Genotoxic evaluation of sodium fluoride and sodium perborate in mouse bone marrow cells.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
G Chamorro
Publications and source records attributed to G Chamorro.
In vitro genotoxic evaluation of three alpha-asarone analogues.
alpha-Asarone has shown a significant capacity to reduce the level of lipids, including cholesterol. However, several toxic and genotoxic studies have determined that its use may pose a risk to human health. Therefore, a series of compounds structurally analogous to alpha-asarone were prepared in order to maintain the same pharmacological properties but with low toxicity. In this study we evaluated the potential of three alpha-asarone analogues to induce mutagenicity using the Ames test (strains TA98 and TA100 in the presence of metabolic activation), as well as the induction of sister chromatid exchanges (SCE) in cultured human lymphocytes. The tested compounds were: 1-(2,4,5-trimethoxyphenyl)propan-1-one (D1), 1-(2-chloro-4,5-dimethoxyphenyl)propan-1-one (D2), and 1-(4,5-dimethoxy-2-nitrophenyl)propan-1-ol (D3). The results in the first assay showed no mutagenic effect for the three tested analogues; in the TA100 strain, certain cytotoxicity did appear in the case of D2 and D3 only at high concentrations. In regard to the SCE assay, compounds D1 and D2 presented no statistical differences in comparison with the control culture values; however, the high dose of D3 (300 microg/ml) produced a significant increment in SCE (68% above the control value). With respect to the mitotic index and the cellular proliferation kinetics, we observed a reduction when compounds D2 and D3 were used at the higher concentrations. Our results encourage further preclinical studies of these compounds in both in vitro and in vivo models (particularly for analogues D1 and D2), to determine their toxicological profile and establish the possibility of using them in humans.
Allylbenzene Derivatives↗
Genotoxic and cytotoxic studies of beta-sitosterol and pteropodine in mouse.
Beta-sitosterol (BS) and pteropodine (PT) are constituents of various plants with pharmacological activities potentially useful to man. The chemicals themselves possess biomedical properties related to the modulation of the immune and the nervous systems, as well as to the inflammatory process. Therefore, safety evaluation of the compounds is necessary in regard to their probable beneficial use in human health. The present study evaluates their genotoxic and cytotoxic potential by determining the capacity of the compounds to induce sister chromatid exchanges (SCE), or to alter cellular proliferation kinetics (CPK) and the mitotic index (MI) in mouse bone marrow cells. Besides, it also determines their capacity to increase the rate of micronucleated polychromatic erythrocytes (MNPE) in peripheral mouse blood, and the relationship polychromatic erythrocytes/normochromatic erythrocytes (PE/NE) as an index of cytotoxicity. For the first assay, four doses of each compound were tested: 200, 400, 600, and 1000 mg/kg in case of BS, and 100, 200, 300, and 600 mg/kg for PT. The results in regard to both agents showed no SCE increase induced by any of the tested doses, as well as no alteration in the CPK, or in the MI. With respect to the second assay, the results obtained with the two agents were also negative for both the MNPE and the PE/NE index along the daily evaluation made for four days. In the present study, the highest tested dose corresponded to 80% of the LD(50) obtained for BS and to 78% in the case of PT. The results obtained establish that the studied agents have neither genotoxic nor cytotoxic effect on the model used, and therefore they encourage studies on their pharmacological properties.
Journal Article↗
Neutral endopeptidase and angiotensin I converting enzyme insertion/deletion gene polymorphism in humans.
Neutral endopeptidase (NEP) hydrolyses angiotensins (Ang) I and II and generates angiotensin-(1-7) [Ang-(1-7)]. In humans, the insertion/deletion (I/D) angiotensin-I converting enzyme (ACE) gene polymorphism determined plasma ACE levels by 40%. In rats, a similar polymorphism determines ACE levels which are inversely associated to NEP activity. The objective of this study is to evaluate the relationship between ACE expression and plasma NEP activity in normotensive subjects and in hypertensive patients. In total, 58 consecutive patients with hypertension, evaluated in our Hypertension Clinic, were compared according to their ACE I/D genotypes with 54 control subjects in terms of both plasma ACE activity and NEP activities. Plasma ACE activity was elevated 51 and 70% in both DD ACE groups (normotensives and hypertensives) compared with their respective ID and II ACE groups (P<0.001). A significant effect of the ACE polymorphism and of the hypertensive status on ACE activity was observed (P<0.001). In normotensive DD ACE subjects, NEP activity was 0.30+/-0.02 U/ml, whereas in the normotensive II ACE and in the normotensive ID ACE subjects NEP activity was increased 65 and 48%, respectively (P<0.001). In the hypertensive DD ACE patients, NEP activity was 0.47+/-0.03 U/mg. An effect of the I/D ACE genotypes on NEP activity (P<0.04) and an interaction effect between the I/D ACE genotype and the hypertensive status were also observed (P<0.001). These results are consistent with a normal and inverse relationship between the ACE polymorphism and NEP activity in normotensive humans (as is also observed in rats). This normal relationship is not observed in hypertensive patients.
Analysis of Variance↗
Inhibitory effect of chlorophyllin on the frequency of micronuclei induced by sodium nitrite in mice.
In this report the potency of chlorophyllin (CHL) was evaluated to prevent two types of damage produced by nitrite in mice: the increase of micronucleated polychromatic erythrocytes (MNPE) and the bone marrow toxicity, measured as the index of polychromatic erythrocytes/normochromatic erythrocytes (PE/NE). The study was done in eight groups of male mice. The first three groups were administered orally for 4 days with sodium nitrite (10, 15 and 20 mg/kg), the daily administration with nitrite was followed by an intraperitoneal administration of CHL (4 mg/kg), three more groups were administered with the same amounts of nitrite, a seventh group of mice was treated with distilled water while another was treated with CHL (4 mg/kg). Our study produced two main results: (a) no bone marrow injury was induced by any of the tested chemicals, as indicated with the PE/NE index, and (b) CHL protected (as high as 44%) the MNPE produced in nitrite treated mice.
Administration, Oral↗
Effects of chlorophyllin on acetaldehyde: lack of modulation of the rate of sister-chromatid exchanges in mouse bone marrow, and of complex formation in aqueous solution.
Acetaldehyde (Ace) is a reactive compound widely found in natural and industrialized products. On the other hand, chlorophyllin (Chl) is a chloropyll derivative which has shown DNA modulatory effects in several models. The first aim of the present study was to determine the capacity of Ace to increase the rate of sister-chromatid exchanges (SCEs) in mouse bone marrow cells in vivo, as well as to determine its capacity to modify the mitotic index (MI) and the average generation time (AGT). For this experiment we tested four dosages of Ace by the i.p. route (0.4, 4.0, 40.0 and 400 mg/kg), and found a genotoxic effect with the two highest dosages (more than double the basal level was observed with 400 mg/kg). We also found that none of the doses tested modified the MI or the AGT. A second objective was to explore the potential of Chl to modulate the genotoxicity of Ace in the same model. We evaluated whether an oral administration of Chl (2.0, 6.0 and 10.0 mg/kg), given 1 h before an i.p. administration of Ace (100 mg/kg), could modulate the SCEs produced by the mutagen. The result showed a similar SCE rate in both, the Ace-treated mice and those administered with the two chemicals, indicating that Chl was not a modulatory chemical on the genotoxicity of Ace. No modifications were observed concerning the MI or the AGT either. A third objective was to determine whether the two compounds (Ace and Chl) may form a molecular complex in aqueous solution. In agreement with the lack of modulatory effect by Chl, a reversed HPLC and a spectrophotometric analysis showed that the two compounds were unable to form a complex. This report confirms the importance of the specificity concerning the interaction mutagen/antimutagen.
Acetaldehyde↗
Induction of sister chromatid exchanges by 2,4-dichlorophenoxyacetic acid in somatic and germ cells of mice exposed in vivo.
2,4-dichlorophenoxyacetic acid (2,4-D) is one of the most widely used selective herbicides throughout the world; however, the studies that have been conducted to establish its genotoxic potential have given conflicting results. The aim of this investigation was to determine whether the herbicide increases the frequency of sister chromatid exchanges (SCEs) in bone marrow and spermatogonial cells of mice exposed in vivo. The experiment included an oral administration of 2,4-D to three groups of mice (50,100 and 200 mg/kg), as well as to a control group of animals administered with distilled water, pH 10.5 and another group injected with cyclophosphamide (50 mg/kg). In somatic cells, the results showed a significant SCE increase with the two high doses tested, a response that was manifested in a dose-dependent manner. With regard to the mitotic index and the cell proliferation kinetics, there were no modifications exerted by 2,4-D; however, cyclophosphamide induced cytotoxic damage and a cell-cycle delay. With respect to the germ cells, the genotoxic results were similar to those described earlier; that is, there was a significant SCE increase induced by the two high 2,4-D doses tested and a higher genotoxic damage was observed in the animals treated with cyclophosphamide. Our investigation established that 2,4-D is a moderate genotoxicant in mice treated in vivo with high doses, and suggests a minor hazard for humans in the present conditions of its use.
2,4-Dichlorophenoxyacetic Acid↗
Synthesis and hypolipidemic activity of modified side chain alpha-asarone homologues.
A series of homologues of alpha-asarone (1), containing variable size and functionality on the side chain attached to the aromatic ring, has been subjected to a study of structure-activity relationship. For most of the prepared derivatives, either with a carbonyl (8a-8e), a hydroxy group (9a-9e), or with a conjugated double bond (10a-10d), significant effects on serum lipoprotein cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were displayed. The results showed an enhancement of the hypocholesterolemic activity as the length of the chain is decreased. Theoretical conformational and electrostatic potential analyses of I and olefins 10 suggest unfavorable steric interactions in the bulky superior side-chain homologues as the deactivating biological effect.
Allylbenzene Derivatives↗
Lead induces endothelium- and Ca2+-independent contraction in rat aortic rings.
The contractile effect of lead on rat aortic rings was examined. Lead (0.1-3.1 mM) elicited concentration-dependent but endothelium-independent contractions, which were unaffected by prazosin (1 microM). The contractile effects of lead were similar when the aortic rings were bathed either in the absence or presence of external Ca2+. Lanthanum (1 mM) but not verapamil (I pM) inhibited the lead contractions; hence non-L-calcium channels are involved in such effect. In addition, lead induced contractions on aortic rings incubated in Ca2+-free EGTA-containing solution for 70 min., an experimental condition in which intracellular Ca2+-stores are depleted. Finally, the contractile effect of lead was not modified by calphostin C (an inhibitor of protein kinase C). In conclusion, the present results suggest that in rat aorta, the lead-induced contraction is independent of extra- and intracellular calcium stores. In addition, the effect of lead is independent of either catecholamines or protein kinase C. It is likely that in rat aorta, lead enters into the smooth muscle cells through non-L-calcium channels, and when acting like calcium on the contractile machinery it produces contraction. The differences observed between our results and those obtained by other authors may indicate that the mechanism of the contractile effect of lead varies among the different blood vessels.
Animals↗
[Treatment of advanced heart failure by heart transplantation].
BACKGROUND: Heart transplantation currently provides the most effective treatment for advanced heart failure. However, medical therapy for this condition has also improved, heart donors are scarce and the cost of the procedure is high. Therefore the indications and management of these patients need reevaluation. AIM: To analyze the results of 24 patients submitted to heart transplantation for end-stage heart failure needing repeated hospitalizations and i.v. inotropes for compensation. PATIENTS AND METHODS: The group was comprised by 21 men and 3 women with a mean age of 36.8 years, mean left ventricular ejection fraction 19 +/- 4.5%, mean systolic pulmonary artery pressure 48 +/- 13 mmHg (24-70) and mean pulmonary vascular resistance 2.6 Wood Units (1-5). Fourteen patients (58%) had a previous median sternotomy. Immunosuppression did not include induction therapy and steroids were discontinued early. RESULTS: Operative mortality was 4% at 30 days. Actuarial survival at one year was 90% and at 5 years 72%. Freedom from rejection at one year was 76% and at 5 years 50%. Freedom from infection was 70% at one year and 56.5% at five years. All patients with more than 3 months of follow-up were in functional class I. CONCLUSIONS: These results justify the proposed modifications for transplantation protocols.
Actuarial Analysis↗
[Aortic valve multiple papillary fibroelastoma complicated with a cerebrovascular accident: Report of one case].
The echocardiographic identification of cardiac tumors as cause of embolic episodes is infrequent, and the finding of multiple papillary fibroelastoma is even less common. We report a 70 years old female with a history of a rheumatic mitral valve lesion, subjected to a commissurotomy in 1970. She was admitted with a cerebrovascular accident and the transesophageal echocardiogram revealed the presence of a multiple papillary fibroelastoma in the aortic valve. The patient was operated and the tumor excised, the pathological analysis confirmed the diagnosis. The patient was discharged in good conditions and after 8 months of follow up, she has no neurological abnormality and is in functional class I.
Aged↗
[Infective endocarditis: short and long-term results in 261 cases managed by a multidisciplinary approach].
BACKGROUND: Early diagnosis, an effective treatment and prompt recognition of complications are essential to improve the prognosis of infective endocarditis (IE). AIM: To report the results of a multidisciplinary approach to diagnosis and management of patients with IE at the Universidad Católica de Chile Hospital. PATIENTS AND METHODS: The clinical history, diagnosis, treatment and outcome of 261 episodes (Duke criteria) of IE admitted between January 1980 and January 1999 were analyzed. These included 185 episodes of native, 73 of prosthetic valve and 3 of nonvalvular IE. RESULTS: Sixty nine percent of patients were men and the mean age was 49 +/- 16 years. Seventy five percent had a definite diagnosis of IE (Duke). S. viridans, staphylococci and enterococci together constituted 85% of the isolated bacterial strains. Twenty seven had culture-negative IE, related to a high incidence of antibiotic therapy prior to diagnosis. Transesophageal echocardiography was performed in 102 cases and it detected vegetations in 91% of aortic and 96% of mitral IE, rupture or prosthesis dehiscence in 67% of aortic and 52% of mitral IE and abscesses in 51% of aortic and 15% of mitral IE. Fifty one percent developed heart failure and 34% had embolic events. S. aureus IE was associated to a higher incidence of embolic events, complications which contraindicated surgery and increased mortality rate (27%). Of all patients, 40% were treated exclusively with antibiotics, 52% were operated on and 8% had surgical indication but were nonoperable because of serious complications. The overall mortality was 16.3%: 13% in the medical, 9% in the surgical and 81% in the non-operable groups. The type of treatment and mortality rates did not differ between IE of native valves and prosthetic valves. Long term follow up showed survival rates of 73% at 5 years and 66% at 10 years. CONCLUSION: A multidisciplinary approach may be very helpful to improve the prognosis of IE.
Adolescent↗
Dominant lethal study of alpha-asarone in male and female mice after sub-chronic treatment.
Dominant lethal studies were conducted in male and female mice with alpha-asarone, the active hypolipidaemic component of Guatteria gaumeri Greenman, by per os sub-chronic treatment (10 and 20 mg/kg, 5 days/week, for 8 weeks) and subsequent mating. alpha-Asarone did not produce germinal mutations in either males or females. Epididymal sperm examination of male mice immediately after treatment failed to reveal any alteration in sperm count on shape. No significant alterations were observed in testicular or epididymal weights or testicular histology.
Allylbenzene Derivatives↗
Sister-chromatid exchanges induced by disulfiram in bone marrow and spermatogonial cells of mice treated in vivo.
Disulfiram is a widely used drug to treat alcoholism due to its capacity to inhibit the metabolism of acetaldehyde; however, its genotoxic potential is not well known. Thus, the aim of this investigation was to determine whether the chemical may induce sister-chromatid exchanges (SCEs) in an in vivo study using mouse bone marrow and spermatogonial cells. We used doses of 200, 400 and 800 mg/kg body weight and compared the obtained data with the values determined in a negative control group as well as with a positive control group (cyclophosphamide, 50 mg/kg). The results in both systems indicated a weak genotoxic response by the chemical. In the case of bone marrow, a significant SCE level was achieved only with the high tested dose, but in spermatogonial cells the three doses tested showed a significant difference with respect to the negative control. No significant alterations in the mitotic index or in the cell proliferation kinetics were observed in somatic cells. Concerning the effect of cyclophosphamide, an increase in the level of SCEs was observed in both types of cells, reaching more than three times the values obtained in their respective control groups.
Alcohol Deterrents↗
Prevalence of the angiotensin I converting enzyme insertion/deletion polymorphism, plasma angiotensin converting enzyme activity, and left ventricular mass in a normotensive Chilean population.
The aim of this study was to estimate the prevalence of the different alleles of the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and associated plasma ACE activity, as well as cardiac echocardiographic structure, in a healthy Chilean population. We selected 117 healthy normotensive subjects (aged 45 to 60 years, middle socioeconomic status, nonobese, and nondiabetic) from a population-based study concerning the prevalence of risk factors for chronic diseases (Conjunto de Acciones Para la Reducción Multifactorial de las Enfermedades no Transmisibles [CARMEN]). The frequencies of the I and D alleles were 0.57 and 0.43, respectively. Mean plasma ACE activity was 15.3 +/- 3.9 U/mL. Compared with subjects with the II genotype, plasma ACE activity was significantly higher in subjects with the ID and DD genotypes with no difference between them. No correlation was observed between blood pressure and plasma ACE activity. Among the three different genotypes there was no difference in left ventricular (LV) dimensions or in LV mass. No correlation between plasma ACE activity and LV mass was observed for either gender or different genotypes. Multivariate linear regression analysis using LV mass and LV mass index as dependent variables showed independent effects (P < .05) for gender (higher LV mass in men) and diastolic blood pressure, but not for the DD genotype. In conclusion, in this population, the presence of the D allele on the ACE gene determined higher circulating ACE activity. However, in this normotensive healthy population, male gender and diastolic blood pressure, but not the presence of the D allele, were associated with increased LV mass.
Alleles↗
Acute and nongenomic effects of testosterone on isolated and perfused rat heart.
Gonadal steroid hormones influence vascular tone and the development of hypertension. There are sex differences in the incidence of cardiovascular diseases, and great attention has been placed on the study of estrogen cardiovascular effects. However, there are only a few reports on the effects of testosterone on the vasculature. It is commonly accepted that the mechanism of the action of steroid hormones on target tissues is mediated through the binding of hormones to cytoplasmic or nuclear receptors. However, some studies indicate that steroid action can be extremely rapid and therefore unlikely to be through a genomic mechanism. The purpose of this study was to assess the effect of intravascularly confined testosterone on an isolated rat heart to demonstrate acute and possibly nongenomic effects of the steroid. Our results show that testosterone blocked the adenosine vasodilator effect and increased vascular resistance, even when its presence was restricted to the coronary vascular lumen. These effects were exerted rapidly and possibly through nongenomic mechanisms.
Adenosine↗
Synthesis and hypolipidaemic evaluation of a series of alpha-asarone analogues related to clofibrate in mice.
A series of alpha-asarone analogues related to clofibrate, containing an acetic acid group at C-2 of the aromatic ring, has been prepared as the acids or as the ethyl and methyl esters. The corresponding alcohols were also synthesized by reduction of the ethyl esters. The compounds were examined in hyperlipidaemic male mice to evaluate their ability to modify serum lipoprotein cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides after oral administration of 40 and 80 mg kg(-1) for 6 days. Except for methyl 2-methoxy-5-nitro-4-(2-propenyl)phenoxyacetate at either dose, these clofibrate-related phenoxyacetic acid derivatives were found to have significant hypocholesterolaemic activity. Levels of low-density lipoprotein cholesterol and triglycerides were significantly reduced and those of high-density lipoprotein cholesterol were elevated. 2-Methoxy-5-nitro-4-(2-propenyl)phenoxyacetic acid was active at both doses in all the tests. Clofibrate (150 mg kg(-1)) was more potent at reducing low-density lipoprotein cholesterol. No activity was detected for the alcohol derivatives. These preliminary results suggest that this class of compound might have more promise as potential hypolipidaemic agents than other alpha-asarone derivatives. Further investigation and characterization should be performed to determine the mode of action of these agents on lipid metabolism.
Allylbenzene Derivatives↗
[Long-term results of reconstructive surgery for mitral insufficiency].
BACKGROUND: Surgical repair is the procedure of choice for mitral insufficiency since it preserves better left ventricular structure and function. AIM: To assess the long term clinical and echocardiographic results of mitral valve reconstructive surgery. MATERIAL AND METHODS: A review of clinical and echocardiographic data of 68 patients (34 male, age range 17 to 82 years), subjected to surgical mitral valve repair between December 1991 and March 1998. Preoperative functional capacity of these patients was 2.96 +/- 0.7. Surgical repair was assessed using transesophagic echocardiography in all subjects. RESULTS: The etiology of mitral insufficiency was degenerative in 43 patients, rheumatic in 10, infectious in 6, ischemic in 5 and miscellaneous in 4. The most frequent pathological findings were dilatation of the mitral ring in 42% of patients, chordae tendinae rupture in 32% and enlargement in 24%. A mitral anuloplasty was done in 90% of patients, a cuadrilateral resection of posterior leaflet in 52% and chordae tendinae transference in 12%. An additional surgical procedure was done in 34% of subjects. Three patients died during hospitalization (4.4%). During the follow up of 36.5 +/- 22.3 months, five patients died and one required a mitral valve replacement. The actuarial survival probability was 95.3 +/- 2.6% at one year and 83.5 +/- 6.5% at five years. The reoperation free survival was 100% at one year and 97.4 +/- 2.5% at five years. At the end of follow up the functional capacity improved to 1.25 +/- 0.4. Echocardiography showed absence of mitral insufficiency in 48.4% of patients, minimal, mild and moderate insufficiency in 35.5, 14.5 and 1.6% of patients respectively. CONCLUSIONS: Surgical valve reconstruction in mitral insufficiency has satisfactory long term results and should be the procedure of choice for eligible patients.
Adolescent↗