in the disappearance of (-)-HF, whereas in HL hepatocytes, a substantially decreased apparent metabolism was noted for both enantiomers. Compared with NL serum, (-)-HF disappearance was significantly lowered upon preincubation of NL hepatocytes with HL serum. A combination of factors including diminished drug metabolizing or lipoprotein receptor expression, and increased plasma protein binding in the wells, may have contributed to a decrease in apparent metabolism of the HF enantiomers in the presence of lipoproteins from HL rat serum.  相似文献   

10.
K H Byington 《Life sciences》1987,40(21):2091-2095
The 3 or 4 phosphate ester of dopamine (PD) was hydrolyzed by homogenates of rat tissues to give inorganic phosphate (Pi) and dopamine. The rate of hydrolysis of PD by kidney homogenates was increased by exogenous MgCl2 but not CaCl2 or KCl. The activity of brain, heart or liver homogenates was insensitive to the added salts. Several lines of evidence indicate that alkaline phosphatase activity contributes to the high rate of PD hydrolysis by the kidney but not brain homogenate. The intravenous infusion of PD at 12 mumole/kg in one hr to anesthetized rats increased the dopamine content of the plasma, kidney and heart without altering brain or liver dopamine. The results suggest that PD may be more effective than dopamine for increasing dopamine levels of the kidney. In addition, the hydrolysis of PD by brain homogenates, which is independent of alkaline phosphatase activity, suggests that specific enzymes exist for the metabolism of PD.  相似文献   

11.
Effect of aqueous extract of garlic on hepatic injury due to lead-induced oxidative stress in experimental rats has been investigated. Lead acetate (LA) at a dose of 15 mg/kg body wt was administered ip to rats for 7 consecutive days to induce hepatic injury. Freshly prepared aqueous garlic extract (AGE) at a dose of 50 mg/kg body wt was fed orally to rats 1 h before LA treatment for similar period. LA treatment caused hepatic injury as evident from increased activities of serum glutamate pyruvate transaminase (SGPT) and alkaline phosphatase (ALP), increased serum bilirubin level and damage in the tissue morphology. Lead-induced oxidative stress in liver was evident from increased levels of lipid peroxidation and reduced glutathione. The decreased activity of superoxide dismutase (SOD) and an increased activity of catalase as well as an increased activity of xanthine oxidase (XO) indicate generation and possible accumulation of reactive oxygen intermediates. Furthermore, altered activities of lactate dehydrogenase (LDH), isocitrate dehydrogenase (ICDH), alpha-keto glutarate dehydrogenase (alpha-KGDH) and succinate dehydrogenase (SDH) also indicate an impaired substrate utilization and generation of oxidative stress. All these changes were found to be mitigated when the rats were pre-treated with the AGE. Results indicate that AGE has the potential to ameliorate lead-induced hepatic injury due to oxidative stress in rats. The protective effects may be due to the antioxidant properties of AGE and may have future therapeutic relevance.  相似文献   

12.
Treatment of acute cobalt intoxication in rats with L-methionine   总被引:1,自引:0,他引:1  
The antidotal action of L-methionine in acute cobalt (II) chloride intoxication given orally or intraperitoneally to rats has been investigated in this paper. The doses of CoCl2 (2.73 mmole/kg oral, 0.21 mmole/kg i.p.) are always above their LD50 for both means of administration, reaching during oral administration values above its LD95 (4.20 mmole/kg). The doses of L-methionine varied from 0.63 mmole/kg (i.p.) to 8.19 mmole/kg (orally). L-methionine did not show a significant antidotal action (mortality rates) against the other sulphurous aminoacid: L-cysteine, which is considered an effective antidote. The administration of Co2+-methionine chelates prepared in vitro, showed rates of 10% mortality when given orally and 30% when given intraperitoneally, against Co2+-cysteine and co2+-N-acetylcysteine chelates with rates of 0% mortality. No significant functional changes were observed in the survivors killed seven days after administration in groups receiving L-methionine. Although L-methionine cannot be considered an effective antidote, it is likely to reduce partially the toxic effects of cobalt.  相似文献   

13.
Mitochondrial dysfunction and oxidative damage are highly involved in the pathogenesis of Parkinson's disease (PD). Some mitochondrial antioxidants/nutrients that can improve mitochondrial function and/or attenuate oxidative damage have been implicated in PD therapy. However, few studies have evaluated the preventative effects of a combination of mitochondrial antioxidants/nutrients against PD, and even fewer have sought to optimize the doses of the combined agents. The present study examined the preventative effects of two mitochondrial antioxidant/nutrients, R-α–lipoic acid (LA) and acetyl-L-carnitine (ALC), in a chronic rotenone-induced cellular model of PD. We demonstrated that 4-week pretreatment with LA and/or ALC effectively protected SK-N-MC human neuroblastoma cells against rotenone-induced mitochondrial dysfunction, oxidative damage and accumulation of α-synuclein and ubiquitin. Most notably, we found that when combined, LA and ALC worked at 100–1000-fold lower concentrations than they did individually. We also found that pretreatment with combined LA and ALC increased mitochondrial biogenesis and decreased production of reactive oxygen species through the up-regulation of the peroxisome proliferator-activated receptor-γ coactivator 1α as a possible underlying mechanism. This study provides important evidence that combining mitochondrial antioxidant/nutrients at optimal doses might be an effective and safe prevention strategy for PD.  相似文献   

14.
Platycodin D (PD) is a major active component of the roots of Platycodon grandiflorum (Jacq.) A.DC. and possesses multiple biological and pharmacological properties, including anti-cancer activity. The aim of this study was to characterize PD-induced cytoplasmic vacuolation in human cancer cells and investigate the underlying mechanisms. PD-induced cancer cell death was associated with cytoplasmic pinocytic and autophagic vacuolation. Cellular energy levels were decreased by this compound, leading to the activation of AMP-activated protein kinase (AMPK). Additionally, compound C, an inhibitor of AMPK, completely prevented PD-induced vacuolation. These results suggest that PD induces cancer cell death, associated with excessive vacuolation through AMPK activation when cellular energy levels are low. Therefore, our findings provide a mechanistic rationale for a novel combinatorial approach using PD to treat cancer.  相似文献   

15.
The acute cytogenetic effects of tyramine and MTCAs, precursors of the mutagen present in soy sauce, were studied with the in vivo chromosome aberration test in rat bone marrow cells. The chemicals were administered intraperitoneally. Statistically significant positive results were obtained with tyramine at a dose of 5 mmole/kg (686 mg/kg) body weight and with MTCAs at doses over 0.50 mmole/kg (115 mg/kg) body weight, respectively. Chromosome aberrations (CA) induced by L-proline co-administered with either tyramine or MTCAs were significantly lower than those induced by each chemical alone. These data suggest that L-proline, after endogenous nitrosation, became nitrosoproline and suppressed CA, and that, as a result of in vivo nitrosation of tyramine and MTCAs, they became mutagenic nitroso compounds showing positive results. Statistically significant positive results were obtained by administration of 40 mmole NaCl/kg body weight (2338 mg/kg). The cocarcinogenic role of NaCl with tyramine was suggested because soy sauce contains about 18% NaCl.  相似文献   

16.
Effect of N-linked glycosylation on hepatic lipase activity   总被引:2,自引:0,他引:2  
Hepatic lipase (HL) is a secretory protein synthesized in hepatocytes and bound to liver endothelium. Previous studies have suggested that HL N-linked glycans are required for catalytic activity. To directly test this hypothesis, Xenopus laevis oocytes were used to express native rat HL or HL lacking one or both N-linked glycosylation sites. The expressed and secreted native HL had an apparent molecular mass of 53 kDa, consistent with purified rat liver HL. The mutant lacking both glycosylation sites, while poorly secreted, had an apparent molecular mass of 48 kDa, the same size observed for HL after enzymatic removal of N-linked oligosaccharides. Mutants lacking one of the two sites were intermediate in size and showed reduced secretion. Each of these expressed and secreted proteins had full catalytic activity that was inhibited by antisera to rat HL. Thus, N-linked glycosylation of rat HL, while important to lipase secretion, is not essential for the expression of lipase activity.  相似文献   

17.
Studies of renal and other tissues suggest that chronic elevation or reduction of dietary potassium intake could affect vascular smooth muscle sodium pump (Na-pump) activity. To examine this possibility, the effects of 3 weeks of low (LK: 4 mmole KCl/kg chow), normal (NK; 162 mmole/kg), and high (HK; 1350 mmole/kg) dietary potassium intake on Na-pump activity, the Na-pump activity response to changes in extracellular potassium concentration, and Na-pump site density were determined in tail arteries of rats. Plasma potassium concentration was elevated by 21% in HK rats and reduced by 45% in LK rats. When incubated in autologous plasma, compared to arteries from NK rats, Na-pump activity was decreased in the tail arteries from LK rats but not altered in those from HK rats. When arteries from NK and LK rats were incubated in autologous plasma with the potassium concentration increased to equal that of the HK rats, Na-pump activity exceeded that of HK rat arteries: Na-pump activity of arteries incubated in autologous plasma did not differ from that of arteries incubated in Krebs-Henseleit buffer with the potassium concentration adjusted to equal that of the plasma. Tail artery Na-pump activity for all three dietary potassium groups increased as potassium concentration of the incubation medium was increased from 1 to 12 mM; Na-pump activity was similar for the NK and LK rats at all potassium concentrations, but Na-pump activity of HK rat arteries was less than that of NK arteries at high extracellular potassium concentrations. Na-pump site density was not altered by either HK or LK diet. It is concluded that in tail arteries of rats fed the LK diet, chronically decreased extracellular potassium results in chronically decreased Na-pump activity. In contrast, an adaptive change occurs in tail arteries of rats fed HK diet, such that Na-pump activity remains at normal levels despite elevated extracellular potassium; this adaptive response to chronically increased dietary potassium does not appear to be the result of decreased Na-pump site density.  相似文献   

18.
The human promyelocytic cell line HL 60 can be induced to differentiate toward more mature myeloid or monocytic forms by a variety of agents. This process is thought to require several days of exposure to the inducer, thus making it difficult to identify the early cellular changes which are fundamental to the differentiation program, and to relate the induction to phases of the cell cycle. In order to study the kinetics of leukemic cell differentiation we have developed a system for the induction of rapid monocytic maturation in a subpopulation of HL 60 cells. The cells are exposed to 10(-7) M 1,25-dihydroxycholecalciferol for 4 hr in serum-free medium. Subsequent incubation in a complete medium results in cellular differentiation recognizable by several criteria (phagocytosis, nonspecific esterase reaction, adherence to substratum, cell morphology) beginning at 10 hr from the exposure to the inducer. Approximately 20 hr later 30-40% of the cells in culture show the differentiated phenotype and are capable of phagocytosis. The proportion of differentiated cells in culture decreases thereafter. This system has been utilized to study the expression of c-myc oncogene in relation to the kinetics of maturation, and it was found that the inhibition of the expression of this gene precedes the onset of phenotypic differentiation by approximately 8 hr, is transient, and is accompanied by a brief retardation of cell proliferation, which resumes the normal rate within 24 hr of the exposure to the inducer.  相似文献   

19.
Induction of back mutations to prototrophy by methylene blue (MB)-sensitized photodynamic (PD) treatment has been studied in wild-type and repair-deficient strains of Salmonella typhimurium carrying either the base-pair substitution mutation hisG46 or the frameshift mutation hisD3052. We found that reversion of the hisG46 mutation was increased in a strain carrying a uvrB deletion and decreased in a strain carrying a recA-type mutation. Reversion of the hisD3052 (frameshift) mutation, on the other hand, was decreased in both uvrB deletion and recA-type strains. The former results are consistent with the hypothesis that the majority of MB-sensitized PD-induced base-pair substitution mutations arise by a mechanism similar to that currently believed to be involved in UV mutagenesis. The latter results suggest that PD-induced frameshift mutations may arise in some other way, and two possible mechanisms involving sequential action of the excision repair and recombinational repair pathways are considered.  相似文献   

20.
The effect of cysteamine-induced duodenal ulcers on calcium transport across rat duodenum was investigated. Intracellular calcium accumulation measured after 24 hr and 3 days of cysteamine injection showed a significant increase (P less than 0.001) in the duodenal strips isolated after 3 days with no change noticed in those isolated after 24 hr, although the morphological changes in both were very similar. The relationship between increasing calcium concentration in the incubation medium and intracellular calcium concentration is a saturable process that conforms to the Michaelis-Menten type of kinetics. The average maximal flux (Vmax) increased from 8.93 nmole/hr-gdw in normal to 12.5 nmole/hr-gdw in 3-day-ulcerated rats, with no apparent change in the Michaelis constant (Kt) (0.8 mM). Unidirectional influx of calcium across the mucosal membrane was significantly increased (P less than 0.001) in 3-day-ulcerated duodenum suggesting that the increase in calcium transport could be due to the activation of the active step at the mucosal border.  相似文献   

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