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Biomedical subjects

M F Sorrell

Publications and source records attributed to M F Sorrell.

At least 73 records · Page 4Linked to original sources
PubMed1993

Reaction of acetaldehyde with proteins: formation of stable fluorescent adducts.

The properties of stable acetaldehyde-protein adducts, using bovine serum albumin as a model protein, were investigated. Upon prolonged incubation at 37 degrees C and pH 7.4, the reaction of acetaldehyde and albumin yielded stable adducts that exhibited fluorescent properties. Reaction mixtures of acetaldehyde with polylysine or ethylamine also formed fluorescent products with similar fluorescent spectral properties like acetaldehyde-albumin adducts, indicating that the amino groups of protein alone can generate fluorescent products on reaction with acetaldehyde. When reactions of acetaldehyde with albumin or polylysine were conducted at 22 degrees C, stable binding reached a maximum after 24 hr of incubation and essentially remained at this level during the remaining 216 hr of incubation, and minimal-to-no fluorescence was associated with this binding. At 37 degrees C, stable binding was greater and increased continuously over the entire 216 hr of incubation. After an initial lag period of 24 to 48 hr, increases in fluorescence intensity paralleled the increases in stable binding. The presence of sodium cyanoborohydride, which reduces Schiff bases, in the reaction mixtures prevented fluorescence, indicating that Schiff bases are intermediates in the formation of fluorescent products. Both stable binding and fluorescence intensities were minimally affected by exhaustive dialysis (up to 144 hr), indicating that the fluorescent products were quite stable. These results suggest that an initial reaction of a Schiff base with another acetaldehyde molecule via an aldol condensation reaction gives rise to the formation of a crotonaldehyde Schiff base derivative. This reactive intermediate could then undergo further condensation reactions and form advanced conjugated products, some of which could be fluorescent.

Acetaldehyde↗
PubMed1993

Results of liver transplantation in diabetic recipients.

BACKGROUND: The results of orthotopic liver transplantation (OLTx) in patients with diabetes mellitus (DM) are not well defined. METHODS: Between 1985 and 1991, 45 adult patients with pretransplantation DM (5 type I, 40 type II) underwent OLTx at our center as identified by retrospective chart review. We compared this diabetic recipient group to a case-control nondiabetic group matched for age, gender, primary liver disease, weight, and timing of OLTx. A total of 30 variables were collected and analyzed with McNemar's test for categorical data, paired t tests for continuous data, and survival and repeated measures analysis for longitudinal data. RESULTS: No differences between diabetic and nondiabetic recipients were noted in patient or graft survival, the incidence or severity of rejection, blood transfusions, operative complications, readmissions, major infections, or number of hospital days after OLTx. However, the incidence of minor bacterial (p = 0.046) and minor fungal (p = 0.035) infections were higher in the DM group. Serum blood urea nitrogen (p = 0.02) and creatinine (p = 0.03) levels were also higher in patients with diabetes versus control patients during the first year after OLTx. CONCLUSIONS: In carefully selected patients with pretransplantation DM, OLTx can be accomplished with results similar to nondiabetic recipients in spite of a higher incidence of minor infections and renal dysfunction.

Diabetes Complications↗
PubMed1993

Successful application of extracorporeal liver perfusion: a technology whose time has come.

We have used extracorporeal liver perfusion (ECLP) to aid in the management of three patients with fulminant hepatic failure (FHF). Organs were used for ECLP only if they would have gone otherwise unused through United Network for Organ Sharing. In all three patients treated, serial serum bilirubin and arterial ammonia values trended toward the normal range. The neurologic examinations improved dramatically in two patients, and metabolic function of the extracorporeally perfused livers was unequivocally demonstrated by the clearance of theophylline in the last two patients. Two patients ultimately had successful liver transplants, whereas the third patient failed to improve neurologically despite evidence of metabolic function by the extracorporeally perfused liver, and died 7 days after ECLP was discontinued, from pulmonary and renal failure. These studies suggest that, 30 yr after initial clinical trials, ECLP can be applied safely without the need for arterial access 1) as a bridge to transplantation, 2) to assess whether patients in FHF will benefit from improved hepatic function and therefore transplantation, and 3) potentially, to evaluate the "usability" of questionable donor organs.

Adolescent↗
PubMed1992

Substoichiometric inhibition of microtubule formation by acetaldehyde-tubulin adducts.

We have shown previously that acetaldehyde forms stable covalent adducts with tubulin, resulting in impaired microtubule formation. The present study explored the mechanism responsible for impaired microtubule formation caused by the substoichiometric stable binding of acetaldehyde to tubulin. The free tubulin dimer was much more reactive with acetaldehyde than microtubules, binding more than twice as much aldehyde. The dimer also formed nearly twice as many stable adducts on its alpha-chain as on its beta-chain, whereas microtubules exhibited an equal distribution of adducts between the two subunits. These data confirm that the alpha-chain of free tubulin, but not microtubules, has an accessible highly reactive lysine (HRL) residue that is a preferential target of acetaldehyde binding. Adduct formation with the HRL residue also correlated with impaired tubulin polymerization, and only 0.08 moles of acetaldehyde bound per mole of HRL was required for complete inhibition; however, adducts with other lysine residues (bulk adducts) did not affect assembly. Adducts to microtubule-associated proteins (MAPs) also impaired the assembly of tubulin, but were much less effective than HRL adducts. In a copolymerization assay, HRL-adducted tubulin, in addition to being itself assembly incompetent, also interfered with polymerization of normal (unadducted) tubulin. Bulk adducts did not alter assembly and were incorporated normally into the growing polymer. When tubulin was cleaved by the proteolytic enzyme, subtilisin, microtubule formation could readily take place in the absence of MAPs. In this polymerization system, HRL adducts, but not bulk adducts, still markedly inhibited assembly. When low concentrations of acetaldehyde (50 microM) were used to generate HRL adducts, an adduct on only 1 out of 20 tubulin molecules was sufficient to totally block polymerization. These findings indicate that substoichiometric amounts of acetaldehyde bound to HRL of tubulin can markedly inhibit microtubule formation via direct interference of dimer-dimer interactions, and further suggest that low concentrations of acetaldehyde could generate sufficient amounts of HRL adducts in cellular systems to alter microtubule formation and function.

Acetaldehyde↗
PubMed1992

Liver transplantation at the University of Nebraska Medical Center from 1985 to 1992.

Based on our 7 and one-half-year experience with liver transplantation at the University of Nebraska Medical Center: 1. Success and growth of the program has been, in part, the result of close interaction and support of the various specialists involved. 2. We have demonstrated that outstanding patient and graft survival rates can be obtained with cyclosporine/prednisone immunosuppression. 3. Few, if any, technical contraindications exist to liver transplantation. 4. Surgical advances have allowed allografts to be salvaged which would otherwise require replacement. 5. Routine donor-liver biopsy prior to implantation has reduced the rate of primary nonfunction. 6. New strategies to improve survival for patients with hepatitis-B-related liver disease and hepatic malignancies undergoing liver transplantation need to be developed. 7. The management of patients with fulminant hepatic failure is evolving and now includes innovative approaches such as the use of ECLS and auxiliary transplants.

Academic Medical Centers↗
PubMed1992

Impaired attachment of hepatocytes to extracellular matrix components after chronic ethanol administration.

BACKGROUND: Previous studies have shown that the assembly and properties of the hepatocyte plasma membrane are altered by ethanol administration, indicating possible changes in the receptor-mediated binding of the plasma membrane to extracellular matrix substrates. In the present study, the effects of chronic ethanol consumption on the ability of hepatocytes to attach to various components of the extracellular matrix were investigated. EXPERIMENTAL DESIGN: Rats were pair-fed for 5 weeks with a liquid diet containing either ethanol (as 36% of total calories) or isocaloric carbohydrate. The effects of ethanol treatment on hepatocyte-extracellular matrix interactions was ascertained by determining the ability of isolated hepatocytes to attach to various extracellular matrix substrates. RESULTS: The attachment of hepatocytes, isolated from the ethanol-fed rats, to laminin-coated plates was significantly decreased compared with hepatocytes from chow-fed or pair-fed controls. Greater decreases in attachment were seen when higher numbers of hepatocytes were seeded in the plates. Similar inhibitions of attachment were also observed when fibronectin or type I collagen were used as matrices. Time-course cell attachment assays indicated that the maximum extent of attachment rather than the rate of attachment was primarily altered by chronic ethanol feeding. Hepatocytes from the ethanol-fed rats also detached more readily from the matrix-coated plates than those from the controls. A reduced number of functional surface receptors for matrix components is likely the most important factor that accounts for the ethanol-induced impairment of hepatocyte attachment. CONCLUSIONS: These results indicate that chronic ethanol administration impairs the interactions of hepatocytes with their extracellular matrix and that this defect could lead to alterations of hepatocyte structure and function.

Animals↗
PubMed1992

A jejunoileal bypass rat model for rapid study of the effects of vitamin malabsorption.

Jejunoileal bypass operation was originally done to promote weight loss for treatment of morbid obesity. We used such a model to determine if dietary vitamin absorption is compromised by such an operation. Six rats were subjected to a jejunoileal bypass, 6 control rats were pair-fed to bypassed rats; and 6 were fed ad libitum. Vitamin content of folic, B6, riboflavin, nicotinate, pantothenate, thiamin, biotin, B12, vitamins A, E, and carotene in blood and liver was determined after 8 postoperative weeks. Aside from riboflavin, blood vitamin levels were significantly depressed in bypassed rats. The deepest depression was seen for B12, carotene and vitamin E. Liver vitamin stores of folate, riboflavin, thiamin, B12, clearly were significantly depressed in the bypassed animals compared to the pair-fed and ad libitum-fed controls. This model can serve for rapidly studying micronutrient depletion due to malabsorption without dietary manipulation or antibiotics for gut sterilization.

Animals↗
PubMed1991

Chronic ethanol-induced impairments in receptor-mediated endocytosis of insulin in rat hepatocytes.

The effects of chronic ethanol administration on the receptor-mediated endocytosis of insulin were investigated in isolated hepatocytes. When hepatocytes were isolated from rats that were fed an ethanol liquid diet for 5-6 weeks, these cells bound 25% less insulin to their surface membrane than did cells from the chow-fed or pair-fed controls. This decreased binding was likely a result of reduced surface receptor number rather than changes in receptor affinity. Rates of insulin degradation were also reduced by 25-30% in hepatocytes from the ethanol-fed animals. In addition, chronic ethanol feeding induced a defect in the internalization of the receptor-insulin complex and altered the hepatocellular processing of the internalized insulin. These results indicate that chronic ethanol administration impairs both the surface binding and the endocytosis of insulin by the liver.

Alcoholism↗
PubMed1991

Acetaldehyde and microtubules.

Acetaldehyde covalently binds to tubulin to form stable and unstable adducts. Although tubulin has numerous lysine residues available to react with acetaldehyde, a key highly reactive lysine (HRL) on the alpha chain appears to be a preferential target for stable binding. The HRL residue is available for selective binding when tubulin is in the free (dimer) state but not when it is in the polymerized (microtubule) state. Stable binding of acetaldehyde to the HRL residue markedly inhibits tubulin assembly into microtubules, whereas stable binding to other residues (bulk adducts) has little influence on assembly. Substoichiometric stable binding of acetaldehyde to the HRL is sufficient to inhibit polymerization, via direct interference of tubulin dimer-dimer interactions, and an HRL adduct on only one out of 20 tubulin molecules can totally inhibit polymerization. These findings, along with our previous studies demonstrating impaired microtubule-dependent protein trafficking pathways in livers of ethanol-fed animals, indicate that low acetaldehyde concentrations, formed during ethanol oxidation in vivo, could generate sufficient amounts of HRL adducts on the alpha chain of tubulin in cellular systems to alter microtubule formation and function. In addition to alpha-tubulin, calmodulin and actin have also been found to have enhanced reactivity toward acetaldehyde. Thus, a general hypothesis to describe cellular injury induced by acetaldehyde adducts can be formulated: during ethanol oxidation, acetaldehyde forms stable adducts via binding to reactive lysine residues of preferential target proteins, resulting in selective functional impairment of these proteins and ultimately leading to cellular injury.

Acetaldehyde↗
PubMed1991

Effects of alcohol on hepatic protein metabolism and trafficking.

Ethanol administration disorders protein trafficking in the liver. The protein secretory and plasma membrane assembly pathways have been shown to be impaired in the liver of ethanol-treated animals; however, traffic along the receptor-mediated endocytosis (RME) pathway appears to be especially susceptible to alterations by ethanol. Using asialoglycoproteins as model ligands for studying RME, we have identified at least three steps of this multi-step pathway that are affected by ethanol treatment. These altered steps are recycling of the receptor, internalization of the receptor-ligand complex and dissociation of the ligand from its receptor in endosomes. Ethanol-induced derangements of RME are more severe in the perivenule region, where alcoholic liver injury starts and predominates, than in the periportal region of the liver. Recent studies have shown that the endocytosis of other ligands, including epidermal growth factor and insulin, is also altered by ethanol treatment. Mechanisms which have been proposed to explain faulty RME include: acetaldehyde adducts to tubulin resulting in impaired microtubule function, improper acidification of endosomes and defective receptor clustering in coated pits. Since RME represents an important process by which levels of various hormones, growth factors and other ligands are regulated, and since RME may also be an integral process by which the biological effects of various ligands are elicited, changes in this important process could disrupt numerous metabolic and homeostatic events in the liver.

Alcoholism↗