Publications by authors named "Adolfo Cruz"

18 Publications

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and founder mutations account for 78% of germline carriers among hereditary breast cancer families in Chile.

Oncotarget 2017 Sep 29;8(43):74233-74243. Epub 2017 Jun 29.

Department of Cell and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.

Identifying founder mutations in and in specific populations constitute a valuable opportunity for genetic screening. Several studies from different populations have reported recurrent and/or founder mutations representing a relevant proportion of mutation carriers. In Latin America, only few founder mutations have been described. We screened 453 Chilean patients with hereditary breast cancer for mutations in and . For recurrent mutations, we genotyped 11 microsatellite markers in and in order to determine a founder effect through haplotype analysis. We found a total of 25 mutations (6 novel) in 71 index patients among which, nine are present exclusively in Chilean patients. Our analysis revealed the presence of nine founder mutations, 4 in and 5 in , shared by 2 to 10 unrelated families and spread in different regions of Chile. Our panel contains the highest amount of founder mutations until today and represents the highest percentage (78%) of and mutation carriers. We suggest that the dramatic reduction of Amerindian population due to smallpox and wars with Spanish conquerors, a scarce population increase during 300 years, and the geographic position of Chile constituted a favorable scenario to establish founder genetic markers in our population.
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http://dx.doi.org/10.18632/oncotarget.18815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650336PMC
September 2017

Alcoholic liver disease, oxidative stress, and antioxidants.

Rev Esp Enferm Dig 2011 Aug;103(8):393-5

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August 2011

Renal function after dopamine and fluid administration in patients with malignant obstructive jaundice. A prospective randomized study.

J Gastrointestin Liver Dis 2011 Jun;20(2):161-7

Gastroenterology Department, Puerta del Mar University Hospital, Cadiz, Spain.

Background And Aims: Acute renal failure is a relevant complication in obstructive jaundice (OJ). The extracellular water volume (ECW) depletion and myocardial dysfunction affects haemodynamic and renal disturbance in patients with OJ.

Methods: A prospective open randomised study was conducted to evaluate the effect of peridrainage saline infusion associated with dopamine administration on hormonal and renal function derangements in 102 patients with malignant OJ. Patients were randomly distributed according to whether (n=64) or not (n=38) received dopamine with saline solution before endoscopic biliary drainage. Furthermore, patients receiving dopamine were randomly distributed whether (n=31) or not (n=33) received additional dopamine administration during the postdrainage phase. Different parameters such as ECW, serum levels of aldosterone, renin, atrial natriuretic peptide (ANP), antidiuretic hormone (ADH), endothelin-1 (ET-1), urine PGE2 and creatinine clearance (CrCl) were analyzed.

Results: Fluid administration was accompanied by an increase in the ECW (p=0.01) and an improvement in the CrCl (p=0.01). Dopamine increased CrCl by 11% (p=0.04) and reduced urinary PGE2 concentration (p=0.02). After drainage, a transient worsening of CrCl was seen in patients on i.v. fluid infusion alone but not in dopamine groups (p=0.001). Improvement of CrCl after dopamine administration was found in patients with serum bilirubin > 16 mg/dl and sodium urine excretion <145 mEq/l.

Conclusions: The administration of dopamine associated with appropriate i.v. fluid infusion in the peridrainage period has an impact on renal function only in selected patients with malignant biliary obstruction. This effect is more relevant in patients with higher marked cholestasis.
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June 2011

Cytoprotective properties of rifampicin are related to the regulation of detoxification system and bile acid transporter expression during hepatocellular injury induced by hydrophobic bile acids.

J Hepatobiliary Pancreat Sci 2011 Sep;18(5):740-50

Liver Research Unit, Hospital Universitario Reina Sofía, IMIBIC (Instituto Maimónides para la Investigación Biomédica de Córdoba), Av. Menéndez Pidal s/n, 14004 Córdoba, Spain.

Background/purpose: Rifampicin has been used for the treatment of patients with jaundice and pruritus. This study evaluated the effect of rifampicin on the expression of different detoxification systems and bile acid transporters during in-vivo and in-vitro experimental models of cholestasis.

Methods: Rifampicin was administered to glycochenodeoxycholic acid (GCDCA)-treated human hepatocytes and bile duct-obstructed rats. Different parameters related to cell death, and the expression of phase I and II drug metabolizing enzymes (DME) and bile acid transporters were determined.

Results: The induction of hepatocellular injury induced by cholestasis was associated with a reduction in cytochrome P4503A4 (CYP3A4), CYP7A1, and UDP-glucuronosyltransferase 2B4 (UGT2B4) expression, as well as an increase in import (Na(+)-taurocholate co-transporting polypeptide, NTCP) system expression. The beneficial properties of rifampicin were associated with an increase in DME and export bile acid systems (multidrug resistance-associated protein 4, MRP4, and bile acid export pump to bile duct, BSEP) expression, as well as a reduction in NTCP expression.

Conclusions: The beneficial effect of rifampicin in cholestasis is associated with an increase in DME expression involved in toxic, bile acid and cholesterol metabolism, as well as a reduction in the bile acid importing system in hepatocytes.
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http://dx.doi.org/10.1007/s00534-011-0396-3DOI Listing
September 2011

Nitric oxide mimics transcriptional and post-translational regulation during α-tocopherol cytoprotection against glycochenodeoxycholate-induced cell death in hepatocytes.

J Hepatol 2011 Jul 26;55(1):133-44. Epub 2010 Nov 26.

Instituto Maimónides para la Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.

Background & Aims: Reactive oxygen species (ROS) and nitric oxide (NO) exert a relevant role during bile acid-induced hepatotoxicity. Whether α-Tocopherol regulates oxidative and nitrosative stress, bile acid transporter expression and their NO-dependent post-translational modifications, and cell death were assessed in vitro and in vivo.

Methods: α-Tocopherol and/or NO donors (DETA-NONOate or CSNO, and V-PYRRO/NO) were administered to glycochenodeoxycholic acid (GCDCA)-treated cultured human hepatocytes or to bile duct obstructed rats. Cell injury, superoxide anion (O⁻₂) production, as well as inducible nitric oxide synthase (NOS-2), cytochrome P4507A1 (CYP7A1), heme oxygenase-1, (HO-1) and bile acid transporter expression were determined. Cysteine S-nitrosylation and tyrosine nitration of Na(+)-taurocholate co-transporting polypeptide (NTCP), as well as taurocholic acid (TC) uptake were also evaluated.

Results: GCDCA-induced cell death was associated with increased (O⁻₂) production, NTCP and HO-1 expression, and with a reduction of CYP7A1 and NOS-2 expression. α-Tocopherol reduced cell death, (O⁻₂) production, CYP7A1, NTCP, and HO-1 expression, as well as increased NOS-2 expression and NO production in GCDCA-treated hepatocytes. α-Tocopherol and NO donors increased NTCP cysteine S-nitrosylation and tyrosine nitration, and reduced TC uptake in hepatocytes. α-Tocopherol and V-PYRRO/NO reduced liver injury and NTCP expression in obstructed rats.

Conclusions: The regulation of CYP7A1, NTCP, and HO-1 expression may be relevant for the cytoprotective properties of α-Tocopherol and NO against mitochondrial dysfunction, oxidative stress and cell death in GCDCA-treated hepatocytes. The regulation of NO-dependent post-translational modifications of NTCP by α-Tocopherol and NO donors reduces the uptake of toxic bile acids by hepatocytes.
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http://dx.doi.org/10.1016/j.jhep.2010.10.022DOI Listing
July 2011

Effects of capecitabine and celecoxib in experimental pancreatic cancer.

Pancreatology 2010 5;10(5):641-7. Epub 2010 Nov 5.

Department of General Surgery, Reina Sofía University Hospital, Cordoba, Spain.

Introduction: Pancreatic cancer is a major health problem because of its aggressiveness and the lack of effective systemic therapies. The aim of the study was the identification of beneficial properties of combined celecoxib and capecitabine treatment during an experimental pancreatic cancer model.

Methods: N-nitrosobis (2-oxopropyl)amine (BOP) was used as a tumoral agent for 12 weeks. Celecoxib and capecitabine were administered either as monotherapy or combined 12 weeks after cancer induction for a period of 24 weeks. The presence of well-developed or moderate adenocarcinoma was evaluated in the pancreas. Several markers of stress, such as lipoperoxides, reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GHS-Px) were determined.

Results: BOP induced the presence of pancreatic tumors associated with a rise in lipoperoxides and the reduction of the antioxidant status in the pancreas. The administration of celecoxib and capecitabine reduced the number of animals with tumors (33 and 66%, respectively). This antitumoral effect was associated with a recovery of GSH, SOD and CAT activity in the pancreas of BOP-treated animals. The combined treatment exerted a synergic antitumoral effect and reduced pancreatic oxidative stress.

Conclusion: The combined administration of celecoxib and capecitabine exerted a synergistic antitumoral effect and increased the antioxidant status restoration in pancreatic cancer.
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http://dx.doi.org/10.1159/000288708DOI Listing
April 2011

Melatonin and celecoxib improve the outcomes in hamsters with experimental pancreatic cancer.

J Pineal Res 2010 Oct 7;49(3):264-70. Epub 2010 Jul 7.

Department of General Surgery, Virgen del Rocio University Hospital (IBiS), Seville, Spain.

Pancreatic cancer is a major health problem because of the aggressiveness of the disease and the lack of effective systemic therapies. Melatonin (MEL) has antioxidant activity and prevents experimental genotoxicity. The specific inhibitor of cyclooxygenase-2 (COX-2), celecoxib (CEL), increases the efficacy of chemoradiotherapy in advanced pancreatic cancer. The objective of the study was the comparison and synergic effect of MEL and CEL during either the induction or progression phases of the tumor process, measuring parameters of oxidative stress, number of tumor nodules and survival of animals with pancreatic cancer. Pancreatic cancer was induced by N-nitrosobis (2-oxopropyl)amine) (BOP) in Syrian hamsters. Melatonin and/or CEL were administered during the induction, postinduction as well as during both phases. The presence of tumor nodules were observed macroscopically in pancreatic and splenic areas, and the levels of lipoperoxides (LPO), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in pancreatic tissue were measured. The increases in tumor nodules and LPO as well as the reductions in GSH and enzymatic antioxidants in the pancreas induced by BOP were related to a lower survival rate of animals. The administration of MEL exerted a more potent beneficial effect than CEL treatment on the reduction in tumor nodules, oxidative stress and death of experimental BOP-treated animals. The combined treatment only exerted a synergistic beneficial effect when administered during the induction phase. Melatonin by itself had significant beneficial actions in improving the survival of hamsters.
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http://dx.doi.org/10.1111/j.1600-079X.2010.00791.xDOI Listing
October 2010

Melatonin exerts a more potent effect than S-adenosyl-l-methionine against iron metabolism disturbances, oxidative stress and tissue injury induced by obstructive jaundice in rats.

Chem Biol Interact 2008 Jul 18;174(2):79-87. Epub 2008 May 18.

Liver Research Unit, Reina Sofía University Hospital, Córdoba, Spain.

Melatonin and S-adenosyl-l-methionine (SAMe) prevent oxidative stress and tissue dysfunction in obstructive jaundice (OJ). Lipid peroxidation is exacerbated in the presence of trace amounts of iron (Fe). The study investigated the regulation by melatonin and SAMe the induction of oxidative stress, iron metabolism disturbances and tissue injury in an experimental model of OJ. Different parameters of lipid peroxidation, antioxidant status, tissue injury and Fe metabolism were determined in liver and blood. OJ induced Fe accumulation in liver, and increased transferrin (Tf) saturation and loosely bound Fe content in blood. Melatonin, and SAMe at lesser extent, enhanced protein Tf content in liver and blood, that reduced loosely bound Fe content in blood. Melatonin and SAMe did not affect ferritin (FT) and Tf mRNA expression, but reduced Tf receptor (TfR) mRNA expression in liver. In conclusion, the effect of melatonin and SAMe on Fe metabolism may be included in the beneficial properties of these agents on lipid peroxidation and tissue injury induced by OJ.
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http://dx.doi.org/10.1016/j.cbi.2008.05.016DOI Listing
July 2008

Beneficial properties of melatonin in an experimental model of pancreatic cancer.

J Pineal Res 2007 Oct;43(3):270-5

Department of General Surgery, Reina Sofia University Hospital, Cordoba, Spain.

Pancreatic cancer is a major health problem because of the aggressiveness of the disease and the lack of effective systemic therapies. Melatonin has antioxidant activity and prevents experimental genotoxicity. However, the effect of melatonin in pancreatic cancer has not been tested. Pancreatic carcinogenesis was induced by N-nitrosobis (2-oxopropyl)amine (BOP) in Syrian hamsters. Melatonin was administered during the BOP-induction phase (12 wk) and/or following the postinduction phase (12 wk). Different parameters of oxidative stress including lipid peroxides (LPO) and antioxidants (superoxide dismutase, catalase, reduced glutathione and glutathione peroxidase) were determined in pancreatic tissue. Also, the presence of atypical hyperplasia (AH), well and moderately differentiated adenomacarcinoma (ADC-WD and ADC-MD, respectively) were studied. The administration of BOP induced an intense oxidative stress and ADC induction in the pancreas. The administration of melatonin during the induction or postinduction phase reduced LPO and improved the antioxidant status, as well as drastically reducing the presence of ADC but some AH remained. In conclusion, treatment with melatonin reduced oxidative damage and cancer nodules induced by BOP in the pancreas.
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http://dx.doi.org/10.1111/j.1600-079X.2007.00472.xDOI Listing
October 2007

Melatonin prevents brain oxidative stress induced by obstructive jaundice in rats.

J Neurosci Res 2007 Dec;85(16):3652-6

Department of General Surgery, Reina Sofía University Hospital, Avenida Menendez Pidal s/n, Córdoba, Spain.

The aim of the study was to analyze the impact of melatonin on brain oxidative stress in experimental biliary obstruction. Cholestasis was done by a double ligature and section of the extrahepatic biliary duct. Melatonin was injected intraperitoneally (500 microg/kg/day). Malondialdehyde (MDA), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) contents were determined in the brain tissue. Biliary obstruction raised MDA and reduced GSH contents in the cortex, cerebellum, and hypothalamus areas. Moreover, the scavenger enzyme activity significantly dropped in all areas of the brain. Melatonin drastically reduced MDA concentration and enhanced GSH concentration, as well as all antioxidant enzyme activity in all brain areas obtained from the bile duct-ligated animals. In conclusion, the treatment with melatonin decreased lipid peroxidation and recovered the antioxidant status in the brain from cholestatic animals.
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http://dx.doi.org/10.1002/jnr.21436DOI Listing
December 2007

Melatonin reduces apoptosis and necrosis induced by ischemia/reperfusion injury of the pancreas.

J Pineal Res 2006 Apr;40(3):195-203

Department of General Surgery, Reina Sofia University Hospital, Cordoba, Spain.

The pancreas is highly susceptible to the oxidative stress induced by ischemia/reperfusion (IR) injury leading to the generation of acute pancreatitis. Melatonin has been shown to be useful in the prevention of the damage by ischemia-reperfusion in liver, brain, myocardium, gut and kidney. The aim of the study was to evaluate the cytoprotective properties of melatonin against injury induced by IR in pancreas. The obstruction of gastro-duodenal and inferior splenic arteries induced pancreatic IR in male Wistar rats. Melatonin was intraperitoneally administered before or/and after IR injury. The animals were killed at 24 and 48 hr after reperfusion and there were evaluated parameters of oxidative stress (lipoperoxides, superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione), glandular endocrine and exocrine function (lipase, amylase, insulin) and cell injury (apoptosis and necrosis). The IR induced a marked enhancement of oxidative stress and impaired pancreatic function. The histological analysis showed that IR induced acute pancreatitis with the accumulation of inflammatory infiltrate, disruption of tissue structure, cell necrosis and hemorrhage. Melatonin administration before or after pancreatic IR prevented all tissue markers of oxidative stress, biochemical and histological signs of apoptosis and necrosis, and restored glandular function. No histological signs of pancreatitis were observed 48 hr after reperfusion in 80% of the animals treated with melatonin, with only a mild edematous pancreatitis being observed in the remaining rats. Preventive or therapeutic administration of melatonin protected against the induction of oxidative stress and tissue injury, and restored cell function in experimental pancreatic IR in rats.
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http://dx.doi.org/10.1111/j.1600-079X.2005.00291.xDOI Listing
April 2006

Incidence of BRCA1 and BRCA2 mutations in 54 Chilean families with breast/ovarian cancer, genotype-phenotype correlations.

Breast Cancer Res Treat 2006 Jan 27;95(1):81-7. Epub 2005 Oct 27.

Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Casilla 114-D, Santiago, Chile.

Our aim was to analyze the incidence of mutations in BRCA1 and BRCA2 genes in 54 families with breast/ovarian cancer. Families were selected from three Institutions following the standard criteria for hereditary breast/ovarian cancer. PCR amplification of all exons was performed, followed by SSCP, heteroduplex, PTT and sequencing analysis. We identified eight truncation mutations, three in the BRCA1 gene and five in the BRCA2 gene. Three of these mutations have not been reported previously by other groups: 308insA in one family, 3936 C>T in two families, for BRCA1, and 4970insTG in one family for BRCA2. In addition two families having Ashkenazi Jewish ancestors present the well known mutations 185delAG and 6174delT. Interestingly, 5 out of 11 families have mutations recurrent in Spanish families. Among the 54 families selected, seven have breast and ovary cancer cases, and only two presented a mutation in BRCA1 or BRCA2 genes. Other cancers as prostate and stomach are frequent among relatives carrying the mutation. Five cases of very early onset (<31 years old) breast cancer were detected. The frequencies of BRCA1 (0.074) and BRCA2 (0.13) mutations in our families is low but similar to the incidence found in other populations, like in Spain. Since is widely known that risk factors that modulate the development of breast cancer such as lifestyle risk factors, geographic location, country of origin and socioeconomic status, besides a familial history of breast cancer our findings suggest that the history of colonization and immigrations is very relevant when studying hereditary factors associated to breast cancer.
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http://dx.doi.org/10.1007/s10549-005-9047-1DOI Listing
January 2006

Melatonin prevents experimental liver cirrhosis induced by thioacetamide in rats.

J Pineal Res 2005 Sep;39(2):143-50

Department of General Surgery, Reina Sofia University Hospital, Córdoba, Spain.

Liver cirrhosis is a critical stage of chronic liver diseases that can produce liver failure, portal hypertension and hepatocarcinoma. Sustained oxidative stress plays a key role in cell damage and fibrosis induced during liver cirrhosis. We evaluated the effect of oxidative stress regulation by melatonin on the development of parenchymal destruction and stellate cell activation in experimental liver cirrhosis. Melatonin was administered to rats with liver cirrhosis induced by thioacetamide (TAA) for 1 or 3 months. Liver injury was assessed by serological analysis, as well as hematoxylin-eosin staining and the in situ apoptosis detection assay in liver sections. Oxidative stress was evaluated by lipoperoxide and reduced glutathione levels, and by the measurement of catalase and superoxide dismutase activities in liver and serum respectively. The activation of stellate cells was evaluated by alpha-smooth muscle actin expression in liver sections. Our results showed that TAA induced oxidative stress with extensive tissue damage and enhanced alpha-smooth muscle actin expression in liver. Melatonin prevented the oxidative stress-related changes associated with TAA toxicity. In conclusion, the study showed that melatonin prevents the tissue damage and fibrosis associated with TAA-induced liver cirrhosis in rats.
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http://dx.doi.org/10.1111/j.1600-079X.2005.00227.xDOI Listing
September 2005

Melatonin prevents oxidative stress and hepatocyte cell death induced by experimental cholestasis.

Free Radic Res 2004 Jul;38(7):697-704

Unit of Hepatobiliary Surgery, Department of General Surgery, Reina Sofía University Hospital, Avda Menendez Pidal s/n 14.004, Córdoba, Spain.

The induction of oxidative stress precedes liver injury during experimental obstructive jaundice (OJ). In this sense, different evidences suggest that melatonin (MEL), as antioxidant, may be useful in the protection against apoptosis and necrosis during experimental cholestasis. In addition, we will also assess if MEL-dependent protection is related to a recovery of antioxidant status disturbances induced by OJ. Cholestasis was achieved by double ligature and sectioning of the principal bile duct. MEL was injected intraperitoneally (500 microg/kg/day). Lipid peroxidation was evaluated by the measurement of malondialdehyde (MDA) content in liver. Different parameters related to antioxidant status, such as reduced glutathione (GSH), glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD) were determined in liver. Liver injury was assessed by alanine amino-transferase (ALT) in serum, histological examination, DNA fragmentation and TUNEL assay. The activation of perisinusoidal stellate cells was evaluated by immunohistochemical measurement of alpha-smooth muscle actin in liver sections. The induction of OJ increased all the parameters related to apoptosis and necrosis in liver. The induction of liver injury was associated with stellate cell activation, as well as an increase in MDA (p < 0.0001) and a reduction in GSH, GPx, catalase and SOD content (p < 0.0001) in liver. MEL reduced hepatic apoptosis and necrosis (p < 0.004) with a significant improvement in all oxidative stress markers. In conclusion, our results showed that MEL recovered the antioxidant status and reduced apoptosis and necrosis induced by experimental cholestasis.
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http://dx.doi.org/10.1080/10715760410001705131DOI Listing
July 2004

[Determination of a BRCA1 gene mutation in a family with hereditary breast cancer].

Rev Med Chil 2004 Feb;132(2):203-10

Laboratorio de Genética Molecular Humana, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile.

Background: Breast cancer is the main cause of death among women between 40 and 55 years old, in whom the hereditary cases are common. Therefore, the molecular diagnosis of germ line mutations involved in breast cancer susceptibility is relevant. BRCA1 and BRCA2 have been described as the two major genes involved in familial breast/ovarian cancer. We are performing a screening of BRCA1 and BRCA2 genes, in a group of 50 high risk Chilean families for breast/ovarian cancer. We have detected a mutation, 3936 C>T, that leads to a truncated protein, in two affected women from one of the families in study.

Aim: To report the results of the screening for 3936 C>T in healthy relatives of index women.

Material And Methods: The molecular diagnosis of this mutation was offered to the healthy members of this family, and 17 relatives accepted to be tested. The region of the BRCA1 gene that includes the 3936 C>T mutation, was analyzed through PCR amplification, digestion with restriction enzyme BstNI, and direct sequencing.

Results: 3936 C>T DNA mutation was present in 8 relatives.

Conclusions: Considering the high risk of having a mutation in the BRCA1 gene, specially in pre-menopausal women, the molecular diagnosis, genetic and clinical counseling are highly relevant. In Chile the molecular diagnosis is still not widely applied.
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http://dx.doi.org/10.4067/s0034-98872004000200010DOI Listing
February 2004

Effect of melatonin on cholestatic oxidative stress under constant light exposure.

Cell Biochem Funct 2003 Dec;21(4):377-80

Department of General Surgery, Reina Sofía University Hospital, Córdoba, Spain.

This study was designed to evaluate the effect of melatonin on cholestatic oxidative stress under constant light exposure. Cholestasis was induced by double ligature and section of the extra-hepatic bile duct. Melatonin was injected i.p.(1000 microg kg(-1) day(-1)). Malondialdehyde, reduced glutathione, catalase, superoxide dismutase, glutathione reductase, peroxidase and transferase were determined in liver. After bile-duct obstruction and under constant light exposure, an increase in malondialdehyde (p < 0.05) and a slight decrease in reduced glutathione were seen. Enzyme activity, with the exception of glutathione reductase, had significantly diminished. After melatonin administration, malondialdehyde fell (p < 0.001), whereas there was an increase in reduced glutathione (p < 0.0001) compared with untreated controls. Constant light exposure was associated with an increase in hepatic oxidative stress. Treatment with melatonin decreased lipid peroxide synthesis, and permitted a recovery of both reduced glutathione and scavenger enzyme activity.
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http://dx.doi.org/10.1002/cbf.1046DOI Listing
December 2003