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Biomedical subjects

D Lopez

Publications and source records attributed to D Lopez.

At least 37 records · Page 2Linked to original sources
PubMed1998

Compensatory responses to inhibition of hepatic squalene synthase.

The mechanism by which depletion of hepatic cholesterol levels, achieved by inhibition of squalene synthase, alters hepatic LDL receptor, HMG-CoA reductase, and cholesterol 7alpha-hydroxylase gene expression was investigated by measuring transcription rates, mRNA stability, rates of translation, translational efficiency, and levels of sterol response element binding proteins. It was found that the transcription of both hepatic LDL receptor and HMG-CoA reductase were increased about twofold. The increase in LDL receptor transcription occurred within 2 h after giving 2 mg/kg zaragozic acid A, a potent inhibitor of squalene synthase. This preceded the increase in transcription of HMG-CoA reductase that occurred at 4 h. Increases in the stability of both of these mRNAs were also observed. These changes account for the increases in LDL receptor and HMG-CoA reductase mRNA levels previously observed. The rate of transcription of hepatic cholesterol 7alpha-hydroxylase was decreased to about 25% of control within 3 h after administration of zaragozic acid A, which correlates with the decrease in this mRNA. The rates of translation, as determined by pulse labeling, of both hepatic HMG-CoA reductase and LDL receptor were increased two- to threefold. The translational efficiency of these two mRNAs was also increased as judged by polysome profile analysis. There was an increase in mRNA associated with the heaviest polysome fraction and a decrease in that associated with monosomes. No significant change was observed in the levels of sterol response element binding protein 2, the form that mediates induced transcription, in response to zaragozic acid A treatment, indicating that this protein might not be involved in mediating the observed transcriptional changes. An increase in sterol response element binding protein -1 was observed 30 min after giving zaragozic acid A. The results suggest that compensatory responses to depletion of squalene-derived products involve alterations in the rates of transcription, mRNA stability, and translational of key proteins involved in cholesterol homeostasis.

Animals↗
PubMed1998

Atorvastatin action involves diminished recovery of hepatic HMG-CoA reductase activity.

The effects of atorvastatin on the expression of the hepatic HMG-CoA reductase and LDL receptor genes were investigated in rats. Like the other statins, atorvastatin increased the rate of degradation and presumably cycling of the hepatic LDL receptor. In atorvastatin-treated rats, the half-life of the receptor was decreased by over 60%. Hepatic HMG-CoA reductase mRNA levels were increased about 3-fold by feeding a diet containing 0.04% atorvastatin while reductase protein levels were increased by as much as 700-fold. Apparent HMG-CoA reductase activity was not increased as much as protein levels. Washing experiments revealed that atorvastatin is more difficult to remove from microsomes than lovastatin. The results support the conclusion that the potent hypocholesterolemic action of atorvastatin involves decreased hepatic VLDL production due to effective inhibition of in vivo cholesterol biosynthesis resulting from diminished recovery of HMG-CoA reductase activity following drug treatment.

Animals↗
PubMed1997

Case-control study of phyto-oestrogens and breast cancer.

BACKGROUND: Phyto-oestrogens are a group of naturally occurring chemicals derived from plants; they have a structure similar to oestrogen, and form part of our diet. They also have potentially anticarcinogenic biological activity. We did a case-control study to assess the association between phyto-oestrogen intake (as measured by urinary excretion) and the risk of breast cancer. METHODS: Women with newly diagnosed early breast cancer were interviewed by means of questionnaires, and a 72 h urine collection and blood sample were taken before any treatment started. Controls were randomly selected from the electoral roll after matching for age and area of residence. 144 pairs were included for analysis. The urine samples were assayed for the isoflavonic phyto-oestrogens daidzein, genistein, and equol, and the lignans enterodiol, enterolactone, and matairesinol. FINDINGS: After adjustment for age at menarche, parity, alcohol intake, and total fat intake, high excretion of both equol and enterolactone was associated with a substantial reduction in breast-cancer risk, with significant trends through the quartiles: equol odds ratios were 1.00, 0.45 (95% CI 0.20, 1.02), 0.52 (0.23, 1.17), and 0.27 (0.10, 0.69)--trend p = 0.009--and enterolactone odds ratios were 1.00, 0.91 (0.41, 1.98), 0.65 (0.29, 1.44), 0.36 (0.15, 0.86)--trend p = 0.013. For most other phytoestrogens there was a reduction in risk, but it did not reach significance. Difficulties with the genistein assay precluded analysis of that substance. INTERPRETATION: There is a substantial reduction in breast-cancer risk among women with a high intake (as measured by excretion) of phyto-oestrogens-particularly the isoflavonic phyto-oestrogen equol and the lignan enterolactone. These findings could be important in the prevention of breast cancer.

4-Butyrolactone↗
PubMed1997

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase unmask transcriptional regulation of hepatic low-density lipoprotein receptor gene expression by dietary cholesterol.

The mechanism by which dietary cholesterol regulates expression of the hepatic low-density lipoprotein (LDL) receptor was investigated. In a previous study (Arch. Biochem. Biophys. 325, 242-248, 1996), we demonstrated that dietary cholesterol reduces the rate of LDL receptor protein degradation without affecting steady-state levels of receptor protein. In view of these findings, it was expected that dietary cholesterol would decrease the rate of transcription of the hepatic LDL receptor gene, resulting in lower mRNA levels and lower rates of synthesis of LDL receptor protein. Surprisingly, neither the rate of transcription nor the level of LDL receptor mRNA was reduced in response to dietary cholesterol, even though hepatic cholesterol levels were increased twofold. This suggests that under normal conditions, dietary cholesterol does not affect LDL receptor gene expression at the level of transcription. In contrast, feeding 2% cholesterol to rats fed a diet supplemented with 0.04% lovastatin significantly decreased hepatic LDL receptor mRNA levels and transcription rates. These results suggest that lovastatin unmasks transcriptional regulation of the hepatic LDL receptor by dietary cholesterol. The levels of the mature nuclear forms of sterol response element binding proteins-1 and -2 were unaffected despite significant changes in hepatic cholesterol levels, mRNA levels, and transcription rates caused by lovastatin treatment. This suggests that the observed changes in transcription rates may not be mediated by these proteins in rat liver.

Animals↗
PubMed1997

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors unmask cryptic regulatory mechanisms.

The possibility that potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase may alter the mechanisms by which dietary cholesterol and farnesol regulate this gene was investigated by comparing the regulatory responses of rats maintained on diets with or without 0.04% Lovastatin supplementation to dietary cholesterol. It was found that the rate of hepatic HMG-CoA reductase transcription was significantly decreased by dietary cholesterol in animals fed Lovastatin-supplemented diets, whereas animals maintained on a normal chow diet showed no decrease in the rate of transcription. The levels of reductase mRNA were decreased to about 10% of controls in Lovastatin-supplemented animals in response to dietary cholesterol but not affected in nonsupplemented animals. Administration of farnesol, reputed to be the nonsterol regulator of reductase, to rats maintained on a diet containing Lovastatin decreased hepatic HMG-CoA reductase protein by 30% and the half-life of reductase immunoreactive protein to 4.0 h, which is close to that observed in chow-fed animals. In contrast, farnesol treatment does not affect the turnover rate of reductase protein in rats fed a normal chow diet. These results suggest that potent inhibitors of HMG-CoA reductase may unmask transcriptional regulation by dietary cholesterol and accelerated degradation of the reductase by the putative nonsterol regulator farnesol.

Animals↗
PubMed1997

Increased expression of low-density lipoprotein receptors in a Smith-Lemli-Opitz infant with elevated bilirubin levels.

We report on an infant girl with severe RSH or Smith-Lemli-Opitz syndrome with hyperbilirubinemia. The infant died at age 2 months. Sterol analysis of liver and brain tissues showed marked elevations of 7-dehydrocholesterol with decreased levels of cholesterol. Immunocytochemical analysis demonstrated remarkable increases in low-density lipoprotein (LDL) receptors in these tissues, indicative of a deficiency in available cholesterol for tissue needs.

Bilirubin↗
PubMed1996

Inhibitors of cholesterol biosynthesis increase hepatic low-density lipoprotein receptor protein degradation.

Inhibitors of cholesterol biosynthesis are believed to lower serum cholesterol levels by enhancing the removal of serum low-density lipoprotein (LDL) by increasing hepatic LDL receptor function. Thus, the effects of several different inhibitors of cholesterol biosynthesis were examined for their effects on the expression of the hepatic LDL receptor in rats. We found that administration of inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase such as lovastatin, pravastatin, fluvastatin, and rivastatin resulted in increased hepatic LDL receptor mRNA levels. Surprisingly, these agents failed to increase levels of immunoreactive LDL receptor protein in rat liver even when the dose and length of treatment were increased. Treatment of rats with zaragozic acid A, an inhibitor of squalene synthase, caused even greater increases in hepatic LDL receptor mRNA levels, but did not increase levels of immunoreactive protein. Further investigation revealed that the rate of degradation of the hepatic LDL receptor was increased in rats given inhibitors of cholesterol biosynthesis. The greatest increase in the rate of degradation was seen in animals treated with zaragozic acid A which caused the largest increase in hepatic LDL receptor mRNA levels. In contrast, hepatic LDL receptor protein was stabilized in cholesterol-fed rats. It appears that increased potential for LDL receptor protein synthesis, reflected in increased mRNA levels, is offset by a corresponding increase in the rate of receptor protein degradation resulting in constant steady-state levels of hepatic LDL receptor protein. These findings are suggestive of increased cycling of the hepatic LDL receptor. This postulated mechanism can provide for enhanced hepatic uptake of lipoproteins without increasing steady-state levels of LDL receptor protein.

Animals↗
PubMed1995

Transcriptional regulation of rat hepatic low-density lipoprotein receptor and cholesterol 7 alpha hydroxylase by thyroid hormone.

Utilizing hypophysectomized and thyroidectomized rats, it is demonstrated that the rapid increase in expression of hepatic low-density lipoprotein (LDL) receptor and cholesterol 7 alpha-hydroxylase in response to thyroid hormone is due to increases in the rates of transcription of these genes. An increase in transcription of the hepatic LDL receptor gene was seen within 30 min after administration of triiodothyronine. The increase in transcription fully accounted for the increase in hepatic LDL receptor protein. Stimulation of transcription of these two genes provides for enhanced removal of LDL from serum and elimination from the body.

Animals↗
PubMed1995

The contributions of proprioceptive deficits, muscle function, and anatomic laxity to functional instability of the ankle.

Functional instability is a common complication following an acute ankle sprain. Three potential contributing factors underlying the ankle which chronically gives way are proprioceptive deficits, muscle weakness, and ligamentous laxity. This study's purpose was to document the presence or absence of these concerns in a sample of subjects with unilateral functional ankle instability. Both ankles of 42 subjects were randomly assessed for passive movement sense into inversion and generation of peak torque by the evertors isokinetically. Thirty-four subjects were available for documentation of talar tilt of both ankles through inversion stress radiographs. Analysis found significantly greater mean values for passive movement sense and talar tilt for the involved ankles compared with the uninvolved, while no significant strength differences in peak torque of the evertors were present. Fifty-eight percent of the sample demonstrated clinical impairments in at least one of these three categories. In conclusion, deficits in passive movement sense and anatomic stability are greater concerns than strength deficits when managing the ankle with functional instability.

Adolescent↗
PubMed1995

Acute pancreatitis in north-eastern peninsular Malaysia: an unusual demographic and aetiological pattern.

A survey of 142 cases of acute pancreatitis was undertaken in two major hospitals serving the state of Kelantan in Malaysia. Females outnumbered males by a ratio of more than 3:1. The incidence among females peaked in the third decade of life. Twenty-one percent (23/109) of the females were pregnant. Ultrasonography revealed gallstones in only 9.4% (13/138). However, abnormalities of serum transaminases were found in 35% (35/100), suggesting that occult gallstones or microlithiasis may be the cause in a significant proportion of patients. Alcohol was virtually absent as an aetiological factor. There was a higher frequency of Ascaris infection in this group than a control hospital population (11/35 vs 33/242; p < 0.02) suggesting that ascariasis may be an important cause of acute pancreatitis in Kelantan. Only 8.4% fell into the category of severe pancreatitis. The overall mortality rate was 2.1%.

Acute Disease↗
PubMed1994

Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene expression by sterols and nonsterols in rat liver.

The mechanisms by which sterols and nonsterols regulate hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase gene expression was investigated by measuring mRNA, protein, and enzyme activity in rats fed cholesterol or given drugs that deplete both endogenous sterols and nonsterols or that selectively deplete sterols. It was found that while dietary cholesterol had little effect on HMG-CoA reductase mRNA levels; immunoreactive protein was reduced to barely detectable levels, as was enzyme activity. Any possible effect on catalytic efficiency is thus ruled out. When rats were fed diets containing Lovastatin, a potent HMG-CoA reductase inhibitor which blocks synthesis of both nonsterols and sterols, similar 15- to 20-fold increases were observed for both HMG-CoA reductase mRNA and activity. However, HMG-CoA reductase immunoreactive protein was increased more than 200-fold. When endogenous sterols were selectively depleted by inhibiting squalene synthase with Zargozic acid A, the increase observed in reductase mRNA was similar to that seen in immunoreactive protein and enzyme activity. This is consistent with the concept that endogenous sterols exert their effects at the level of transcription while endogenous nonsterols act at the level of translation. The results suggest that in whole animals, sterols likely act at the level of mRNA while nonsterols exert their regulatory effects at the level of HMG-CoA reductase protein.

Animals↗
PubMed1994

Tyrosinase-based ruthenium dispersed carbon paste biosensor for phenols.

Highly sensitive biosensors for phenolic compounds, based on the incorporation of the enzyme tyrosinase within metal-dispersed carbon paste matrices are described. In particular, ruthenium-doped carbon pastes display excellent electrocatalytic activity for the reduction of the enzymatically generated quinone species. Hence, convenient quantitation of micromolar concentrations is feasible at 0.0 V (vs. Ag/AgCl reference), with a greatly enhanced response compared to conventional carbon-paste tyrosinase biosensors. The influence of various experimental variables is explored. Fast, sensitive and reproducible flow injection detection of phenolic compounds is illustrated. Analogous improvements are reported for tyrosinase-rich plant tissue electrodes.

Biosensing Techniques↗
PubMed1994

Organic-phase biosensing of secondary alcohols with a Ta. brockii alcohol dehydrogenase electrode.

An organic-phase enzyme electrode for monitoring secondary alcohols is described. The new biosensor relies on the biocatalytic activity of Ta. brockii alcohol dehydrogenase in non-aqueous media. The Eastman-AQ 55D polymeric coating, known for its stability in organic solvents, is used to entrap the enzyme and its NADP+ cofactor onto the glassy carbon surface. Various experimental variables, influencing the response of the reagentless sensor, are explored for optimum performance. The solvent-induced changes in the enzymatic activity result in an extended linear range. The work expands the scope of organic-phase biosensors towards additional substrates of analytical significance.

Alcohol Dehydrogenase↗
PubMed1994

Amperometric biosensor for phenols based on a tyrosinase-graphite-epoxy biocomposite.

A new biocomposite, based on the incorporation of the enzyme tyrosinase into a graphite-epoxy resin matrix, was used for the effective biosensing of phenolic compounds. The enzyme retains its bioactivity on confinement in the epoxy resin environment. This renewable (polishable) and rigid bioprobe offers convenient quantification for various phenolic substrates. The fast response (steady-state time = 25 s) accrues from the close proximity of the enzyme and graphite sites. The influence of various experimental variables was explored for optimum biosensing performance. Flow-injection monitoring of phenolic compounds at a rate of 50 samples h-1 yielded a detection limit of 1 x 10(-6) mol l-1 and a relative standard deviation of 1.4% (n = 40).

Biosensing Techniques↗